OBJECTIVE About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray. METHODS This was a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures. RESULTS Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=-4.0, SE=1.69, 95% CI=-7.31, -0.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points. The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event. Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing. CONCLUSIONS Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability. Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression.

中文翻译：

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灵活剂量的艾氯胺酮鼻喷雾剂与新启动的口服抗抑郁药联合治疗耐药性抑郁症的疗效和安全性：一项随机双盲主动对照研究。

目的尽管有多种抗抑郁药治疗，约有三分之一的抑郁症患者仍未实现缓解。这项研究比较了将抗药性抑郁症患者从无效的抗抑郁药改为灵活剂量的艾氯胺酮鼻喷剂加新开始的抗抑郁药或新开始的抗抑郁药（活性比较剂）加安慰剂鼻喷剂之间切换的有效性和安全性。方法这是在39个门诊转诊中心进行的3期，双盲，主动控制，多中心研究。这项研究招募了患有中度至重度非精神病性抑郁症且在当前发作中对至少两种抗抑郁药无反应的病史的成年人，其中一种抗抑郁药经过前瞻性评估。确认无反应者被随机分配使用艾氯胺酮鼻喷雾剂（每周两次两次56或84 mg）以及抗抑郁药或抗抑郁药和安慰剂鼻喷雾剂治疗。主要疗效终点是蒙哥马利-Åsberg抑郁评分量表（MADRS）评分从基线到第28天的变化，是通过使用重复测量的混合效应模型来评估的。结果在筛选的435例患者中，有227例接受了随机分组，其中197例完成了为期28天的双盲治疗阶段。在第28天，使用氯胺酮加抗抑郁药的MADRS评分的变化显着大于使用抗抑郁药加安慰剂的MADRS评分（最小二乘均数= -4.0，SE = 1.69，95％CI = -7.31，-0.64）。同样，在较早的时间点，艾司他敏加抗抑郁药组的临床意义得到改善。在五氯胺酮加抗抑郁药组中观察到的五个最常见的不良事件（解离，恶心，眩晕，消化不良和头晕）均比在抗抑郁药加安慰剂组中观察到的频率更高。由于不良事件，在各个治疗组中分别有7％和0.9％的患者停用研究药物。依他命胺加抗抑郁药的不良反应通常在给药后不久出现，并在给药后1.5小时内消除。结论当前对于治疗性抑郁症的治疗选择在功效和患者可接受性方面有相当大的局限性。依沙酮胺有望通过其新的作用机制和抗抑郁药效的快速发作来解决这一人群中尚未满足的医疗需求。