Ketamine-Induced Glutamatergic Mechanisms of Sleep and Wakefulness: Insights for Developing Novel Treatments for Disturbed Sleep and Mood.
Ketamine-Induced Glutamatergic Mechanisms of Sleep and Wakefulness: Insights for Developing Novel Treatments for Disturbed Sleep and Mood.
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DOI：
10.1007/164_2017_51
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发表时间：
2019
影响因子：
--
通讯作者：
Zarate CA
中科院分区：
文献类型：
--
作者：
Duncan WC Jr;Ballard ED;Zarate CA
氯胺酮是一种具有快速抗抑郁作用的药物，对慢波睡眠（SWS）有良好的作用，是研究新型治疗方法中涉及的睡眠-觉醒机制的有用干预措施。该药物迅速（在几分钟到几小时内）减轻重度抑郁症（MDD）或双相情感障碍（BD）患者的抑郁症状，包括那些难治性抑郁症患者。氯胺酮治疗提高了前额叶皮层的细胞外谷氨酸。谷氨酸，反过来，在氯胺酮引发的分子级联中起着关键作用，作为近端元件，增加突触强度和可塑性，最终导致情绪迅速改善。在MDD中，氯胺酮的快速抗抑郁反应与觉醒减少以及总睡眠、SWS、慢波活动（SWA）和快速眼动（REM）睡眠增加有关。氯胺酮也会增加脑源性神经营养因子（BDNF）的水平。在MDD患者中，氯胺酮的临床反应可通过低基线δ睡眠比率预测，这是一种衡量夜间SWS产生不足的指标。值得注意的是，MDD和BD之间存在重要差异，可能与诊断或情绪稳定剂的影响有关。与其对生物钟相关分子的作用一致，氯胺酮改变了MDD快速反应者与无反应者的昼夜节律活动模式的时间和幅度，表明其影响情绪依赖性中枢神经回路。睡眠稳态和生物钟基因之间的分子相互作用可能介导氯胺酮及其活性代谢物的临床反应的快速和持久的元素。
Ketamine, a drug with rapid antidepressant effects and well-described effects on slow wave sleep (SWS), is a useful intervention for investigating sleep–wake mechanisms involved in novel therapeutics. The drug rapidly (within minutes to hours) reduces depressive symptoms in individuals with major depressive disorder (MDD) or bipolar disorder (BD), including those with treatment-resistant depression. Ketamine treatment elevates extracellular glutamate in the prefrontal cortex. Glutamate, in turn, plays a critical role as a proximal element in a ketamine-initiated molecular cascade that increases synaptic strength and plasticity, which ultimately results in rapidly improved mood. In MDD, rapid antidepressant response to ketamine is related to decreased waking as well as increased total sleep, SWS, slow wave activity (SWA), and rapid eye movement (REM) sleep. Ketamine also increases brain-derived neurotrophic factor (BDNF) levels. In individuals with MDD, clinical response to ketamine is predicted by low baseline delta sleep ratio, a measure of deficient early night production of SWS. Notably, there are important differences between MDD and BD that may be related to the effects of diagnosis or of mood stabilizers. Consistent with its effects on clock-associated molecules, ketamine alters the timing and amplitude of circadian activity patterns in rapid responders versus non-responders with MDD, suggesting that it affects mood-dependent central neural circuits. Molecular interactions between sleep homeostasis and clock genes may mediate the rapid and durable elements of clinical response to ketamine and its active metabolite.