Esmethadone Shows Potential in MDD Patients With Antidepressant Tolerance

Key Clinical Summary

• Esmethadone (REL-1017) demonstrated a significant reduction in depressive symptoms in patients with major depressive disorder (MDD) and antidepressant tolerance (AT).
• A mean difference of 5.4 points in MADRS score favored esmethadone versus placebo by day 28.
• Post hoc analysis findings suggest therapeutic potential but require validation in larger, prospective studies.

According to a post hoc analysis published in The Journal of Clinical Psychiatry, esmethadone (REL-1017) may be an effective adjunctive treatment for patients with major depressive disorder (MDD) and antidepressant tolerance/tachyphylaxis (AT). 

Researchers analyzed data from a phase 3, double-blind, placebo-controlled trial of esmethadone with an intent to treat population (ITT) of 227 adult patients with MDD. Patients were independently assessed for AT before randomization using the MGH Antidepressant Treatment Response Questionnaire. AT was defined as an initial response (>50% improvement) to antidepressant treatment and a subsequent relapse on the same adequate dose. 

The researchers calculated the mean difference in Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from baseline to primary endpoint (day 28) in the AT subgroup from the ITT population, the per-protocol (PP) population, and patients with severe depression (baseline MADRS ≥35).

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Of the ITT population, 87 experienced AT.  In their analysis, the researchers found that this subgroup had a nominally statistically significant mean difference of 5.4 (P=.023, Cohen effect size 0.53) for esmethadone vs placebo in MADRS total score change from baseline to day 28. The subgroup also experienced a significant difference in response rate compared to placebo (P=.0004).

Further analyses showed that these improvements were consistent among the PP patients with AT and severely depressed patients with AT. 

“These post hoc analyses, based on data collected independently pre-randomization, suggest that esmethadone may be an effective adjunctive treatment for patients with AT,” wrote Clotilde Guidetti, MD, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, and study coauthors. 

While their findings suggest that esmethadone may offer therapeutic benefit for this patient population, the authors note that the results “need to be confirmed in larger prospective trials.”  

References
Guidetti C, Papakostas GI, Pani L, et al. Esmethadone (REL-1017) in patients with major depressive disorder and antidepressant tachyphylaxis: an exploratory post hoc analysis from a phase 3 randomized controlled trial. J Clin Psychiatry. 2025;86(4):24m15748 Published online October 6, 2025. doi:10.4088/JCP.24m15748

Derman C. Esmethadone shows promise as adjunctive treatment for antidepressant tolerance. HCPLive. Published online October 17, 2025.