The antidepressant efficacy and safety of seltorexant monotherapy in major depressive disorder (MDD) was investigated in a placebo-controlled, placebo lead-in, randomized, double-blind, phase 1b study. Participants were randomized to receive seltorexant (20 mg or 40 mg) or placebo. The treatment effect was assessed by changes in the Hamilton Rating Scale for Depression-17 item (HDRS₁₇) from treatment-period baseline to week 5 in lead-in placebo non-responders (“enriched” intent-to-treat analysis set). As a secondary outcome, the effect of seltorexant on HDRS₁₇ was assessed in patients with and without subjective insomnia. Seltorexant’s effects on polysomnography, serum cortisol, and cortisol waking response were also measured. In total, 128 participants were enrolled, including 86 in the enriched sample (lead-in placebo non-responders). The mean changes from baseline (SD) in HDRS₁₇ score at week 5 differed significantly across arms: −7.0 (5.04) for seltorexant 20 mg, −5.5 (4.34) for seltorexant 40 mg, and −4.4 (3.67) for placebo (p = 0.0456), which was attributable to the difference between the 20 mg and placebo arms (p = 0.0049). Improvement in depression severity at week 5 for seltorexant 20 mg was greater in patients with higher baseline insomnia severity (nominal p = 0.0059). The treatment benefit in the 20 mg arm remained significant when HDRS scores were adjusted by removing the sleep items (nominal p = 0.0289). The mean HDRS₁₇ change versus placebo was numerically larger in the 20 mg than the 40 mg arm, consistent with data from a previous study in which seltorexant was administered adjunctively to conventional antidepressants. In secondary analyses, the waking cortisol response decreased in the 20 mg arm but not the 40 mg or placebo arms, and while total sleep increased more in the 40 mg arm, this arm also showed reduced REM onset latency and increased stage N1 sleep, which were not evident in the 20 mg arm. These biomarker data suggest mechanistic hypotheses that may account for the apparent curvilinear dose-response relationship of seltorexant. Trial Registration: ClinicalTrials.gov, NCT03374475.

在一项安慰剂对照、安慰剂导入、随机、双盲、1b 期研究中研究了 seltorexant 单药治疗重度抑郁症 （MDD） 的抗抑郁疗效和安全性。参与者被随机分配接受 seltorexant（20 毫克或 40 毫克）或安慰剂。通过导入安慰剂无反应者（“富集”意向治疗分析集）的抑郁 17 项目汉密尔顿评定量表 （HDRS₁₇） 从治疗期基线到第 5 周的变化来评估治疗效果。作为次要结局，在有和没有主观失眠的患者中评估 seltorexant 对 HDRS₁₇ 的影响。还测量了 Seltorexant 对多导睡眠图、血清皮质醇和皮质醇清醒反应的影响。总共招募了 128 名参与者，其中 86 名是富集样本（导入安慰剂无反应者）。第 5 周时 HDRS₁₇ 评分相对于基线 （SD） 的平均变化在各组之间存在显著差异：seltorexant 20 mg 为 -7.0 （5.04），seltorexant 40 mg 为 -5.5 （4.34），安慰剂为 -4.4 （3.67） （p = 0.0456），这归因于 20 mg 和安慰剂组之间的差异 （p = 0.0049）。在基线失眠严重程度较高的患者中，seltorexant 20 mg 在第 5 周时抑郁严重程度的改善更大 （名义 p = 0.0059）。当通过去除睡眠项目来调整 HDRS 评分时，20 mg 组的治疗益处仍然显着 （名义 p = 0.0289）。与安慰剂相比，20 mg 组的平均 HDRS₁₇ 变化在数值上大于 40 mg 组，这与之前一项研究的数据一致，其中 seltorexant 辅助常规抗抑郁药。 在二次分析中，20 mg 组的清醒皮质醇反应降低，但 40 mg 或安慰剂组没有降低，虽然 40 mg 组的总睡眠增加更多，但该组还显示 REM 起效潜伏期降低和 N1 期睡眠增加，这在 20 mg 组中并不明显。这些生物标志物数据表明了可能解释 seltorexant 明显的曲线剂量-反应关系的机制假设。试用注册：ClinicalTrials.gov、NCT03374475。