Departments of Psychiatry and Neurobiology, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA.
Neuropharmacology. 2012 Jan;62(1):35-41. doi: 10.1016/j.neuropharm.2011.08.044. Epub 2011 Sep 2.
Currently available medications have significant limitations, most notably low response rate and time lag for treatment response. Recent clinical studies have demonstrated that ketamine, an NMDA receptor antagonist produces a rapid antidepressant response (within hours) and is effective in treatment resistant depressed patients. Molecular and cellular studies in rodent models demonstrate that ketamine rapidly increases synaptogenesis, including increased density and function of spine synapses, in the prefrontal cortex (PFC). Ketamine also produces rapid antidepressant actions in behavioral models of depression, and reverses the deficits in synapse number and behavior resulting from chronic stress exposure. These effects of ketamine are accompanied by stimulation of the mammalian target of rapamycin (mTOR), and increased levels of synaptic proteins. Together these studies indicate that ketamine rapidly reverses the atrophy of spines in the PFC and thereby causes a functional reconnection of neurons that underlies the rapid behavioral responses. These findings identify new targets for rapid acting antidepressants that are safer than ketamine. This article is part of a Special Issue entitled 'Anxiety and Depression'.
目前可用的药物存在明显的局限性，最显著的是治疗反应的低应答率和时间滞后。最近的临床研究表明，NMDA 受体拮抗剂氯胺酮可产生快速抗抑郁反应（数小时内），并对治疗抵抗性抑郁患者有效。在啮齿动物模型中的分子和细胞研究表明，氯胺酮可迅速增加前额叶皮质（PFC）中的突触形成，包括增加棘突突触的密度和功能。氯胺酮也可在抑郁的行为模型中产生快速的抗抑郁作用，并逆转慢性应激暴露导致的突触数量和行为缺陷。氯胺酮的这些作用伴随着哺乳动物雷帕霉素靶蛋白（mTOR）的刺激和突触蛋白水平的增加。这些研究表明，氯胺酮可迅速逆转 PFC 中棘突的萎缩，从而导致神经元的功能重新连接，这是快速行为反应的基础。这些发现确定了比氯胺酮更安全的快速作用抗抑郁药的新靶点。本文是主题为“焦虑和抑郁”的特刊的一部分。
