Ketamine-Induced Glutamatergic Mechanisms of Sleep and Wakefulness: Insights for Developing Novel Treatments for Disturbed Sleep and Mood
Open accessAbstract
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.
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Improving SWS/SWA, especially early in the night, is thought to be a critical factor in ketamine's mechanism of rapid antidepressant action in MDD, and similar results have been seen with repetitive transcranial magnetic stimulation.
“Improving SWS/SWA, especially early in the night, is thought to be a critical factor in ketamine’s mechanism of rapid antidepressant action in MDD, and similar results have been seen with repetitive transcranial magnetic stimulation (rTMS).134”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [134]
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Matveychuk, D., Thomas, R. K., Swainson, J., Khullar, A., MacKay, M.-A., Baker, G. B., & Dursun, S. M. (2020) · Therapeutic Advances in Psychopharmacology · doi:10.1177/2045125320916657 · Cited by 209 · see citing works
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- Authors
- Duncan, W. C., Ballard, E. D., & Zarate, C. A.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Duncan, Wallace C.
- Venue
- Handbook of Experimental Pharmacology
- Publisher
- Springer International Publishing
- Published
- 2017
- Volume
- 253
- Pages
- 337-358
- ISSN
- 0171-2004 (ISSN-L)
- 1865-0325
- PMC
- PMC5866161
- OpenAlex
- W2757339434
- Cited by
- 58
- References
- 119
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 6 · 2023: 10 · 2022: 3 · 2021: 11 · 2020: 6 · 2019: 7 · 2018: 2
- FWCI
- 8.52
- Type
- book chapter
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Handbook of experimental pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (ZIAMH002857)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
- Keywords
- ketamine, glutamate, sleep-wake regulation, slow-wave sleep, major depressive disorder, bipolar disorder, treatment-resistant depression, antidepressant response, brain-derived neurotrophic factor, circadian rhythm, clock genes, sleep homeostasis, synaptic plasticity, ketamine metabolites, mood stabilizers
- MeSH terms
- Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, Humans, Ketamine, Sleep, Wakefulness
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