For decades, symptoms of depression have been treated primarily with medications that directly target the monoaminergic brain systems, which typically take weeks to exert measurable effects and months to exert remission of symptoms. Low, subanesthetic doses of ( R,S)-ketamine (ketamine) result in the rapid improvement of core depressive symptoms, including mood, anhedonia, and suicidal ideation, occurring within hours following a single administration, with relief from symptoms typically lasting up to a week. The discovery of these actions of ketamine has resulted in a reconceptualization of how depression could be more effectively treated in the future. In this review, we discuss clinical data pertaining to ketamine and other rapid-acting antidepressant drugs, as well as the current state of pharmacological knowledge regarding their mechanism of action. Additionally, we discuss the neurobiological circuits that are engaged by this drug class and that may be targeted by a future generation of medications, for example, hydroxynorketamine; metabotropic glutamate receptor 2/3 antagonists; and N-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and γ-aminobutyric acid receptor modulators.

中文翻译：

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速效抗抑郁药的分子药理学和神经生物学。


几十年来，抑郁症症状主要通过直接针对单胺能大脑系统的药物来治疗，通常需要数周才能发挥可测量的效果，几个月才能缓解症状。低、亚麻醉剂量的（R,S）-氯胺酮（氯胺酮）可快速改善核心抑郁症状，包括情绪、快感缺乏和自杀意念，这些症状在单次给药后数小时内发生，症状通常持续长达一周。氯胺酮这些作用的发现使人们重新认识了未来如何更有效地治疗抑郁症。在这篇综述中，我们讨论了有关氯胺酮和其他速效抗抑郁药物的临床数据，以及有关其作用机制的药理学知识的现状。此外，我们还讨论了此类药物所涉及的神经生物学回路，并且可能是下一代药物的目标，例如羟基去甲氯胺酮；代谢型谷氨酸受体2/3拮抗剂； N-甲基-d-天冬氨酸、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸和γ-氨基丁酸受体调节剂。