Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Antidepressant Tachyphylaxis: An Exploratory Post Hoc Analysis From a Phase 3 Randomized Controlled Trial

Clotilde Guidetti, MD; George I. Papakostas, MD; Luca Pani, MD; Sara De Martin, PhD; Giulia Serra, MD; Massimo Apicella, MD; Cornelia Kröger, PhD; Paggard Champasa, PhD; Stefano Comai, PhD; Andrea Mattarei, PhD; Franco Folli, MD; Marco Pappagallo, MD; Paolo L. Manfredi, MD; Maurizio Fava, MD

J Clin Psychiatry 2025;86(4):24m15748

Abstract

Background: Antidepressant tolerance/ tachyphylaxis (AT) is defined as initial response (≥ 50% improvement) to antidepressant treatment followed by relapse while on the same adequate dose. The impact of AT as prognostic indicator for response to subsequent antidepressant treatment is unknown.

Objective: To test the efficacy of esmethadone (REL-1017) in a subgroup of patients with major depressive disorder (MDD) and AT.

Methods: A phase 3, double-blind, randomized, placebo-controlled trial of esmethadone was conducted in adult outpatients with MDD. Prior to randomization, AT was independently assessed by clinicians from the Massachusetts General Hospital Clinical Trials Network and Institute using the MGH Antidepressant Treatment Response Questionnaire. Data for the primary efficacy end point were analyzed using mean difference in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to primary end point (Day 28) in the AT subgroup from the intent to treat (ITT) population, the per-protocol (PP) population, and in patients with severe depression (baseline MADRS ≥35).

Results: Among 227 ITT patients, 87 experienced AT. For this subgroup, there was 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 primary end point (Day 28). Additionally, there was a nominally statistically significant difference in response rate (P=.0004). Consistent results were seen in the PP population with AT and in the severely depressed subgroup of patients with AT.

Conclusions: These post hoc analyses, based on data collected independently pre-randomization, suggest that esmethadone may be an effective adjunctive treatment for patients with AT. These results need to be confirmed in larger prospective clinical trials.

J Clin Psychiatry 2025;86(4):24m15748

Author affiliations are listed at the end of this article.

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