Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects
Open accessAbstract
Ketamine's mechanism of action was assessed using gamma power from magnetoencephalography (MEG) as a proxy measure for homeostatic balance in 35 unmedicated subjects with major depressive disorder (MDD) and 25 healthy controls enrolled in a double-blind, placebo-controlled, randomized cross-over trial of 0.5 mg/kg ketamine. MDD subjects showed significant improvements in depressive symptoms, and healthy control subjects exhibited modest but significant increases in depressive symptoms for up to 1 day after ketamine administration. Both groups showed increased resting gamma power following ketamine. In MDD subjects, gamma power was not associated with the magnitude of the antidepressant effect. However, baseline gamma power was found to moderate the relationship between post-ketamine gamma power and antidepressant response; specifically, higher post-ketamine gamma power was associated with better response in MDD subjects with lower baseline gamma, with an inverted relationship in MDD subjects with higher baseline gamma. This relationship was observed in multiple regions involved in networks hypothesized to be involved in the pathophysiology of MDD. This finding suggests biological subtypes based on the direction of homeostatic dysregulation and has important implications for inferring ketamine's mechanism of action from studies of healthy controls alone.
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Animal studies show that ketamine-induced increases in synaptic proteins and density.
“While animal studies show that ketamine-induced increases in synaptic proteins and density 14 67 40”
From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [67]
The Introduction (page unavailable) reports that preclinical studies found ketamine rapidly induces synaptogenesis and reverses stress-related synaptic deficits, supporting the claim’s general point about increased synapses. It does not state that animal studies found increases in synaptic proteins or explicitly report a measure of synaptic density. (LLM, conf=0.84)
Experimental — accuracy not yet measuredGamma power has been found to be consistently increased after subanesthetic ketamine administration in participants with depression.
“Gamma power has been found to be consistently increased after subanesthetic ketamine administration in participants with depression [205,206]”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [205]
PET is generally not as sensitive as techniques such as Western blot analysis and two-photon microscopy.
“PET is generally not as sensitive as techniques such as Western blot analysis and two-photon microscopy 67”
From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [67]
The Materials and Methods passages describe MEG analysis, and the Discussion addresses gamma power; neither compares PET with Western blot analysis or two-photon microscopy. Searches for those techniques and for PET sensitivity found no passage addressing the claimed comparison. Page numbers are unavailable in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measuredLower baseline gamma power and subsequent elevation after ketamine administration have been shown to predict better antidepressant responses in TRD.
“In that regard, lower baseline gamma power (reflective of GABA and glutamate functional balance) and subsequent elevation after ketamine administration have been shown to predict better antidepressant responses in TRD [88], though further validation is needed.”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [88]
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- Authors
- Nugent, A. C., Ballard, E. D., Gould, T. D., Park, L. T., Moaddel, R., Brutsche, N. E., & Zarate, C. A.
- Affiliations
- National Institutes of Health (US)
- University of Maryland, Baltimore (US)
- National Institute on Aging (US)
- Corresponding author
- Nugent, Allison C.
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2018-02-27
- Volume
- 24
- Issue
- 7
- Pages
- 1040-1052
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC6111001
- OpenAlex
- W2792218734
- Cited by
- 250
- References
- 90
- Citations by year
- 2026: 16 · 2025: 30 · 2024: 20 · 2023: 30 · 2022: 21 · 2021: 60 · 2020: 33 · 2019: 23 · 2018: 17
- FWCI
- 21.46
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01BX004062)
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health (Z99 MH999999)
- National Institute of Mental Health (Z01MH002857, R01MH107615, 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, gamma power, resting-state brain activity, homeostatic balance, antidepressant response, magnetoencephalography
- MeSH terms
- Adult, Antidepressive Agents, Depression, Major Depressive Disorder, Double-Blind Method, Female, Humans, Ketamine, Male, Middle Aged, Magnetoencephalography, Case-Control Studies, Cross-Over Studies, Electrophysiological Phenomena, Depressive Disorder, Treatment-Resistant
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