Comparative Augmentative Efficacy of Second-Generation Antipsychotics in Adult Treatment-Resistant Depression: A...

Treatment-resistant depression (TRD) affects a substantial proportion of patients with major depressive disorder and remains a major therapeutic challenge. Augmentation with second-generation antipsychotics (SGAs) is commonly used; however, comparative evidence regarding their efficacy and safety remains limited. This systematic review aimed to evaluate the augmentative efficacy and tolerability of SGAs in adults with TRD. A systematic search of PubMed/MEDLINE, Embase, Web of Science, Scopus, and the Cochrane Library was conducted for randomized controlled trials published between 2016 and 2025. Eligible studies included adults with TRD receiving SGA augmentation. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Cochrane RoB 2 tool. Due to clinical heterogeneity across interventions and outcomes, findings were synthesized narratively. Eleven randomized controlled trials including 5,300 participants were analyzed, evaluating brexpiprazole, cariprazine, aripiprazole, and quetiapine XR. Most studies reported greater reductions in depressive symptoms compared with placebo, commonly measured by changes in the Montgomery-Åsberg Depression Rating Scale. Brexpiprazole and the aripiprazole-sertraline combination showed the most consistent improvements, with brexpiprazole augmentation yielding remission rates ranging from 22 to 31% and cariprazine augmentation showing rates of 22-32% across flexible-dose trials. Several agents demonstrated early onset of action within 2-3 weeks. Common adverse events included akathisia, insomnia, restlessness, and weight gain. Discontinuation due to adverse events ranged from 0.4% to 8.6%. Ten studies were assessed as having a low risk of bias. SGA augmentation is an effective treatment strategy for TRD, with brexpiprazole showing particularly consistent benefits. Careful risk-benefit assessment and monitoring for adverse effects are essential. Further head-to-head and long-term studies are needed to guide personalized treatment.