Clinical Summary: 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
Many patients with major depressive disorder remain symptomatic despite an adequate antidepressant trial, yet current adjunctive options often carry meaningful tolerability burdens. This trial tests whether adjunctive oral esmethadone can improve outcomes in patients with major depressive disorder and inadequate response to standard antidepressants without adding signals for withdrawal, abuse, or major cardiometabolic adverse effects.
Key Findings
- The primary end point was not met in the ITT population: mean (SD) CFB to day 28 for the MADRS total score was 15.1 (11.3) for esmethadone (n=113) and 12.9 (10.4) for placebo (n=114) (MD: 2.3 (10.9); P =.154; ES=0.21).
- At day 28, response favored esmethadone: 39.8% with esmethadone versus 27.2% with placebo (MD: 12.6%, 95% CI, 0.5 to 24.8; P =.044; OR: 1.77, 95% CI, 0.98 to 3.23).
- Remission at day 28 numerically favored esmethadone but was not statistically significant: 22.1% with esmethadone and 13.2% with placebo (MD: 9.0%, 95% CI, −0.9 to 18.8; P=.076; OR: 1.88, 95% CI, 0.88 to 4.08).
- In post hoc analyses of patients with severe depression (MADRS score ≥35 at baseline), esmethadone separated from placebo in both the ITT and PP populations (MD CFB 6.9 and 7.9; P = .0059 and P = .0015; ES = 0.57 and 0.68, respectively).
- Safety was broadly comparable to placebo: mean (SD) CFB to day 28 for the QTcF interval was 0.24 (13.5) ms for esmethadone and −3.1 (11.9) ms for placebo, with no QTcF increase ≥60 ms and no QTcF >480 ms; no cases of withdrawal, misuse, abuse, or diversion were recorded in MADDERS.
Adjunctive esmethadone did not meet the primary efficacy end point in the overall intent-to-treat sample, but it improved response rates and showed a stronger signal in patients with severe major depressive disorder. The short-term safety profile was favorable, with no signal for withdrawal, abuse, or clinically meaningful QT prolongation.
Practice Implications
- Do not view esmethadone as proven broadly effective for all patients with inadequate antidepressant response, because the primary MADRS outcome in the ITT population was not significant (P =.154).
- If considering where esmethadone may have the most clinical relevance, pay attention to baseline severity: patients with MADRS score ≥35 had larger benefits, including remission rates of 27.5% versus 11.5% and response rates of 43.1% versus 21.3% in the ITT population.
- When discussing treatment goals with patients, frame the signal around response rather than remission in this trial, since response reached significance (39.8% versus 27.2%; P =.044) while remission did not (22.1% versus 13.2%; P=.076).
- Short-term monitoring can focus on routine adverse-effect and ECG surveillance rather than expecting dissociation, withdrawal, or abuse-related problems, because no QTcF increase ≥60 ms, no QTcF >480 ms, and no cases of withdrawal, misuse, abuse, or diversion were observed.
