Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1)
Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1)
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DOI：
10.1093/ijnp/pyz039
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发表时间：
2019-10-01
影响因子：
4.8
通讯作者：
Singh, Jaskaran B.
中科院分区：
文献类型：
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作者：
Fedgchin, Maggie;Trivedi, Madhukar;Singh, Jaskaran B.
背景资料：约三分之一的抑郁症患者未能达到缓解，尽管与多种抗抑郁药治疗，并被认为是有治疗抵抗性depress.Methods：这3期，双盲，多中心研究招募了成人中度至重度抑郁症和无反应>= 2抗抑郁药在当前的抑郁发作。合格患者（N = 346）随机（1：1：1）接受每周两次鼻用喷雾剂治疗（艾司氯胺酮[56或84 mg]或安慰剂）加一种新启用的开放标签口服抗抑郁药，每日服用一次，持续4周。主要疗效终点为蒙哥马利-阿斯伯格抑郁评定量表总分自基线至第28天的变化，由设盲的远程评定者进行。根据预定义的统计检验序列，艾司氯胺酮84 mg/抗抑郁药对于要进行正式检验的艾司氯胺酮56 mg/抗抑郁药必须具有显著性。结果如下：与抗抑郁药/安慰剂相比，艾司氯胺酮84 mg/抗抑郁药未达到统计学显著性（最小二乘[LS]均值差异[95% CI]：-3.2 [-6.88，0.45];双侧P值= 0.088）。虽然无法正式检验艾司氯胺酮56 mg/抗抑郁药，但LS均值差异为-4.1 [-7.67，-0.49]（标称双侧P值= 0.027）。艾司氯胺酮/抗抑郁药报告的最常见（>20%）不良事件为恶心、分离、头晕、眩晕和头痛。结论：主要终点未达到统计学显著性;然而，艾司氯胺酮/抗抑郁药组的治疗效果（蒙哥马利-阿斯伯格抑郁评定量表）超过了获批抗抑郁药与安慰剂相比被认为具有临床意义的效果。艾司氯胺酮/抗抑郁药组之间的安全性相似，未发现新的剂量相关安全性问题。本研究为艾司氯胺酮鼻用喷雾剂作为一种新型速效抗抑郁药治疗难治性抑郁症患者的安全性和疗效提供了支持性证据。
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.