Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder
Open accessAbstract
The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery–Åsberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity – as reflected by increased SWA, individual slow wave parameters and plasma BDNF – is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response.
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A single IV infusion of 0.5 mg/kg ketamine is associated with significantly increased plasma BDNF levels at 230 min post-infusion compared with baseline.
“a single intravenous infusion of 0.5 mg/kg ketamine was associated with significantly increased plasma BDNF levels at 230 min post-infusion compared with baseline measurements [95].”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [95]
Ketamine has well-described effects on increasing total sleep and slow-wave sleep/slow-wave activity, and its antidepressant response has been linked to this effect.
“Ketamine has well-described effects on increasing total sleep and slow-wave sleep/slow-wave activity (SWS/SWA),133 and its antidepressant response has been linked to this effect.113”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [113]
Ketamine responders with treatment-resistant depression demonstrated rapid elevations in plasma BDNF levels, although another study did not support this finding.
“Ketamine responders with TRD demonstrated rapid elevations in plasma BDNF levels112,113; however, another study did not support this finding.114”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [113]
The increase in SWA correlates strongly with increases in synaptic plasticity and plasma BDNF preclinically and in ketamine-responsive MDD patients.
“This increase in SWA correlates strongly with increases in synaptic plasticity and plasma BDNF preclinically,135 and in ketamine-responsive MDD patients.113,133”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [113]
Higher levels of BDNF were correlated with lower severity of depressive symptoms on rating scales.
“In the aforementioned investigations, higher levels of BDNF were correlated with lower severity of depressive symptoms on rating scales.”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [113]
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Self-citation
- Authors
- Duncan, W. C., Sarasso, S., Ferrarelli, F., Selter, J., Riedner, B. A., Hejazi, N. S., Yuan, P., Brutsche, N., Manji, H. K., Tononi, G., & Zarate, C. A.
- Affiliations
- National Institutes of Health (US)
- University of Wisconsin–Madison (US)
- Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
- Johnson and Johnson Pharmaceutical Research and Development, Titusville, NJ, USA
- Corresponding author
- Zarate, Carlos A.
- ORCID
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-06-07
- Volume
- 16
- Issue
- 2
- Pages
- 301-311
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- PMC
- PMC3510337
- OpenAlex
- W2108898741
- Cited by
- 256
- References
- 44
- Citations by year
- 2026: 21 · 2025: 22 · 2024: 16 · 2023: 20 · 2022: 19 · 2021: 34 · 2020: 17 · 2019: 15 · 2018: 14 · 2017: 10 · 2016: 21 · 2015: 18 · 2014: 9 · 2013: 16 · 2012: 4
- FWCI
- 11.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The International Journal of Neuropsychopharmacology (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
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Keywords
- ketamine, major depressive disorder, treatment-resistant depression, brain-derived neurotrophic factor, EEG slow-wave activity, REM sleep, synaptic plasticity, NMDA receptor antagonists, antidepressant response, biomarkers, plasma BDNF
- MeSH terms
- Adult, Analysis of Variance, Major Depressive Disorder, Electroencephalography, Enzyme-Linked Immunosorbent Assay, Female, Humans, Ketamine, Male, Middle Aged, Psychiatric Status Rating Scales, Sleep Stages, Statistics as Topic, Time Factors, Single-Blind Method, Excitatory Amino Acid Antagonists, Brain-Derived Neurotrophic Factor, Riluzole, Brain Waves
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