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The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use inBipolar Disorders
November 2014David L. Fogelson, M.D.Clinical Professor of PsychiatryDavid Geffen School of Medicine at UCLAAnd TheSemelInstitute for Neuroscience and Human Behavior at UCLA
Seeking Consensus recommendations on Antidepressants in Bipolar Disorder
Systematic Review of the LiteratureSerial Consensus Revisions created final recommendationsWeak evidence base for efficacy and safety of antidepressantsInsufficient evidence to support benefits when combined with mood stabilizersMajor concern that they cause switchingMay be used on a case by case basisNever prescribe without mood stabilizers in Bipolar I patients
Sparse High-Quality Clinical Data
Difficult to formulate sound clinical recommendationsDevelop Consensus formed by clinical and academic expertsAssembled a global panel of expertsDeveloped a process for Literature Review
Literature Review & Consensus
Peer-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 PubMed
TCAsTetracyclicsMAOIsBupropionSSRIs & 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 DStatements of use in Bipolar Disorder were createdAcute treatmentMaintenance treatmentMonotherapySwitch to Mania, hypomania, or mixed states & rapid cyclingUse in mixed statesDrug Class
Statements rated as essential or important by 80% of experts made the cut
Rerated ItemsItems rated as essential or important by 65%-79% of panel were reratedItems rerated once, either they made 80% cut or were droppedItems not included by 65% on first cut were dropped12/25 items were endorsed and form the final recommendations
Antidepressant Monotherapy
widely regarded as contraindicatedforbipolardisorderbecause weakevidence forefficacy, potentialrisk for excessive moodelevation (switches)Imipramine monotherapy > switches than lithium plus IMIIMI monotherapy = lithium for prophylaxis; IMI was not better than Lithium; Lithium is an effective antidepressantLargest study QTP v Paroxetine v Placebo740 acutely depressed patientsQTP (600 or 300) > paroxetine = PBBipolar II Depression:Escitalopram, FLX, some efficacy without switching
Conclusions: Antidepressant Monotherapy
Inadequate support for efficacy in acute Bipolar DepressionEvidence base is poor, rated D, inconclusiveEvidence 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 trialsN = 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 improvementSmaller StudiesPX= IMI = PB as adjuncts to mood stabilizersPX vVLFxv PB; as adjuncts to mood stabilizers; single blind;PX &VLFx> PB
Meta-analyses ofAdjunctive antidepressants:short-term efficacy in acute depression
Three meta-analyses performedOne was heavily weighted by the FLX-OLZ studyOne found no difference from placeboA third one found superiority of antidepressants over PBNaturalistic Study, n = 1,036, found antidepressants to be similarly effective in BPI, BPII, and unipolar depressionPredictors of responsePrior responseLess severe illness course
Conclusions:Adjunctive antidepressants forshort-term efficacy in acute depression
Evidence is B quality for efficacy of FLX-OLZ in bipolar depressionLack of benefit from Paroxetine or BupropionInconsistent for other antidepressantsOverall quality of predictors of response is rated D, poor.
Adjunctive Antidepressants: Long-term maintenance studies
Two randomized controlled trials (no Placebo) BPIExamined long-term maintenance after favorable short term responseVLFxvBupv Sertraline plus mood stabilizer, one year duration20 % remained in remissionIn those with initial response; more likely to remain in remission when maintained on same medicationSecond Study: similar design, antidepressants delayed onset of a depressive episode except in rapid cyclers where they made things worse; no decrease in overall depressive symptomsNonrandomized study; antidepressants provided protection by increasing time to relapse and decreasing frequency of relapse into depression
Meta-analysis:Adjunctive Antidepressants,Long-termmaintenance studies
Compared with mood stabilizer aloneLittle protection from DepressionIncreased risk for hypomania and maniaUnfavorablerisk-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 efficacyClinically mixed states are associated with the prescription of antidepressantsMost likely related to failure to diagnose Bipolar DisorderIncorrect diagnoses include: Panic Disorder & Agitated DepressionOverall 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 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 MoodSwitches
8 week prospective trial, bupropion v.desipramine5/10 DMI patients switched1/10 BP patients switchedSeveralPbcontrolled trials with mood stabilizersNo elevated switch rate associated with SSRIs or BPFor example, 10.1% with SSRI or BP plus mood stabilizer v. 10.7% on mood stabilizer aloneEven in Monotherapy with antidepressantsParoxetine did not cause more switching thanPbIn a 12 month study Sertraline and BP associated with a 10% switch rate v. 29% for venlafaxineIn a 6 week study VLFX > Paroxetine
Is mood switching associated with antidepressants limited to certain classes of antidepressants?
Aretricyclics,tetracyclics, & SNRIs riskier?Meta-analyses have reviewed this questionThis work group concludes the answer is yes.They deem SSRIs and MAOIs as less riskyBupropion may also be less riskyIt 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 monotherapyMeta-analytic review of 13 studies supports Bipolar I patients have higher anti-depressant associated switch rate; relative risk 1.78The 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 antidepressantsSubsyndromalmanic symptoms associated withIncreased risk of switch to hypomania/maniaMore severe manic episodesHigher rates of unsatisfactory response to antidepressantsHistory of Suicide attempt/aggressive-disruptive behaviorsHigher risk of switchingPatients presenting with Major DepressionHigher risk of switching if “bipolar features” presentHigher risk if history of antidepressant treatment resistance
Conclusions: Mood Switching Associated with Antidepressants
Risk is greater in Bipolar 1 patients compared to Bipolar 2Risk is greater withtricyclics,tetracyclics, and SNRIsQuality 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 switchingAgitated depression with new onset insomnia, impulsivity, suicidal preoccupation associated with antidepressant RxAgitated depression and irritable dysphoria decrease with discontinuation of antidepressant and treatment with mood stabilizersThe 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 persistentProspective study found those treated with antidepressants were depressed 29% of time v 14.8% for those treated without antidepressantsAnother prospective trial demonstrated that patients with history of rapid cycling had three times as many depressive recurrences with continued antidepressant treatmentA non-randomized trial demonstrated that duration of exposure to antidepressants correlated with days ill, mixed episodes, more cyclingOne prospective placebo controlled trial ofFlxmonotherapyfound no cycle acceleration or increased risk for relapseCriticisms of this study: selection bias for mild bipolar patients; poor measures
Antidepressants and Cycle Acceleration: Conclusions
Quality of evidence is rated D, poorLimitationsExclusion of rapid cycling patients from clinical studiesLack of baseline cycling ratesLack of placebo comparisonLack of true randomization in studies
Antidepresantsand Suicidal Behavior
Studies are limitedTwo retrospective studies find an association of suicidal behaviors with antidepressantsOne prospective study of 425 patients found no association of antidepressants with suicidal behaviorsAnother prospective study with 184 patients found no associationIn another prospective study the rate of suicidal behaviors was 35%-54% lower, risk was lowest in bipolar I disorderTwo large studies, over 1,300 patients each,subsyndromalmania is associated with suicidal behaviorsThree 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 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 TreatmentAdjunctive Antidepressants may be useful for acute Bipolar I or II depressive episode when there is a history of previous responseAdjunctiveAntidepressants should be avoided for depression with two or more co-occurring manic symptoms or psychomotor agitation or rapid cyclingMaintenance TreatmentConsider maintenance treatment if depressive relapse occursoffantidepressant

ISBDRecommendations for Antidepressant Use in BPD’s
MonotherapyAntidepressant Monotherapy should be avoided in BPI depressionAntidepressant Monotherapy should be avoided in BPI & II depression with two or more co-occurring manic symptomsSwitch to mania, hypomania, mixed states, or rapid cyclingBipolar patients starting antidepressants must be closely monitored for mania and agitationDiscontinue antidepressants if signs of mania occurDiscourage antidepressant if there is a history of antidepressant induced mania/agitationAvoid antidepressants in patients with history of rapid cycling
International Society fro Bipolar Disorders (ISBD) Recommendations for Antidepressant Use in BPD’s
Use in Mixed StatesAvoid antidepressant prescription in patients with predominantly mixed statesAvoid antidepressants in mania/depression with mixed featuresDiscontinue antidepressants if patient is currently in a mixed stateDrug ClassAdjunctive treatment with SNRIs or tri- or tetracyclic antidepressants are second line after other treatments have failedSNRIs andtri-ortetracyclicantidepressants must be closely monitored because of increased risk for switching or destabilization
Consensus Statements
Evidence is limitedEvidence is methodologically weak1. Non-antidepressants should be considered asmonotherapybefore Rx antidepressantsLithiumLamotrigineOlanzapineQuetiapineLurasidone
Consensus Statements
2. If antidepressants are prescribed in Bipolar I Disorder they should be prescribed with a mood stabilizerThis recommendation is made even though evidence is mixed for antidepressant induced mood switchingAnd even though the ability of mood stabilizers to prevent switching is unproven3. Antidepressants in acute depression in Bipolar II Disorder are relatively well tolerated but may or may not be effective4. 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 dangerousExceptions are tri- andtetracyclicsand venlafaxine, which carry high risk for inducing elevated mood states6. Antidepressants can neither be condemned nor endorsed without consideration of each unique clinical case & presentation





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