Clinical Question

What are the efficacy and tolerability of combination therapy compared with monotherapy for acute severe depression and recurrent depression in adults?

Bottom Line

The review found that combination therapy using a reuptake inhibitor (i.e., a selective serotonin reuptake inhibitor, serotonin-noradrenaline reuptake inhibitor, or tricyclic antidepressant) with an alpha₂-adrenergic receptor antagonist (mirtazapine [Remeron] or trazodone) is more effective than monotherapy for first-line treatment of acute severe depression and for patients who do not respond to monotherapy. Dropout rates due to adverse events are similar for combination therapy and monotherapy. (Level of Evidence = 1a)

Synopsis

The optimal management of an initial episode of acute severe depression and nonresponsive depression in adults remains uncertain. The investigators thoroughly searched, without language restrictions, multiple databases, including MEDLINE, PsycINFO, Embase, and the Cochrane Central Register of Controlled Trials, for randomized trials that compared antidepressant monotherapy with a combination of two antidepressants. Eligible trials included first-line antidepressant treatment and patients with depression resistant to initial therapy. In studies that included depression that did not respond to monotherapy (control group), patients received continued monotherapy with the same antidepressant at the same or higher dose or monotherapy with a different antidepressant. Two individuals independently evaluated trials for study eligibility and risk of bias using the Cochrane scoring tool. Disagreements were resolved by consensus agreement. The primary outcome was treatment efficacy measured as the standardized mean difference. Of the 39 trials, 15 were classified as low risk of bias. Heterogeneity was minimal when restricted to studies with low risk of bias, and an analysis for publication bias found minimal risk for altering the results.

Combination therapy provided superior efficacy vs. monotherapy for first-line treatment and for depression that did not respond to monotherapy (standardized mean difference = 0.31; 95% CI, 0.19 to 0.44). Results were similar when restricting the analyses to only studies with low risk of bias. The combination of a monoamine reuptake inhibitor with an alpha₂-adrenergic receptor antagonist is associated with superior efficacy compared with monotherapy for first-line treatment and for depression that did not respond to monotherapy. Combination therapy with bupropion (Wellbutrin) was not associated with superior outcomes compared with monotherapy for first-line treatment, but it was superior for depression that did not respond to monotherapy. Drop-out rates due to adverse events were similar for both types of therapy.

Study design: Meta-analysis (randomized controlled trials)

Funding source: Industry and foundation

Setting: Various (meta-analysis)

Reference: Henssler J, Alexander D, Schwarzer G, et al. Combining antidepressants vs antidepressant monotherapy for treatment of patients with acute depression: a systematic review and meta-analysis. JAMA Psychiatry. 2022;79(4):300-312.