Ketamine for a Boost of Neural Plasticity: How, but Also When?
Ketamine for a Boost of Neural Plasticity: How, but Also When?
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DOI：
10.1016/j.biopsych.2021.03.014
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发表时间：
2021-06-01
影响因子：
10.6
通讯作者：
Kwan AC
中科院分区：
文献类型：
--
作者：
Wu H;Savalia NK;Kwan AC
重度抑郁症影响数百万人并导致虚弱症状。尽管传统的抗抑郁药已经可用并且通常是有益的，但它们具有许多局限性，包括起效缓慢以及对相当一部分患者的反应不足。最近，氯胺酮（主要是一种非竞争性 N-甲基-D-天冬氨酸受体 (NMDAR) 拮抗剂，除其他作用外）被批准作为治疗难治性抑郁症和自杀意念的新型疗法。这是一个令人兴奋的进展，因为氯胺酮可以快速缓解抑郁症状并具有持续效果。氯胺酮快速抗抑郁作用的生物学基础是什么？获得实证支持的一个框架是氯胺酮促进神经可塑性。具体来说，氯胺酮似乎可以促进内侧额叶皮层和海马等大脑区域的突触发生，对抗与慢性压力和抑郁相关的树突萎缩和突触损失。这一框架得到了多项研究的支持，这些研究表明单剂量氯胺酮可通过提高额叶皮层中树突棘的形成率来增加树突棘的数量 (1) (2, 3)。但仍不清楚可塑性何时以及如何增强。具体来说，氯胺酮何时会增强神经可塑性的倾向——到目前为止，研究只关注突触连接，这是事件链中的最后一个环节。此外，氯胺酮如何实现神经可塑性——分子和细胞因子的完整补充仍有待阐明。了解氯胺酮促进可塑性潜力的时间和机制将是利用速效抗抑郁药的关键。在本期《生物精神病学》中，Wu 等人 (4) 提供了令人信服的数据来定义氯胺酮可塑性潜力的时间窗口，同时揭示多巴胺作为该机制的关键组成部分。
Major depression affects millions of people and leads to debilitating symptoms. Although conventional antidepressants have been available and are often beneficial, they have a number of limitations including slow onset of action and inadequate response for a substantial fraction of patients. Recently, ketamine–primarily a noncompetitive N-Methyl-D-aspartic acid receptor (NMDAR) antagonist, among other actions–was approved as a novel treatment for treatment-resistant depression and suicidal ideation. This was an exciting development because ketamine can relieve depressive symptoms rapidly and with sustained effect. What is the biological basis for ketamine’s rapid antidepressant action? One framework gaining empirical support is that ketamine promotes neural plasticity. Specifically, ketamine appears to promote synaptogenesis in brain regions such as the medial frontal cortex and hippocampus, countering the dendritic atrophy and synapse loss associated with chronic stress and depression. This framework is supported by several studies that demonstrate a single dose of ketamine increases the number of dendritic spines (1) by elevating their formation rate in the frontal cortex (2, 3). Still unclear though, is when and how the plasticity is boosted. Specifically, when does ketamine enhance the propensity for neural plasticity–so far studies have looked only at synaptic connections, which is the final link in the chain of events. Moreover, how does ketamine enable neural plasticity–the full complement of molecular and cellular factors remains to be elucidated. Knowledge of both the timing and mechanisms underlying ketamine’s plasticity-promoting potential will be key to harnessing fast-acting antidepressants. In the current issue of Biological Psychiatry, Wu et al.(4) present compelling data to define a time window for ketamine’s plasticity potential, while uncovering dopamine as a crucial component of the mechanism.
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影响因子：
16.2
作者：
Kavalali ET;Monteggia LM
通讯作者：
Monteggia LM
影响因子：
10.6
作者：
Wu M;Minkowicz S;Dumrongprechachan V;Hamilton P;Kozorovitskiy Y
通讯作者：
Kozorovitskiy Y
DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
影响因子：
64.8
作者：
Kwon, Hyung-Bae;Sabatini, Bernardo L.
通讯作者：
Sabatini, Bernardo L.
影响因子：
16.6
作者：
Hare, Brendan D.;Shinohara, Ryota;Duman, Ronald S.
通讯作者：
Duman, Ronald S.