Esmethadone Shows Numerically Greater Improvement in Depression Than Rapastinel: Study

A new review published in the journal of East Asian Archives of Psychiatry found that esmethadone and rapastinel may offer modest improvements in depressive symptoms among adults with major depressive disorder (MDD), although the overall benefits were not statistically significant compared with placebo.

The analysis, designed to synthesise evidence on the efficacy and safety of the two investigational treatments, included 11 RCTs identified through searches of PubMed, Scopus, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. Studies published from database inception through December 2025 included trials in which esmethadone or rapastinel was administered either as monotherapy or along with existing antidepressant treatment.

For efficacy, investigators assessed changes in the Montgomery-Åsberg Depression Rating Scale (MADRS), a commonly used measure of depressive symptom severity. Across the included trials, patients receiving esmethadone or rapastinel experienced a numerically greater reduction in MADRS scores than those receiving placebo. However, the pooled mean difference was -0.62 points, and the result did not reach statistical significance (p=0.264).

The pooled risk ratio for experiencing at least one adverse event was 1.09 (p=0.223), indicating no statistically significant difference in adverse-event rates between patients receiving the investigational treatments and those receiving placebo. The reduction in MADRS scores was -0.82 for monotherapy and -0.57 for adjunctive therapy, with no significant difference between the approaches (p=0.891). Safety outcomes were likewise comparable, with risk ratios of 0.90 for monotherapy and 1.12 for adjunctive treatment (p=0.478). 

When the two drugs were examined separately, esmethadone produced a numerically larger reduction in MADRS scores than rapastinel. The respective mean differences were -3.77 and -0.04, although the difference between the treatments was not statistically significant (p=0.140). Their safety profiles were also broadly similar, with risk ratios of 1.10 for esmethadone and 1.03 for rapastinel (p=0.771).

The findings suggest that both agents showed a consistent direction of improvement in depressive symptoms without evidence of significantly higher overall adverse-event rates than placebo. However, the lack of statistical significance means the results do not establish a clear efficacy advantage over placebo. 

Reference:

Muneer, M. A., Ain, Q. U., Zahid, S., Farooq, O., Talha, M., Waqas, M., Amin, F., Tawab, M. A., Jabbar, F. A., Jafri, H. M., Aala, A., & Haider, S. T. (2026). Efficacy and safety of esmethadone and rapastinel for major depressive disorder: a systematic review and meta-analysis of randomised controlled trials. East Asian Archives of Psychiatry : Official Journal of the Hong Kong College of Psychiatrists = Dong Ya Jing Shen Ke Xue Zhi : Xianggang Jing Shen Ke Yi Xue Yuan Qi Kan, 36(3), 205-213. https://doi.org/10.12809/eaap2664