Center for Neuroscience and Department of Psychiatry of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Mental Health Center, Zhejiang University, Hangzhou 310058, China.
Center for Neuroscience and Department of Psychiatry of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China; The Key Laboratory of Mental Disorder Management in Zhejiang Province, Brain Research Institute of Zhejiang University, Hangzhou 310003, China.
Trends Neurosci. 2019 Mar;42(3):179-191. doi: 10.1016/j.tins.2018.12.002.
The revolutionary discovery of the rapid antidepressant ketamine has been a milestone in psychiatry field in the last half century. Unlike conventional antidepressants that often take weeks to months to show efficacy, ketamine causes rapid antidepressant effects, emerging as early as within 1h after administration. However, how ketamine improves mood symptoms so quickly has remained elusive. Here, we first introduce the historical background of ketamine as a rapid antidepressant. We then discuss current hypotheses underlying ketamine's rapid antidepressant effects, with a focus on our latest discovery that ketamine silences NMDAR-dependent burst firing in the 'anti-reward center', the lateral habenula. While ketamine may act on many brain regions, we argue that its rapid antidepressant effects are critically dependent on ketamine's action in the lateral habenula, with this brain region acting as a primary site of action (or one among a few primary nodes). This molecular-, cellular-, and circuit-based mechanism advances our understanding of the etiology of depression and suggests a new conceptual framework for the rapid antidepressant effects of ketamine.
在过去的半个世纪中，快速抗抑郁药氯胺酮的革命性发现是精神病学领域的一个里程碑。与通常需要数周或数月才能显示疗效的传统抗抑郁药不同，氯胺酮能迅速产生抗抑郁作用，在给药后 1 小时内即可出现。然而，氯胺酮如何能如此迅速地改善情绪症状仍然难以捉摸。在这里，我们首先介绍氯胺酮作为快速抗抑郁药的历史背景。然后，我们讨论了目前氯胺酮快速抗抑郁作用的假设，重点介绍了我们的最新发现，即氯胺酮沉默了“抗奖赏中心”外侧缰核中 NMDA 受体依赖性爆发式放电。虽然氯胺酮可能作用于许多脑区，但我们认为，其快速抗抑郁作用主要取决于氯胺酮在外侧缰核中的作用，而该脑区是其主要作用部位（或少数主要节点之一）。这种基于分子、细胞和回路的机制增进了我们对抑郁症病因的理解，并为氯胺酮的快速抗抑郁作用提供了一个新的概念框架。
