Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei, China; Anhui Psychiatric Center, Anhui Medical University, Hefei, China.
Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei, China; Anhui Psychiatric Center, Anhui Medical University, Hefei, China.
Neuropharmacology. 2023 Jan 1;222:109305. doi: 10.1016/j.neuropharm.2022.109305. Epub 2022 Oct 30.
Depression is a well-known serious mental illness, and the onset of treatment using traditional antidepressants is frequently delayed by several weeks. Moreover, numerous patients with depression fail to respond to therapy. One major breakthrough in antidepressant therapy is that subanesthetic ketamine doses can rapidly alleviate depressive symptoms within hours of administering a single dose, even in treatment-resistant patients. However, specific mechanisms through which ketamine exerts its antidepressant effects remain elusive, leading to concerns regarding its rapid and long-lasting antidepressant effects. N-methyl-d-aspartate receptor (NMDAR) antagonists like ketamine are reportedly associated with serious side effects, such as dissociative symptoms, cognitive impairment, and abuse potential, limiting the large-scale clinical use of ketamine as an antidepressant. Herein, we reviewed the pharmacological properties of ketamine and the mechanisms of action underlying the rapid antidepressant efficacy, including the disinhibition hypothesis and synaptogenesis, along with common downstream effector pathways such as enhanced brain-derived neurotrophic factor and tropomyosin-related kinase B signaling, activation of the mechanistic target of rapamycin complex 1 and transforming growth factor β1. We focused on evidence supporting the relevance of these potential mechanisms of ketamine and its metabolites in mediating the clinical efficacy of the drug. Given its reported antidepressant efficacy in preclinical studies and limited undesirable adverse effects, (R)-ketamine may be a safer, more controllable, rapid antidepressant. Overall, understanding the potential mechanisms of action of ketamine and its metabolites in combination with pharmacology may help develop a new generation of rapid antidepressants that maximize antidepressant effects while avoiding unfavorable adverse effects. This article is part of the Special Issue on 'Ketamine and its Metabolites'.
抑郁症是一种众所周知的严重精神疾病，传统抗抑郁药的治疗通常需要数周时间才能开始。此外，许多抑郁症患者对治疗没有反应。抗抑郁治疗的一个主要突破是，亚麻醉剂量的氯胺酮可以在单次给药后数小时内迅速缓解抑郁症状，即使是在治疗抵抗的患者中也是如此。然而，氯胺酮发挥抗抑郁作用的确切机制仍不清楚，这导致人们对其快速和持久的抗抑郁作用产生了担忧。据报道，氯胺酮等 N-甲基-D-天冬氨酸受体 (NMDAR) 拮抗剂与严重的副作用有关，例如分离症状、认知障碍和滥用潜力，这限制了氯胺酮作为抗抑郁药的大规模临床应用。在此，我们回顾了氯胺酮的药理学特性以及其快速抗抑郁疗效的作用机制，包括抑制假说和突触发生，以及常见的下游效应途径，如增强脑源性神经营养因子和原肌球蛋白相关激酶 B 信号转导、机械靶蛋白雷帕霉素复合物 1 和转化生长因子β1 的激活。我们重点介绍了支持这些潜在机制在介导氯胺酮及其代谢物的药物临床疗效中的相关性的证据。鉴于其在临床前研究中显示出的抗抑郁疗效和有限的不良副作用，(R)-氯胺酮可能是一种更安全、更可控、快速的抗抑郁药。总的来说，了解氯胺酮及其代谢物的潜在作用机制与药理学相结合可能有助于开发新一代快速抗抑郁药，最大限度地发挥抗抑郁作用，同时避免不利的不良影响。本文是“氯胺酮及其代谢物”特刊的一部分。
