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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
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: Longterm 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
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