Background Seltorexant, a selective antagonist of human orexin-2 receptors, demonstrated antidepressant effects in a previous exploratory study in patients with major depressive disorder (MDD). Methods To replicate and extend this observation, a double-blind, adaptive dose-finding study was performed in patients with MDD who had an inadequate response to 1–3 selective serotonin/serotonin-norepinephrine reuptake inhibitors in the current episode. Patients were randomized (2:1:1) to placebo or seltorexant (20 mg or 40 mg) once-daily, administered adjunctively to the antidepressant the patient had been receiving at screening. After an interim analysis (6 weeks post-randomization of 160th patient), newly recruited patients randomly received (3:3:1) placebo or seltorexant 10 mg or 20 mg; the 40-mg dose was no longer assigned. Patients were stratified by baseline Insomnia Severity Index (ISI) scores (ISI ≥ 15 vs < 15). The primary endpoint was change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6. Results Mixed-Model for Repeated Measures analysis showed a greater improvement in MADRS total score in the seltorexant 20-mg group vs placebo at weeks 3 and 6; least-square means difference (90% CI): −4.5 (−6.96; −2.07), P = .003; and −3.1 (−6.13; −0.16), P = .083, respectively. The improvement in MADRS score at week 6 for seltorexant 20 mg was greater in patients with baseline ISI ≥ 15 vs those with ISI < 15; least-square means difference (90% CI) vs placebo: −4.9 (−8.98; −0.80) and −0.7 (−5.16; 3.76), respectively. The most common (≥5%) adverse events with seltorexant were somnolence, headache, and nausea. Conclusions A clinically meaningful reduction of depressive symptoms was observed for seltorexant 20 mg. In the subset of patients with sleep disturbance (ISI ≥ 15), a larger treatment difference between seltorexant 20 mg and placebo was observed, warranting further investigation. No new safety signal was identified. Registration ClinicalTrials.gov Identifier: NCT03227224 Previous presentation Poster presented at 58th Annual Meeting of American College of Neuropsychopharmacology (ACNP), December 8–11, 2019, Orlando, FL.

中文翻译：

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Seltorexant 作为重度抑郁症辅助治疗的疗效和安全性：2b 期、随机、安慰剂对照、适应性剂量发现研究

背景 Seltorexant 是人类食欲素 2 受体的选择性拮抗剂，在先前对重度抑郁症 (MDD) 患者的探索性研究中显示出抗抑郁作用。方法 为了复制和扩展这一观察结果，对当前发作中对 1-3 种选择性 5-羟色胺/5-羟色胺-去甲肾上腺素再摄取抑制剂反应不足的 MDD 患者进行了一项双盲、适应性剂量发现研究。患者被随机分配（2:1:1）至安慰剂或 seltorexant（20 毫克或 40 毫克），每天一次，与患者在筛选时接受的抗抑郁药辅助给药。经过中期分析（第 160 名患者随机分组后 6 周），新招募的患者随机接受（3:3:1）安慰剂或 seltorexant 10 mg 或 20 mg；不再分配 40 mg 剂量。患者按基线失眠严重程度指数（ISI）评分（ISI ≥ 15 vs < 15）进行分层。主要终点是第 6 周时基线蒙哥马利-埃斯伯格抑郁评定量表 (MADRS) 总分的变化。结果 重复测量混合模型分析显示，在第 3 周，seltorexant 20 毫克组与安慰剂组相比，MADRS 总分有更大的改善6；最小二乘均值差 (90% CI)：-4.5 (-6.96；-2.07)，P = .003；和 -3.1（-6.13；-0.16），P = .083，分别。基线 ISI ≥ 15 的患者与 ISI < 15 的患者相比，使用 seltorexant 20 mg 在第 6 周时 MADRS 评分的改善更大。15; 最小二乘均值差 (90% CI) 与安慰剂：分别为 -4.9 (-8.98; -0.80) 和 -0.7 (-5.16; 3.76)。seltorexant 最常见（≥5%）的不良事件是嗜睡、头痛和恶心。结论 20 mg seltorexant 观察到抑郁症状有临床意义的减轻。在睡眠障碍患者（ISI ≥ 15）的亚组中，观察到 seltorexant 20 mg 和安慰剂之间的治疗差异较大，需要进一步研究。没有发现新的安全信号。注册 ClinicalTrials.gov 标识符：NCT03227224 先前的展示海报于 2019 年 12 月 8 日至 11 日在佛罗里达州奥兰多举行的美国神经精神药理学会 (ACNP) 第 58 届年会上发表。