Comparative efficacy and safety of 4 atypical antipsychotics augmentation treatment for major depressive disorder in adults: A systematic review and network meta-analysis

BACKGROUND: Atypical antipsychotic (AAP) augmentation is an alternative strategy for patients with major depressive disorder (MDD) who had an inadequate response to antidepressant therapy (ADT). We aimed to compare and rank the efficacy and safety of 4 AAPs in the adjuvant treatment of MDD. METHODS: We searched randomized controlled trials (RCTs) published and unpublished from the date of databases and clinical trial websites inception to April 30, 2023. The evidence risk of bias (RoB) and certainty are assessed using the Cochrane bias risk tool and grading of recommendations assessment, development, and evaluation (GRADE) framework, respectively. Using network meta-analysis, we estimated summary risk ratios (RRs) or standardized mean difference (SMD) based on the random effects model. RESULTS: 56 eligible studies comprising 11448 participants were included. In terms of primary efficacy outcome, compared with placebo (PBO), all AAPs had significant efficacy (SMD = −0.40; 95% CI, −0.68 to −0.12 for quetiapine (QTP); −0.35, −0.59 to −0.11 for olanzapine (OLA); −0.28, −0.47 to −0.09 for aripiprazole (ARI) and −0.25, −0.42 to −0.07 for brexpiprazole (BRE), respectively). In terms of acceptability, no significant difference was found, either agents versus agents or agents versus PBO. In terms of tolerability, compared with the PBO, QTP (RR = 0.24; 95% CI,0.11–0.53), OLA (0.30,0.10–0.55), ARI (0.39,0.22–0.69), and BRE (0.37,0.18–0.75) were significantly less well tolerated. 8 (14.2%) of 56 trials were assessed as low RoB, 38 (67.9%) trials had moderate RoB, and 10 (17.9%) had high RoB; By the GRADE, the certainty of most evidence was low or very low. CONCLUSION: Adjuvant AAPs had significant efficacy compared with PBO, but treatment decisions must be made to balance the risks and benefits.