Zarate Carlos A, Singh Jaskaran B, Carlson Paul J, Brutsche Nancy E, Ameli Rezvan, Luckenbaugh David A, Charney Dennis S, Manji Husseini K
Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, MD 20892, USA.
Arch Gen Psychiatry. 2006 Aug;63(8):856-64. doi: 10.1001/archpsyc.63.8.856.
Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders.
To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression.
A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005.
Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects with DSM-IV major depression (treatment resistant).
After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale.
Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.
Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.
现有的重度抑郁症治疗方法起效滞后数周，导致相当高的发病率。探索能在数天内迅速起效且疗效持久的药理学策略将对患者护理产生巨大影响。越来越多的证据表明谷氨酸能系统在情绪障碍的病理生理学和治疗中发挥作用。
确定在重度抑郁症患者中使用N-甲基-D-天冬氨酸受体拮抗剂是否能实现快速抗抑郁效果。
2004年11月至2005年9月进行的一项随机、安慰剂对照、双盲交叉研究。
国立精神卫生研究所情绪障碍研究室。患者18名符合《精神疾病诊断与统计手册》第四版（DSM-IV）标准的重度抑郁症（难治性）患者。
经过2周的停药期后，在2个相隔一周的测试日，受试者分别接受静脉输注盐酸氯胺酮（0.5mg/kg）或安慰剂。在基线以及输注后40、80、110和230分钟以及1、2、3和7天对受试者进行评分。主要结局指标主要疗效指标21项汉密尔顿抑郁量表得分的变化。
与接受安慰剂的受试者相比，接受氯胺酮的受试者在注射后110分钟内抑郁症状有显著改善，且在接下来的一周内一直保持显著。用药差异的效应量在24小时后非常大（d = 1.46 [95%置信区间，0.91 - 2.01]），1周后为中等至大（d = 0.68 [95%置信区间，0.13 - 1.23]）。在接受氯胺酮治疗的17名受试者中，71%在氯胺酮输注后的第二天达到反应标准，29%达到缓解标准。35%的受试者至少维持反应1周。
单次静脉注射N-甲基-D-天冬氨酸拮抗剂可产生强大而快速的抗抑郁效果；起效发生在输注后2小时内，并在1周内持续显著。
