Ketamine and the next generation of antidepressants with a rapid onset of action.
Ketamine and the next generation of antidepressants with a rapid onset of action.
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DOI：
10.1016/j.pharmthera.2009.02.010
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发表时间：
2009-08
影响因子：
13.5
通讯作者：
Zarate, Carlos A., Jr.
中科院分区：
文献类型：
--
作者：
Machado-Vieira, Rodrigo;Salvadore, Giacomo;DiazGranados, Nancy;Zarate, Carlos A., Jr.
现有的重度抑郁症（MDD）治疗通常需要数周至数月才能达到其抗抑郁作用，而且相当多的患者即使在治疗数月后也没有足够的改善。此外，在标准抗抑郁药治疗的第一个月，自杀企图的风险增加是一个主要的公共卫生问题。因此，迫切需要改进的治疗方法，可以发挥其抗抑郁作用的几个小时或几天内，他们的管理，是一个更好地理解与这些快速抗抑郁作用的推测机制。在这种情况下，N-甲基-D-天冬氨酸（NMDA）拮抗剂氯胺酮在给药后几小时内一直显示出抗抑郁作用。这使得它成为一个有价值的研究工具，以确定反应的生物标志物，以开发下一代快速作用的抗抑郁药。在这篇综述中，我们描述了临床，电生理，生物化学和成像相关的相关目标，在研究与氯胺酮相关的抗抑郁反应，以及它们对开发新型，快速作用的抗抑郁药的影响。我们还审查了证据表明，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）的NMDA吞吐量可能代表了氯胺酮的快速抗抑郁作用的收敛机制。总体而言，理解这项工作的分子基础将可能导致最终开发出MDD的改进疗法。
Existing treatments for major depressive disorder (MDD) usually take weeks to months to achieve their antidepressant effects, and a significant number of patients do not have adequate improvement even after months of treatment. In addition, increased risk of suicide attempts is a major public health concern during the first month of standard antidepressant therapy. Thus, improved therapeutics that can exert their antidepressant effects within hours or a few days of their administration are urgently needed, as is a better understanding of the presumed mechanisms associated with these rapid antidepressant effects. In this context, the N-methyl-D-aspartate (NMDA) antagonist ketamine has consistently shown antidepressant effects within a few hours of its administration. This makes it a valuable research tool to identify biomarkers of response in order to develop the next generation of fast-acting antidepressants. In this review, we describe clinical, electrophysiological, biochemical, and imaging correlates as relevant targets in the study of the antidepressant response associated with ketamine, and their implications for the development of novel, fast-acting antidepressants. We also review evidence that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to NMDA throughput may represent a convergent mechanism for the rapid antidepressant actions of ketamine. Overall, understanding the molecular basis of this work will likely lead to the ultimate development of improved therapeutics for MDD.
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