Background: Many patients with major depressive disorder (MDD) do not respond adequately to first-line antidepressant treatment (ADT). Adjunctive treatment with second-generation antipsychotics has demonstrated efficacy for patients with MDD, but is limited by tolerability and safety issues. The recently introduced serotonin-dopamine activity modulator, brexpiprazole, has demonstrated efficacy as an adjunctive treatment for MDD.Objective/Method: We report tolerability and safety results for adjunctive brexpiprazole from four 6-week short-term (ST; pooled phase 2 and 3, placebo-controlled) and two 52-week long-term (LT; pooled, openlabel) studies. Results: Approximately 90% of patients completed the ST studies, and 48.8% of patients completed the LT studies. In the ST studies, 2.9% of patients discontinued because of an adverse event (AE); in the LT studies, 14.1% of patients discontinued because of an AE. In the ST and LT studies, the most frequently reported treatment-emergent AEs (TEAEs) were akathisia (8.6% and 10.0%, respectively) and weight gain (7.3% and 25.5%, respectively). Rates of sedation and somnolence were low (ST and LT: sedation, 0.8% and 3.7%, respectively; somnolence, 3.4% and 9.4%, respectively). In the ST and LT studies, brexpiprazole was associated with small changes in metabolic parameters and moderate weight increase. Conclusions: Collectively, these data suggest brexpiprazole is well tolerated as an adjunctive treatment for MDD.