Ketamine and its metabolites: Potential as novel treatments for depression
Ketamine and its metabolites: Potential as novel treatments for depression
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DOI：
10.1016/j.neuropharm.2022.109305
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发表时间：
2022-10
影响因子：
4.7
通讯作者：
Kai Zhang;Yitan Yao;K. Hashimoto
中科院分区：
文献类型：
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作者：
Kai Zhang;Yitan Yao;K. Hashimoto
抑郁症是一种众所周知的严重精神疾病，使用传统抗抑郁药的治疗通常会延迟数周。此外，许多抑郁症患者对治疗没有反应。抗抑郁治疗的一个重大突破是亚麻醉氯胺酮剂量可以在单次给药后数小时内迅速缓解抑郁症状，即使是在治疗抵抗性患者中。然而，氯胺酮发挥其抗抑郁作用的具体机制仍不清楚，导致其快速和持久的抗抑郁作用受到关注。据报道，N-甲基-d-天冬氨酸受体（NMDAR）拮抗剂如氯胺酮与严重的副作用相关，如分离症状，认知障碍和滥用潜力，限制了氯胺酮作为抗抑郁药的大规模临床使用。本文综述了氯胺酮的药理学特性及其快速抗抑郁作用的机制，包括去抑制假说和突触发生，沿着共同的下游效应通路，如增强脑源性神经营养因子和原肌球蛋白相关激酶B信号通路，激活雷帕霉素复合物1和转化生长因子β1的机制靶点。我们重点关注支持氯胺酮及其代谢物的这些潜在机制在介导药物临床疗效中的相关性的证据。鉴于其在临床前研究中报告的抗抑郁疗效和有限的不良反应，（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，结合药理学，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，同时避免不利的副作用。
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’.