Esmethadone Shows Promise as Adjunctive Treatment for Antidepressant Tolerance

A post-hoc analysis of a phase 3 trial showed the potential of esmethadone (REL-1017) as an adjunctive treatment for patients with antidepressant tolerance.1

Tachyphylaxis, defined in this study as an initial antidepressant response of at least 50% improvement followed by relapse despite continued treatment at the same adequate dose, affects an estimated 9% to 57% of patients with major depressive disorder (MDD).2 The prevalence varies based on population and follow-up duration.

Approximately 50% to 60% of individuals with MDD do not achieve adequate benefit from initial antidepressant therapy.3 Although, like participants in this post-hoc analysis, some may experience early symptom relief but eventually relapse. Earlier studies, including a phase 2 trial, showed promise for esmethadone in treatment-resistant depression, with improvements observed by day 4 in the 25- and 50-mg dosage groups, sustained through day 14; 31% of participants reached remission (P =.035).3 Esmethadone is a novel NMDA receptor channel blocker that targets hyperactive channels while maintaining physiological glutamatergic neurotransmission.

The subsequent phase 3, double-blind, randomized, placebo-controlled trial, however, did not meet its primary endpoint due to mixed results.4 Esmethadone demonstrated stronger efficacy in the per-protocol population, including participants who completed treatment without major protocol deviations, than in the intent-to-treat population, which included all randomized participants. Investigators noted that differences in efficacy were unrelated to adverse events affecting adherence.

“The overall results from this trial are clearly consistent with the evidence, produced by the prior phase 2 trial, for the efficacy, safety, and tolerability of esmethadone as a promising antidepressant for the adjunctive treatment of major depressive disorder,” said Maurizio Fava, MD, lead Investigator of the Reliance phase 3 trial, in a statement.5 “The side-effect profile of esmethadone compares quite favorably with the side effects of the currently FDA-approved adjunctive treatments for MDD.”

A post-hoc analysis assessing participants with severe depression (Montgomery-Äsberg Depression Rating Scale (MADRS) score ≥ 35) also suggested an impact.4 In the analysis, patients with severe depression on esmethadone vs placebo demonstrated significant improvement in MADRS score in both the pre-protocol and intent-to-treat populations (P = .0059 and P = .0015, respectively). Still, the impact of tachyphylaxis as a prognostic factor of responding to future antidepressant treatment remained unclear.

To address this, Clotilde Guidetti, MD, and colleagues at Massachusetts General Hospital conducted a new post-hoc analysis of the phase 3 trial, focusing specifically on participants with antidepressant tachyphylaxis.1 Clinicians independently assessed tachyphylaxis before randomization using the MGH Antidepressant Treatment Response Questionnaire.

Investigators evaluated the effectiveness of esmethadone by measuring the mean change in MADRS total score from baseline to day 28 in the tachyphylaxis subgroup, examining results in the intent-to-treat population, per-protocol, and severe depression populations.

Among 227 participants in the intent-to-treat population, 87 experienced tachyphylaxis. Those treated with esmethadone showed significant improvements in depressive symptoms versus placebo, with a mean difference of 5.4 in the MADRS total score from baseline (P =.023), and a statistically significant improvement in response rate (P =.0004). Unlike prior trials, consistent improvements were observed across per-protocol and severe depression populations, supporting the potential utility of esmethadone in this difficult-to-treat subgroup.1

“These post hoc analyses, based on data collected independently pre-randomization, suggest that esmethadone may be an effective adjunctive treatment for patients with [tachyphylaxis],” investigators concluded.1 “These results need to be confirmed in larger prospective clinical trials.”

References

1. 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 2025 Oct 6. doi:10.4088/JCP.24m15748

2. Kinrys G, Gold AK, Pisano VD, et al. Tachyphylaxis in major depressive disorder: A review of the current state of research. J Affect Disord. 2019;245:488-497. doi:10.1016/j.jad.2018.10.357

3. Nonacs, R. Esmethadone: A Novel, Rapidly Effective Treatment for Depression - MGH Psychiatry News. MGH Psychiatry News. Published January 17, 2022. Accessed October 17, 2025. https://mghpsychnews.org/esmethadone-a-novel-rapidly-effective-treatment-for-depression/

4. Fava M, Stahl SM, Pani L, et al. Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants: A Phase 3 Randomized Controlled Trial. J Clin Psychiatry. 2024;85(3):24m15265. Published 2024 Jun 17. doi:10.4088/JCP.24m15265

5. Relmada Therapeutics, Inc. Relmada Therapeutics, Inc. Published June 18, 2024. Accessed October 17, 2025. https://www.relmada.com/for-investors/news/detail/299/relmada-therapeutics-announced-publication-of-results-from