Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy.
Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy; Division of Psychiatry, University College London, 149 Tottenham Ct Rd, London W1T 7NF, United Kingdom.
Neurosci Lett. 2024 May 14;831:137791. doi: 10.1016/j.neulet.2024.137791. Epub 2024 Apr 24.
The antidepressant effects of ketamine and esketamine are well-documented. Nonetheless, most of the underlying molecular mechanisms have to be uncovered yet. In the last decade, metabolomics has emerged as a useful means to investigate the metabolic phenotype associated with depression as well as changes induced by antidepressant treatments. This mini-review aims at summarizing the main findings from preclinical and clinical studies that used metabolomics to investigate the metabolic effects of subanesthetic, antidepressant doses of ketamine and esketamine and their relationship with clinical response. Both animal and human studies report alterations in several metabolic pathways - including the tricarboxylic acid cycle, glycolysis, the pentose phosphate pathway, lipid metabolism, amino acid metabolism, the kynurenine pathway, and the urea cycle - following the administration of ketamine or its enantiomers. Although more research is needed to clarify commonalities and differences in molecular mechanisms of action between the racemic compound and its enantiomers, these findings comprehensively support an influence of ketamine and esketamine on mitochondrial and cellular energy production, membrane homeostasis, neurotransmission, and signaling. Metabolomics may thus represent a promising strategy to clarify molecular mechanisms underlying treatment-resistant depression and related markers of clinical response to ketamine and esketamine. This body of preclinical and clinical evidence, if further substantiated, has the potential to guide clinicians towards personalized approaches, contributing to new paradigms in the clinical management of depression.
氯胺酮和艾司氯胺酮的抗抑郁作用已有充分的文献记载。然而，其大多数潜在的分子机制尚待揭示。在过去的十年中，代谢组学已成为一种有用的手段，可以研究与抑郁症相关的代谢表型以及抗抑郁治疗引起的变化。本篇综述旨在总结使用代谢组学研究亚麻醉剂量的氯胺酮和艾司氯胺酮的代谢作用及其与临床反应关系的临床前和临床研究的主要发现。动物和人类研究都报告了在给予氯胺酮或其对映异构体后，几种代谢途径发生改变，包括三羧酸循环、糖酵解、磷酸戊糖途径、脂质代谢、氨基酸代谢、犬尿氨酸途径和尿素循环。尽管需要更多的研究来阐明外消旋化合物及其对映异构体之间作用机制的异同，但这些发现全面支持氯胺酮和艾司氯胺酮对线粒体和细胞能量产生、膜稳态、神经递质传递和信号转导的影响。因此，代谢组学可能是阐明氯胺酮和艾司氯胺酮治疗抵抗性抑郁症的分子机制以及相关临床反应标志物的有前途的策略。如果这些临床前和临床证据得到进一步证实，它们有可能指导临床医生采用个性化的方法，为抑郁症的临床管理带来新的模式。
