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Depressive Disorders

PG I

2007

Part 2

Clinical IssuesTreatmentGuidelines

Arlene: 45 y/o woman with double depressionswitched from a TCA to an SSRI

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IDEAL TREATMENT =WHICH MEDICATION(S)

Management of DepressiveDisorders

Psychotherapy• Interpersonal• Cognitive behavioral• Psychodynamic

Medication Therapy• Antidepressants• Antipsychotics•Other

Education• Patient• Family

Reduce/eliminatesymptoms- remission

Restore “wellness” -recovery

Prevent relapseand recurrence

Goals of Treatment

APA Practice Guideline, 2000; Schulberg et al., 1998

If mood disorders are biopsychosocialdisorders

Treatment should be biopsychosocial

If mood disorders are chronic/recurrent

Treatment should involvelifetime

disease management

Treatment

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Management

Principles of disease management

Selection Psychotherapy Medication Other

Phases of treatment Acute Continuation/maintenance

Psychiatric Management

Perform a diagnostic evaluation

Evaluate safety of patients and others

Determine a treatment setting

Evaluate level of functional impairments

Minimize stress

Consider temporarily alleviatingobligations/responsibilities

Availability and empathy are “healing”

Psychiatric Management (Cont’d)

Enlist patient participation in treatment decisions

Monitor symptomatic status and safety

Enhance treatment adherence

Work with patient and family to identify and addressearly signs of relapse/recurrence

Consider impact of life events on mooddisorder/treatment, e.g.

Bereavement and other losses

General medical illnesses

Childbirth

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Psychiatric Management (Cont’d): KeyEducation Points

Mood Disorders are illnesses Characteristic symptoms and course High morbidity and mortality Major life decisions and changes should be

postponed Alcohol is not an FDA approved treatment – for a

reason Treatable

Treatment aims at recovery and maintainingwell-being Full symptomatic remission (8 – 12 weeks) Side effects often precede improvement Be patient!

Functional restoration (week to monthslater)

Prevention of new episodes

Psychiatric Management (Cont’d): KeyEducation Points

Untreated, recurrence is the norm Major Depression >50% after 1 episode >70% after 2 episodes >90% after 3 episodes

Bipolar Disorder - >90%

Treatment helps prevent recurrence

More Information www.nim.nih.gov/medlineplus/depression.html

www.ndmda.org

www.nami.org

www.nmha.org

www.depression.org

www.edc.gsph.pitt.edu/stard/

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Initial Selection

• Mild – if preferred and available• Moderate/severe

• pregnancy, lactation or wish to become pregnant• Previous good response• Medications ineffective

Chose psychotherapy only

• Mild – if preferred• Moderate/severe –treatment of choice

Chose medication only

• Clinically significant psychosocial issues, interpersonal problems,history physical or sexual trauma, or a comorbid personality disorder

• History of only partial response to single treatment modality• Poor adherence to past medication trials• Chronic major depressions (e.g. chronic major depression, double

depression)

Chose psychotherapy plus medication

Psychodynamic PsychotherapyCognitive Behavioral TherapyInterpersonal Therapy

Psychotherapies

Nefazodone Vs CBT Vs Both For ChronicMajor Depression (N=681)

Duration current episodeMDD 8 yrs

43% double depression

30% history anxietydisorder

60% personality disorder

33% historyalcohol/substance abusedisorder

20% no prior treatment

Nefazodone workedfaster

Per

cent

Rem

issi

on

Keller, et al, NEJM, 2000

CBT more effective thanNefazodone if history ofchildhood abuse/trauma

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Psychotherapy for Mood Disorders CBT and IPT empirically validated treatments for MDD

Better studied in Major Depression than in BipolarDisorder

As effective as medications in acute treatment of mild-moderate major depression

May augment medication treatment in moderate to severedepression – especially in chronic or recurrentdepressions

May help prevent relapse/recurrence by providing copingskills and strategies

Differential advantages IPT and CBT may enhance medication adherence IPT may broaden range of response CBT may prolong effectiveness

“Your tale is very sad, Ben. I’m almost sorryI took an anti-depressant.”

Which Medication for WhichPatient?

Review of 46 head-to-head randomized, controlled trialsfrom multiple sources to evaluate comparative data onefficacy, effectiveness and tolerability of commonlyprescribed second-generation antidepressants intreatment of MDD.

Conclusion: Overall, second-generation antidepressantsprobably do not differ substantially for treatment of majordepressive disorder.

Choosing the agent that is most appropriate for agiven patient is difficult.

Hansen, R. A., et. al., Ann Intern Med. 2005;143:415-426.

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Selecting The “Right”Antidepressant

All classes equally effective,sooooo…..Past and family historyClinical

features/ComorbiditiesSide effects and toxicities

Monoamine OxidaseInhibitors

Side Effect Profile orthostatic

hypotension

insomnia

sexual dysfunction

drug and dietaryrestrictions

Tyraminecontaining foods

Demerol

Stimulants

Serotoninagonists

lethal in overdose

Niche broad spectrum

atypicalfeatures

bipolar

Block degradationof serotonin,norepinepherineand dopamine

Tricyclic Antidepressants

Side effect profile dry mouth blurred vision constipation urinary retention confusion (especially

in the elderly) sedation orthostatic

hypotension Conduction slowing dizziness weight gain lethal in overdose

Niche broad spectrum severe depression pain

Block reuptake ofnorepinepherineand serotonin

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Selective Serotonin ReuptakeInhibitors

Side effect profiles Anxiety/Agitation

Insomnia

Sexual dysfunction

GI distress

Headache Sweating

Discontinuationeffects

Serotoninsyndrome

Long term wearingoff of efficacy?

Niche Depression

Anxiety disorders

Late lifedepression

Adolescentdepression

Eating Disorders

PMDD

Block reuptake ofserotonin

Boyer, E. W. et al. N Engl J Med 2005;352:1112-1120

Findings in a Patient with Moderately SevereSerotonin Syndrome

SSRIs: Are they all alike?

Citalopram- most selective (especially Es-Citalopram)

Fluoxetine - longest acting, most activating(?)

Fluvoxamine- not approved for depression

Paroxetine - most noradrenergic, sedating(?)

Sertraline- most dopaminergic

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YEARDRUG // ACTIVE

METABOLITEDOSE WT

GAIN SEDATION P-450 INTER-ACTIONS

PROTEINBINDING ½ LIFE

FDAINDICATIONS

1989PROZAC(Fluoxetine)

10-60 +/- +/- 2D6 +++ 94% 96 hrs

ANOREXIANERVOSA

BULIMIA, MDE,

ADOLESCENTMDE

N/A Norfluoxetine 2D6 +++ 290 hrs

1991LUVOX

(Fluvoxamine)50-300 ++ +++

1A2 +++Many Others

93% 30 hrs OCD

1993PAXIL

(Paroxetine)20-60 +++ +++ 2D6 +++ 95% 21 hrs

OCD, GAD, PTSD,

MDE, PANIC D/O

SOCIAL PHOBIA,PMDD

1994ZOLOFT(Sertraline)

50-200 + +2D6 +

(High Dose)98% 26 hrs

OCD, PTSD, MDE

GAD, PANIC D/O,

N/A Desmethylsertraline 92 hrs

1998CELEXA

(Citalopram)20-60 + +/- +/- 80% 35 hrs MDE

2002LEXAPRO

(Escitalopram)10-20 + +/- 0 50% 30 hrs MDE, GAD

Norepinepherine Dopamine ReuptakeInhibitor (NDRI): Bupropion

Side effect profile Anxiety/agitation

Nausea

Insomnia

Headache

Rarehypertension

Rash

Niche Fatigue/retardation

Bipolar depression

Sexual, weight orsedative concerns

ADHD

Smoking

Add-on for sexual sideeffects, incompleteresponse or poop-out

SAD (prevention)

Block reuptake ofnorepinepherineand dopamine

Serotonin 2 Antagonist and SerotoninReuptake Inhibitors (SARI’s): Trazodone and

Nefazodone

Side effect profile Somnolence

Orthostasis(trazodone)

Palinopsia (visualstreaking; rare)

3A4 inhibition(Nefazodone)

Liver disease(Nefazodone)

Priapism, PVCs,Hypotension(Trazodone)

Niche Anxious

depression

PTSD

Concerns aboutsexual side effectsor weight gain

Sleep

HT2 Antagonist andreuptake inhibitor

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Serotonin and Norepinepherine ReupakeInhibitors (SNRIs): Venlafaxine and Duloxetine

Side Effect Profile

Nausea

Agitation

Sleepdisturbance

Sexualdysfunction

Headache

Hypertensionat high doses(venlafaxine)

NICHE Depression

Melancholia

Refractory depression

Generalized anxiety disorder

Pain/Fibromyalgia (duloxetine)

Block reuptake ofserotonin andnorepinepherine

Noradrenergic & Selective SerotoninAntagonists (NaSSAs): Mirtazapine

Side effectprofile Sedation

Weight gain

Niche Anxious

depression

Frail patient

Concernsabout sexualside effects

Alpha-2, 5HT-2&3inhibitor

Patients with OCD, Panic Disorder, Social Anxiety Disorder,PTSD and GAD comorbid with MDE should be given SSRImonotherapy first.

Venlafaxine (Effexor XR) is indicated for GAD and SocialAnxiety Disorder as well, and should be considered for thesecomorbidities.

Duloxetine (Cymbalta) shows promise in Neurogenic Pain andhas approval for diabetic neuropathy.

Bupropion (Wellbutrin XL) is a first choice in comorbid ADHD,SSRI induced sexual dysfunction, and coincident smokingcessation – maybe bipolar depression

Mirtazapine (Remeron) lacks sexual dysfunction but posesweight gain challenges often overcome with high dosing (75mg).

Nefazodone (Serzone) has caused 53 liver deaths, and shouldbe a last resort drug.

Do not neglect Family History of drug response; it is a veryimportant consideration in choosing an appropriate agent.

The AntidepressantsMatching patient to drug

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Antidepressant OverviewAntidepressant Antianxiety

(anxietydisorders)*

Weight gain Sexual sdeeffects

Lethal inoverdose

MAOIs + + + + +

TCAs + +/- + + +

SSRIs + + +/- + -

NDRI + +/- - - -

SNRIs + + - + -

SARIs + +/- - - -

NaSSA + +/- + - -

*All decrease anxiety associated with Major Depression; some more effective for anxiety disorders than others

Matching Patient to Medication: ClinicalSubtype

Example of Subtype TreatmentConsiderations

Comorbid anxiety disorder SSRI or SNRIBipolar depression Lamotrigine, atypical

antipsychotics,conservatism

Neuropathic pain SNRIPsychotic features Antipsychotic

augmentation, ECTSeasonal Bright light, Bupropion XLAtypical features MAOIsSevere, highly refractory ECT, VNS

Don’t forget past and family history of response and side effects

General principles of treatment of depression:How long do you treat?

Allow at least 3 weeks for initiation of response Let the patient know this up front

With no or partial response at 3-4 weeks, increase thedose

If partial response by 6-8 weeks, increase dose,augment ( e.g. lithium) or combine (eg anotherantidepressant)

If no response by 6-8 weeks, it may be time changemedications

Initial goal is remission by 12 weeks

Acute Treatment Phase

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Acute(6-12 weeks)

Seve

rity

Continuation(4-9 months)

Maintenance(1 or more years)

“Normalcy”

Response

Relapse

Relapse Recurrence

RecoveryRemission

Phases Of Treatment

Symptoms

Syndrome

PhaseAHCPR Depression in Primary Care. 1993Stahl. Essential Psychopharmacology. 1996Kupfer. J Clin Psychiatry. 1991

Prevention

Is Exercise An Antidepressant In OlderPatients With Major Depression?

Blumenthal et al Arch Intern Med,1999

All effective

No significant difference

Does Exercise Provide LastingEffects?

Both severity of depression at4 mos and exercise between 4-10 mos predicted recovery

Babyak et al, Psychosom Med, 2000

*

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General principles of treatment of depression

After remission, how long do you keep patientson their antidepressants?

Continue successful treatment for 9-12 months foruncomplicated first episode

Longer 2nd ‘close’ recurrence (within 2 yrs)

Chronic, severe or complicated depressions

Residual symptoms

Severe, ongoing stressors

Bipolar family history

Early or late onset

Patient preference

Even longer (perhaps life-time) maintenance for clearlyrecurrent depression

Continuation/Maintenance Treatment Phases

Other Treatments

Electroconvulsive Therapy (ECT)

Bright Light

Hormones

Exercise

Stimulants

Herbs

Sleep Deprivation

rTMS

VNS

DBS

Treatment Strategies for Non-RemissionExamples Pros Cons Strategy

Switch Same classDifferent classPsychotherapy

SimpleLose side

effects

Responsedelayed

Lose benefits

1st failureSide effects

Minimalresponse

Augment LithiumThyroid

StimulantsHormones

Atypicalantipsychotics

Responserapid

Maintainbenefits

Side effectsDrug

interactionsExpense

Multiplefailures

Fair-goodresponseFew sideeffects

Combine Bupropion SRVenlafaxine XR

MirtazapinePsychotherapy

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Treatment Strategies for Non-Remission OverallResults of STAR*D

Level Strategy Drug Remission Rate (%) Intolerance Rate(%)*

Relapse During 1-Year Follow-Up

I CIT 36.8 16 40

II 30.6 19 55

SwitchBUP-SRSERTVEN-XRCT

27262725

23212116

Combine/AugmentBUP-SR+CITBUS+CITCT+CIT

393331

132111

III 13.7 26 65

SwitchMIRTNTP

118

13

323233

Combine/AugmentLi+Bup-SR, SERT,VEN-XR or CitT3+Bup-SR, SERT,VEN-XR or Cit

211526

152110

IV 13.0 34 71

SwitchTCPMIRT+VEN-XR

131516

344020

Zisook et al, JCP, 2008

Unmet Needs in TreatingMajor Depressive Disorder (MDD)

1. Stigma

2. Access to care

3. Adherence

4. Tolerability

5. Psychotherapy availability

6. Onset of action

7. Response and remission

8. Prediction of “best”treatment

9. Recovery and long-termprevention

Summary: DepressiveDisorders

Prevalent

Painful

Affect individuals, families and society

Chronic and recurrent

Can be fatal

Under-diagnosed, mistreated

TreatableMany effective choicesGoals: get well and stay well