Andrashko Veronika, Novak Tomas, Brunovsky Martin, Klirova Monika, Sos Peter, Horacek Jiri
Clinical Research of Mental Disorders, National Institute of Mental Health, Klecany, Czechia.
Third Faculty of Medicine, Charles University, Prague, Czechia.
Front Psychiatry. 2020 Aug 28;11:844. doi: 10.3389/fpsyt.2020.00844. eCollection 2020.
The rapid antidepressant effect of ketamine has become a breakthrough in the research and treatment of depression. Although predictive and modulating factors of the response to ketamine are broadly studied, little is known about optimal concurrent medication protocols. Concerning gamma-aminobutyric acid neurotransmission being a shared target for both ketamine and benzodiazepines (BZD), we evaluated the influence of BZD on the antidepressant effect of a single ketamine infusion in depressed patients. Data from 47 patients (27 females) with major depression (MADRS ≥ 20, ≥ 1 prior nonresponse to antidepressant treatment in current episode) who participated in two previous studies (EudraCT Number: 2009-010625-39 and 2013-000952-17) entered the analysis. All of the subjects were given an infusion of a subanesthetic dose of racemic ketamine (0.54 mg per kg) as an add-on medication to ongoing antidepressant treatment. Thirteen patients (28%) reached ≥ 50% reduction in MADRS within one week after ketamine administration. Nineteen (40%) patients took concomitant benzodiazepines on a daily basis. The doses of BZDs were significantly higher in nonresponders (p=0.007). ROC analysis distinguished responders from nonresponders by a criterion of >8mg of diazepam equivalent dose (DZ equivalent) with a sensitivity of 80% and a specificity of 85% (p<0.001). RM-ANOVA revealed a different time pattern of response to ketamine between the BZD+ (>8mg of DZ equivalent) and BZD- (≤8mg of DZ equivalent) groups, with a significantly worse outcome in BZD+ on day 3 (p=0.04) and day 7 (p=0.02). The results of the study indicate that concomitant benzodiazepine treatment in higher doses may attenuate ketamine's antidepressant effect. The pathophysiological, clinical and methodological implications of this finding should be considered in future research and ketamine treatment.
氯胺酮的快速抗抑郁作用已成为抑郁症研究和治疗的一项突破。尽管对氯胺酮反应的预测和调节因素已得到广泛研究，但对于最佳联合用药方案却知之甚少。鉴于γ-氨基丁酸神经传递是氯胺酮和苯二氮䓬类药物（BZD）的共同靶点，我们评估了BZD对抑郁症患者单次输注氯胺酮抗抑郁效果的影响。来自47例重度抑郁症患者（27例女性）的数据（蒙哥马利-阿斯伯格抑郁量表≥20，本次发作中既往至少有1次对抗抑郁治疗无反应）纳入分析，这些患者参与了之前的两项研究（欧盟临床试验注册号：2009-010625-39和2013-000952-17）。所有受试者均接受亚麻醉剂量的消旋氯胺酮（0.54mg/kg）输注，作为正在进行的抗抑郁治疗的附加药物。13例患者（28%）在氯胺酮给药后1周内蒙哥马利-阿斯伯格抑郁量表评分降低≥50%。19例（40%）患者每天服用苯二氮䓬类药物。无反应者的苯二氮䓬类药物剂量显著更高（p=0.007）。ROC分析以>8mg地西泮等效剂量（DZ等效）为标准区分反应者和无反应者，敏感性为80%，特异性为85%（p<0.001）。重复测量方差分析显示，BZD+组（>8mg DZ等效）和BZD-组（≤8mg DZ等效）对氯胺酮的反应时间模式不同，BZD+组在第3天（p=0.04）和第7天（p=0.02）的结果明显更差。研究结果表明，高剂量的苯二氮䓬类药物联合治疗可能会减弱氯胺酮的抗抑郁作用。这一发现的病理生理学、临床和方法学意义应在未来的研究和氯胺酮治疗中予以考虑。
