Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants
Maurizio Fava, Stephen M. Stahl, Luca Pani, Sara De Martin, Andrew J. Cutler, Vladimir Maletic, Charles W. Gorodetzky, Frank J. Vocci, Frank L. Sapienza, Thomas R. Kosten, Cornelia Kröger, Paggard Champasa, Cedric O’Gorman, Clotilde Guidetti, Andrea Alimonti, Stefano Comai, Andrea Mattarei, Franco Folli, David Bushnell, Sergio Traversa, Charles E. Inturrisi, Paolo L. Manfredi, M. Pappagallo
Abstract
To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants. ) were randomized to daily oral esmethadone (75 mg on day 1, followed by 25 mg daily on days 2 through 28) or placebo between December 2020 and December 2022. The primary efficacy measure was change from baseline (CFB) to day 28 in the Montgomery-Asberg Depression Rating Scale (MADRS) score. The intent-to-treat (ITT) population included all randomized participants. The per-protocol (PP) population included completers without major protocol deviations impacting assessment. Post hoc analyses included participants with severe depression (baseline MADRS score ≥35). = .0015; ES = 0.69. Adverse events (AEs) were predominantly mild or moderate and transient, with no significant differences between groups. The primary end point was not met. Esmethadone showed stronger efficacy in PP than in ITT analyses, with the discrepancy not attributable to AEs impacting treatment adherence. Significant efficacy occurred in post hoc analyses of patients with severe depression. Esmethadone was well tolerated, consistent with prior studies. ClinicalTrials.gov identifier: NCT04688164.