Duncan Wallace C, Ballard Elizabeth D, Zarate Carlos A
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institute of Health, Bethesda, MD, 20892, USA.
Handb Exp Pharmacol. 2019;253:337-358. doi: 10.1007/164_2017_51.
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.
氯胺酮是一种具有快速抗抑郁作用且对慢波睡眠（SWS）影响已得到充分描述的药物，是研究新型治疗方法中涉及的睡眠 - 觉醒机制的有用干预手段。该药物能迅速（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。氯胺酮治疗可提高前额叶皮质中的细胞外谷氨酸水平。反过来，谷氨酸作为氯胺酮引发的分子级联反应中的近端元素发挥关键作用，该级联反应可增加突触强度和可塑性，最终导致情绪迅速改善。在MDD中，对氯胺酮的快速抗抑郁反应与清醒时间减少以及总睡眠时间、SWS、慢波活动（SWA）和快速眼动（REM）睡眠增加有关。氯胺酮还会增加脑源性神经营养因子（BDNF）水平。在MDD患者中，低基线δ睡眠比率可预测对氯胺酮的临床反应，δ睡眠比率是衡量夜间早期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，这可能与诊断或心境稳定剂的作用有关。与其对时钟相关分子的作用一致，氯胺酮会改变MDD快速反应者与无反应者昼夜活动模式的时间和幅度，表明它会影响与情绪相关的中枢神经回路。睡眠稳态和时钟基因之间的分子相互作用可能介导了对氯胺酮及其活性代谢物临床反应的快速和持久因素。
