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BACKGROUND: Brexpiprazole augmentation is an effective treatment strategy for antidepressant-refractory depression, but its optimal dosage remains unclear. AIMS: To find the optimal dosage of brexpiprazole as augmentation of other antidepressants. METHODS: We searched multiple electronic databases (from inception to September 16th, 2021) to identify double-blind, randomized placebo-controlled fixed-dose trials evaluating brexpiprazole augmentation therapy in adults (≥18 years old, both genders) with major depressive disorder not adequately responding to one or more antidepressant treatment. Our outcomes of interest at 8 weeks (range 4-12 weeks) were efficacy (treatment response defined as 50% or greater reduction in depression severity), tolerability (dropouts due to adverse effects) and acceptability (dropouts for any reason). We performed a random-effects, one-stage dose-effect meta-analysis with restricted cubic splines. RESULTS: Six studies met the inclusion criteria, including 1671 participants in total. The dose-efficacy curve showed an increase up to doses around 2 mg (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.12-2.06) and then a decreasing trend through the higher licensed dose up to 3 mg (OR 1.40, 95% CI 0.95-2.08). The shape of the dose-tolerability curve was comparable to that of the efficacy and the dose-acceptability curve showed a monotonic increasing trend but both had wide confidence bands. CONCLUSIONS: One to two milligrams of brexpiprazole as augmentation treatment may achieve an optimal balance between efficacy, tolerability, and acceptability in the acute treatment of antidepressant-refractory depression. However, the small number of included studies limit the reliability of the results. Further research is required to validate the findings.

Original publication




Journal article


Psychiatry Clin Neurosci

Publication Date



antipsychotic agents, brexpiprazole, depressive disorder, dose-response relationship, drug, meta-analysis, treatment-resistant