The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant - PowerPoint Presentation

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The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders

November 2014

David L. Fogelson, M.D.

Clinical Professor of Psychiatry

David Geffen School of Medicine at UCLA

And The

Semel

Institute for Neuroscience and Human Behavior at UCLA

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Seeking Consensus recommendations on Antidepressants in Bipolar Disorder

Systematic Review of the Literature

Serial Consensus Revisions created final recommendations

Weak evidence base for efficacy and safety of antidepressants

Insufficient evidence to support benefits when combined with mood stabilizers

Major concern that they cause switching

May be used on a case by case basis

Never prescribe without mood stabilizers in Bipolar I patients

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Sparse High-Quality Clinical DataDifficult to formulate sound clinical recommendations

Develop Consensus formed by clinical and academic experts

Assembled a global panel of experts

Developed a process for Literature Review

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Literature Review & Consensus

Peer-reviewed Research

Reviews

Meta-analyses

Clinical trial Reports

From these sources developed initial summary

These findings were then subject to expert consensus

And integrated with clinical experience and judgment

To create final guidelines

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Literature Search PubMedTCAs

Tetracyclics

MAOIs

Bupropion

SSRIs & SNRIs

Mirtazapine &

Mianserin

Trazodone

&

Nefazodone

Agomelatine

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Review Methods

Rated Reports methodologically as poor (1-2) or good (3-5)

Rated Overall Quality of Evidence A, B, C, or D

Statements of use in Bipolar Disorder were created

Acute treatment

Maintenance treatment

Monotherapy

Switch to Mania, hypomania, or mixed states & rapid cycling

Use in mixed states

Drug Class

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Statements rated as essential or important by 80% of experts made the cut

Rerated Items

Items rated as essential or important by 65%-79% of panel were rerated

Items rerated once, either they made 80% cut or were dropped

Items not included by 65% on first cut were dropped

12/25 items were endorsed and form the final recommendations

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Antidepressant Monotherapywidely regarded as contraindicated

for

bipolar

disorder

because weak

evidence for

efficacy, potential

risk for excessive mood

elevation (switches)

Imipramine monotherapy > switches than lithium plus IMI

IMI monotherapy = lithium for prophylaxis; IMI was not better than Lithium; Lithium is an effective antidepressant

Largest study QTP v Paroxetine v Placebo

740 acutely depressed patients

QTP (600 or 300) > paroxetine = PB

Bipolar II Depression:

Escitalopram

, FLX, some efficacy without switching

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Conclusions: Antidepressant Monotherapy

Inadequate support for efficacy in acute Bipolar Depression

Evidence base is poor, rated D, inconclusive

Evidence base is C in Bipolar II, but marred by methodological shortcomings and selective reporting

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Adjunctive antidepressants:short-term efficacy in acute depression

Mixed results in two large trials

N = 377; OLZ v OLZ +FLX v PB; OLZ+FLX>OLZ/PB; limitations, no FLX arm and drop out rate of 38.5%

N = 366; Lithium v VPA v CBZ; random assignment to adjunctive bupropion, paroxetine, or PB.

BuP

= PX = PB; limitations patients already well treated & required sustained improvement

Smaller Studies

PX= IMI = PB as adjuncts to mood stabilizers

PX v

VLFx

v PB; as adjuncts to mood stabilizers; single blind;

PX &

VLFx

> PB

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Meta-analyses of Adjunctive antidepressants:short-term efficacy in acute depression

Three meta-analyses performed

One was heavily weighted by the FLX-OLZ study

One found no difference from placebo

A third one found superiority of antidepressants over PB

Naturalistic Study, n = 1,036, found antidepressants to be similarly effective in BPI, BPII, and unipolar depression

Predictors of response

Prior response

Less severe illness course

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Conclusions: Adjunctive antidepressants forshort-term efficacy in acute depression

Evidence is B quality for efficacy of FLX-OLZ in bipolar depression

Lack of benefit from Paroxetine or Bupropion

Inconsistent for other antidepressants

Overall quality of predictors of response is rated D, poor.

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Adjunctive Antidepressants: Long-term maintenance studies

Two randomized controlled trials (no Placebo) BPI

Examined long-term maintenance after favorable short term response

VLFx

v

Bup

v Sertraline plus mood stabilizer, one year duration

20 % remained in remission

In those with initial response; more likely to remain in remission when maintained on same medication

Second Study: similar design, antidepressants delayed onset of a depressive episode except in rapid cyclers where they made things worse; no decrease in overall depressive symptoms

Nonrandomized study; antidepressants provided protection by increasing time to relapse and decreasing frequency of relapse into depression

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Meta-analysis: Adjunctive Antidepressants,

Long-term

maintenance studies

Compared with mood stabilizer alone

Little protection from Depression

Increased risk for hypomania and mania

Unfavorable

risk-benefit ratio

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Conclusions about Adjunctive Antidepressants for Long-Term Maintenance

Few trials

Ambiguous, inconclusive findings

Lack of adequate controls & enriched patient samples led to a D rating of evidence

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Antidepressant use in Mania and Mixed StatesNo evidence for efficacy

Clinically mixed states are associated with the prescription of antidepressants

Most likely related to failure to diagnose Bipolar Disorder

Incorrect diagnoses include: Panic Disorder & Agitated Depression

Overall the quality of the evidence to support this approach is rated a D

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Safety: Antidepressants and Mood Switching

Antidepressant Associated switches into hypomania, mania, or mixed states is controversial

Difficult to attribute causality

Switching occurs over the natural course of the illness

Few Randomized trials of mood stabilizer v mood stabilizer plus antidepressant

Quality of studies is poor

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Safety: Differential Association of Types of Antidepressants with Mood Switches

8 week prospective trial, bupropion v.

desipramine

5/10 DMI patients switched

1/10 BP patients switched

Several

Pb

controlled trials with mood stabilizers

No elevated switch rate associated with SSRIs or BP

For example, 10.1% with SSRI or BP plus mood stabilizer v. 10.7% on mood stabilizer alone

Even in Monotherapy with antidepressants

Paroxetine did not cause more switching than

Pb

In a 12 month study Sertraline and BP associated with a 10% switch rate v. 29% for venlafaxine

In a 6 week study VLFX > Paroxetine

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Is mood switching associated with antidepressants limited to certain classes of antidepressants?

Are

tricyclics

,

tetracyclics

, & SNRIs riskier?

Meta-analyses have reviewed this question

This work group concludes the answer is yes.

They deem SSRIs and MAOIs as less risky

Bupropion may also be less risky

It is unknown if Mood stabilizers protect from antidepressant associated switching

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Is there less risk for antidepressant associated switches in Bipolar 2 patients?

Four studies suggest a low risk with antidepressant monotherapy

Meta-analytic review of 13 studies supports Bipolar I patients have higher anti-depressant associated switch rate; relative risk 1.78

The meta-analysis suggested that switches into hypomania may be problematic for Bipolar 2 patients

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Clinical Correlates of risk for antidepressant associated switching

Retrospective Studies of Mood Stabilizers and adjunct antidepressants

Subsyndromal

manic symptoms associated with

Increased risk of switch to hypomania/mania

More severe manic episodes

Higher rates of unsatisfactory response to antidepressants

History of Suicide attempt/aggressive-disruptive behaviors

Higher risk of switching

Patients presenting with Major Depression

Higher risk of switching if “bipolar features” present

Higher risk if history of antidepressant treatment resistance

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Conclusions: Mood Switching Associated with Antidepressants

Risk is greater in Bipolar 1 patients compared to Bipolar 2

Risk is greater with

tricyclics

,

tetracyclics

, and SNRIs

Quality of evidence is rated C

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Are newly emerging/increasing irritability and agitation during antidepressant Rx a form of switching?

Irritable dysphoria associated with antidepressant treatment may be more likely in patients with a history antidepressant associated switching

Agitated depression with new onset insomnia, impulsivity, suicidal preoccupation associated with antidepressant Rx

Agitated depression and irritable dysphoria decrease with discontinuation of antidepressant and treatment with mood stabilizers

The evidence is poor to answer this question and is rated D

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Antidepressants and Cycle Acceleration

Can antidepressants accelerate episode frequency or induce rapid cycling?

Case Reports suggest induction of rapid cycling that is persistent

Prospective study found those treated with antidepressants were depressed 29% of time v 14.8% for those treated without antidepressants

Another prospective trial demonstrated that patients with history of rapid cycling had three times as many depressive recurrences with continued antidepressant treatment

A non-randomized trial demonstrated that duration of exposure to antidepressants correlated with days ill, mixed episodes, more cycling

One prospective placebo controlled trial of

Flx

monotherapy

found no cycle acceleration or increased risk for relapse

Criticisms of this study: selection bias for mild bipolar patients; poor measures

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Antidepressants and Cycle Acceleration: Conclusions

Quality of evidence is rated D, poor

Limitations

Exclusion of rapid cycling patients from clinical studies

Lack of baseline cycling rates

Lack of placebo comparison

Lack of true randomization in studies

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Antidepresants and Suicidal Behavior

Studies are limited

Two retrospective studies find an association of suicidal behaviors with antidepressants

One prospective study of 425 patients found no association of antidepressants with suicidal behaviors

Another prospective study with 184 patients found no association

In another prospective study the rate of suicidal behaviors was 35%-54% lower, risk was lowest in bipolar I disorder

Two large studies, over 1,300 patients each,

subsyndromal

mania is associated with suicidal behaviors

Three studies find that mixed episodes are associated with antidepressants; mixed episodes are associated with suicidal behaviors

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Antidepressants and Suicidal Behavior: Conclusions

Evidence is poor, rated D

Difficult to assess due to low rate of suicidal behaviors

Difficult to design ethical studies

Unable to reach a conclusion as to whether or not an association exists

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International Society for Bipolar Disorders (ISBD) Recommendations for Antidepressant Use in BPD’s

Acute Treatment

Adjunctive Antidepressants may be useful for acute Bipolar I or II depressive episode when there is a history of previous response

Adjunctive

Antidepressants should be avoided for depression with two or more co-occurring manic symptoms or psychomotor agitation or rapid cycling

Maintenance Treatment

Consider maintenance treatment if depressive relapse occurs

off

antidepressant

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ISBD Recommendations for Antidepressant Use in BPD’s

Monotherapy

Antidepressant Monotherapy should be avoided in BPI depression

Antidepressant Monotherapy should be avoided in BPI & II depression with two or more co-occurring manic symptoms

Switch to mania, hypomania, mixed states, or rapid cycling

Bipolar patients starting antidepressants must be closely monitored for mania and agitation

Discontinue antidepressants if signs of mania occur

Discourage antidepressant if there is a history of antidepressant induced mania/agitation

Avoid antidepressants in patients with history of rapid cycling

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International Society fro Bipolar Disorders (ISBD) Recommendations for Antidepressant Use in BPD’s

Use in Mixed States

Avoid antidepressant prescription in patients with predominantly mixed states

Avoid antidepressants in mania/depression with mixed features

Discontinue antidepressants if patient is currently in a mixed state

Drug Class

Adjunctive treatment with SNRIs or tri- or tetracyclic antidepressants are second line after other treatments have failed

SNRIs and

tri-or

tetracyclic

antidepressants must be closely monitored because of increased risk for switching or destabilization

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Consensus StatementsEvidence is limited

Evidence is methodologically weak

1. Non-antidepressants should be considered as

monotherapy

before Rx antidepressants

Lithium

Lamotrigine

Olanzapine

Quetiapine

Lurasidone

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Consensus Statements 2. If antidepressants are prescribed in Bipolar I Disorder they should be prescribed with a mood stabilizer

This recommendation is made even though evidence is mixed for antidepressant induced mood switching

And even though the ability of mood stabilizers to prevent switching is unproven

3. Antidepressants in acute depression in Bipolar II Disorder are relatively well tolerated but may or may not be effective

4. Long term prophylactic value is poorly studied in BP I &II

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Consensus Statements5. There is little evidence to support one antidepressant being more or less effective or more or less dangerous

Exceptions are tri- and

tetracyclics

and venlafaxine, which carry high risk for inducing elevated mood states

6. Antidepressants can neither be condemned nor endorsed without consideration of each unique clinical case & presentation