Importance Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy, negatively affecting both mother and child. Objective To demonstrate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid receptor-positive allosteric modulator, in PPD. Design, Setting, and Participants This phase 3, double-blind, randomized, outpatient, placebo-controlled clinical trial was conducted between January 2017 and December 2018 in 27 enrolling US sites. Participant were women aged 18 to 45 years, 6 months or fewer post partum, with PPD (major depressive episode beginning third trimester or ≤4 weeks postdelivery), and baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 26 or higher. Analysis was intention to treat and began December 2018 and ended March 2019. Interventions Randomization 1:1 to placebo:zuranolone, 30 mg, administered orally each evening for 2 weeks. Main Outcomes and Measures Primary end point was change from baseline in HAMD-17 score for zuranolone vs placebo at day 15. Secondary end points included changes from baseline in HAMD-17 total score at other time points, HAMD-17 response (≥50% score reduction) and remission (score ≤7) rates, Montgomery-Åsberg Depression Rating Scale score, and Hamilton Rating Scale for Anxiety score. Safety was assessed by adverse events and clinical assessments. Results Of 153 randomized patients, the efficacy set comprised 150 patients (mean [SD] age, 28.3 [5.4] years), and 148 (98.7%) completed treatment. A total of 76 patients were randomized to placebo, and 77 were randomized to zuranolone, 30 mg. Zuranolone demonstrated significant day 15 HAMD-17 score improvements from baseline vs placebo (-17.8 vs -13.6; difference, -4.2; 95% CI, -6.9 to -1.5; P = .003). Sustained differences in HAMD-17 scores favoring zuranolone were observed from day 3 (difference, -2.7; 95% CI, -5.1 to -0.3; P = .03) through day 45 (difference, -4.1; 95% CI, -6.7 to -1.4; P = .003). Sustained differences at day 15 favoring zuranolone were observed in HAMD-17 response (odds ratio, 2.63; 95% CI, 1.34-5.16; P = .005), HAMD-17 score remission (odds ratio, 2.53; 95% CI, 1.24-5.17; P = .01), change from baseline for Montgomery-Åsberg Depression Rating Scale score (difference, -4.6; 95% CI, -8.3 to -0.8; P = .02), and Hamilton Rating Scale for Anxiety score (difference, -3.9; 95% CI, -6.7 to -1.1; P = .006). One patient per group experienced a serious adverse event (confusional state in the zuranolone group and pancreatitis in the placebo group). One patient in the zuranolone group discontinued because of an adverse event vs none for placebo. Conclusions and Relevance In this randomized clinical trial, zuranolone improved the core symptoms of depression as measured by HAMD-17 scores in women with PPD and was generally well tolerated, supporting further development of zuranolone in the treatment of PPD. Trial Registration ClinicalTrials.gov Identifier: NCT02978326.

中文翻译：

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Zuranolone 与安慰剂对产后抑郁症的影响：一项随机临床试验。

重要性 产后抑郁症 (PPD) 是怀孕期间和怀孕后最常见的医疗并发症之一，对母亲和孩子都有负面影响。目的 验证神经活性类固醇 γ-氨基丁酸受体阳性变构调节剂 zuranolone 在治疗 PPD 中的有效性和安全性。设计、设置和参与者 这项 3 期、双盲、随机、门诊、安慰剂对照临床试验于 2017 年 1 月至 2018 年 12 月在美国 27 个招募地点进行。参与者是年龄 18 至 45 岁、产后 6 个月或更短时间、患有 PPD（妊娠晚期或产后 ≤ 4 周开始的严重抑郁发作）且基线 17 项汉密尔顿抑郁评定量表 (HAMD-17) 得分为 26 分的女性或更高。分析以意向治疗为目的，于 2018 年 12 月开始，于 2019 年 3 月结束。 干预措施 随机分组至安慰剂：zuranolone，30 mg，每晚口服给药，持续 2 周。主要结果和措施 主要终点是第 15 天时 zuranolone 与安慰剂相比 HAMD-17 评分相对于基线的变化。次要终点包括其他时间点 HAMD-17 总分相对于基线的变化、HAMD-17 反应（≥50%）评分减少）和缓解（评分≤7）率、蒙哥马利-阿斯伯格抑郁评定量表评分和汉密尔顿焦虑评定量表评分。通过不良事件和临床评估来评估安全性。结果 在 153 名随机患者中，疗效组包括 150 名患者（平均 [SD] 年龄，28.3 [5.4] 岁），其中 148 名 (98.7%) 完成了治疗。共有 76 名患者被随机分配至安慰剂组，77 名患者被随机分配至 zuranolone 30 mg 组。与安慰剂相比，Zuranolone 在第 15 天的 HAMD-17 评分较基线显着改善（-17.8 与 -13.6；差异，-4.2；95% CI，-6.9 至 -1.5；P = .003）。从第 3 天（差异，-2.7；95% CI，-5.1 至 -0.3；P = .03）到第 45 天（差异，-4.1；95% CI，-6.7）观察到 HAMD-17 评分存在持续差异，有利于 zuranolone至 -1.4；P = .003)。第 15 天时，在 HAMD-17 反应（比值比，2.63；95% CI，1.34-5.16；P = 0.005）、HAMD-17 评分缓解（比值比，2.53；95% CI，1.24）中观察到有利于 zuranolone 的持续差异。 -5.17；P = .01），蒙哥马利-阿斯伯格抑郁评定量表评分相对于基线的变化（差异，-4.6；95% CI，-8.3至-0.8；P = .02），以及汉密尔顿焦虑评定量表评分（差异，-3.9；95% CI，-6.7 至 -1.1；P = .006）。每组有一名患者经历了严重的不良事件（zuranolone 组的混乱状态和安慰剂组的胰腺炎）。zuranolone 组中的一名患者因不良事件而停药，而安慰剂组则没有。结论和相关性 在这项随机临床试验中，zuranolone 改善了 PPD 女性的抑郁症核心症状（通过 HAMD-17 评分衡量），并且总体耐受性良好，支持 zuranolone 在 PPD 治疗中的进一步开发。试验注册 ClinicalTrials.gov 标识符：