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Neurobiology of the Rapid Acting Antidepressant Effects of Ketamine: Impact and Opportunities
Biological Psychiatry ( IF 10.6 ) Pub Date : 2020-12-01 , DOI: 10.1016/j.biopsych.2020.12.006
Ryota Shinohara 1 , George K Aghajanian 1 , Chadi G Abdallah 2
Affiliation  

ABSTRACT The discovery of the rapid-acting antidepressant effects of ketamine have ( 1 ) led to a paradigm shift in our perception of what is possible in treating severe depression, ( 2 ) spurred a wave of basic, translation, and clinical research, and ( 3 ) provided an unprecedented investigational tool to conduct longitudinal mechanistic studies that may capture behavioral changes as complex as clinical remission and relapse within hours and days of treatment. Unfortunately, these advances did not yet translate into clinical biomarkers or novel treatments, beyond ketamine. In contrast to slow-acting antidepressants where targeting the monoaminergic receptors identified several efficacious drugs with comparable mechanisms, the focus on the receptor targets of ketamine has failed in several clinical trials over the past decade. Thus, it is becoming increasingly crucial that we concentrate our effort on the downstream molecular mechanisms of ketamine and their effects on the brain circuitry and networks. In the current special issue, honoring the legacy of our mentor, friend and colleague Ron Duman, we provide a historical note on the discovery of ketamine and its putative mechanisms. We then detail the molecular and circuits effect of ketamine based on preclinical findings, followed by a summary of the impact of this work on our understanding of chronic stress pathology across psychiatric disorders, with particular emphasis on the role of synaptic connectivity and its brain network effects in the pathology and treatment of clinical depression.

中文翻译:

氯胺酮快速抗抑郁作用的神经生物学:影响和机遇

摘要:氯胺酮的速效抗抑郁作用的发现(1)导致我们对治疗严重抑郁症的可能性的看法发生了范式转变,(2)激发了基础、转化和临床研究的浪潮,以及( 3) 提供了一种史无前例的研究工具来进行纵向机制研究,这些研究可能会在治疗的数小时和数天内捕捉到与临床缓解和复发一样复杂的行为变化。不幸的是,这些进展尚未转化为氯胺酮以外的临床生物标志物或新疗法。与靶向单胺能受体的慢效抗抑郁药确定了几种具有相似机制的有效药物相比,在过去十年中,对氯胺酮受体靶标的关注在几项临床试验中都失败了。因此,我们将精力集中在氯胺酮的下游分子机制及其对大脑回路和网络的影响变得越来越重要。在本期特刊中,为了纪念我们的导师、朋友和同事 Ron Duman 的遗产,我们提供了关于氯胺酮发现及其假定机制的历史记录。然后,我们根据临床前发现详细介绍了氯胺酮的分子和回路效应,然后总结了这项工作对我们对精神疾病慢性应激病理学的理解的影响,特别强调了突触连接的作用及其大脑网络效应在临床抑郁症的病理学和治疗方面。
更新日期:2020-12-01
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