Kohtala S, Alitalo O, Rosenholm M, Rozov S, Rantamäki T
Laboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Finland; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Finland.
Laboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Finland; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Finland.
Pharmacol Ther. 2021 May;221:107741. doi: 10.1016/j.pharmthera.2020.107741. Epub 2020 Nov 12.
Several studies have demonstrated the effectiveness of ketamine in rapidly alleviating depression and suicidal ideation. Intense research efforts have been undertaken to expose the precise mechanism underlying the antidepressant action of ketamine; however, the translation of findings into new clinical treatments has been slow. This translational gap is partially explained by a lack of understanding of the function of time and circadian timing in the complex neurobiology around ketamine. Indeed, the acute pharmacological effects of a single ketamine treatment last for only a few hours, whereas the antidepressant effects peak at around 24 hours and are sustained for the following few days. Numerous studies have investigated the acute and long-lasting neurobiological changes induced by ketamine; however, the most dramatic and fundamental change that the brain undergoes each day is rarely taken into consideration. Here, we explore the link between sleep and circadian regulation and rapid-acting antidepressant effects and summarize how diverse phenomena associated with ketamine's antidepressant actions - such as cortical excitation, synaptogenesis, and involved molecular determinants - are intimately connected with the neurobiology of wake, sleep, and circadian rhythms. We review several recently proposed hypotheses about rapid antidepressant actions, which focus on sleep or circadian regulation, and discuss their implications for ongoing research. Considering these aspects may be the last piece of the puzzle necessary to gain a more comprehensive understanding of the effects of rapid-acting antidepressants on the brain.
多项研究已证明氯胺酮在快速缓解抑郁和自杀意念方面的有效性。人们已展开深入研究以揭示氯胺酮抗抑郁作用的精确机制；然而，研究成果转化为新的临床治疗方法的进程却很缓慢。这种转化差距部分可归因于对氯胺酮周围复杂神经生物学中时间和昼夜节律功能的理解不足。事实上，单次氯胺酮治疗的急性药理作用仅持续数小时，而抗抑郁作用在约24小时达到峰值，并在接下来的几天持续存在。众多研究已调查了氯胺酮诱导的急性和长期神经生物学变化；然而，大脑每天经历的最显著和最根本的变化却很少被考虑在内。在此，我们探讨睡眠与昼夜节律调节和快速起效抗抑郁作用之间的联系，并总结与氯胺酮抗抑郁作用相关的各种现象——如皮质兴奋、突触形成和相关分子决定因素——如何与觉醒、睡眠和昼夜节律的神经生物学紧密相连。我们回顾了最近提出的几个关于快速抗抑郁作用的假说，这些假说聚焦于睡眠或昼夜节律调节，并讨论它们对正在进行的研究的意义。考虑这些方面可能是更全面理解快速起效抗抑郁药对大脑影响所需的最后一块拼图。
