Ketamine, Sleep, and Depression: Current Status and New Questions
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Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has well-described rapid antidepressant effects in clinical studies of individuals with treatment-resistant major depressive disorder (MDD). Preclinical studies investigating the effects of ketamine on brain-derived neurotrophic factor (BDNF) and on sleep slow wave activity (SWA) support its use as a prototype for investigating the neuroplastic mechanisms presumably involved in the mechanism of rapidly acting antidepressants. This review discusses human EEG slow wave sleep parameters and plasma BDNF as central and peripheral surrogate markers of plasticity, and their use in assessing ketamine’s effects. Acutely, ketamine elevates BDNF levels, as well as early night SWA and high-amplitude slow waves; each of these measures correlates with change in mood in depressed patients who respond to ketamine. The slow wave effects are limited to the first night post-infusion, suggesting that their increase is part of an early cascade of events triggering improved mood. Increased total sleep and decreased waking occur during the first and second night post infusion, suggesting that these measures are associated with the enduring treatment response observed with ketamine.
KeywordsKetamine NMDA antagonist Sleep Major depressive disorder MDD Synaptic plasticity Slow wave sleep Slow wave activity SWA AMPA Mood Rapid antidepressant response Neurotrophic factors Brain-derived neurotrophic factor BDNF Treatment-resistant depression Bipolar depression Sleep disorders Psychiatry
Compliance with Ethics Guidelines
Conflict of Interest
Wallace C. Duncan, Jr., declares that he has no conflict of interest.
Carlos A. Zarate, Jr., is listed as a coinventor on a patent application for the use of ketamine and its metabolites in major depression. Dr. Zarate has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government.
Human Rights and Informed Consent
The MDD and BP patients that are discussed in this review were part of studies that were approved by the Combined Neuroscience Institutional Review Board of the National Institutes of Health. All subjects provided written informed consent before entry into the studies.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
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