Xu Ying, Hackett Maree, Carter Gregory, Loo Colleen, Gálvez Verònica, Glozier Nick, Glue Paul, Lapidus Kyle, McGirr Alexander, Somogyi Andrew A, Mitchell Philip B, Rodgers Anthony
The George Institute for Global Health, The University of Sydney, Sydney, Australia (Drs Xu, Hackett, and Rodgers); Centre for Translational Neuroscience and Mental Health, University of Newcastle, Australia (Dr Carter); School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia (Drs Loo, Gálvez, and Mitchell); Brain and Mind Research Institute, University of Sydney, Australia (Dr Glozier); Department of Psychiatry, University of Otago, New Zealand (Dr Glue); Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY (Dr Lapidus); Department of Psychiatry, University of British Colombia, Canada (Dr McGirr); Discipline of Pharmacology, Faculty of Health Sciences, The University of Adelaide, Adelaide, Australia (Dr Somogyi).
Int J Neuropsychopharmacol. 2016 Apr 20;19(4). doi: 10.1093/ijnp/pyv124. Print 2016 Apr.
Several recent trials indicate low-dose ketamine produces rapid antidepressant effects. However, uncertainty remains in several areas: dose response, consistency across patient groups, effects on suicidality, and possible biases arising from crossover trials.
A systematic search was conducted for relevant randomized trials in Medline, Embase, and PsycINFO databases up to August 2014. The primary endpoints were change in depression scale scores at days 1, 3 and 7, remission, response, suicidality, safety, and tolerability. Data were independently abstracted by 2 reviewers. Where possible, unpublished data were obtained on treatment effects in the first period of crossover trials.
Nine trials were identified, including 201 patients (52% female, mean age 46 years). Six trials assessed low-dose ketamine (0.5 mg/kg i.v.) and 3 tested very low-dose ketamine (one trial assessed 50 mg intra-nasal spray, another assessed 0.1-0.4 mg/kg i.v., and another assessed 0.1-0.5 mg/kg i.v., intramuscular, or s.c.). At day 3, the reduction in depression severity score was less marked in the very low-dose trials (P homogeneity <.05) and among bipolar patients. In analyses excluding the second period of crossover trials, response rates at day 7 were increased with ketamine (relative risk 3.4, 95% CI 1.6-7.1, P=.001), as were remission rates (relative risk 2.6, CI 1.2-5.7, P=.02). The absolute benefits were large, with day 7 remission rates of 24% vs 6% (P=.02). Seven trials provided unpublished data on suicidality item scores, which were reduced on days 1 and 3 (both P<.01) but not day 7.
Low-dose ketamine appears more effective than very low dose. There is substantial heterogeneity in clinical response, with remission among one-fifth of patients at 1 week but most others having benefits that are less durable. Larger, longer term parallel group trials are needed to determine if efficacy can be extended and to further assess safety.
近期的多项试验表明，低剂量氯胺酮可产生快速抗抑郁作用。然而，在几个方面仍存在不确定性：剂量反应、不同患者群体间的一致性、对自杀倾向的影响以及交叉试验可能产生的偏差。
截至2014年8月，在Medline、Embase和PsycINFO数据库中对相关随机试验进行了系统检索。主要终点为第1、3和7天抑郁量表评分的变化、缓解情况、反应、自杀倾向、安全性和耐受性。数据由2名审阅者独立提取。在可能的情况下，获取了交叉试验第一阶段治疗效果的未发表数据。
共识别出9项试验，包括201名患者（52%为女性，平均年龄46岁）。6项试验评估了低剂量氯胺酮（静脉注射0.5mg/kg），3项试验测试了极低剂量氯胺酮（一项试验评估50mg鼻内喷雾，另一项评估静脉注射0.1 - 0.4mg/kg，另一项评估静脉注射、肌肉注射或皮下注射0.1 - 0.5mg/kg）。在第3天，极低剂量试验（P同质性<.05）和双相情感障碍患者中，抑郁严重程度评分的降低不太明显。在排除交叉试验第二阶段的分析中，氯胺酮治疗使第7天的反应率增加（相对风险3.4，95%CI 1.6 - 7.1，P =.001），缓解率也增加（相对风险2.6，CI 1.2 - 5.7，P =.02）。绝对获益很大，第7天的缓解率分别为24%和6%（P =.02）。7项试验提供了关于自杀倾向项目评分的未发表数据，在第1天和第3天评分降低（均P<.01），但第7天未降低。
低剂量氯胺酮似乎比极低剂量更有效。临床反应存在很大异质性，五分之一的患者在1周时缓解，但大多数其他患者的获益不太持久。需要进行更大规模、更长期的平行组试验来确定疗效是否可以延长，并进一步评估安全性。
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