Murrough James W, Wade Elizabeth, Sayed Sehrish, Ahle Gabriella, Kiraly Drew D, Welch Alison, Collins Katherine A, Soleimani Laili, Iosifescu Dan V, Charney Dennis S
Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
J Affect Disord. 2017 Aug 15;218:277-283. doi: 10.1016/j.jad.2017.04.072. Epub 2017 Apr 29.
At least one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD), defined as lack of response to two or more adequate antidepressant trials. For these patients, novel antidepressant treatments are urgently needed.
The current study is a phase IIa open label clinical trial examining the efficacy and tolerability of a combination of dextromethorphan (DM) and the CYP2D6 enzyme inhibitor quinidine (Q) in patients with TRD. Dextromethorphan acts as an antagonist at the glutamate N-methyl-d-aspartate (NMDA) receptor, in addition to other pharmacodynamics properties that include activity at sigma-1 receptors. Twenty patients with unipolar TRD who completed informed consent and met all eligibility criteria we enrolled in an open-label study of DM/Q up to 45/10mg by mouth administered every 12h over the course of a 10-week period, and constitute the intention to treat (ITT) sample. Six patients discontinued prior to study completion.
There was no treatment-emergent suicidal ideation, psychotomimetic or dissociative symptoms. Montgomery-Asberg Depression Rating Scale (MADRS) score was reduced from baseline to the 10-week primary outcome (mean change: -13.0±11.5, t=5.0, p<0.001), as was QIDS-SR score (mean change: -5.9±6.6, t=4.0, p<0.001). The response and remission rates in the ITT sample were 45% and 35%, respectively.
Open-label, proof-of-concept design.
Herein we report acceptable tolerability and preliminary efficacy of DM/Q up to 45/10mg administered every 12h in patients with TRD. Future larger placebo controlled randomized trials in this population are warranted.
至少三分之一的重度抑郁症（MDD）患者患有难治性抑郁症（TRD），难治性抑郁症定义为对两种或更多种充分的抗抑郁药物试验均无反应。对于这些患者，迫切需要新型抗抑郁治疗方法。
本研究是一项IIa期开放标签临床试验，旨在研究右美沙芬（DM）与CYP2D6酶抑制剂奎尼丁（Q）联合用药对难治性抑郁症患者的疗效和耐受性。右美沙芬除了具有其他药效学特性（包括对σ-1受体的活性）外，还作为谷氨酸N-甲基-D-天冬氨酸（NMDA）受体的拮抗剂。20名单相难治性抑郁症患者完成了知情同意并符合所有入选标准，他们参加了一项DM/Q的开放标签研究，在10周的时间里，每12小时口服一次，剂量高达45/10mg，构成意向性治疗（ITT）样本。6名患者在研究完成前退出。
未出现治疗中出现的自杀观念、类精神病或分离症状。蒙哥马利-艾斯伯格抑郁评定量表（MADRS）评分从基线降至10周主要结局（平均变化：-13.0±11.5，t=5.0，p<0.001）；快速抑郁症状自评量表（QIDS-SR）评分也有下降（平均变化：-5.9±6.6，t=4.0，p<0.001）。ITT样本中的缓解率和治愈率分别为45%和35%。
开放标签的概念验证设计。
在此，我们报告了难治性抑郁症患者每12小时口服高达45/10mg的DM/Q具有可接受的耐受性和初步疗效。未来有必要在该人群中进行更大规模的安慰剂对照随机试验。
