Fava Maurizio, Pani Luca, De Martin Sara, Cutler Andrew J, Gorodetzky Charles W, Vocci Frank J, Sapienza Frank L, Kosten Thomas R, Kröger Cornelia, Champasa Paggard, Guidetti Clotilde, Comai Stefano, Mattarei Andrea, Folli Franco, Bushnell David, Traversa Sergio, Inturrisi Charles E, Manfredi Paolo L, Pappagallo Marco
Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts.
Department of Psychiatry and Behavioral Sciences, School of Medicine, University of Miami, Coral Gables, Florida.
J Clin Psychiatry. 2025 Feb 17;86(1):24m15438. doi: 10.4088/JCP.24m15438.
Esmethadone is a novel -methyl-D-aspartate receptor (NMDAR) uncompetitive antagonist in development as adjunctive treatment for major depressive disorder (MDD). This 12-month, open-label study evaluated the safety and efficacy of esmethadone in patients with MDD meeting criteria who completed 1 of 3 double-blind studies () and in patients with MDD and no prior participation in esmethadone studies (). Safety was assessed from adverse events, laboratory parameters, vital signs, electrocardiogram, and the Columbia-Suicide Severity Rating Scale. Efficacy assessments used measures of depression, anxiety, sleep, sexual function, cognitive function, and quality of life. The safety population comprised patients who received at least 1 dose of study drug, and the full analysis set (FAS) comprised patients who had at least 1 postbaseline efficacy assessment. Safety population included 624 patients; FAS included 586 patients (384 and 202 de novo); mean age was 42.9 (13.6) years, and mean baseline Montgomery-Asberg Depression Rating Scale (MADRS10) was 34.5 (4.8). Most common treatment-related treatment emergent adverse events were headache (4.6%), nausea (4.2%), and dizziness (2.6%). There were no signals of meaningful neurological, cardiovascular, metabolic, or sexual adverse events and no case of suicide or suicidal attempt. For the FAS, mean (SD) change from baseline for MADRS10 at 3, 6, 9, and 12 months was -20.1 (10.7), -21.0 (10.8), -21.6 (10.7), and -21.6 (10.4). For the de novo population, mean (SD) was -19.9 (10.0), -19.9 (10.4), -20.1 (10.2), and -22.5 (9.7). Consistent improvements occurred with other tested efficacy measures. Long-term treatment with esmethadone was safe and well tolerated. The antidepressant efficacy of esmethadone was sustained over 12 months. ClinicalTrials.gov identifier: NCT04855760.
埃斯美沙酮是一种新型的N-甲基-D-天冬氨酸受体（NMDAR）非竞争性拮抗剂，正在研发用于重度抑郁症（MDD）的辅助治疗。这项为期12个月的开放标签研究评估了埃斯美沙酮在符合标准且完成了3项双盲研究之一的MDD患者（）以及未参与过埃斯美沙酮研究的MDD患者（）中的安全性和有效性。通过不良事件、实验室指标、生命体征、心电图以及哥伦比亚自杀严重程度评定量表评估安全性。疗效评估采用抑郁、焦虑、睡眠、性功能、认知功能和生活质量等指标。安全人群包括接受了至少1剂研究药物的患者，全分析集（FAS）包括至少有1次基线后疗效评估的患者。安全人群包括624例患者；FAS包括586例患者（384例 和202例初治患者）；平均年龄为42.9（13.6）岁，平均基线蒙哥马利-阿斯伯格抑郁评定量表（MADRS10）为34.5（4.8）。最常见的与治疗相关的治疗中出现的不良事件为头痛（4.6%）、恶心（4.2%）和头晕（2.6%）。没有出现有意义的神经、心血管、代谢或性方面不良事件的信号，也没有自杀或自杀未遂的病例。对于FAS，在3、6、9和12个月时，MADRS₁₀相对于基线的平均（标准差）变化分别为-20.1（10.7）、-21.0（10.8）、-21.6（10.7）和-21.6（10.4）。对于初治人群，平均（标准差）分别为-19.9（10.0）、-19.9（10.4）、-20.1（10.2）和-22.5（9.7）。其他测试的疗效指标也出现了持续改善。埃斯美沙酮长期治疗安全且耐受性良好。埃斯美沙酮的抗抑郁疗效在12个月内持续存在。ClinicalTrials.gov标识符：NCT04855760。
