The International Society for Bipolar Disorders

This lecture reviews the use of Antidepressants in Bipolar Disorder. How to prescribe them, the dangers, and other recommendations.

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 Data

• Difficult 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

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

Literature Search PubMed

• TCAs
• Tetracyclics
• MAOIs
• Bupropion
• SSRIs & SNRIs
• Mirtazapine & Mianserin
• Trazodone & Nefazodone
• Agomelatine

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 dropped
• 12/25 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  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

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 for short-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.

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

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 alone
  • Little protection from Depression
  • Increased risk for hypomania and mania
  • Unfavorable risk-benefit ratio

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

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 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

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: 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

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
• 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
• 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