Bipolar Depression: Misdiagnosis Leads to Mistreatmentcdn.neiglobal.com/content/encore/congress/2015/slides_at-enc15-15... · Janet is a 43-year-old patient with bipolar disorder

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Bipolar Depression:

Misdiagnosis Leads to

Mistreatment

Handout for the Neuroscience Education Institute (NEI) online activity:


Learning Objectives

• Apply evidence-based strategies to differentially

diagnose patients presenting in depressive

states

• Apply evidence-based treatment strategies to

the management of patients with bipolar

disorder

• Optimize treatment for bipolar disorder based on

the long-term needs of the patient


Pre-Poll Question 1

I feel competent diagnosing patients with bipolar

depression.

1. 1 (strongly disagree)

2. 2

3. 3

4. 4

5. 5 (strongly agree)


Pre-Poll Question 2

I feel competent optimizing treatment for patients with

bipolar depression.

1. 1 (strongly disagree)

2. 2

3. 3

4. 4

5. 5 (strongly agree)


Pretest Question 1

A 28-year-old obese woman presents with a depressive episode. She

has previously been hospitalized and treated for a manic episode but is

not currently taking any medication. The agent with the lowest risk of

cardiometabolic side effects is:

1. Lithium

2. Lurasidone

3. Valproate


Pretest Question 2

Janet is a 43-year-old patient with bipolar disorder. She is currently

depressed with some features of hypomania. Practice guidelines

recommend treatment with an antidepressant in patients with bipolar

disorder under the following conditions:

1. As adjunct for acute bipolar I or II depressive episode with ≥2

concomitant manic symptoms, psychomotor agitation, or rapid

cycling

2. During manic and depressive episodes with mixed features

3. In patients with predominantly mixed states

4. All of the above

5. None of the above

DIFFERENTIAL DIAGNOSIS


We Can Do Better

• Correct diagnosis of BP within the first year of symptom

onset is made in only 20% of cases

• Average time between onset of BP symptoms and first

appropriate treatment = 10 years

• Undiagnosed BP = 49%

• Misdiagnosed BP = As high as 60%

• 78% of PCPs fail to detect or misdiagnose BP

• Up to 12.5% of individuals diagnosed with MDD will

experience a manic or hypomanic episode over an

11-year period

Conus P et al. Bipolar Disord 2014;16(5):548-56; Kleine-Budde et al. Bipolar Disord 2013; Epub

ahead of print; Knezevic V, Nedic A. Eur Rev Med Pharmacol Sci 2013;17:1542-5; Philips ML,

Kupfer DJ. Lancet 2013;381:1663-71; Sasdelli A et al. Psychiatry J 2013;2013:548349.


Why Is An Early, Accurate Diagnosis

Important?

• Consequences of not identifying bipolar depression

early:

– Worse quality of life

– Inaccurate and potentially harmful treatment

– Increased cycling and risk of relapse

– Reduced treatment response (e.g., lithium)

– Increased risk of suicide

– Increased subsequent morbidity

– High economic costs

Conus P et al. Bipolar Disord 2014;16(5):548-56.


Increased Risk of Cycling and Relapse

Knezevic V, Nedic A. Eur Rev Med Pharmacol Sci 2013;17:1542-5.

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

Properly Diagnosed Wrongly Diagnosed

Mean

# o

f E

pis

od

es O

ver

5 Y

ears


Suicide

• 29% of patients with BD attempt suicide at least

once in their life

• 10–20% of patients with BD take their own life

• Suicide rates are 20X higher for BD compared to the

general population

• Suicide rates are 2X higher for BD compared to

MDD


Holma KM et al. Bipolar Disord 2014;16(6):652-61.


Risk of Suicide Attempt Depends On Mood

Phase

0

10

20

30

40

50

60

70

Euthymic Subthreshold depression

Major depressive episode

Mixed episode

Inc

ide

nce

of

Su

icid

e A

tte

mp

t R

ela

tive

to

Eu

thym

ia

Holma KM et al. Bipolar Disord 2014;16(6):652-61.


Depressed Manic Mixed

•2X higher risk of

suicide


Axis-II comorbidity

•Depressive or mixed

1st episode

•Longer duration to

diagnosis

•Female

•Ever in a mixed state

•Ever married

•Ever received ECT

Predominantly

Depressed Predominantly

Depressed + Mixed

Predominantly

Manic


suicide


Axis-II comorbidity

•Depressive or mixed

1st episode

•Longer duration to

diagnosis

•Female

•Ever in a mixed state

•Ever married

•Ever received ECT

•1.38 higher risk of

drug abuse

•Manic or psychotic

1st episode

•12 years or more of

education

•Family history of an

affective illness

Predominantly

Manic + Mixed

•1.28 higher risk of

drug abuse

•Manic or psychotic

1st episode

•12 years or more of

education

•Family history of an

affective illness

Baldessarini RJ et al. Acta Psychiatr Scand 2012;125:293-302.

Clinical Characteristics

(at least 25% more prevalent compared to opposite pole)

Clinical Characteristics and Implications of Polarity

Categorization


Dudek D et al. J Affective Disord 2013;144(1-2):112-5.

Diagnostic Conversion From MDD to BD


*p<0.05


Characteristics of Patients With Diagnostic

Conversion From MDD to BD


***p<0.0005





***p<0.0005





Subthreshold Hypomania in MDD

• Up to 40% of patients diagnosed with unipolar

depression have symptoms of hypomania

– Most common symptoms include:

• Irritability, mental overactivity, psychomotor agitation,

talkativeness

– Individuals with subthreshold hypomania have a more severe

illness course

• High impulsivity increases the rate of conversion

• BPII versus MDD: distinct disorders or continuity on the

mood spectrum?

Alloy LB et al. J Abnorm Psychol 2012;121(1):16-27; Angst J et al. Arch Gen Psychiatry

2011;68(8):791-9; Benazzi F. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:1043-50;

Benazzi F. Psychiatry Clin Neurosci 2005;59:570-5; Mazza et al. J Nerv Ment Dis

2013;201(5):435-7; Phillips ML, Kupfer DJ. Lancet 2013;381:1663-71.


Progression to Bipolar Disorder In Patients

With 3+ Hypomanic Symptoms

Fiedorowicz JG et al. Am J Psychiatry 2011;168(1):40-8.


Why Is Making An Early and Accurate

Diagnosis of Bipolar Depression So Difficult?

• Most patients present when depressed

• Hypomania is often pleasant for patients and may not be

mentioned

• Strict diagnostic criteria in DSM-IV

– DSM-5 now recognizes the importance of changes in activity as

well as mood

– Mixed specifiers now acknowledge depression with hypomanic

features as well as hypomania with depressive features

• Mania is often atypical (especially in youth) with

irritability and flight of ideas rather than euphoria and

grandiosity


Phillips ML, Kupfer DJ. Lancet 2013;381:1663-71.


Long-term Symptomatic Status of Patients

With Bipolar II Disorder

Judd LL et al. Arch Gen Psychiatry 2003;60:261-9.

Euthymic 46%

Depressed 50%

Hypomanic 2%

Cycling/Mixed 2%

How

patients

typically

present

What you must

search for

Finding a Needle In the Haystack…

THE PROBABILISTIC APPROACH

TO DIFFERENTIAL DIAGNOSIS

Beyond Symptoms of Mania/Hypomania:


Mood reactivity

Overeating/weight gain

Hypersomnia

Melancholic

features

Catatonic

features

Family history

of BP

More previous

depressive

episodes

Psychotic

symptoms

Psychomotor

agitation (BP-II)

Psychomotor

retardation (BP-I)

Early age of

onset (<25

years)

Restlessness

History of

suicide

attempts

Irritability Feelings of

guilt Comorbid

substance use

disorder

Comorbid

personality

disorder

Shorter

depressive

episodes

Morning

worsening of

symptoms

Early morning

insomnia

Family history of

substance abuse

More Common In Bipolar Depression

Benazzi F. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:1043-50; Schaffer A et al. J Affect Disord

2010;125:103-10; Motovxky B, Pecenak J. Psychiatr Danub 2013;25(1):34-9; Mitchell P et al. Br J Psychiatr

2011;199:303-9; Moreno C et al. Bipolar Disord 2012;14:271-82; Galvão F et al. Comp Psychiatry

2013;54:605-10; Mitchell PB et al. Bipolar Disord 2008;10:144-52; Noto MN et al. Expert Rev Neurother

2013;13(7):795-806.

Melancholic

features Family

history of BP

Comorbid

personality

disorder

Early age of

onset (<25

years)

More

previous

depressive

episodes Catatonic

features Morning

worsening of

symptoms

Family history

of substance

abuse

Psychomotor

retardation

(BP-I)

Feelings of

guilt Irritability

Restlessness

UNIPOLAR

DEPRESSION Comorbid

substance use

disorder

Psychomotor

agitation (BP-II) Hypersomnia Shorter

depressive

episodes

Psychotic

symptoms History of

suicide

attempts Overeating/

weight gain

Mood reactivity Early

morning

insomnia

BIPOLAR

DEPRESSION


The Probabilistic Approach:

Diagnostic Guidelines

Suspect Bipolar Depression If 5+ Are

Present:

Suspect Unipolar Depression If 4+ Are

Present:

Hypersomnia and/or increased daytime

napping

Initial insomnia/reduced sleep

Hyperphagia and/or increased weight Appetite loss and/or weight loss

Other atypical depressive symptoms (e.g.,

leaden paralysis)

Psychomotor retardation Normal or increased activity level

Psychotic features and/or pathological guilt Somatic complaints

Mood lability

Early onset of first depression

(<25 years?)

Later onset of first depression

(>25 years?)

Multiple prior episodes (>4?) Long duration of current episode

(>6 months?)

Positive family history of bipolar disorder Negative family history of bipolar disorder

Mitchell PB et al. Bipolar Disord 2008;10:144-52.


Potential Caveats to the Probabilistic

Approach: Psychomotor Disturbance

• Some studies find psychomotor retardation more

common in bipolar depression than unipolar

depression, other studies do not

• Some studies find psychomotor agitation more

common in bipolar depression than unipolar

depression, other studies do not

• Psychomotor retardation may be more indicative of

BP-I

• Psychomotor agitation may be more indicative of

BP-II

Mitchell P et al. Br J Psychiatry 2011;199:303-9; Benazzi F. Prog Neuropsychopharmacol Biol

Psychiatry 2006;30:471-7.


Potential Caveats to the Probabilistic

Approach: Sleep Disturbance

• Some studies have found that patients with BP

depression have hypersomnia, whereas patients

with MDD have initial insomnia and reduced sleep

• One recent study in women showed:

– Patients with MDD reported either insomnia or

hypersomnia

– Patients with BP II complained of both insomnia and

hypersomnia

. Noto et al. Exper Rev Neurother 2013;13(7):795-807; Rastelli CPB et al. J Affect Disord

2013;150:1120-24.


Family History

• Although the majority of patients with BP depression

do not have a family history of BP, family history of

BP is arguably the most robust and reliable risk

factor for BP depression

• Individuals with a first-degree relative with BP

disorder are at an 8X greater risk of developing BP

disorder compared to the general population

• The importance of questioning depressed patients

about family history of affective disorders cannot be

overemphasized

Duffy A et al. BJP 2014;204:122-8; Mahli et al. Bipolar Disord 2014;16(5):455-70;

Wilde A et al. J Affect Disord 2014;158:37-47.


Bipolar Depression Rating Scale (BDRS)

• Clinician administered 20–item scale including 3

subscales

– Psychological Depression

• Anxiety, guilt, suicidality, worthlessness, irritability, etc

– Somatic depression

• Sleep disturbance, energy reduction, reduced

concentration, etc

– Mixed

• Psychotic symptoms, lability, increased speech, etc

• http://www.barwonhealth.org.au/bdrs

Berk M et al. Bipolar Disord 2007;9:571-9; Galvão F et al. Comp Psychiatry 2013;54:605-10.

32-Item Hypomania Checklist (HCL-32) I need less sleep I am more flirtatious and/or am more sexually active

I feel more energetic and more active I talk more

I am more self-confident I think faster

I enjoy my work more I make more jokes or puns when I am talking

I am more sociable (make more phone calls, go out more) I am more easily distracted

I want to travel and/or do travel more I engage in lots of new things

I tend to drive faster or take more risks when driving My thoughts jump from topic to topic

I spend more money/too much money I do things more quickly and/or more easily

I take more risks in my daily life (in my work and/or other

activities)

I am more impatient and/or get irritable more easily

I am physically more active (sport, etc) I can be exhausting or irritating for others

I plan more activities or projects I get into more quarrels

I have more ideas, I am more creative My mood is higher, more optimistic

I am less shy or inhibited I drink more coffee

I wear more colorful and more extravagant

clothes/make-up

I smoke more cigarettes

I want to meet or actually do meet more people I drink more alcohol

I am more interested in sex, and/or have increased sexual

desire

I take more drugs (sedatives, anti-anxiety pills, stimulants)

15-Item Hypomania Checklist (HCL-15) Less sleep

More drive or energy

More self-confidence

Increased social activity and work motivation

Increased physical activity

More plans and ideas

Less shy, less inhibited

More talkative than usual

More puns and jokes, faster thinking, laughing more

More irritable, impatient

Increased consumption of coffee, cigarettes

Increased consumption of alcohol

Extremely happy mood, overeuphoric

Increased sex drive, interest in sex

Over-activity (e.g., shopping, business, telephone calls, travelling, visiting people)

He et al. Gen Hosp Psychiatry 2014;36(3):347-51.

A depressed

patient who

endorses less

than 7 items has a

93% likelihood of

having MDD

rather than BPII


Mood Disorders Questionnaire (MDQ)

• 13 yes/no self-report answers

• Screens for lifetime history of manic/hypomanic

symptoms

• Shorter and possibly more accurate than the

HCL-32

• However, the HCL may be better for detecting

subthreshold hypomania symptoms

Sasdelli A et al. Psychiatry J 2013;548349.


Mood Swings Questionnaire (MSQ)

• Score of 22 or more warrants detailed clinical

assessment

• Available as an anonymous online self-test at:

www.blackdoginstitute.org.au

• 35% of patients who consulted a health care

professional following an online MSQ positive

screen had a diagnosis of BP confirmed

• Superior sensitivity and specificity compared to the

MDQ

Parker G, Fletcher K. J Affect Disord 2013;150:276-83; Parker G et al. J Affect Disord

2012;138:104-9.

TREATMENT OF BIPOLAR

DEPRESSION: EFFICACY


Study MADRS WMD (95% CI)

Calabrese et al. 2005 -6.47 (-8.67; -4.27)

Thase et al. 2006 -4.07 (-6.03; -2.11)

Young et al. 2010 -4.29 (-6.28; -2.3)

McElroy et al. 2010 -3.71 (-6.22; -1.2)

Quetiapine 600 pooled -4.64 (-5.82; -3.46)

Heterogeneity: Q=3.64; p=0.303

Overall: Z=-7.71; p=0; n=1396

Calabrese et al. 2005 -6.13 (-8.33; -3.93)

Thase et al. 2006 -5.01 (-6.95; -3.07)

Young et al. 2010 -3.55 (-5.55; -1.55)

McElroy et al. 2010 -3.59 (-6.1; -1.08)

Suppes et al. 2010 -5.51 (-7.88; -3.14)

Quetiapine 200 pooled -4.76 (-5.75; -3.76)

Heterogeneity: Q=4.19; p=0.381

Overall: Z=-9.37; p=0; n=1661

Quetiapine in Bipolar Depression

Chiesa A et al. Int Clin Psychopharmacol 2012;27(2):76-90.

Favors: QUET PBO


OFC in Bipolar Depression

Data from two 8-week randomized clinical trials for bipolar depression. Primary measure was

change in MADRS; OFC was significantly superior to both OLZ and PBO.

OFC: n=86, mean daily dose 7.4 mg/39.3 mg. OLZ: n=370, mean daily dose 9.7 mg. PBO: n=377.

Citrome L. Expert Opinion Pharmacother 2011;12(17):2751-8.


Lurasidone in Bipolar Depression:

Monotherapy

*p<0.05 **p<0.01 ***p<0.001

Placebo (n=162) Lurasidone 20–60 mg (n=161) Lurasidone 80–120 mg (n=162)

Baseline mean = 30.5 Baseline mean = 30.3 Baseline mean = 30.6

Loebel A et al. Am J Psychiatry 2014;171(2):160-8.

Change From Baseline in MADRS (MMRM)

Effect size (MMRM)

Lurasidone 20–60 mg: 0.51

Lurasidone 80–120 mg: 0.51


Lurasidone in Bipolar Depression:

Adjunct

*p<0.05 **p<0.01 ***p<0.001

Placebo + Li/VPA (N=161) Lurasidone + Li/VPA (N=179)

Baseline mean = 30.8 Baseline mean = 30.6

Mean daily dose of lurasidone: 66.3 mg (90% of participants received ≥60 mg)

Loebel A et al. Am J Psychiatry 2014;171(2):169-77.

Change From Baseline in MADRS (MMRM)

Effect size: 0.34 (MMRM)


Bipolar Depression: NEI Practice Guideline

On VAL On Li On atypical

antipsychotic

(QUE or LUR)

Not on

medication

Add/

switch to

Li, LAM,

QUE, or

LUR

Add/

switch to

LAM,

QUE, or

LUR

Add/

switch

to

LAM

Add/

switch

to Li

Switch

to OLZ

+SSRI

Add

VAL

Add

Li +

VAL

Add/

switch

to Li

Add/

switch

to LAM

Add Li

or

LAM

Add

Li or

LAM

Goodwin GM. J Psychopharmacol 2009;23(4):346-88; Goodwin GM et al. Eur Neuropsychopharmacol

2008;18(7):535-49; Grunze H et al. World J Biol Psychiatry 2010;11:81-109; Hirschfeld RMA et al. American

Psychiatric Association 2002; Kasper S et al. J Clin Psychiatry 2008;69:1632-46; Yatham LN et al. Bipolar Disord

2009;11(3):225-55..


Recommended Doses in Bipolar Depression

Drug Daily dose

lamotrigine (mono) 100–200 mg

lithium 0.6–1.0 mEq/L

lurasidone 20–120 mg

olanzapine-fluoxetine 6–12/25–50 mg

quetiapine 300 mg

valproate 70–90 mg/L

Drug Daily dose

aripiprazole 15–30 mg (maint)

asenapine 5–10 mg (maint)

carbamazepine 4–15 mg/L (maint)

iloperidone 12–24 mg (maint)

oxcarbazepine 1200–2400 mg (mania)

paliperidone 6 mg (schiz)

risperidone 25–50 mg IM q2wks

(maint)

ziprasidone 80–160 mg (maint)


What's the Role of Antidepressants?

Recent Recommendations From ISBD

• When to avoid ADs

– As adjunct for acute bipolar I or II depressive episode

with ≥2 concomitant manic symptoms, psychomotor

agitation, or rapid cycling

– As monotherapy in bipolar I disorder

– As monotherapy in bipolar II depression with ≥2

concomitant manic symptoms

– During manic and depressive episodes with mixed

features

– In patients with predominantly mixed states

10th International Conference on Bipolar Disorders (ICBD). Abstract 13. 2013.


What's the Role of Antidepressants?

Recent Recommendations From ISBD

• When to consider ADs

– As adjunct for acute bipolar I or II depressive episode

in patients with a history of good AD response

– As maintenance (adjunct) for patients who relapse

into a depressive episode after stopping an AD

10th International Conference on Bipolar Disorders (ICBD). Abstract 13. 2013.


Bipolar Depression: NEI Practice Guideline

Cautiously consider adding bupropion

Add modafinil, armodafinil, or pramipexole

Replace one or both agents with alternate

first- or second-line agents

Consider ECT, third-line agents, and

novel or experimental options

Add-on Novel or Experimental Agents

Stahl SM. CNS Spectrums; in press.


Armodafinil in Bipolar Depression:

Adjunct 150 mg

46.2

5.6 1.6

34.2

3.5 4.4

0 5

10 15 20 25 30 35 40 45 50

Response Rates AE Discontinuation ≥7% Weight Gain

armodafinil

placebo

Ketter TA et al. Presented at US Psychiatric Mental Health Congress; 2012.

% P

atients

Response: ≥50% decrease in IDS-C30


Armodafinil in Bipolar Depression:

Adjunct

Frye MA et al. Int J Bipolar Disord 2015;31(1):34.

Response: ≥50% decrease in IDS-C30


Pramipexole in Bipolar Depression:

Adjunct

Zarate CA Jr et al. Biol Psychiatry 2004;56(1):54-60.


Omega-3 Fatty Acids

• Principal dietary sources include fatty cold water fish

and fish oil supplements

• Increased fish intake is associated with reduced

lifetime prevalence of mood disorders

• 1-4 g/day omega-3 supplementation may:

– Reduce manic and depressive symptom severity

– Reduce BP relapse rates

– Reduce risk of suicide

– Protect against adverse cardiometabolic effects

– Has little safety risk

McNamara RK, Strawn JR. PharmaNutrition 2013;1(2):41-9.


Why Treat Bipolar Disorder With

Psychotherapy?

• Increase adherence to medication

• Enhance social and occupational functioning

• Enhance capacity to manage stressors in the social-occupational milieu

• Enhance protective effects of family and other social supports

• Decrease denial and trauma and encourage acceptance of the disorder

• Decrease the risk of recurrence

Swartz HA et al. Psychotherapy for bipolar disorder. In Stein DJ, Kupfer DJ & Schatzberg AF (eds.)

The American Psychiatric Publishing textbook of mood disorders. 2006;405-420.


Empirically Tested Psychotherapies for

Bipolar Disorder

• Cognitive Behavioral Therapy (CBT)

• Psychoeducation (Group)

• Psychoeducation (Individual)

• Family Focused Therapy (FFT)

• Interpersonal and Social Rhythm Therapy (IPSRT)

Geddes et al. Lancet 2013;381:1672-82.

TREATMENT OF BIPOLAR

DEPRESSION: SAFETY AND

TOLERABILITY


Metabolic Syndrome and Obesity in Bipolar

Disorder

• 68% of BP patients are overweight

• 32% of BP patients meet criteria for obesity (relative to <

20% of controls)

• Patients with BP are 3X more likely to have metabolic

syndrome compared to healthy controls

– Despite consuming fewer calories, carbohydrates, fats,

and more fiber than healthy controls!

• Thus, although diet and lifestyle are factors, the story is

much more complicated

– Effects of pharmacological agents?

– Common etiology of metabolic syndrome and BP?

Fagiolini A et al. Am J Psychiatry 2003;160(1):112-7;

Bly MJ et al. Bipolar Disord 2014;16(3):277-88.


0

2

4

6

8

10

12

14

16

18

20

Non-obese BMI 30 BMI 35

Mean

# o

f L

ifeti

me

(Hyp

o)M

an

ic S

ym

pto

ms

Obesity May Predict Bipolarity in Depressed

Patients

Vannucchi et al. J Affect Disord 2014;156:118-22.


Obesity Decreases Time to Depressive

Recurrence C

um

ula

tive P

roport

ion

Rem

ain

ing W

ell

Weeks in Maintenance Treatment

0.0

0.2

0.4

0.6

0.8

1.0

0 20 40 60 80 100 120

Non-obese

Obese

Obese patients had a shorter time to depressive recurrence than non-obese patients

Fagiolini A et al. Am J Psychiatry 2003;160:112-117.

Log Rank Chi-square = 7.33, df = 1, p < 0.007)


0

1

2

3

4

5

HTN CVD

Control

Depression

Bipolar

Goldstein et al. Bipolar Disord 2009.

Cardiovascular Disease and Hypertension

Among Adults With Bipolar I Disorder O

dd

s R

ati

o (

ad

justi

ng

fo

r ag

e, sex,

an

d r

ace)


Other

LMG 0 0 0 0 0 + rash

LI 0 0 ++ ++ 0 0 tremor, GI, acne,

thyroid, renal

LUR + + 0 + 0 0

OLZ + + +++ ++ + ++

QUET 0 0 ++ +++ ++ ++

VAL 0 0 ++ +++ 0 + tremor, GI

Mood Stabilizers: Side Effects

Stahl SM. Stahl's essential psychopharmacology: the prescriber's guide. 4th ed. 2011;



Other

ARIP + 0 0 0 0 0 nausea

ASEN + + + ++ + 0 oral

hypoesthesia

CBZ 0 0 + +++ 0 + nausea,

headache, rash

ILOP 0 + + + +++ 0

OXC 0 0 + + 0 0 nausea, rash

PAL ++ +++ ++ + ++ 0

RSP ++ +++ ++ + + 0

ZIP + + 0 + 0 0 activation (low

dose)

Mood Stabilizers: Side Effects (cont.)

Stahl SM. Stahl's essential psychopharmacology: the prescriber's guide. 4th ed. 2011;



Metabolic Changes With Olanzapine and

Quetiapine: Total Cholesterol (mg/dL)

Rummel-Kluge C et al. Schizophr Res 2010;123:225-33.

-40.0 -20.0 0.0 20.0 40.0

Aripiprazole Clozapine

Quetiapine

Risperidone

Ziprasidone

Risperidone

Ziprasidone Quetiapine

FAVORS FAVORS

Olanzapine

Olanzapine


Metabolic Changes With Olanzapine and

Quetiapine: Glucose (mg/dL)

Rummel-Kluge C et al. Schizophr Res 2010;123:225-33.

-40.0 -20.0 0.0 20.0 40.0

Aripiprazole Clozapine

Quetiapine

Risperidone

Ziprasidone

Olanzapine

Risperidone

Ziprasidone Quetiapine

FAVORS FAVORS

Olanzapine


BL Mean 197.4 mg/dL 196.0 mg/dL 202.2 mg/dL 125.2 mg/dL 132.4 mg/dL 133.9 mg/dL

-3.0

0.0

-3.0

-10.0

-8.0

-6.0

-4.0

-2.0

0.0

2.0

4.0

6.0

8.0

10.0 8.0

3.0

-2.0

-10.0

-8.0

-6.0

-4.0

-2.0

0.0

2.0

4.0

6.0

8.0

10.0

Metabolic Changes With Lurasidone

Safety Population

Cholesterol

Me

dia

n C

ha

ng

e

Fro

m B

as

eli

ne

(m

g/d

L)

Me

dia

n C

ha

ng

e

Fro

m B

as

eli

ne

(m

g/d

L)

Triglycerides

Placebo

(n=147)

Lurasidone

20–60 mg

(n=140)

Lurasidone

80–120 mg

(n=144)

Placebo

(n=147)

Lurasidone

20–60 mg

(n=140)

Lurasidone

80–120 mg

(n=144)

Loebel A et al. Poster presented at APA; 2012.


Metabolic Changes With Lurasidone

Safety Population

Me

dia

n C

ha

ng

e F

rom

B

as

eli

ne

(m

g/d

L)

Glucose

0.5

-1.0

0.0

-2.0

0.0

2.0

4.0

6.0

8.0

10.0

Placebo

(n=148)

Lurasidone 20–60 mg

(n=140)

Lurasidone 80–120 mg

(n=143)

BL Mean 94.5 mg/dL 94.3 mg/dL 94.7 mg/dL

Loebel A et al. Poster presented at APA; 2012.


Mood Stabilizers: Monitoring Guidelines

L: lithium D: divalproex C: carbamazepine A: atypical antipsychotic

*Stable patients **For first 3 months of treatment ***For first year of treatment

Mahli GS et al. Bipolar Disord 2012;14(suppl 2):1-21.

Parameter Baseline Monthly 3 Months 6 Months 12 Months

Liver D, C C** D*** D, C

Renal L C** L C

TSH L L

CBC C C** D*** C, D

Menstrual change D***

Calcium L L

Serum levels* L

Weight D, A A** D***, A L L, D, A

BP A A*** A

Fasting lipids A A A

Fasting glucose A A A

BIPOLAR MAINTENANCE


Major Goals of Treatment in

Bipolar Disorder

• Prevent future episodes of mania

• Prevent mixed episodes

• Prevent episodes of depression

• Diminish the presence of subsyndromal

depression over extended periods of time

• Improve functioning

• Decrease morbidity and mortality


Bipolar Maintenance:

General Management

• Maintain medication – Educate on chronicity of disorder – Help establish routine for taking medication

• Maintain psychoeducation and psychotherapy – Include caregiver psychoeducation

• Monitor for and address adverse effects

• Encourage regular physical and social activity

• Encourage regular sleep pattern

• Address interepisode impairment – Neurocognitive difficulty with sustained attention – Sleep disturbance

Swan AC. J Clin Psychiatry 2010;71(12):e35.


Bipolar Maintenance:

General Management

• Train to monitor for prodromal symptoms

– Change in motivated activity, sleep cycle, impulsivity,

or interpersonal behavior

– Change in affect (usually later in prodromal stage)

– Usually consistent within individual

• Train to address prodromal symptoms

– Small medication adjustment

– Change in daily routine

– Stress reduction

– Increase in social interaction

Swan AC. J Clin Psychiatry 2010;71(12):e35.


NEI Practice Guideline:

Choice of Long-term Medications

Continue current medication if effective. Otherwise, consider (alphabetical order):


Maintenance Medication to

Prevent

Manic Relapse Depressive

Relapse

Aripiprazole

Carbamazepine

Lamotrigine

Lithium

Lurasidone

Olanzapine

Oxcarbazepine

Quetiapine

Valproate


Psychiatric assessment

Risk factor assessment

– Weight, BMI, hypertension,

glucose tolerance, lipids,

C-reactive protein

Summary: Assessment and Treatment

of Interepisodic Symptom Domains

Domain Assessment

Abnormal emotional

reactivity

Cognitive

impairment

Sleep and circadian

rhythm disturbances

Psychiatric and medical

comorbidities

Treatment

BMI, body mass index

Affective Lability Scale

Affect Intensity Measure

Sleep diary

Pittsburgh Sleep Quality

Index

Neuropsychological

assessment

Stress management

Relaxation

Treatment to be developed

Psychoeducation

Interpersonal and social

rhythm therapy

Cognitive behavioral

therapy

Cognitive remediation

Treatment of comorbid

psychiatric and medical

disorders

Diet, exercise, and smoking

cessation…

Patient follow-up is pivotal; also important to consider

benefit-risk profile of current or planned psychotropic medication

Leboyer, Kupfer. J Clin Psychiatry 2010;71:1689.


NEI Practice Guideline:

Residual Symptoms or Relapse

• If the burden of disease is mania

– Consider combining predominantly anti-manic agents

(e.g., lithium, valproate, antipsychotic)

• If the burden of disease is depression

– Lamotrigine, quetiapine, or lurasidone

• Lamotrigine may require combination with an anti-manic

• Consider clozapine in treatment-refractory patients

• Consider long-acting depot antipsychotics for

frequently relapsing bipolar disorder



Treatment Nonadherence

• As many as 77% of patients with BP may be

intentionally or unintentionally nonadherent

• Reasons for nonadherence

– Forgetting to take dose

– Side effects

– Insufficient illness knowledge

– Family/friends who advise against medication

– Access problems

– Alcohol and drug use

Sajatovic M. Compr Psychiatry 2011;52:280-7; Pompili M et al. Expert Rev Neurother

2013;13(7):809-25; Gibson S et al. BMC Psychiatry 2013;13:153; Crowe M et al. Int J Nurs Stud

2011;48:894-903; Baldessarini RJ et al. Hum Psychopharmacol 2008;23:95-105.


Interventions to Improve Adherence

• Most effective interventions only lead to small

improvement in adherence or outcomes

– More convenient care

– Reminders

– Self-monitoring

– Reinforcement

– Counseling

– Family therapy

– Psychological therapy

– Crisis intervention

– Telephone follow-up Haynes R et al. Cochrane Database Syst Rev 2005;(4):CD000011; Sylvia LG. J Clin

Psychophamacol 2013;33(3):343-50.


Summary

• Standard depression rating scales do not differentiate

between bipolar and unipolar depression

• It is essential that all patients presenting with depression

are carefully screened for symptoms and risk factors

associated with bipolar disorder

• The 3 agents with the most evidence of efficacy for

bipolar depression are quetiapine, olanzapine-fluoxetine,

and lurasidone

• Patient and family psychosocial interventions are

integral, particularly for being vigilant for and addressing

prodromal symptoms, as well as improving treatment

adherence

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