Division of Systems Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH), New York State Psychiatric Institute (NYSPI), New York, NY, 10032, USA; Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New York, NY, 10032, USA.
Neuropharmacology. 2023 Feb 15;224:109345. doi: 10.1016/j.neuropharm.2022.109345. Epub 2022 Nov 23.
Exposure to stress is one of the greatest contributing factors to developing a psychiatric disorder, particularly in susceptible populations. Enhancing resilience to stress could be a powerful intervention to reduce the incidence of psychiatric disease and reveal insight into the pathophysiology of psychiatric disorders. (R,S)-ketamine and its metabolites have recently been shown to exert protective effects when administered before or after a variety of stressors and may be effective, tractable prophylactic compounds against psychiatric disease. Drug dosing, sex, age, and strain in preclinical rodent studies, significantly influence the prophylactic effects of (R,S)-ketamine and related compounds. Due to the broad neurobiological actions of (R,S)-ketamine, a variety of mechanisms have been proposed to contribute to the resilience-enhancing effects of this drug, including altering various transcription factors across the genome, enhancing inhibitory connections from the prefrontal cortex, and increasing synaptic plasticity in the hippocampus. Promisingly, select data have shown that (R,S)-ketamine may be an effective prophylactic against psychiatric disorders, such as postpartum depression (PPD). Overall, this review will highlight a brief history of the prophylactic effects of (R,S)-ketamine, the potential mechanisms underlying its protective actions, and possible future directions for translating prophylactic compounds to the clinic. This article is part of the Special Issue on 'Ketamine and its Metabolites'.
暴露于压力是导致精神障碍发展的最大因素之一，尤其是在易感人群中。增强对压力的适应能力可能是一种强大的干预措施，可以降低精神疾病的发病率，并深入了解精神障碍的病理生理学。（R，S）-氯胺酮及其代谢物最近已被证明在各种应激源之前或之后给药时具有保护作用，并且可能是针对精神疾病的有效、可处理的预防化合物。在临床前啮齿动物研究中，药物剂量、性别、年龄和品系极大地影响了（R，S）-氯胺酮和相关化合物的预防作用。由于（R，S）-氯胺酮具有广泛的神经生物学作用，因此已经提出了多种机制来解释这种药物增强适应能力的作用，包括改变基因组中的各种转录因子、增强来自前额叶皮层的抑制性连接以及增加海马体中的突触可塑性。有希望的是，一些选择的数据表明，（R，S）-氯胺酮可能是一种有效的预防产后抑郁症（PPD）等精神障碍的药物。总的来说，这篇综述将重点介绍（R，S）-氯胺酮的预防作用的简要历史、其保护作用的潜在机制以及将预防化合物转化为临床应用的可能方向。本文是“氯胺酮及其代谢物特刊”的一部分。
