Dose-response efficacy and safety of lumateperone in bipolar depression: A preliminary meta-analysis of randomized controlled trials

Abstract

Background: The optimal lumateperone dose for bipolar depression remains uncertain. Aims: To examine its dose–response relationship for efficacy and safety. Methods: We systematically searched major databases to 1 July 2025. Efficacy outcomes included change in depression severity, global illness severity, quality of life, responder, and remitter rates. Safety outcomes included all-cause dropout, discontinuations due to adverse event (AE), treatment-emergent AE, mania, suicidality, extrapyramidal symptoms, body weight, lipid profile, and fasting glucose. A one-step dose–response meta-analysis generated effect sizes, reported as standardized mean differences (SMDs) and risk ratios (RRs) with 95% confidence intervals (CIs). Results: Three randomized controlled trials involving 1454 patients showed that a 42-mg daily dose of lumateperone significantly improved depressive symptoms (SMD = −0.26; 95% CI: −0.51, −0.02), Clinical Global Impression-Bipolar-Severity (CGI-BP-S) overall bipolar illness (SMD = −0.31; 95% CI: −0.45, −0.16), CGI-BP-S bipolar depression (SMD = −0.33; 95% CI: −0.48, −0.17), quality of life (SMD = 0.22; 95% CI: 0.07, 0.36), and responder rate (RR = 1.27; 95% CI: 1.05, 1.53), but not remitter rate (1.06; 95% CI: 0.81, 1.38). Compared with placebo, discontinuation due to AE significantly increased at the 42 mg dose (RR = 3.12; 95% CI: 1.68, 5.80), but not at 28 mg (1.58; 95% CI: 0.25, 9.89). Moreover, dropout rates (42 mg RR = 1.15; 95% CI: 0.76, 1.73) and other safety outcomes did not exhibit a dose–response trend. Conclusions: Preliminary evidence suggests that 42 mg daily of lumateperone may provide clinical benefit in bipolar depression, yet the higher rate of AE-related discontinuation warrants caution in practice. However, current data remain limited, requiring further studies to establish the optimal dosing range balancing efficacy and safety.