依他佐辛鼻喷剂固定剂量联合新型抗抑郁药治疗难治性抑郁症的疗效和安全性：一项随机、双盲、阳性对照研究（TRANSFORM-1）的结果。

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).

机构信息

Janssen Research and Development, Department of Neuroscience, Titusville, New Jersey.

University of Texas Southwestern Medical Center, Department of Psychiatry, Dallas, Texas.

出版信息

Int J Neuropsychopharmacol. 2019 Oct 1;22(10):616-630. doi: 10.1093/ijnp/pyz039.

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.

背景

尽管许多患者使用多种抗抑郁药进行治疗，但仍有大约三分之一的患者未能缓解抑郁症状，被认为患有治疗抵抗性抑郁症。

方法

这是一项 3 期、双盲、多中心研究，共纳入了当前抑郁发作期间使用≥2 种抗抑郁药但无应答的中度至重度抑郁症成人患者。符合条件的患者（n=346）按 1:1:1 的比例随机分为每周 2 次鼻腔喷雾治疗（依他佐辛[56 或 84 mg]或安慰剂）加新开始的、每日 1 次的开放性标签口服抗抑郁药治疗 4 周。主要疗效终点为基线至第 28 天的蒙哥马利-艾斯伯格抑郁评定量表总分，由盲法、远程评估者进行评估。基于预先规定的统计检验顺序，只有当依他佐辛 84 mg/抗抑郁药与抗抑郁药/安慰剂相比具有统计学意义时，才对依他佐辛 56 mg/抗抑郁药进行正式检验。

结果

与抗抑郁药/安慰剂相比，依他佐辛 84 mg/抗抑郁药未达到统计学意义（最小二乘[LS]均值差值[95%CI]：-3.2[-6.88，0.45]；双侧 P 值=0.088）。虽然不能对依他佐辛 56 mg/抗抑郁药进行正式检验，但 LS 均值差值为-4.1[-7.67，-0.49]（名义双侧 P 值=0.027）。依他佐辛/抗抑郁药组报告的最常见（>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意义；然而，依他佐辛/抗抑郁药组的治疗效果（蒙哥马利-艾斯伯格抑郁评定量表）均超过了已批准的抗抑郁药与安慰剂相比被认为具有临床意义的效果。依他佐辛/抗抑郁药组之间的安全性相似，未发现新的与剂量相关的安全性问题。本研究为依他佐辛鼻喷雾剂作为一种新的、快速起效的治疗难治性抑郁症的抗抑郁药的安全性和疗效提供了支持性证据。