Handout for the Neuroscience Education Institute (NEI) online activity

Mood Disorders A Spectrum Analysis

Learning Objectives

bull Utilize evidence-based strategies to identify where patients lie on the mood disorder spectrum

bull Optimize treatment strategies for patients based on where they lie along the mood disorder spectrum

PrePoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Pretest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Pretest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Pretest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Pretest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

The Mood Disorder Spectrum

bull Although categorical classifications may be useful for clinical practice the overwhelming majority of the evidence points to a dimensional (spectrum) view of mood disordersndash eg treatment response (antidepressant vs mood stabilizing

agent) and links with family history of BP

bull Individuals with unipolar depression and a little bit of mania are more likely to have an eventual diagnostic conversion to bipolar disorder

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Benazzi F Eur Psychiatry 20082340-8 Hu J et al Primary Care Companion CNS Disord 201416(2)PCC13r01599 Sato T et al J Affective Disord 200481103-13

Vieta E Valenti M J Affective Disord 201314828-36

So You Think Its Unipolar Depression

bull Over one-third of unipolar patients are eventually re-diagnosed as bipolar

bull As many as 60 of patients with BPII are initially diagnosed as unipolar

bull Presence of even subthreshold (hypo)mania symptoms is strongly associated with conversion to bipolar disorderndash Each (hypo)mania symptom increases risk by ~30

Akiskal HS Benazzi J Affective Disord 200373113-22 Dudek D et al J Affective Disord 2013144(1-2)112-5 Fiedorowicz JG et al Am J Psychiatry 201116840-8

Progression to Bipolar Disorder From MDD With Subthreshold Hypomania

N=550 individuals followed for gt1 year (mean follow-up 175 years) after a diagnosis of major depression at intake

196 of patients converted to bipolar disorder during follow-up

Fiedorowicz JG et al Am J Psychiatry 201116840-8

Time to Hypomania or ManiaTime to Hypomania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

070 1040 1300 1560

08

780520260

Time to Mania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

050 1040 1300 1560

08

780520260

ge3 Symptomslt3 Manic symptoms

06

07

Unipolar Bipolar

Psychotic features

Family history of bipolar disorder

Hostility

Early age at onset of first depressive episode (lt25 years)

of lifetime affective episodes

Atypical depressive symptoms

Subsyndromal hypomanic symptoms

Impulsivity

Aggression

Worse response to antidepressants

Antidepressant-induced hypomania

Postpartum depressive episodes

Rapid onset of depressive episodes

of hospitalizations

Clues Across The Spectrum

Dervic K et al Eur Psychiatry 201530(1)106-13 Angst J et al Arch Gen Psychiatry 201168(8)791-9 Musetti L et al CNS Spectrums 201318(4)177-87

Clin

ical

His

tory

Trea

tmen

t H

isto

rySy

mpt

oms

Greater severity of depressive episodes

Comorbid SUD

Converters328

Non-Converters672

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

34

36

38

40

42

44

Non-Converters Converters

Age

of I

llnes

s O

nset

(yrs

)

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

6

65

7

75

8

85

Non-Converters Converters

of

Dep

ress

ive

Epis

odes

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

Learning Objectives

bull Utilize evidence-based strategies to identify where patients lie on the mood disorder spectrum

bull Optimize treatment strategies for patients based on where they lie along the mood disorder spectrum

PrePoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Pretest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Pretest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Pretest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Pretest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

The Mood Disorder Spectrum

bull Although categorical classifications may be useful for clinical practice the overwhelming majority of the evidence points to a dimensional (spectrum) view of mood disordersndash eg treatment response (antidepressant vs mood stabilizing

agent) and links with family history of BP

bull Individuals with unipolar depression and a little bit of mania are more likely to have an eventual diagnostic conversion to bipolar disorder

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Benazzi F Eur Psychiatry 20082340-8 Hu J et al Primary Care Companion CNS Disord 201416(2)PCC13r01599 Sato T et al J Affective Disord 200481103-13

Vieta E Valenti M J Affective Disord 201314828-36

So You Think Its Unipolar Depression

bull Over one-third of unipolar patients are eventually re-diagnosed as bipolar

bull As many as 60 of patients with BPII are initially diagnosed as unipolar

bull Presence of even subthreshold (hypo)mania symptoms is strongly associated with conversion to bipolar disorderndash Each (hypo)mania symptom increases risk by ~30

Akiskal HS Benazzi J Affective Disord 200373113-22 Dudek D et al J Affective Disord 2013144(1-2)112-5 Fiedorowicz JG et al Am J Psychiatry 201116840-8

Progression to Bipolar Disorder From MDD With Subthreshold Hypomania

N=550 individuals followed for gt1 year (mean follow-up 175 years) after a diagnosis of major depression at intake

196 of patients converted to bipolar disorder during follow-up

Fiedorowicz JG et al Am J Psychiatry 201116840-8

Time to Hypomania or ManiaTime to Hypomania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

070 1040 1300 1560

08

780520260

Time to Mania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

050 1040 1300 1560

08

780520260

ge3 Symptomslt3 Manic symptoms

06

07

Unipolar Bipolar

Psychotic features

Family history of bipolar disorder

Hostility

Early age at onset of first depressive episode (lt25 years)

of lifetime affective episodes

Atypical depressive symptoms

Subsyndromal hypomanic symptoms

Impulsivity

Aggression

Worse response to antidepressants

Antidepressant-induced hypomania

Postpartum depressive episodes

Rapid onset of depressive episodes

of hospitalizations

Clues Across The Spectrum

Dervic K et al Eur Psychiatry 201530(1)106-13 Angst J et al Arch Gen Psychiatry 201168(8)791-9 Musetti L et al CNS Spectrums 201318(4)177-87

Clin

ical

His

tory

Trea

tmen

t H

isto

rySy

mpt

oms

Greater severity of depressive episodes

Comorbid SUD

Converters328

Non-Converters672

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

34

36

38

40

42

44

Non-Converters Converters

Age

of I

llnes

s O

nset

(yrs

)

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

6

65

7

75

8

85

Non-Converters Converters

of

Dep

ress

ive

Epis

odes

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

PrePoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Pretest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Pretest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Pretest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Pretest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

The Mood Disorder Spectrum

bull Although categorical classifications may be useful for clinical practice the overwhelming majority of the evidence points to a dimensional (spectrum) view of mood disordersndash eg treatment response (antidepressant vs mood stabilizing

agent) and links with family history of BP

bull Individuals with unipolar depression and a little bit of mania are more likely to have an eventual diagnostic conversion to bipolar disorder

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Benazzi F Eur Psychiatry 20082340-8 Hu J et al Primary Care Companion CNS Disord 201416(2)PCC13r01599 Sato T et al J Affective Disord 200481103-13

Vieta E Valenti M J Affective Disord 201314828-36

So You Think Its Unipolar Depression

bull Over one-third of unipolar patients are eventually re-diagnosed as bipolar

bull As many as 60 of patients with BPII are initially diagnosed as unipolar

bull Presence of even subthreshold (hypo)mania symptoms is strongly associated with conversion to bipolar disorderndash Each (hypo)mania symptom increases risk by ~30

Akiskal HS Benazzi J Affective Disord 200373113-22 Dudek D et al J Affective Disord 2013144(1-2)112-5 Fiedorowicz JG et al Am J Psychiatry 201116840-8

Progression to Bipolar Disorder From MDD With Subthreshold Hypomania

N=550 individuals followed for gt1 year (mean follow-up 175 years) after a diagnosis of major depression at intake

196 of patients converted to bipolar disorder during follow-up

Fiedorowicz JG et al Am J Psychiatry 201116840-8

Time to Hypomania or ManiaTime to Hypomania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

070 1040 1300 1560

08

780520260

Time to Mania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

050 1040 1300 1560

08

780520260

ge3 Symptomslt3 Manic symptoms

06

07

Unipolar Bipolar

Psychotic features

Family history of bipolar disorder

Hostility

Early age at onset of first depressive episode (lt25 years)

of lifetime affective episodes

Atypical depressive symptoms

Subsyndromal hypomanic symptoms

Impulsivity

Aggression

Worse response to antidepressants

Antidepressant-induced hypomania

Postpartum depressive episodes

Rapid onset of depressive episodes

of hospitalizations

Clues Across The Spectrum

Dervic K et al Eur Psychiatry 201530(1)106-13 Angst J et al Arch Gen Psychiatry 201168(8)791-9 Musetti L et al CNS Spectrums 201318(4)177-87

Clin

ical

His

tory

Trea

tmen

t H

isto

rySy

mpt

oms

Greater severity of depressive episodes

Comorbid SUD

Converters328

Non-Converters672

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

34

36

38

40

42

44

Non-Converters Converters

Age

of I

llnes

s O

nset

(yrs

)

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

6

65

7

75

8

85

Non-Converters Converters

of

Dep

ress

ive

Epis

odes

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

Pretest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Pretest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Pretest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Pretest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

The Mood Disorder Spectrum

bull Although categorical classifications may be useful for clinical practice the overwhelming majority of the evidence points to a dimensional (spectrum) view of mood disordersndash eg treatment response (antidepressant vs mood stabilizing

agent) and links with family history of BP

bull Individuals with unipolar depression and a little bit of mania are more likely to have an eventual diagnostic conversion to bipolar disorder

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Benazzi F Eur Psychiatry 20082340-8 Hu J et al Primary Care Companion CNS Disord 201416(2)PCC13r01599 Sato T et al J Affective Disord 200481103-13

Vieta E Valenti M J Affective Disord 201314828-36

So You Think Its Unipolar Depression

bull Over one-third of unipolar patients are eventually re-diagnosed as bipolar

bull As many as 60 of patients with BPII are initially diagnosed as unipolar

bull Presence of even subthreshold (hypo)mania symptoms is strongly associated with conversion to bipolar disorderndash Each (hypo)mania symptom increases risk by ~30

Akiskal HS Benazzi J Affective Disord 200373113-22 Dudek D et al J Affective Disord 2013144(1-2)112-5 Fiedorowicz JG et al Am J Psychiatry 201116840-8

Progression to Bipolar Disorder From MDD With Subthreshold Hypomania

N=550 individuals followed for gt1 year (mean follow-up 175 years) after a diagnosis of major depression at intake

196 of patients converted to bipolar disorder during follow-up

Fiedorowicz JG et al Am J Psychiatry 201116840-8

Time to Hypomania or ManiaTime to Hypomania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

070 1040 1300 1560

08

780520260

Time to Mania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

050 1040 1300 1560

08

780520260

ge3 Symptomslt3 Manic symptoms

06

07

Unipolar Bipolar

Psychotic features

Family history of bipolar disorder

Hostility

Early age at onset of first depressive episode (lt25 years)

of lifetime affective episodes

Atypical depressive symptoms

Subsyndromal hypomanic symptoms

Impulsivity

Aggression

Worse response to antidepressants

Antidepressant-induced hypomania

Postpartum depressive episodes

Rapid onset of depressive episodes

of hospitalizations

Clues Across The Spectrum

Dervic K et al Eur Psychiatry 201530(1)106-13 Angst J et al Arch Gen Psychiatry 201168(8)791-9 Musetti L et al CNS Spectrums 201318(4)177-87

Clin

ical

His

tory

Trea

tmen

t H

isto

rySy

mpt

oms

Greater severity of depressive episodes

Comorbid SUD

Converters328

Non-Converters672

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

34

36

38

40

42

44

Non-Converters Converters

Age

of I

llnes

s O

nset

(yrs

)

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

6

65

7

75

8

85

Non-Converters Converters

of

Dep

ress

ive

Epis

odes

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

Pretest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Pretest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Pretest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

The Mood Disorder Spectrum

bull Although categorical classifications may be useful for clinical practice the overwhelming majority of the evidence points to a dimensional (spectrum) view of mood disordersndash eg treatment response (antidepressant vs mood stabilizing

agent) and links with family history of BP

bull Individuals with unipolar depression and a little bit of mania are more likely to have an eventual diagnostic conversion to bipolar disorder

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Benazzi F Eur Psychiatry 20082340-8 Hu J et al Primary Care Companion CNS Disord 201416(2)PCC13r01599 Sato T et al J Affective Disord 200481103-13

Vieta E Valenti M J Affective Disord 201314828-36

So You Think Its Unipolar Depression

bull Over one-third of unipolar patients are eventually re-diagnosed as bipolar

bull As many as 60 of patients with BPII are initially diagnosed as unipolar

bull Presence of even subthreshold (hypo)mania symptoms is strongly associated with conversion to bipolar disorderndash Each (hypo)mania symptom increases risk by ~30

Akiskal HS Benazzi J Affective Disord 200373113-22 Dudek D et al J Affective Disord 2013144(1-2)112-5 Fiedorowicz JG et al Am J Psychiatry 201116840-8

Progression to Bipolar Disorder From MDD With Subthreshold Hypomania

N=550 individuals followed for gt1 year (mean follow-up 175 years) after a diagnosis of major depression at intake

196 of patients converted to bipolar disorder during follow-up

Fiedorowicz JG et al Am J Psychiatry 201116840-8

Time to Hypomania or ManiaTime to Hypomania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

070 1040 1300 1560

08

780520260

Time to Mania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

050 1040 1300 1560

08

780520260

ge3 Symptomslt3 Manic symptoms

06

07

Unipolar Bipolar

Psychotic features

Family history of bipolar disorder

Hostility

Early age at onset of first depressive episode (lt25 years)

of lifetime affective episodes

Atypical depressive symptoms

Subsyndromal hypomanic symptoms

Impulsivity

Aggression

Worse response to antidepressants

Antidepressant-induced hypomania

Postpartum depressive episodes

Rapid onset of depressive episodes

of hospitalizations

Clues Across The Spectrum

Dervic K et al Eur Psychiatry 201530(1)106-13 Angst J et al Arch Gen Psychiatry 201168(8)791-9 Musetti L et al CNS Spectrums 201318(4)177-87

Clin

ical

His

tory

Trea

tmen

t H

isto

rySy

mpt

oms

Greater severity of depressive episodes

Comorbid SUD

Converters328

Non-Converters672

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

34

36

38

40

42

44

Non-Converters Converters

Age

of I

llnes

s O

nset

(yrs

)

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

6

65

7

75

8

85

Non-Converters Converters

of

Dep

ress

ive

Epis

odes

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

Pretest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Pretest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

The Mood Disorder Spectrum

bull Although categorical classifications may be useful for clinical practice the overwhelming majority of the evidence points to a dimensional (spectrum) view of mood disordersndash eg treatment response (antidepressant vs mood stabilizing

agent) and links with family history of BP

bull Individuals with unipolar depression and a little bit of mania are more likely to have an eventual diagnostic conversion to bipolar disorder

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Benazzi F Eur Psychiatry 20082340-8 Hu J et al Primary Care Companion CNS Disord 201416(2)PCC13r01599 Sato T et al J Affective Disord 200481103-13

Vieta E Valenti M J Affective Disord 201314828-36

So You Think Its Unipolar Depression

bull Over one-third of unipolar patients are eventually re-diagnosed as bipolar

bull As many as 60 of patients with BPII are initially diagnosed as unipolar

bull Presence of even subthreshold (hypo)mania symptoms is strongly associated with conversion to bipolar disorderndash Each (hypo)mania symptom increases risk by ~30

Akiskal HS Benazzi J Affective Disord 200373113-22 Dudek D et al J Affective Disord 2013144(1-2)112-5 Fiedorowicz JG et al Am J Psychiatry 201116840-8

Progression to Bipolar Disorder From MDD With Subthreshold Hypomania

N=550 individuals followed for gt1 year (mean follow-up 175 years) after a diagnosis of major depression at intake

196 of patients converted to bipolar disorder during follow-up

Fiedorowicz JG et al Am J Psychiatry 201116840-8

Time to Hypomania or ManiaTime to Hypomania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

070 1040 1300 1560

08

780520260

Time to Mania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

050 1040 1300 1560

08

780520260

ge3 Symptomslt3 Manic symptoms

06

07

Unipolar Bipolar

Psychotic features

Family history of bipolar disorder

Hostility

Early age at onset of first depressive episode (lt25 years)

of lifetime affective episodes

Atypical depressive symptoms

Subsyndromal hypomanic symptoms

Impulsivity

Aggression

Worse response to antidepressants

Antidepressant-induced hypomania

Postpartum depressive episodes

Rapid onset of depressive episodes

of hospitalizations

Clues Across The Spectrum

Dervic K et al Eur Psychiatry 201530(1)106-13 Angst J et al Arch Gen Psychiatry 201168(8)791-9 Musetti L et al CNS Spectrums 201318(4)177-87

Clin

ical

His

tory

Trea

tmen

t H

isto

rySy

mpt

oms

Greater severity of depressive episodes

Comorbid SUD

Converters328

Non-Converters672

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

34

36

38

40

42

44

Non-Converters Converters

Age

of I

llnes

s O

nset

(yrs

)

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

6

65

7

75

8

85

Non-Converters Converters

of

Dep

ress

ive

Epis

odes

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

Pretest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

The Mood Disorder Spectrum

bull Although categorical classifications may be useful for clinical practice the overwhelming majority of the evidence points to a dimensional (spectrum) view of mood disordersndash eg treatment response (antidepressant vs mood stabilizing

agent) and links with family history of BP

bull Individuals with unipolar depression and a little bit of mania are more likely to have an eventual diagnostic conversion to bipolar disorder

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Benazzi F Eur Psychiatry 20082340-8 Hu J et al Primary Care Companion CNS Disord 201416(2)PCC13r01599 Sato T et al J Affective Disord 200481103-13

Vieta E Valenti M J Affective Disord 201314828-36

So You Think Its Unipolar Depression

bull Over one-third of unipolar patients are eventually re-diagnosed as bipolar

bull As many as 60 of patients with BPII are initially diagnosed as unipolar

bull Presence of even subthreshold (hypo)mania symptoms is strongly associated with conversion to bipolar disorderndash Each (hypo)mania symptom increases risk by ~30

Akiskal HS Benazzi J Affective Disord 200373113-22 Dudek D et al J Affective Disord 2013144(1-2)112-5 Fiedorowicz JG et al Am J Psychiatry 201116840-8

Progression to Bipolar Disorder From MDD With Subthreshold Hypomania

N=550 individuals followed for gt1 year (mean follow-up 175 years) after a diagnosis of major depression at intake

196 of patients converted to bipolar disorder during follow-up

Fiedorowicz JG et al Am J Psychiatry 201116840-8

Time to Hypomania or ManiaTime to Hypomania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

070 1040 1300 1560

08

780520260

Time to Mania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

050 1040 1300 1560

08

780520260

ge3 Symptomslt3 Manic symptoms

06

07

Unipolar Bipolar

Psychotic features

Family history of bipolar disorder

Hostility

Early age at onset of first depressive episode (lt25 years)

of lifetime affective episodes

Atypical depressive symptoms

Subsyndromal hypomanic symptoms

Impulsivity

Aggression

Worse response to antidepressants

Antidepressant-induced hypomania

Postpartum depressive episodes

Rapid onset of depressive episodes

of hospitalizations

Clues Across The Spectrum

Dervic K et al Eur Psychiatry 201530(1)106-13 Angst J et al Arch Gen Psychiatry 201168(8)791-9 Musetti L et al CNS Spectrums 201318(4)177-87

Clin

ical

His

tory

Trea

tmen

t H

isto

rySy

mpt

oms

Greater severity of depressive episodes

Comorbid SUD

Converters328

Non-Converters672

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

34

36

38

40

42

44

Non-Converters Converters

Age

of I

llnes

s O

nset

(yrs

)

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

6

65

7

75

8

85

Non-Converters Converters

of

Dep

ress

ive

Epis

odes

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

The Mood Disorder Spectrum

bull Although categorical classifications may be useful for clinical practice the overwhelming majority of the evidence points to a dimensional (spectrum) view of mood disordersndash eg treatment response (antidepressant vs mood stabilizing

agent) and links with family history of BP

bull Individuals with unipolar depression and a little bit of mania are more likely to have an eventual diagnostic conversion to bipolar disorder

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Benazzi F Eur Psychiatry 20082340-8 Hu J et al Primary Care Companion CNS Disord 201416(2)PCC13r01599 Sato T et al J Affective Disord 200481103-13

Vieta E Valenti M J Affective Disord 201314828-36

So You Think Its Unipolar Depression

bull Over one-third of unipolar patients are eventually re-diagnosed as bipolar

bull As many as 60 of patients with BPII are initially diagnosed as unipolar

bull Presence of even subthreshold (hypo)mania symptoms is strongly associated with conversion to bipolar disorderndash Each (hypo)mania symptom increases risk by ~30

Akiskal HS Benazzi J Affective Disord 200373113-22 Dudek D et al J Affective Disord 2013144(1-2)112-5 Fiedorowicz JG et al Am J Psychiatry 201116840-8

Progression to Bipolar Disorder From MDD With Subthreshold Hypomania

N=550 individuals followed for gt1 year (mean follow-up 175 years) after a diagnosis of major depression at intake

196 of patients converted to bipolar disorder during follow-up

Fiedorowicz JG et al Am J Psychiatry 201116840-8

Time to Hypomania or ManiaTime to Hypomania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

070 1040 1300 1560

08

780520260

Time to Mania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

050 1040 1300 1560

08

780520260

ge3 Symptomslt3 Manic symptoms

06

07

Unipolar Bipolar

Psychotic features

Family history of bipolar disorder

Hostility

Early age at onset of first depressive episode (lt25 years)

of lifetime affective episodes

Atypical depressive symptoms

Subsyndromal hypomanic symptoms

Impulsivity

Aggression

Worse response to antidepressants

Antidepressant-induced hypomania

Postpartum depressive episodes

Rapid onset of depressive episodes

of hospitalizations

Clues Across The Spectrum

Dervic K et al Eur Psychiatry 201530(1)106-13 Angst J et al Arch Gen Psychiatry 201168(8)791-9 Musetti L et al CNS Spectrums 201318(4)177-87

Clin

ical

His

tory

Trea

tmen

t H

isto

rySy

mpt

oms

Greater severity of depressive episodes

Comorbid SUD

Converters328

Non-Converters672

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

34

36

38

40

42

44

Non-Converters Converters

Age

of I

llnes

s O

nset

(yrs

)

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

6

65

7

75

8

85

Non-Converters Converters

of

Dep

ress

ive

Epis

odes

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

So You Think Its Unipolar Depression

bull Over one-third of unipolar patients are eventually re-diagnosed as bipolar

bull As many as 60 of patients with BPII are initially diagnosed as unipolar

bull Presence of even subthreshold (hypo)mania symptoms is strongly associated with conversion to bipolar disorderndash Each (hypo)mania symptom increases risk by ~30

Akiskal HS Benazzi J Affective Disord 200373113-22 Dudek D et al J Affective Disord 2013144(1-2)112-5 Fiedorowicz JG et al Am J Psychiatry 201116840-8

Progression to Bipolar Disorder From MDD With Subthreshold Hypomania

N=550 individuals followed for gt1 year (mean follow-up 175 years) after a diagnosis of major depression at intake

196 of patients converted to bipolar disorder during follow-up

Fiedorowicz JG et al Am J Psychiatry 201116840-8

Time to Hypomania or ManiaTime to Hypomania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

070 1040 1300 1560

08

780520260

Time to Mania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

050 1040 1300 1560

08

780520260

ge3 Symptomslt3 Manic symptoms

06

07

Unipolar Bipolar

Psychotic features

Family history of bipolar disorder

Hostility

Early age at onset of first depressive episode (lt25 years)

of lifetime affective episodes

Atypical depressive symptoms

Subsyndromal hypomanic symptoms

Impulsivity

Aggression

Worse response to antidepressants

Antidepressant-induced hypomania

Postpartum depressive episodes

Rapid onset of depressive episodes

of hospitalizations

Clues Across The Spectrum

Dervic K et al Eur Psychiatry 201530(1)106-13 Angst J et al Arch Gen Psychiatry 201168(8)791-9 Musetti L et al CNS Spectrums 201318(4)177-87

Clin

ical

His

tory

Trea

tmen

t H

isto

rySy

mpt

oms

Greater severity of depressive episodes

Comorbid SUD

Converters328

Non-Converters672

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

34

36

38

40

42

44

Non-Converters Converters

Age

of I

llnes

s O

nset

(yrs

)

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

6

65

7

75

8

85

Non-Converters Converters

of

Dep

ress

ive

Epis

odes

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

Progression to Bipolar Disorder From MDD With Subthreshold Hypomania

N=550 individuals followed for gt1 year (mean follow-up 175 years) after a diagnosis of major depression at intake

196 of patients converted to bipolar disorder during follow-up

Fiedorowicz JG et al Am J Psychiatry 201116840-8

Time to Hypomania or ManiaTime to Hypomania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

070 1040 1300 1560

08

780520260

Time to Mania

Prop

ortio

n W

ithou

t H

ypom

ania

or M

ania

Weeks to Follow-up

10

09

050 1040 1300 1560

08

780520260

ge3 Symptomslt3 Manic symptoms

06

07

Unipolar Bipolar

Psychotic features

Family history of bipolar disorder

Hostility

Early age at onset of first depressive episode (lt25 years)

of lifetime affective episodes

Atypical depressive symptoms

Subsyndromal hypomanic symptoms

Impulsivity

Aggression

Worse response to antidepressants

Antidepressant-induced hypomania

Postpartum depressive episodes

Rapid onset of depressive episodes

of hospitalizations

Clues Across The Spectrum

Dervic K et al Eur Psychiatry 201530(1)106-13 Angst J et al Arch Gen Psychiatry 201168(8)791-9 Musetti L et al CNS Spectrums 201318(4)177-87

Clin

ical

His

tory

Trea

tmen

t H

isto

rySy

mpt

oms

Greater severity of depressive episodes

Comorbid SUD

Converters328

Non-Converters672

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

34

36

38

40

42

44

Non-Converters Converters

Age

of I

llnes

s O

nset

(yrs

)

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

6

65

7

75

8

85

Non-Converters Converters

of

Dep

ress

ive

Epis

odes

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

Unipolar Bipolar

Psychotic features

Family history of bipolar disorder

Hostility

Early age at onset of first depressive episode (lt25 years)

of lifetime affective episodes

Atypical depressive symptoms

Subsyndromal hypomanic symptoms

Impulsivity

Aggression

Worse response to antidepressants

Antidepressant-induced hypomania

Postpartum depressive episodes

Rapid onset of depressive episodes

of hospitalizations

Clues Across The Spectrum

Dervic K et al Eur Psychiatry 201530(1)106-13 Angst J et al Arch Gen Psychiatry 201168(8)791-9 Musetti L et al CNS Spectrums 201318(4)177-87

Clin

ical

His

tory

Trea

tmen

t H

isto

rySy

mpt

oms

Greater severity of depressive episodes

Comorbid SUD

Converters328

Non-Converters672

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

34

36

38

40

42

44

Non-Converters Converters

Age

of I

llnes

s O

nset

(yrs

)

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

6

65

7

75

8

85

Non-Converters Converters

of

Dep

ress

ive

Epis

odes

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

Converters328

Non-Converters672

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

34

36

38

40

42

44

Non-Converters Converters

Age

of I

llnes

s O

nset

(yrs

)

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

6

65

7

75

8

85

Non-Converters Converters

of

Dep

ress

ive

Epis

odes

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

34

36

38

40

42

44

Non-Converters Converters

Age

of I

llnes

s O

nset

(yrs

)

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

6

65

7

75

8

85

Non-Converters Converters

of

Dep

ress

ive

Epis

odes

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

6

65

7

75

8

85

Non-Converters Converters

of

Dep

ress

ive

Epis

odes

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

0

10

20

30

40

Non-Converters Converters

o

f Pat

ient

s R

esis

tant

to

Ant

idep

ress

ants

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

005

115

225

335

4

Non-Converters Converters

of

Hos

pita

lizat

ions

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

0

5

10

15

20

25

30

Non-Converters Converters

Wee

ks S

pent

in a

Ps

ychi

atric

Hos

pita

l

Dudek D et al J Affective Disord 2013144(1-2)112-5

Which Patients With Unipolar Depression Will Convert to Bipolar Disorder

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

DIAGNOSIS ALONG THE SPECTRUM

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

A Rose By Any Other Namehellip

DSM-5 DIAGNOSIS

Major depressive

disorder (unipolar

depression)

Bipolar disorder II

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Bipolar disorder I

With mixed features if subthreshold (hypo)manic symptoms co-occur

with depressive episodes

With mixed features if subthreshold depressive symptoms co-occur with

manic episodes

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

Evolution of the DSM

bull DSM-IV mixed episodendash Diagnostic criteria for major depression and mania

met at the same timebull DSM-5 mixed features specifier

ndash Recognizes the presence of subthreshold (hypo)manic symptoms during a depressive episode

ndash Specifier may be applied to major depressive disorder bipolar II or bipolar I

APA Diagnostic and Statistical Manual of Mental Disorders 4th ed Text Rev 2000APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

DSM-5 Mixed Features Specifier

bull Full criteria for a MDE and ge 3 of these manic symptoms

APA Diagnostic and Statistical Manual of Mental Disorders 5th ed 2013

bull Elevated expansive moodbull Inflated self-esteem or grandiositybull More talkative than usual or pressure to keep talkingbull Flight of ideas or racing thoughtsbull Increase in energy or goal-directed activity (socially at work or

school or sexually)bull Increased or excessive involvement in activities that have a high

potential for painful consequences (eg engaging in unrestrained buying sprees sexual indiscretions foolish business investments)

bull Decreased need for sleep

bull Diagnosis may be complicated by comorbid conditions including untreated ADHD personality disorders and substance abuse

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

McIntyre RS et al J Affective Disord 2015172C259-64

Mixed Features The Exception or the Rule

260340 338

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

n=149 n=65 n=49

MDD BPII BPI

Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder

The International Mood Disorders Collaborative Project

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

Chart1

Column3

of Individuals Who Met Criteria For Mixed Features During an Index Major Depressive Episode

026

034

0338

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

MDD
BD-I
BD-II

Sheet1

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

	Column3		Column1		Column2
MDD		260
BD-I		340
BD-II		338

Depression With Mixed Features (DMX)

bull Associated withndash Family history of BPndash Suicidalityndash Antidepressant-induced

maniandash Young age of onsetndash Long duration of illnessndash Poor prognosisndash Severe depressionndash Antidepressant resistancendash Femalesndash Comorbid anxietyndash Comorbid SUDndash Impulse control

The prognosis for depression with co-occurring

(hypo)mania (DMX) is much worse than for pure unipolar

depression or bipolar depression without mixed

features

Akiskal HS Benazzi F J Affective Disord 200373113-22 Angst J et al Am J Psychiatry 20101671194-201 Goldberg JF et al Am J Psychiatry 2009166173-81

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Symptoms Most Commonly Seen in DMX

bull Irritabilitybull Distractibilitybull Psychomotor agitationbull Racingcrowded

thoughtsbull Increased talkativenessbull Emotional lability

bull Ruminationbull Initial or middle insomniabull Dramatic expressions of

sufferingbull Impulsivitybull Risky behaviors

Akiskal HS Banazzi F J Affective Disord 20058245-58 Benazzi F Akiskal HS Psychiatry Res 200614181-8 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Faedda GL et al J Affective Disord 201517618-23 Goldberg JF et al Am J Psychiatry 2009166173-81 Olgiati P et al Depression

Anxiety 200623389-97 Maj M J Clin Psychiatry 201576(3)e381-2 Perugi G et al J Clin Psychiatry 201576(3)e351-8 Sani G et al J Affective Disord 201416414-8 Suppes T et al Am J Psychiatry 2015

Epub ahead of print Takeshima M Oka T Psychiatry Clin Neurosci 201568109-16

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Symptoms Most Commonly Seen in DMX

0

10

20

30

40

50

60

Freq

uenc

y Am

ong

Patie

nts

With

DM

X

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

DMX Diagnostic Criteria

bull Although irritability distractibility and psychomotor agitation are among the most common symptoms of DMX they are excluded from DSM-5 mixed features criteria due to the overlap of these symptoms with other disorders (eg anxiety disorders) and between mania and depression

bull Some argue that these 3 particular symptoms are the defining features of DMX and that excluding them will lead to misdiagnosis and dangerous treatment strategiesndash Imagine if we excluded psychosis as a

diagnostic feature of schizophrenia

Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Mahli GS et al J Affective Disord 20141588-10

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Non-DSM Criteria for DMX

bull Do not exclude agitation irritability or distractibilityndash Benazzi criteriandash Koukopoulos criteriandash Research-based diagnostic criteria

bull Consider family historybull Consider age of onset of depression

Koukopoulos A Sani G Acta Psychiatr Scand 20141294-16 Benazzi F EurPsychiatry 20082340-8 Mahli GS et al J Affective Disord 20141588-10 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16 Perugi G et al J Clin Psychiatry

201576(3)e351-8

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Non-DSM Criteria for DMX

0

5

10

15

20

25

30

DSM-5 CRITERIA RBDC CRITERIA

75

291

o

f Dep

ress

ed P

atie

nts I

dent

ified

as D

MX

4X as many cases of DMX identified using research-based diagnostic criteria

Perugi G et al J Clin Psychiatry 201576(3)e351-8

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

0

10

20

30

40

50

60

70

80

90

100

DSM-5 CRITERIA BENAZZI CRITERIA

1000

872

51

551

Specificity Sensitivity Sensitivity

Non-DSM Criteria for DMX

Benazzi F Eur Psychiatry 20082340-8 Takeshima M Oka T Psychiatry Clin Neurosci 201569(2)109-16

bull ~10 of patients identified as DMX will not actually have DMX

bull Less than 50 at risk of receiving inappropriate treatment

bull All patients identified as DMX will indeed have DMX

HOWEVERbull Only 51 of

individuals who have DMX will be identified

bull ~95 at risk of receiving inappropriate treatment

Which is potentially more detrimental Misdiagnosing someone who is pure unipolar as DMX

orTreating unidentified DMX with antidepressants

SensitivitySpecificity

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Consequences of MisdiagnosisInappropriate Treatment

bull Years (often a decade or more) of unnecessary suffering

bull Treatment resistancebull Reduced likelihood of responding to eventual

appropriate mood stabilizer treatmentbull Treatment-emergent activation syndrome

(TEAS)bull Suicidality

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Treatment Resistance

bull Patients with DMX are less likely to respond to treatment-as-usual for major depressive disorder

bull Diagnostic conversion from unipolar to bipolar is significantly related to treatment resistancendash As many as two-thirds of patients whose diagnosis is converted from

unipolar to bipolar disorder are treatment resistant

bull Approximately half of patients with treatment-resistant unipolar depression may actually be bipolar

bull Repeated exposure to antidepressants may lead to resistance to mood stabilizers and poorer outcomes in patients without pure unipolar depressionndash It may also be that patients with more antidepressant trials were

always going to be resistantAngst J et al Am J Psychiatry 20101671194-201 Dudek D et al J Affective Disord 2013144(1-2)112-5 Sharma V et al J Affective Disord 200584(2-3)251-7 Rihmer Z Gonda X Depression

Res Treatment 20112011906426 Amsterdam JD Shults J J Affective Disord 2009115(1-2)234-40 Post RM et al J Clin Psychiatry 201273(7)924-30

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Treatment-Emergent Activation Syndrome (TEAS)

bull Over 20 of patients may experience TEAS related to antidepressants

bull Most common with serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)

bull Hypothetically related to high noradrenergic potency

bull The presence of even minor subthreshold (hypo)mania during a depressive episode increases the risk of TEAS

Angst J et al Arch Gen Psychiatry 201168(8)791-9 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Post RM et al J Clin Psychiatry

201273(7)924 Akiskal HS et al J Affective Disord 20058245-58

(Hypo)mania

Agitation

Anxiety

Panic attacks

Irritability

Hostilityaggression

Impulsivity

Insomnia

Suicidality

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Higher Risk of TEAS

bull Bipolar I gt bipolar IIbull History of antidepressant-

induced maniabull Mixed depressionbull Low TSH with TCA usebull Hyperthymic

temperament

bull TCA or SNRI usebull Absence of antimanic

mood stabilizerbull Genetic factorsbull Comorbid alcoholismbull Female gender +

comorbid anxiety disorder

TSH thyroid-stimulating hormone

Bond DJ et al J Clin Psychiatry 2008691589-601 Frye MA et al Am J Psychiatry 2009166164-72 Salvadore G et al J Clin Psychiatry 2010711488-501

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

DMX and Suicidality

bull Non-euphoric (hypo)manic symptoms (including psychomotor agitation impulsivity irritability and racingcrowded thoughts) combined with depressive symptoms (ie DMX) = recipe for suicidality

bull Presence of mixed features increases risk of suicidality by 4X in both unipolar and bipolar depression

bull DMX may underlie the connection between antidepressant use and suicidalityndash Most notably in the pediatric population in which DMX is often

the rule rather than the exceptionndash Both young age of onset of depression and DMX symptoms

indicate bipolarity

Akiskal HS Benazzi F Psychopathology 200538273-80 Balazs J et al J Affective Disord 200691133-8 Benazzi F Lancet 2007369935-45 Olgiati P et al Depression Anxiety 200623389-97 Swann AC et al

Bipolar Disord 20079(3)206-12 Rihmer Z Gonda X Depression Res Treatment 20112011906426

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Every time

One of the Most Important Questions to Ask Any Patient With Depression

Any maniahypomania

symptoms andor

family history of bipolar disorder

Every patient

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

DMX and Family History

bull Family history of BPndash 4X higher in DMX than in pure unipolar depressionndash Highly associated with patients who have 2+

(hypo)manic symptoms during major depressive episodes (MDEs)

ndash As common in DMX as in BPndash Supports the idea of DMX as a soft bipolar disorder

and a dimensional rather than a categorical view of mood disorders

Prieto ML et al J Affective Disord 2015172355-60 Axelson D et al Am J Psychiatry 2015172(7)638-46

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Tools for Assessing DMX

bull Bipolar Depression Rating Scale (BDRS)ndash Clinician-administered assessment of current symptoms

bull Mini International Neuropsychiatric Interview (MINI)bull Patient self-report assessing current (hypo)manic symptoms

bull Clinically Useful Depression Outcome Scale with DSM-5 Mixed (CUDOS-M)ndash Patient self-report assessing current (hypo)manic symptoms

bull Hypomania Checklist (HCL-32)ndash Patient self-report that screens for lifetime (hypo)manic

symptoms

See APPENDIX for more details on each assessment tool

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

TREATMENT ALONG THE SPECTRUM

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant

Mania

Mania withsubsyndromaldepression

MixedStates

Depression withsubsyndromal

mania

Depression

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic

Mania Depression

MixedStates

Mania withsubsyndromaldepression

Depression withsubsyndromal

mania

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Issues With Existing Treatment Guidelines for DMX

bull Any existing guidelines (and FDA approvals) for mixed bipolar disorder refer to DSM-IV criteria (co-occurring threshold-level MDE + threshold-level mania)ndash Recommendations are to treat as mania

bull A diagnosis of MDD implies the use of unipolar depression treatment guidelinesndash Possibly ineffective and potentially harmful

bull Treatment guidelines for bipolar depression are likely the most applicable to DMXndash Many are not up to date with the latest clinical trial data (ie

atypical antipsychotics with mood-stabilizing properties)

bull Very few studies have yet to focus specifically on DMX

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Antidepressant

Mood Stabilizer

Atypical Antipsychotic

Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations

Depression Mixedstates

Mania with subsyndromal depression

Depression with subsyndromal mania

Increasing severity of manic symptoms Increasing severity of depressive symptoms

Mania

Only those patients with essentially NO

symptoms of (hypo)mania should be considered for

antidepressant monotherapy

Unipolar depressionBipolar disorderDoes it matter in terms of choosing the best treatment

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

See DMX treatment guidelines

NoAntidepressant monotherapy

Therapeutic response to

antidepressant monotherapy

Yes

No

Switch to alternate

antidepressant monotherapy

Any maniahypomania symptoms andor family history of

BP

Continue antidepressant monotherapy

No

Resistant to 2 antidepressant monotherapy

trials

Any maniahypomania symptoms andor family history of

BP

Yes

No Yes

Treatment Algorithm for Depression Without Mixed

Features

Follow APA treatment

guidelines but consider DMX

treatment guidelines

Yes

Any maniahypomania symptoms andor family history of

BP

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Patient on antidepressant monotherapyYes NoDiscontinuetaper

antidepressant

Initiate atypical antipsychotic

Continue as maintenance

therapy

Therapeutic response

No

Add or switch to mood stabilizer

or switch to different atypical

antipsychotic

Therapeutic responseNo

Add antidepressant

Therapeutic response

No

Yes

Consider ECT and novelexperimental options

Treatment Algorithm for Depression With Mixed

Features (DMX)

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Atypical Antipsychotics

Cerullo M et al CNS Spectrums 201318(4)199-208 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Fountoulakis KN et al Int J Neuropsychopharmacol

2012151015-26 Grunze H Azorin JM World J Biol Psychiatry 201415(5)355-68 Vieta E ValentiM J Affective Disord 201314828-36 Fornaro M et al Int J Mol Sci 201617(2)241

doi103390ijms17020241 Stahl SM Prescribers Guide 5th ed Cambridge University 2014

Evidence ofEfficacy in

DMX

FDA-Approved for

BP Depression

FDA-Approved for

BP Mania

FDA-Approved for

BP Maintenance

FDA-Approved for

MDD

Aripiprazole (adjunct)

Asenapine Lurasidone Olanzapine

(with fluoxetine)

(with fluoxetine)

Quetiapine (adjunct)

Risperidone Ziprasidone

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Asenapine in DMX

Berk M et al J Clin Psychiatry 201576(6)728-34

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Cut-offs used to define depressive symptom severity in patients with ge3 depressive features mild (score ge1 for MADRS items and ge2 for PANSS items) moderate (score ge2 MADRS ge3 PANSS) and severe (score ge3 MADRS ge4 PANSS) symptoms remission defined as MADRS le12 post hoc analysis

McIntyre et al J Affective Disord 2013150(2)378-83

ple005 ple001 vs placebo

Placebo (n=69)Asenapine (n=113)Olanzapine (n=132)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Placebo (n=12)Asenapine (n=12)Olanzapine (n=16)

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms

Improvement of depressive symptoms at Week 3

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Rem

issi

on ra

te (

)

Placebo (n=40)Asenapine (n=56)Olanzapine (n=66)

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint) groups with and without subsyndromal hypomania

Change from baseline in YMRS score groups with and without subsyndromal hypomania

Lurasidone (20ndash120 mgday) Lurasidone (20ndash120 mgday)plt001

49

512 511532

322 311278

0

10

20

30

40

50

60

70

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

Lurasidone Placebo

-24

-28

01

-23-24

03

-30

-25

-20

-15

-10

-05

00

05

Subsyndromal hypomania

(baseline YMRS ge4)

Subsyndromal hypomania (score of

ge2 for 2 or more YMRS items)

No subsyndromalhypomania

LS m

ean

YMR

S ch

ange

sco

re (W

eek

6)LurasidonePlacebo

Res

pond

er ra

te (

)

McIntyre RS et al J Clin Psychiatry 201576(4)398-405

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

-250

-200

-150

-100

-50

00Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Placebo (N=100) Lurasidone (N=108)

LS M

ean

Cha

nge

From

Bas

elin

e

BL mean = 332BL mean = 333

plt005 plt001 plt0001Mean daily dose of lurasidone was 362 mgday

Effect size = 08

-130

-205

Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Chart1

Placebo (N=100)

Lurasidone (N=108)

0

0

-38

-55

-69

-97

-88

-139

-104

-162

-122

-19

-13

-205

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Baseline		Baseline
Week 1		Week 1
Week 2		Week 2
Week 3		Week 3
Week 4		Week 4
Week 5		Week 5
Week 6		Week 6

Sheet1

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

	Baseline		Week 1		Week 2		Week 3		Week 4		Week 5		Week 6				21
Placebo (N=100)		0		-38		-69		-88		-104		-122		-13				-669
Lurasidone (N=108)		0		-55		-97		-139		-162		-19		-205

Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)

-49

-70

-100

-50

00

Placebo (N=100) Lurasidone (N=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 103

BL mean = 111plt001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

Chart1

Placebo (N=100)

Lurasidone (N=108)

-70

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

-49

-7

Sheet1

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Placebo (N=100)		-49
Lurasidone (N=108)		-70

Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)

-54

-99

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 167

BL mean = 170plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Chart1

Placebo (n=100)

Lurasidone (n=108)

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

-54

-99

Sheet1

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Placebo (n=100)		-54
Lurasidone (n=108)		-99

Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)

-64

-112

-150

-100

-50

00

Placebo (n=100) Lurasidone (n=108)

Mea

n C

hang

e Fr

om B

asel

ine

BL mean = 205BL mean = 199

plt0001

Suppes T et al Am J Psychiatry 2016173(4)400-7

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Chart1

Placebo (n=100)

Lurasidone (n=108)

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

-64

-112

Sheet1

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Placebo (n=100)		-64
Lurasidone (n=108)		-112

Lurasidone Efficacy in DMXSuicide and TEAS

0

2

4

6

8

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Suicidal Behavior

0

2

4

6

PLACEBO LURASIDONE

o

f Pat

ient

s

Treatment-Emergent Mania

Suppes T et al Am J Psychiatry 2016173(4)400-7

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features

Tohen M et al J Affective Disord 201416457-62

n=56 n=93 n=85 n=148 n=17 n=32

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)

Suppes T et al J Affective Disord 2013150(1)37-43

p=0002

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Quetiapine Efficacy in DMX MADRS

p=00138

Suppes T et al J Affective Disord 2013150(1)37-43

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Quetiapine Efficacy in DMX YMRS

Not significant(p=0069)

Suppes T et al J Affective Disord 2013150(1)37-43

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms

Patkar A et al PLOS ONE 20127(4)e34757

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Tolerability of Atypical Antipsychotics

SEDATIONAripiprazoleBrexpiprazoleCariprazineIloperidoneLurasidonePaliperidoneRisperidoneZiprasidoneAsenapineOlanzapineClozapineQuetiapine

WEIGHT GAINAripiprazoleBrexpiprazoleCariprazineLurasidoneZiprasidoneAsenapineIloperidonePaliperidoneRisperidoneQuetiapineClozapineOlanzapine

EPSClozapineIloperidoneQuetiapineAripiprazoleBrexpiprazoleCariprazineAsenapineLurasidoneOlanzapineZiprasidonePaliperidoneRisperidone

Best choice

Worst choice

Patients on atypical antipsychotics should be regularly monitored for side effects including BMI

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Mood Stabilizers for DMX

bull No mood stabilizer is actually approved for use in depression of any kind (unipolar mixed bipolar)

bull There are some data for the efficacy of lamotrigine or valproate for bipolar depression

bull Lithium is well known for its anti-suicide effects however neither lithium nor carbamazepine monotherapy is recommended for the treatment of bipolar depression

Evidence ofEfficacy in

DMX

FDA-Approved for BP

Depression

FDA-Approved for BP Mania

FDA-Approved for BP

Maintenance

FDA-Approved for MDD

Carbamazepine Lamotrigine Lithium Valproate

Stahl SM Prescribers Guide 5th ed Cambridge University Press 2014 Goodwin GM et al J Psychopharmacol200923(4)346-88 Connolly KR Thase MD Primary Care Companion CNS Disord 201113(4)PCC10r01097

Fountoulakis KN et al Eur Arch Clin Neurosci 2012262(suppl 1)S1-48 Musetti L et al CNS Spectrums 201318(4)177-87

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Antidepressant Monotherapy for DMX

bull Nobull Dontbull Seriously just dont do it

bull Antidepressant monotherapy should probably NOT be used in patients with even the slightest hint of (hypo)mania (or a family history of bipolar disorder)

bull You will most likely not know if your depressed patient has ever had any (hypo)manic symptoms andor family history of bipolarity unless you askndash Every patient Every time

bull Any patient on antidepressant monotherapy should be regularly monitored for response and emergence of hypomania

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Combination Therapy

bull The treatment of DMX may require a combination of medicationsbull Common combinations for BP depression include

ndash Atypical antipsychotic + mood stabilizerndash Atypical antipsychotic + antidepressant

bull Olanzapine-fluoxetine combination in particularndash Mood stabilizer + antidepressant

bull The combination of olanzapine or risperidone and carbamazepine is not recommended always check the safety of any particular combination

bull If an antidepressant is prescribed for DMX it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer)

bull It is questionable whether adding an antidepressant to a mood stabilizer or an atypical antipsychotic has any therapeutic benefit

Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2 Nivoli AMA et al J Affective Disord

2012140125-41 Yatham LN et al Bipolar Disord 200911225-55

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features

No significant benefit from adding fluoxetine to olanzapine

Benazzi F et al J Clin Psychiatry 200970(10)1424-31

Response defined as ge 50 reduction in the MADRS total score and lt 2 concurrent manichypomanic symptoms (measured by the YMRS)

0

5

10

15

20

25

30

35

40

45

PLACEBO OLANZAPINE OFC

o

f Res

pond

ers

(p=00006)

(p=0014)

(p=0065)NS

n=166 n=173 n=37

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood

Stabilizers (STEP-BD)

Goldberg et al Am J Psychiatry 2007164(9)1348-55

355 STEP-BD entrants with major depression + 1 or more manic symptoms

n=145

n=190

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Other Adjunctive Pharmacological Treatment Strategies

bull Modafinilarmodafinilndash Stimulants may worsen

symptoms (including irritability agitation and TEAS) in patients with DMX

bull Pramipexolebull Folic acidbull Inositolbull Ketaminebull N-acetyl cysteine

bull Omega-3 fatty acidsbull Ramelteonbull Celecoxibbull Topiramate for weight

managementbull Benzodiazepines (short-

term) for anxiety and agitation

DellOsso B Ketter TA Int J Neuropsychopharmacol 20131655-68 Fountoulakis KN et al Eur Arch Psychiatry Clin Neurosci 2012262(suppl 1)S1-48 Goodwin GM J Psychopharmacol 200923(4)346-88 Grunze H et al

World J Biol Psychiatry 201011(2)81-109 Magiria S et al In Ritsner MS ed Use of Polypharmacy in the Real World New York NY Springer 2013 Polypharmacy in Psychiatry Practice vol 2

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Nonpharmacological Interventions

bull Electroconvulsive therapy (ECT)bull Transcranial magnetic stimulation (TMS)bull Sleep deprivationbull Individual or group psychoeducation

ndash Focus on early warning signs of relapsebull Interpersonal and family therapybull Cognitive behavioral therapy

Connolly KR Thase ME Primary Care Companion CNS Disord201113(4)PCC10r01097 Goodwin GM J Psychopharmacol 200923(4)346-88

Grunze H et al World J Biol Psychiatry 201011(2)81-109 Yatham LN et al Bipolar Disord 2013151-44

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Summary

bull Not all patients with depression should be given an antidepressant

bull The inappropriate overprescribing of antidepressants has contributed to drug-induced (hypo)manic episodes treatment resistance suicidality and overall poor quality of life for many patients suffering from depression

bull If there are any symptoms of (hypo)mania or a family history of bipolar disorder an antipsychotic with mood-stabilizing properties may be the best option

bull You will not know if a depressed patient has (hypo)manic symptoms or a positive family history of bipolar disorder unless you ask Every patient Every time

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

PostPoll Question

How many patients do you see with symptoms of mixed depression each week

1 02 1-53 6-104 11-155 16-206 21 or more

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Posttest Question 1

Sarah is a 20-year-old patient who presents with symptoms of depression (including sadness feelings of worthlessness and suicidal ideation) occurring every day for the past month Which class of medication would be most suitable for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 Either 1 or 25 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Posttest Question 2

Clinical interview with Sarah reveals that she has a maternal aunt with bipolar disorder I Further assessment reveals that Sarah feels distracted and as though her thoughts are racing Upon speaking with her mother it is discovered that Sarah has at times been more talkative than usual and irritable with her friends and family Which class of medication would NOT be recommended as monotherapy for this patient

1 An antidepressant2 A mood stabilizer3 An antipsychotic4 There is not enough information about this patients case to

make an informed treatment decision

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Posttest Question 3

Stacey is a 25-year-old patient with bipolar depression who tends to endorse some manic symptoms during depressive episodes Of the following symptoms which is the most common subsyndromal mania symptom in patients with mixed depression

1 Decreased need for sleep2 Inflated self-esteem3 Distractibility4 Increased goal-directed activity5 High-risk activity

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Posttest Question 4

A 33-year-old obese patient with treatment-resistant depression has agreed to a trial of an atypical antipsychotic Considering this patients current weight and the wish to avoid any treatment-induced weight gain which of the following approved treatments would be the least optimal treatment for this patient

1 Lurasidone2 Olanzapinefluoxetine combination3 Quetiapine

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

APPENDIX

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Bipolar Depression Rating Scale (BDRS)

bull Clinician-administered assessment of current symptoms

Galvao F et al Compr Psychiatry 201354(6)605-10httpwwwbarwonhealthorgaubdrs

Severity of Disturbances to Mood Motivation Self-worth Mood labilitySleep Concentration

memorySuicidality Motor drive

Appetite Anxiety Guilt Increased speechSocial engagement

Anhedonia Psychosis Agitation

Energyactivity Affect Irritability

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Mini International Neuropsychiatric Interview (MINI)

bull Patient self-report assessing current (hypo)manic symptoms

Herqueta T Weiller E Int J Bipolar Disord 2013121 Young AH Ebergard J Neuropsychiatr Dis Treatment 2015111137-43

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Frequency of each symptom during the prior week

0 1 2 3 4

Not at all Rarely Sometimes Often Almost always

I felt so happy and cheerful it was like a high

I had many brilliant creative ideas

I felt extremely self-confident

I slept only a few hours but woke full of energy

My energy seemed endless

I was much more talkative than usual

I spoke faster than usual

My thoughts were racing through my mind

I took on many new projects because I felt I could do everything

I was much more social and outgoing than usual

I did wild impulsive things

I spent money more freely than usual

I had many more thoughts and fantasies about sex

Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)

bull Patient self-report assessing current (hypo)manic symptoms

Zimmerman M et al J Affective Disord 2014168357-62

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)

Hypomania Checklist (HCL-32)

bull Patient self-report that screens for lifetime (hypo)manic symptoms

Prieto ML et al J Affective Disord 2015172355-60 Altinbas K et al J Affective Disord 2014152-154L478-82httpwwwoacbddorgclientuploadsDocs2010Spring20HandoutsSession20220bpdf

• Mood Disorders A Spectrum Analysis
• Learning Objectives
• PrePoll Question
• Pretest Question 1
• Pretest Question 2
• Pretest Question 3
• Pretest Question 4
• The Mood Disorder Spectrum
• So You Think Its Unipolar Depression
• Progression to Bipolar Disorder From MDD With Subthreshold Hypomania
• Clues Across The Spectrum
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Which Patients With Unipolar Depression Will Convert to Bipolar Disorder
• Diagnosis along the spectrum
• A Rose By Any Other Namehellip
• Evolution of the DSM
• DSM-5 Mixed Features Specifier
• Mixed Features The Exception or the Rule
• Depression With Mixed Features (DMX)
• Symptoms Most Commonly Seen in DMX
• Symptoms Most Commonly Seen in DMX
• DMX Diagnostic Criteria
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Non-DSM Criteria for DMX
• Consequences of MisdiagnosisInappropriate Treatment
• Treatment Resistance
• Treatment-Emergent Activation Syndrome (TEAS)
• Higher Risk of TEAS
• DMX and Suicidality
• One of the Most Important Questions to Ask Any Patient With Depression
• DMX and Family History
• Tools for Assessing DMX
• Treatment along the spectrum
• Major Depressive EpisodesA Trace of Depression Means Treat With an Antidepressant
• Major Depressive EpisodesA Trace of Mania Means Treat With an Antipsychotic
• Issues With Existing Treatment Guidelines for DMX
• Bipolar Spectrum-Based First-Line Monotherapy Treatment Recommendations
• Slide Number 43
• Slide Number 44
• Atypical Antipsychotics
• Asenapine in DMX
• Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)
• Lurasidone in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)
• Lurasidone Efficacy in DMXMontgomery-Aringsberg Depression Scale (MADRS)
• Lurasidone Efficacy in DMXYoung Mania Rating Scale (YMRS)
• Lurasidone Efficacy in DMXHamilton Anxiety Rating Scale (HAM-A)
• Lurasidone Efficacy in DMXSheehan Disability Scale (SDS)
• Lurasidone Efficacy in DMXSuicide and TEAS
• Efficacy of Olanzapine Monotherapy in the Treatment of Bipolar Depression With Mixed Features
• Quetiapine Efficacy in DMXClinical Global Impression (CGI-BD)
• Quetiapine Efficacy in DMX MADRS
• Quetiapine Efficacy in DMX YMRS
• Ziprasidone Monotherapy for DMX Improvement in Depressive Symptoms
• Ziprasidone Monotherapy for DMX No Improvement in Manic Symptoms
• Tolerability of Atypical Antipsychotics
• Mood Stabilizers for DMX
• Antidepressant Monotherapy for DMX
• Combination Therapy
• Olanzapine-Fluoxetine Combination in the Treatment of Bipolar Depression With Mixed Features
• Slide Number 65
• Other Adjunctive Pharmacological Treatment Strategies
• Nonpharmacological Interventions
• Summary
• PostPoll Question
• Posttest Question 1
• Posttest Question 2
• Posttest Question 3
• Posttest Question 4
• APPENDIX
• Bipolar Depression Rating Scale (BDRS)
• Mini International Neuropsychiatric Interview (MINI)
• Clinically Useful Depression Outcome Scale With DSM-5 Mixed Features (CUDOS-M)
• Hypomania Checklist (HCL-32)