Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression A Randomized Clinical Trial
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression A Randomized Clinical Trial
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DOI：
10.1001/jamapsychiatry.2017.3739
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发表时间：
2018-02-01
期刊：
影响因子：
25.8
通讯作者：
Drevets, Wayne C.
中科院分区：
文献类型：
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作者：
Daly, Ella J.;Singh, Jaskaran B.;Drevets, Wayne C.
重要性大约三分之一的重性抑郁症（MDD）患者对现有的抗抑郁药没有反应。目的评估鼻内盐酸艾司氯胺酮治疗难治性抑郁症（TRD）患者的疗效、安全性和剂量反应。安慰剂对照研究于2014年1月28日至2015年9月25日在多个门诊转诊中心进行。本研究包括4个阶段：（1）筛选，（2）双盲治疗（第1-15天），包括两个为期1周的阶段，（3）可选的开放标签治疗（第15-74天）和（4）治疗后随访（8周）。筛选了126例经DSM-IV-TR诊断为MDD且有2种或2种以上抗抑郁药（即TRD）疗效不佳病史的成人，67例接受随机分组，60例完成了两个双盲期。干预在第1阶段，参与者被随机（3：1：1：1）分配至安慰剂组（n = 33）、艾司氯胺酮28 mg组（n = 11）、56 mg组（n = 11）或84 mg组（n = 12），每周两次。在第2阶段，28名安慰剂治疗的中度至重度症状的参与者被重新随机分配（1：1：1：1）至4个治疗组之一;轻度症状的参与者继续接受安慰剂治疗。参与者在研究期间继续他们现有的抗抑郁治疗。在开放期，给药频率从每周两次减少到每周一次，然后减少到每2周一次。主要结果和指标主要疗效终点是从基线到第8天的变化（每个阶段）在蒙哥马利-艾斯伯格抑郁量表（MADRS）中的总分。（38名女性，平均[SD]年龄，44.7 [10.0]岁）被纳入疗效和安全性分析。变化MADRS总分（与安慰剂相比的最小二乘均值[SE]差异）所有3个艾司氯胺酮组（两个阶段合并）均上级优于安慰剂组（艾司氯胺酮28 mg：-4.2 [2.09]，P = 0.02; 56 mg：-6.3 [2.07]，P = 0.001; 84 mg：-9.0 [2.13]，P <0.001），具有显著的剂量效应关系（P <0.001）。尽管在开放期降低了给药频率，但抑郁症状的改善似乎持续（-7.2 [1.84]）。在双盲期，56例接受艾司氯胺酮治疗的受试者中有3例（5%）发生导致研究中止的不良事件，而安慰剂组无受试者，开放标签期57例受试者中有1例（2%）发生导致研究中止的不良事件（晕厥、头痛、分离综合征和异位妊娠各1起事件）。结论和相关性在迄今为止鼻内艾司氯胺酮治疗TRD的第一项临床研究中，抗抑郁作用起效快，且与剂量相关。反应似乎持续超过2个月，给药频率较低。结果支持更大规模试验的进一步研究。
IMPORTANCE Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants.OBJECTIVE To assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD).DESIGN, SETTING, AND PARTICIPANTS This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings.INTERVENTIONS In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks.MAIN OUTCOMES AND MEASURES The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Asberg Depression Rating Scale (MADRS) total score.RESULTS Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: -4.2 [2.09], P = .02; 56 mg: -6.3 [2.07], P = .001; 84 mg: -9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (-7.2 [1.84]) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy).CONCLUSIONS AND RELEVANCE In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials.