Long-Term Safety and Efficacy of Esmethadone in Patients With Major Depressive Disorder: Findings From a 12-Month Open-Label Study

Maurizio Fava, MD ; Luca Pani, MD ; Sara De Martin, PhD ; Andrew J. Cutler, MD ; Charles W. Gorodetzky, MD, PhD ; Frank J. Vocci, PhD ; Frank L. Sapienza, MS ; Thomas R. Kosten, MD ; Cornelia Kröger, PhD ; Paggard Champasa, PhD ; Clotilde Guidetti, MD ; Stefano Comai, PhD ; Andrea Mattarei, PhD ; Franco Folli, MD ; David Bushnell, MS ; Sergio Traversa, PharmD ; Charles E. Inturrisi, PhD ; Paolo L. Manfredi, MD ; Marco Pappagallo, MD

J Clin Psychiatry 2025;86(1):24m15438

Abstract

Background: Esmethadone is a novel N-methyl-D-aspartate receptor (NMDAR) uncompetitive antagonist in development as adjunctive treatment for major depressive disorder (MDD).

Methods: This 12-month, open-label study evaluated the safety and efficacy of esmethadone in patients with MDD meeting DSM-5 criteria who completed 1 of 3 double-blind studies (rollover) and in patients with MDD and no prior participation in esmethadone studies (de novo). Safety was assessed from adverse events, laboratory parameters, vital signs, electrocardiogram, and the Columbia-Suicide Severity Rating Scale. Efficacy assessments used measures of depression, anxiety, sleep, sexual function, cognitive function, and quality of life. The safety population comprised patients who received at least 1 dose of study drug, and the full analysis set (FAS) comprised patients who had at least 1 postbaseline efficacy assessment.

Results: Safety population included 624 patients; FAS included 586 patients (384 rollover and 202 de novo); mean age was 42.9 (13.6) years, and mean baseline Montgomery-Asberg Depression Rating Scale (MADRS10) was 34.5 (4.8). Most common treatment-related treatment emergent adverse events were headache (4.6%), nausea (4.2%), and dizziness (2.6%). There were no signals of meaningful neurological, cardiovascular, metabolic, or sexual adverse events and no case of suicide or suicidal attempt. For the FAS, mean (SD) change from baseline for MADRS10 at 3, 6, 9, and 12 months was −20.1 (10.7), −21.0 (10.8), −21.6 (10.7), and −21.6 (10.4). For the de novo population, mean (SD) was −19.9 (10.0), −19.9 (10.4), −20.1 (10.2), and −22.5 (9.7). Consistent improvements occurred with other tested efficacy measures.

Conclusions: Long-term treatment with esmethadone was safe and well tolerated. The antidepressant efficacy of esmethadone was sustained over 12 months.

Trial Registration: ClinicalTrials.gov identifier: NCT04855760.

J Clin Psychiatry 2025;86(1):24m15438

Author affiliations are listed at the end of this article.

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