Elsevier

The Lancet Psychiatry

Volume 3, Issue 12, December 2016, Pages 1138-1146
The Lancet Psychiatry

Articles
Safety and efficacy of adjunctive second-generation antidepressant therapy with a mood stabiliser or an atypical antipsychotic in acute bipolar depression: a systematic review and meta-analysis of randomised placebo-controlled trials

https://doi.org/10.1016/S2215-0366(16)30264-4Get rights and content

Summary

Background

Although mania and hypomania define bipolar disorder, depressive episodes are more common and impairing, with few proven treatments. Adjunctive therapy with second-generation antidepressants is widely used to treat acute bipolar depression, but their efficacy and safety remain controversial.

Methods

In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to Jan 31, 2016, for randomised, double-blind, placebo-controlled trials of second-generation antidepressants adjunctive to a mood stabiliser or an antipsychotic in patients with acute bipolar depression. We extracted data from published reports. The primary outcome was change in clinician-rated depressive symptom score; secondary outcomes were clinical response, clinical remission, treatment-emergent mania or hypomania, and tolerability (using dropout rates as a proxy). We used pooled random-effects models, subgroup comparisons, and meta-regression for analyses. We made subgroup comparisons on the basis of mood stabiliser or antipsychotic treatment and did meta-regression examining trial duration. This study is registered with PROSPERO, number CRD#42015016024.

Findings

We identified six trials representing 1383 patients with bipolar depression. Second-generation antidepressants were associated with a small but significant improvement in clinician-rated depressive symptom score (standardised mean differences 0·165 [95% CI 0·051–0·278], p=0·004). However, clinical response and remission rates did not differ significantly between patients receiving adjunctive antidepressants and those receiving placebo (1·158 [0·840–1·597], p=0·371 for clinical response; 1·220 [0·874–1·703], p=0·243 for remission). Acute treatment was not associated with an increased risk of treatment-emergent mania or hypomania (0·926 [0·576–1·491], p=0·753), but 52 week extension periods were associated with an increase in risk (1·774 [1·018–3·091], p=0·043).

Interpretation

Adjunctive second-generation antidepressants are associated with reduced symptoms of acute bipolar depression, but the magnitude of benefit is small because they do not increase clinical response or remission rates. However, these medications should be used only in the short term because prolonged use is associated with an increased risk of treatment-emergent mania or hypomania.

Funding

None.

Introduction

Bipolar disorder is a common condition and cause of global disability.1 Although it is defined by episodes of mania or hypomania, it is also characterised by chronic and recurring depressive episodes that account for a substantial proportion of disability.2, 3 With an early age of onset,4 patients are reported to spend as much as half of their lives with mood symptoms.2

There are several level 1 pharmacological strategies for the management of acute mania, but few level 1 treatments exist for acute bipolar depression.5 Quetiapine, fluoxetine plus olanzapine, and lurasidone alone or in conjunction with lithium or valproate are the only treatments approved by the US Food and Drug Administration (FDA) for bipolar depression. Many patients with bipolar depression either do not respond to these medications or have difficulty tolerating the side-effects. Thus, treatment for bipolar depression remains a substantial unmet need.

In view of the dearth of proven treatments, clinicians widely use antidepressants to treat acute bipolar depression.6, 7 However, the effectiveness of these med-ications for the relief of depressive symptoms remains controversial because of the small evidence base. Previous meta-analyses that included data from studies of first-generation and second-generation antidepressants reported on the efficacy of antidepressants; of these, two suggest that antidepressants are more efficacious than placebo8, 9 whereas the third did not.10 Overall, antidepressants were no more likely to switch patients into mania or hypomania (ie, affective switch) compared with placebo;8, 10 however, additional analyses suggested that tricyclic antidepressants and SNRIs were more likely to induce mania than were SSRIs or bupropion.8, 10, 11 Furthermore, little evidence suggests that non-SNRI second-generation antidepressants increase the risk of manic switch.8, 10, 12, 13

Research in context

Evidence before this study

The use of antidepressants in the treatment of bipolar depression is a controversial area in psychiatry. We searched MEDLINE from inception to Jan 31, 2016, for meta-analyses using the search term “(bipolar disorder OR bipolar depression) AND antidepressive agents AND meta-analysis”. We found four previous meta-analyses of antidepressants in bipolar depression that included agents and interventions that are discouraged—notably, antidepressant monotherapy, tricyclic antidepressants, and monoamine oxidase inhibitors. Therefore, the clinical relevance of existing evidence is unclear, and additional examination restricted to trials of second-generation antidepressants adjunctive to adequate mood stabilisation, a strategy now widely used by clinicians, is necessary.

Added value of this study

Our systematic review identified six randomised placebo-controlled trials representing a total of 1383 patients treated with a second-generation antidepressant in addition to a mood stabiliser or an antipsychotic. Random-effect analyses showed a small benefit of antidepressant treatment in reducing depressive symptoms, and no evidence of acute risk of treatment-emergent affective switch. However, treatment with second-generation antidepressants over 52 week extension periods was associated with an increased risk of affective switch despite adequate mood stabilisation.

Implications of all the available evidence

Concomitant to adequate mood stabilisation, time-limited use of second-generation antidepressants is associated with a small clinical benefit and no acute risk of treatment-emergent mania or hypomania in the short term. However, prolonged treatment should be avoided.

The International Society for Bipolar Disorders (ISBD) expert consensus statement discourages the use of antidepressant monotherapy for the treatment of acute bipolar depression.14 However, previous meta-analyses have not distinguished between antidepressant monotherapy and antidepressants as adjuncts to adequate mood stabilisation, and therefore this important clinical question remains unaddressed. Additionally, previous meta-analyses included studies of tricyclic antidepressants and inhibitors of monoamine oxidase, classes that carry an increased risk of affective switch and cycle acceleration.15 Therefore, we aimed to determine whether second-generation antidepressant adjunctive therapy is efficacious and safe in the treatment of acute bipolar depression, a crucial consideration in clinical practice.

Section snippets

Search strategy and selection criteria

In this systematic review and meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from their inception until Jan 31, 2016, using the search term “(bipolar disorder OR bipolar depression) AND antidepressive agents AND (clinical trial OR randomized controlled trial”; see appendix for search syntaxes, parameters, and results). We reviewed references and citations of articles retained in this study for additional unidentified studies. We also searched //ClinicalTrials.gov

Results

We initially identified 587 potentially eligible studies (figure 1). Removal of duplicates and screening of titles and abstracts left 21 records, of which 14 were excluded after full-text review; all trials that were excluded because of the nature of the antidepressant also did not meet at least one other inclusion criterion (appendix). One trial identified from ClinicalTrials.gov (NCT00464191) was also excluded because the trial was terminated owing to insufficient recruitment. We included the

Discussion

Although previous meta-analyses have examined the safety and efficacy of antidepressants in bipolar depression, the clinical relevance of their findings is limited by the inclusion of studies of antidepressant monotherapy as well as tricyclic antidepressants and inhibitors of monoamine oxidase. We restricted our analyses to randomised, placebo-controlled trials that tested the efficacy of second-generation antidepressants versus placebo adjunctive to a mood stabiliser or an atypical

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