Kang Melody J Y, Hawken Emily, Vazquez Gustavo Hector
Center of Neuroscience Studies (CNS), Queen's University, Kingston, ON, Canada.
Department of Psychiatry, Queen's University School of Medicine, Kingston, ON, Canada.
Front Psychiatry. 2022 Apr 25;13:860882. doi: 10.3389/fpsyt.2022.860882. eCollection 2022.
The mechanism of action underlying ketamine's rapid antidepressant effects in patients with depression, both suffering from major depressive disorder (MDD) and bipolar disorder (BD), including treatment resistant depression (TRD), remains unclear. Of the many speculated routes that ketamine may act through, restoring deficits in neuroplasticity may be the most parsimonious mechanism in both human patients and preclinical models of depression. Here, we conducted a literature search using PubMed for any reports of ketamine inducing neuroplasticity relevant to depression, to identify cellular and molecular events, relevant to neuroplasticity, immediately observed with rapid mood improvements in humans or antidepressant-like effects in animals. After screening reports using our inclusion/exclusion criteria, 139 publications with data from cell cultures, animal models, and patients with BD or MDD were included (registered on PROSPERO, ID: CRD42019123346). We found accumulating evidence to support that ketamine induces an increase in molecules involved in modulating neuroplasticity, and that these changes are paired with rapid antidepressant effects. Molecules or complexes of high interest include glutamate, AMPA receptors (AMPAR), mTOR, BDNF/TrkB, VGF, eEF2K, p70S6K, GSK-3, IGF2, Erk, and microRNAs. In summary, these studies suggest a robust relationship between improvements in mood, and ketamine-induced increases in molecular neuroplasticity, particularly regarding intracellular signaling molecules.
氯胺酮对患有重度抑郁症（MDD）和双相情感障碍（BD）包括难治性抑郁症（TRD）的患者具有快速抗抑郁作用，其作用机制尚不清楚。在氯胺酮可能起作用的众多推测途径中，恢复神经可塑性缺陷可能是人类患者和抑郁症临床前模型中最简洁的机制。在此，我们使用PubMed进行文献检索，查找有关氯胺酮诱导与抑郁症相关的神经可塑性的任何报告，以确定与神经可塑性相关的细胞和分子事件，这些事件在人类情绪快速改善或动物出现抗抑郁样效应时可立即观察到。在使用我们的纳入/排除标准筛选报告后，纳入了139篇来自细胞培养、动物模型以及BD或MDD患者的数据的出版物（已在PROSPERO注册，ID：CRD42019123346）。我们发现越来越多的证据支持氯胺酮会诱导参与调节神经可塑性的分子增加，并且这些变化与快速抗抑郁作用相关。高度关注的分子或复合物包括谷氨酸、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）、哺乳动物雷帕霉素靶蛋白（mTOR）、脑源性神经营养因子/酪氨酸激酶B（BDNF/TrkB）、非活性涎腺生长因子（VGF）、真核翻译延伸因子2激酶（eEF2K）、核糖体蛋白S6激酶（p70S6K）、糖原合成酶激酶-3（GSK-3）、胰岛素样生长因子2（IGF2）、细胞外信号调节激酶（Erk）和微小核糖核酸（microRNAs）。总之，这些研究表明情绪改善与氯胺酮诱导的分子神经可塑性增加之间存在密切关系，特别是关于细胞内信号分子。
