Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers
Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers
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DOI：
10.1177/2045125320916657
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发表时间：
2020-05-01
影响因子：
4.2
通讯作者：
Dursun, Serdar M.
中科院分区：
文献类型：
--
作者：
Matveychuk, Dmitriy;Thomas, Rejish K.;Dursun, Serdar M.
氯胺酮是一种在20世纪60年代作为麻醉剂引入并仍用于此目的的药物，在过去二十年中作为一种新兴的治疗重度抑郁症的药物引起了人们的极大兴趣。随着越来越多的证据表明其对难治性抑郁症的疗效及其潜在的抗自杀作用，已经进行了大量的研究来阐明氯胺酮对大脑的影响。特别令人感兴趣和治疗潜力的是氯胺酮能够在给药后几小时内发挥快速抗抑郁特性。这与传统抗抑郁药观察到的延迟效应形成鲜明对比，传统抗抑郁药通常需要数周的治疗才能产生临床反应。此外，氯胺酮似乎具有独特的作用机制，涉及通过作用于N-甲基-D-天冬氨酸（NMDA）和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的谷氨酸调节，以及脑源性神经营养因子（BDNF）和雷帕霉素（mTOR）信号传导途径的机制靶点的下游激活，以增强突触可塑性。本文简要概述了氯胺酮的药理学/药代动力学、毒理学、抑郁症临床试验的现状、假设的抗抑郁机制和用于预测氯胺酮治疗效果和/或监测氯胺酮治疗结果的潜在生物标志物（生化、炎症、代谢、神经影像学睡眠相关和认知）。
Ketamine, a drug introduced in the 1960s as an anesthetic agent and still used for that purpose, has garnered marked interest over the past two decades as an emerging treatment for major depressive disorder. With increasing evidence of its efficacy in treatment-resistant depression and its potential anti-suicidal action, a great deal of investigation has been conducted on elucidating ketamine's effects on the brain. Of particular interest and therapeutic potential is the ability of ketamine to exert rapid antidepressant properties as early as several hours after administration. This is in stark contrast to the delayed effects observed with traditional antidepressants, often requiring several weeks of therapy for a clinical response. Furthermore, ketamine appears to have a unique mechanism of action involving glutamate modulation via actions at the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as downstream activation of brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) signaling pathways to potentiate synaptic plasticity. This paper provides a brief overview of ketamine with regard to pharmacology/pharmacokinetics, toxicology, the current state of clinical trials on depression, postulated antidepressant mechanisms and potential biomarkers (biochemical, inflammatory, metabolic, neuroimaging sleep-related and cognitive) for predicting response to and/or monitoring of therapeutic outcome with ketamine.