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

Abstract

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.