BACKGROUND About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression. METHODS This Phase 3, double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (esketamine [56 or 84 mg] or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, esketamine 84 mg/antidepressant had to be significant for esketamine 56 mg/antidepressant to be formally tested. RESULTS Statistical significance was not achieved with esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares [LS] means difference [95% CI]: -3.2 [-6.88, 0.45]; 2-sided P value = .088). Although esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was -4.1 [-7.67, -0.49] (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache. CONCLUSIONS Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02417064.

中文翻译：

---

固定剂量的艾氯胺酮鼻喷雾剂与新型口服抗抑郁药联合治疗抗抑郁症的疗效和安全性：一项随机，双盲，主动对照研究（TRANSFORM-1）的结果。

背景技术尽管有多种抗抑郁药治疗，但约有三分之一的抑郁症患者无法缓解，并被认为具有抗药性抑郁症。方法这项3期，双盲，多中心研究纳入了在当前抑郁发作中患有中度至重度抑郁并且对≥2种抗抑郁药无反应的成年人。符合条件的患者（N = 346）被随机分配（1：1：1），每周两次鼻喷剂治疗（esketamine [56或84 mg]或安慰剂）加上新开始的，开放标签的口服抗抑郁药，每天服用4周。主要疗效终点是蒙哥马利-阿斯伯格抑郁量表总评分从基线到第28天的变化，由盲人，远程评估者进行。根据预定义的统计测试顺序，对于正式测试的esketamine 56 mg /抗抑郁药，esketamine 84 mg /抗抑郁药必须有效。结果与抗抑郁药/安慰剂相比，艾司他敏84 mg /抗抑郁药未达到统计学意义（最小二乘法[LS]表示差异[95％CI]：-3.2 [-6.88，0.45]； 2面P值= 0.088）。尽管无法正式测试esketamine 56 mg /抗抑郁药，但LS均值差为-4.1 [-7.67，-0.49]（名义两面P值= .027）。报道的氯胺酮/抗抑郁药最常见（> 20％）不良事件是恶心，解离，头晕，眩晕和头痛。结论未达到主要终点的统计学显着性。但是，乙草胺/抗抑郁药组的治疗效果（蒙哥马利-阿斯伯格抑郁量表）超过了已批准的抗抑郁药与安慰剂的临床意义。乙草胺/抗抑郁药组之间的安全性相似，并且未发现与剂量相关的新安全性问题。这项研究为依卡他命鼻喷剂作为一种新的，速效抗抑郁药用于抗药性抑郁症患者的安全性和有效性提供了支持性证据。试验注册ClinicalTrials.gov标识符：NCT02417064。速效抗抑郁药，用于难治性抑郁症患者。试验注册ClinicalTrials.gov标识符：NCT02417064。速效抗抑郁药，用于难治性抑郁症患者。试验注册ClinicalTrials.gov标识符：NCT02417064。