Janssen Research and Development, Beerse, Belgium (Popova); Janssen Research and Development, Titusville, N.J. (Daly, Lane, Lim, Hough, Manji, Drevets); the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas (Trivedi); Janssen Research and Development, Spring House, Pa. (Cooper); Janssen Canada, Toronto (Mazzucco); the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia (Thase); the Department of Psychiatry, University of Alabama School of Medicine, Birmingham (Shelton); Clínica Universidad de Navarra, Pamplona, Spain (Molero); Institute of Neuroscience, University of Barcelona, Hospital Clinic, IDIBAPS, CIBERSAM, Barcelona, Spain (Vieta); Charité Universitätsmedizin Berlin, Berlin (Bajbouj); Janssen Research and Development, San Diego (Singh).
Am J Psychiatry. 2019 Jun 1;176(6):428-438. doi: 10.1176/appi.ajp.2019.19020172. Epub 2019 May 21.
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.
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.
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.
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.
尽管使用多种抗抑郁药治疗，仍有约三分之一的抑郁症患者未达到缓解。本研究比较了将治疗抵抗性抑郁症患者从无效的抗抑郁药转换为灵活剂量的依他佐辛鼻喷雾剂加新起始的抗抑郁药或新起始的抗抑郁药（活性对照）加安慰剂鼻喷雾剂的疗效和安全性。
这是一项在 39 家门诊转介中心进行的 3 期、双盲、活性对照、多中心研究。该研究纳入了中度至重度非精神病性抑郁症且当前发作中至少对两种抗抑郁药无反应的成年人，一种抗抑郁药进行前瞻性评估。确诊的无应答者被随机分配接受依他佐辛鼻喷雾剂（56 或 84mg，每周两次）和抗抑郁药或抗抑郁药加安慰剂鼻喷雾剂治疗。主要疗效终点为基线至第 28 天的蒙哥马利-Åsberg 抑郁评定量表（MADRS）评分变化，采用重复测量混合效应模型进行评估。
在 435 名筛选患者中，227 名进行了随机分组，197 名完成了 28 天的双盲治疗阶段。依他佐辛加抗抑郁药治疗的 MADRS 评分变化在第 28 天显著大于抗抑郁药加安慰剂（最小二乘均值差异=-4.0，SE=1.69，95%CI=-7.31，-0.64）；同样，依他佐辛加抗抑郁药组在较早时间点观察到了更有临床意义的改善。依他佐辛加抗抑郁药组最常见的五种不良反应（分离、恶心、眩晕、味觉障碍和头晕）均比抗抑郁药加安慰剂组更频繁；分别有 7%和 0.9%的患者因不良反应而停止研究药物治疗。依他佐辛加抗抑郁药组的不良反应通常在给药后不久出现，并在给药后 1.5 小时内缓解。
目前治疗抵抗性抑郁症的治疗选择在疗效和患者可接受性方面存在很大的局限性。依他佐辛通过其新颖的作用机制和快速抗抑郁疗效有望满足这一人群的未满足的医疗需求。该研究支持依他佐辛鼻喷雾剂作为治疗抵抗性抑郁症患者的快速起效抗抑郁药的疗效和安全性。
