Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.
CNS Drugs. 2012 Mar 1;26(3):189-204. doi: 10.2165/11599770-000000000-00000.
Currently available drugs for unipolar major depressive disorder (MDD), which target monoaminergic systems, have a delayed onset of action and significant limitations in efficacy. Antidepressants with primary pharmacological targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. The glutamate system has been scrutinized as a target for antidepressant drug discovery. The purpose of this article is to review emerging literature on the potential rapid-onset antidepressant properties of the glutamate NMDA receptor antagonist ketamine, an established anaesthetic agent. The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression. The first generation of studies in patients with treatment-resistant depression (TRD) reported the safety and acute efficacy of a single subanaesthetic dose (0.5 mg/kg) of intravenous ketamine. A second generation of ketamine studies is focused on testing alternate routes of drug delivery, identifying methods to prevent relapse following resolution of depressive symptoms and understanding the neural basis for the putative antidepressant actions of ketamine. In addition to traditional depression rating endpoints, ongoing research is examining the impact of ketamine on neurocognition. Although the first clinical report in MDD was published in 2000, there is a paucity of adequately controlled double-blind trials, and limited clinical experience outside of research settings. Given the potential risks of ketamine, safety considerations will ultimately determine whether this old drug is successfully repositioned as a new therapy for TRD.
目前针对单相重性抑郁障碍（MDD）的药物，主要作用于单胺能系统，起效时间延迟，疗效存在显著局限性。作用于单胺系统以外的药理学靶点的抗抑郁药可能具有更快的起效作用，并具有更好的治疗效果。谷氨酸系统已被作为抗抑郁药物研发的靶点进行了深入研究。本文旨在综述新型抗抑郁药物氯胺酮（一种已被广泛应用的麻醉剂）的谷氨酸 NMDA 受体拮抗剂快速抗抑郁作用的相关文献。本文首先回顾了氯胺酮及其对映异构体 S-氯胺酮的药理学特性，然后介绍了其在慢性难治性疼痛疾病（通常与抑郁症共病）的临床应用实例。第一代治疗抵抗性抑郁症（TRD）患者的研究报告了静脉注射氯胺酮（0.5mg/kg）单次亚麻醉剂量的安全性和急性疗效。第二代氯胺酮研究专注于测试替代药物输送途径，确定在抑郁症状缓解后预防复发的方法，并了解氯胺酮潜在抗抑郁作用的神经基础。除了传统的抑郁评分终点外，正在进行的研究还在检测氯胺酮对神经认知的影响。尽管氯胺酮在 MDD 中的首次临床报告发表于 2000 年，但缺乏充分的对照双盲试验，且在研究环境之外的临床经验有限。鉴于氯胺酮的潜在风险，安全性考虑最终将决定这种旧药物是否能够成功重新定位为 TRD 的新疗法。
