Combining Antidepressants in Acute Treatment of Depression: A Meta-Analysis of 38 Studies Including 4511 Patients

Objective: Combining antidepressants (ADs) for therapy of acute depression is frequently employed, but randomized studies have yielded conflicting results. We conducted a systematic review and meta-analysis aimed at determining efficacy and tolerability of combination therapy. Methods: MEDLINE, Embase, PsycINFO, and CENTRAL databases were systematically searched through March 2014 for controlled studies comparing combinations of ADs with AD monotherapy in adult patients suffering from acute depression. The prespecified primary outcome was standardized mean difference (SMD), secondary outcomes were response, remission, and dropouts. Results: Among 8688 articles screened, 38 studies were eligible, including 4511 patients. Combination treatment was statistically, significantly superior to monotherapy (SMD 0.29; 95% CI 0.16 to 0.42). During monotherapy, slightly fewer patients dropped out due to adverse events (OR 0.90; 95% CI 0.53 to 1.53). Studies were heterogeneous (I2 = 63%), and there was indication of moderate publication bias (fail-safe N for an effect of 0.1:44), but results remained robust across prespecified secondary outcomes and subgroups, including analyses restricted to randomized controlled trials and low risk of bias studies. Meta-regression revealed an association of SMD with difference in imipramine-equivalent dose. Combining a reuptake inhibitor with an antagonist of presynaptic α2-autoreceptors was superior to other combinations. Conclusion: Combining ADs seems to be superior to monotherapy with only slightly more patients dropping out. Combining a reuptake inhibitor with an antagonist of presynaptic α2-autoreceptors seems to be significantly more effective than other combinations. Overall, our search revealed a dearth of well-designed studies.