Efficacy and safety of esmethadone and rapastinel for major depressive disorder: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVES: To synthesise data from randomised controlled trials (RCTs) regarding the efficacy and safety of esmethadone and rapastinel for major depressive disorder (MDD). METHODS: PubMed, Scopus, Embase, CENTRAL, and ClinicalTrials.gov were searched from inception to December 2025 for RCTs comparing placebo with esmethadone or rapastinel applied as monotherapy or adjunctive therapy in adults with MDD. Eligible RCTs were required to report efficacy in terms of the Montgomery-Åsberg Depression Rating Scale (MADRS) and safety in terms of the incidence of any adverse events. Mean differences (MDs) in MADRS scores between treatment and control groups were calculated, as were risk ratios (RRs) of participants experiencing at least one adverse event. Random-effects models were used. RESULTS: In total, 11 RCTs were included in the analysis. For efficacy, there was a non-significantly greater reduction in MADRS scores in the treatment group than in the control group (MD = -0.62, p = 0.264). For safety, the pooled RR was 1.09 (p = 0.223), indicating comparable adverse event rates between the two groups. Subgroup analyses showed comparable reductions in MADRS scores between monotherapy and adjunctive therapy (MD = -0.82 vs -0.57, p = 0.891) and between esmethadone and rapastinel (MD = -3.77 vs -0.04, p = 0.140), as well as comparable safety profiles between monotherapy and adjunctive therapy (RR = 0.90 vs 1.12, p = 0.478) and between esmethadone and rapastinel (RR = 1.10 vs 1.03, p = 0.771). CONCLUSION: Esmethadone and rapastinel demonstrated consistent, non-significant improvement in depressive symptoms, with a safety profile comparable to that of placebo. Compared with rapastinel, esmethadone showed a numerically greater improvement in depressive symptoms.