Efficacy and tolerability of esmethadone in patients with major depressive disorder: A meta-analysis of 3 randomized controlled trials

Purpose: To evaluate the efficacy and tolerability of oral esmethadone for major depressive disorder (MDD). Method: We performed a computerized search of MEDLINE, EMBASE, Cochrane Library, Web of Science, Google Scholar, and ClinicalTrials.gov to identify eligible randomized, placebo-controlled trials (RCTs) until June 30, 2024. We calculated standardized mean differences (SMD) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes. Quality assessment of included RCTs was performed using the Cochrane Collaboration tool. The efficacy of esmethadone was evaluated utilizing changes from baseline in the Montgomery-& Aring;sberg Depression Scale (MADRS) score, and tolerability was assessed in terms of serious adverse event (SAE), dropout, and the most common side effects. Results: A total of 3 RCTs with 521 patients were included in the current study. The changes from baseline in MADRS for SMD was -0.28 (95 % CI -0.46 to -0.10; P = 0.003), pooled RRs for response and remission were 1.38 (95 % CI 1.09-1.74; P = 0.007) and 1.82 (95 % CI 1.25-2.64, P = 0.002), respectively. Significantly more patients receiving placebo experienced discontinuation than those receiving esmethadone (RR 0.55, 95 % CI 0.32-0.96; P = 0.035). Headache, dizziness, constipation, nausea, upper respiratory tract infection, and diarrhea were the most common adverse events associated with esmethadone (RR=0.28-2.17). Conclusions: Esmethadone is a rapid-onset antidepressant, showed sustained efficacy of the reduction in depression syndrome during the 14-day treatment period, with mild to moderate side effects. However, no significant difference was observed at day 28. The long-term efficacy and safety of esmethadone are still needed to evaluate in future trials.