The discovery of the antidepressant effects of ketamine has opened a breakthrough opportunity to develop a truly novel class of safe, effective, and rapid-acting antidepressants (RAADs). In addition, the rapid and robust biological and behavioral effects of ketamine offered a unique opportunity to utilize the drug as a tool to thoroughly investigate the neurobiology of stress and depression in animals, and to develop sensitive and reproducible biomarkers in humans. The ketamine literature over the past two decades has considerably enriched our understanding of the mechanisms underlying chronic stress, depression, and RAADs. However, considering the complexity of the pharmacokinetics and in vivo pharmacodynamics of ketamine, several questions remain unanswered and, at times, even answered questions continue to be considered controversial or at least not fully understood. The current perspective paper summarizes our understanding of the neurobiology of depression, and the mechanisms of action of ketamine and other RAADs. The review focuses on the role of glutamate neurotransmission – reviewing the history of the “glutamate inhibition” and “glutamate activation” hypotheses, proposing a synaptic connectivity model of chronic stress pathology, and describing the mechanism of action of ketamine. It will also summarize the clinical efficacy findings of putative RAADs, present relevant human biomarker findings, and discuss current challenges and future directions.

氯胺酮抗抑郁作用的发现为开发一类真正安全、有效、速效的抗抑郁药 (RAAD) 提供了突破性机会。此外，氯胺酮快速而强大的生物学和行为效应为利用该药物作为工具来彻底研究动物应激和抑郁的神经生物学以及开发人类敏感且可重复的生物标志物提供了独特的机会。过去二十年的氯胺酮文献极大地丰富了我们对慢性压力、抑郁和 RAAD 潜在机制的理解。然而，考虑到氯胺酮药代动力学和体内药效学的复杂性，有几个问题仍未得到解答，有时，甚至回答的问题仍然被认为是有争议的或至少没有被完全理解。当前的观点论文总结了我们对抑郁症神经生物学以及氯胺酮和其他 RAAD 作用机制的理解。该综述重点关注谷氨酸神经传递的作用——回顾“谷氨酸抑制”和“谷氨酸激活”假说的历史，提出慢性应激病理学的突触连接模型，并描述氯胺酮的作用机制。它还将总结假定的 RAAD 的临床疗效结果，介绍相关的人类生物标志物研究结果，并讨论当前的挑战和未来的方向。