Combination pharmacotherapy in psychotic depression: A systematic review and pairwise meta-analysis of randomized...

Psychotic depression is a severe and under-researched subtype of major depressive disorder. Although antidepressant-antipsychotic combination therapy is widely recommended, the limited number of randomized controlled trials and heterogeneity of outcome definitions complicate interpretation of the evidence available.

We conducted a systematic review and pairwise meta-analysis of randomized controlled trials evaluating pharmacological treatment of psychotic depression. Electronic searches were performed in PubMed/MEDLINE, Embase, PsycINFO, and Cochrane CENTRAL from database inception up to February 13, 2026. Eligible studies compared combination pharmacotherapy with non-combination treatment during the acute phase. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. The primary outcome was clinical improvement, defined according to each trial's prespecified dichotomous endpoint (response or remission). Sensitivity analyses were also conducted for response-only and remission-only outcomes.

Four acute trials (five comparisons) were included. Combination pharmacotherapy was associated with a significantly higher likelihood of clinical improvement compared with non-combination treatment (RR 1.93, 95% CI 1.53-2.43). Findings were consistent in response-only (RR 2.03, 95% CI 1.51-2.75) and remission-only analyses (RR 1.78, 95% CI 1.27-2.49).

Antidepressant-antipsychotic combination therapy is associated with substantially superior acute outcomes in psychotic depression. These findings are consistent with current guideline recommendations and highlight the need for contemporary randomized trials using standardized outcome measures.