Comparative Efficacy and Tolerability of Adjunctive Pharmacotherapies for Acute Bipolar Depression: A Systematic Review and Network Meta-analysis.

OBJECTIVE: We investigated the comparative efficacy and tolerability of augmentation strategies for bipolar depression. DATA SOURCES: We conducted a systematic review and network meta-analysis of 8 electronic databases for double-blind, randomized controlled trials of adjunctive pharmacotherapies for acute bipolar depression. DATA EXTRACTION AND SYNTHESIS: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and applied the Cochrane risk of bias tool for study quality appraisal. Two reviewers independently abstracted data. We resolved all discrepancies by consensus. MAIN OUTCOMES AND MEASURES: Primary outcomes were response and completion of treatment. We estimated summary rate ratios (RRs) and standardized mean differences (SMDs) relative to placebo controls using frequentist random-effects network meta-analysis. RESULTS: We identified 69 trials meeting eligibility criteria (8,007 participants, 42.8 years, 58.0% female). Adjunctive racemic intravenous ketamine, coenzyme Q10, pramipexole, fluoxetine, and lamotrigine were more effective than placebo. Summary RRs for response ranged between 1.51 (95% confidence interval [CI], 1.11 to 2.06) for fluoxetine and 12.49 (95% CI, 3.06 to 50.93) for racemic intravenous ketamine. For completion of treatment, risperidone appeared less tolerable than placebo (RR = 0.59; 95% CI, 0.38 to 0.94), while fluoxetine seemed more tolerable than placebo (RR = 1.13; 95% CI, 1.02 to 1.24). None of the investigated agents were associated with increased treatment-emergent mood switches. CONCLUSIONS AND RELEVANCE: The evidence for augmentation strategies in bipolar depression is limited to a handful of agents. Fluoxetine appeared to have the most consistent evidence base for both efficacy and tolerability. There remains a need for additional research exploring novel treatment strategies for bipolar depression, particularly head-to-head studies.

Comparative efficacy and tolerability of pharmacological treatments for the treatment of acute bipolar depression: A systematic review and network meta-analysis.

OBJECTIVE: We investigated the comparative efficacy and tolerability of pharmacological treatment strategies for the treatment of acute bipolar depression. DATA SOURCES: A systematic review and network meta-analysis was conducted by searching eight registries for published and unpublished, double-blind, randomized controlled trials of pharmacotherapies for the acute treatment of bipolar depression. DATA EXTRACTION AND SYNTHESIS: PRISMA guidelines were used for abstracting data, while the Cochrane Risk of Bias Tool was used to assess data quality. Data extraction was done independently by two reviewers, with discrepancies resolved by consensus. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES: Primary outcomes were efficacy (response and remission rate) and acceptability (completion of treatment and dropouts due to adverse events). Summary odds ratios (ORs) were estimated using pairwise and network meta-analysis with random effects. RESULTS: Identified citations (4,404) included 50 trials comprising 11,448 participants. Escitalopram, phenelzine, moclobemide, carbamazepine, sertraline, lithium, paroxetine, aripiprazole, gabapentin and ziprasidone appear to be ineffective as compared to placebo in treatment of bipolar depression. Divalproex, olanzapine/fluoxetine, olanzapine, quetiapine, cariprazine, and lamotrigine, appear to be effective as compared to placebo in treatment of bipolar depression according to the network meta-analysis. Aripiprazole showed higher discontinuation rates versus placebo due to the appearance of any adverse event. Quetiapine was better than placebo at reducing treatment-emergent affective switches. For Bipolar I Disorder, cariprazine, fluoxetine, imipramine, lamotrigine, lurasidone, olanzapine-fluoxetine, and olanzapine were significantly better than placebo at response, while fluoxetine, imipramine, cariprazine, lurasidone, olanzapine-fluoxetine, and olanzapine were significantly better than placebo at remission. CONCLUSIONS AND RELEVANCE: These results could serve evidence-based practice and inform patients, physicians, guideline developers, and policymakers on the relative benefits of the different antidepressants, antipsychotics, and mood-stabilizing agents for the treatment of bipolar depression. REGISTRATION: PROSPERO (CRD42019122172).