ABSTRACT: BACKGROUND:This systematic review and meta-analysis included double-blind, randomized, placebo-controlled trials of brexpiprazole adjunctive treatment (0.5-3 mg/d) for major depressive disorder where antidepressant treatment had failed. METHODS:The outcomes were the response rate (primary), remission rate (secondary), Montgomery Åsberg Depression Rating Scale score (secondary), Sheehan Disability Scale scores (secondary), Clinical Global Impression-Improvement/Severity scores, discontinuation rate, and individual adverse events. A subgroup meta-analysis of the data at week 6 compared outcomes by dose >2 mg/d or ?2 mg/d (2 mg/d is the recommended dose). RESULTS:We identified 9 studies (n?=?3391). Compared with placebo, brexpiprazole (any dose) was superior for response rate (risk ratio [RR]?=?0.93, 95% confidence interval [95% CI]?=?0.89-0.97, number needed to treat?=?17), remission rate (RR?=?0.95, 95% CI?=?0.93-0.98, number needed to treat?=?25), Montgomery Åsberg Depression Rating Scale score (standardized mean difference =?-0.20, 95% CI?=?-0.29, -0.11), Sheehan Disability Scale score (standardized mean difference?=?-0.12, 95% CI?=?-0.21, -0.04), and Clinical Global Impression-Improvement/Severity scores but was associated with a higher discontinuation rate, akathisia, insomnia, restlessness, somnolence, and weight increase. Doses >2 mg/d had a significantly higher RR for response rate than ?2 mg/d (0.96 vs 0.89); moreover, compared with placebo, doses >2 mg/d were associated with higher incidences of akathisia (RR?=?4.58) and somnolence (RR?=?7.56) as well as were marginally associated with a higher incidence of weight increase (RR?=?3.14, P?=?.06). Compared with placebo, doses ?2 mg/d were associated with higher incidences of akathisia (RR?=?2.28) and weight increase (RR?=?4.50). CONCLUSIONS:Brexpiprazole adjunctive treatment is effective for major depressive disorder when antidepressant treatment fails. At 6 weeks, doses ?2 mg/d presented a better risk/benefit balance than >2 mg/d.