Objective: The purpose of this study was to examine the effects of REL-1017 (esmethadone), a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker, in patients with major depressive disorder who failed to benefit from one to three standard antidepressant treatments in their current major depressive episode.

Methods: A 7-day phase 2 multicenter randomized double-blind placebo-controlled trial, comprising three arms, was conducted to assess the safety, tolerability, pharmacokinetics, and efficacy of two dosages of REL-1017 (25 mg or 50 mg orally once a day). Patients were randomly assigned in a 1:1:1 ratio to placebo (N=22), REL-1017 25 mg/day (N=19), or REL-1017 50 mg/day (N=21). Safety scales included the 4-item Positive Symptom Rating Scale for psychotomimetic symptoms, the Clinician-Administered Dissociative States Scale for dissociative symptoms, the Clinical Opiate Withdrawal Scale for withdrawal signs and symptoms, and the Columbia-Suicide Severity Rating Scale for suicidality. The primary efficacy endpoint was the Montgomery‐Åsberg Depression Scale (MADRS) score. All 62 randomly assigned patients were included in the full analysis set population analysis.

Results: Patients experienced mild or moderate transient adverse events and no evidence of dissociative or psychotomimetic effects, opioid effects, or withdrawal signs and symptoms. The improvement in MADRS score shown on day 4 in both of the REL-1017 dosage groups was sustained through day 7 (last dose) and day 14 (7 days after the last dose), with effect sizes from 0.7 to 1.0.

Conclusions: This trial showed favorable safety, tolerability, and pharmacokinetic profiles and suggests that REL-1017 may have rapid and sustained antidepressant effects compared with placebo in patients with inadequate responses to antidepressant treatments. These results will need confirmation in larger and longer trials.

目的：本研究的目的是检查 REL-1017（艾美沙酮），一种新型N-甲基-d-天冬氨酸受体 (NMDAR) 通道阻滞剂，对未能从 1 到 3 次治疗中受益的重度抑郁症患者的效果。在他们目前的重度抑郁发作中进行标准抗抑郁治疗。

方法：进行了一项为期 7 天的 2 期多中心随机双盲安慰剂对照试验，包括三组，以评估两种剂量的 REL-1017（每天口服 25 毫克或 50 毫克）的安全性、耐受性、药代动力学和有效性）。患者以 1:1:1 的比例随机分配至安慰剂组 (N=22)、REL-1017 25 mg/天 (N=19) 或 REL-1017 50 mg/天 (N=21)。安全性量表包括用于拟精神病症状的 4 项阳性症状评定量表、用于解离症状的临床医生管理的分离状态量表、用于戒断体征和症状的临床阿片类药物戒断量表和用于自杀的哥伦比亚自杀严重程度评定量表。主要疗效终点是蒙哥马利-埃斯伯格抑郁量表（MADRS）评分。

结果：患者经历了轻度或中度短暂的不良事件，并且没有分离或拟精神病作用、阿片类药物作用或戒断症状和体征的证据。REL-1017 剂量组在第 4 天显示的 MADRS 评分改善持续到第 7 天（最后一剂）和第 14 天（最后一剂后 7 天），效应大小从 0.7 到 1.0。

结论：该试验显示出良好的安全性、耐受性和药代动力学特征，并表明与安慰剂相比，REL-1017 在抗抑郁治疗反应不足的患者中可能具有快速和持续的抗抑郁作用。这些结果需要在更大和更长的试验中得到证实。