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

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

Sparse High-Quality Clinical DataDifficult to formulate sound clinical

recommendationsDevelop Consensus formed by clinical and

academic expertsAssembled a global panel of expertsDeveloped a process for Literature Review

Literature Review & ConsensusPeer-reviewed ResearchReviewsMeta-analysesClinical trial ReportsFrom these sources developed initial summaryThese findings were then subject to expert

consensusAnd integrated with clinical experience and judgmentTo create final guidelines

Literature Search PubMedTCAsTetracyclicsMAOIsBupropionSSRIs & SNRIsMirtazapine & MianserinTrazodone & NefazodoneAgomelatine

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

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

dropped12/25 items were endorsed and form the final

recommendations

Antidepressant Monotherapy widely 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

Conclusions: Antidepressant MonotherapyInadequate 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

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

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

Conclusions: Adjunctive antidepressants forshort-term efficacy in acute depressionEvidence is B quality for efficacy of FLX-OLZ in

bipolar depressionLack of benefit from Paroxetine or Bupropion Inconsistent for other antidepressantsOverall quality of predictors of response is rated D,

poor.

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

Meta-analysis: Adjunctive Antidepressants, Long-term maintenance studies

Compared with mood stabilizer aloneLittle protection from Depression Increased risk for hypomania and maniaUnfavorable risk-benefit ratio

Conclusions about Adjunctive Antidepressants for Long-Term Maintenance

Few trialsAmbiguous, inconclusive findingsLack of adequate controls & enriched patient

samples led to a D rating of evidence

Antidepressant use in Mania and Mixed States No 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

Safety: Antidepressants and Mood SwitchingAntidepressant Associated switches into

hypomania, mania, or mixed states is controversialDifficult to attribute causalitySwitching occurs over the natural course of the

illnessFew Randomized trials of mood stabilizer v mood

stabilizer plus antidepressantQuality of studies is poor

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

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

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

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

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

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

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

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

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

Antidepressants and Suicidal Behavior: ConclusionsEvidence is poor, rated DDifficult to assess due to low rate of suicidal

behaviorsDifficult to design ethical studiesUnable to reach a conclusion as to whether or not

an association exists

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

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

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

Consensus Statements Evidence is limited Evidence is methodologically weak

1. Non-antidepressants should be considered as monotherapy before Rx antidepressants Lithium Lamotrigine Olanzapine Quetiapine Lurasidone

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

Consensus Statements 5. 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