Ketamine improves short-term plasticity in depression by enhancing sensitivity to prediction errors
Abstract
Major depressive disorder negatively impacts the sensitivity and adaptability of the brain's predictive coding framework. The current electroencephalography study into the antidepressant properties of ketamine investigated the downstream effects of ketamine on predictive coding and short-term plasticity in thirty patients with depression using the auditory roving mismatch negativity (rMMN). The rMMN paradigm was run 3-4 h after a single 0.44 mg/kg intravenous dose of ketamine or active placebo (remifentanil infused to a target plasma concentration of 1.7 ng/mL) in order to measure the neural effects of ketamine in the period when an improvement in depressive symptoms emerges. Depression symptomatology was measured using the Montgomery-Asberg Depression Rating Scale (MADRS); 70% of patients demonstrated at least a 50% reduction their MADRS global score. Ketamine significantly increased the MMN and P3a event related potentials, directly contrasting literature demonstrating ketamine's acute attenuation of the MMN. This effect was only reliable when all repetitions of the post-deviant tone were used. Dynamic causal modelling showed greater modulation of forward connectivity in response to a deviant tone between right primary auditory cortex and right inferior temporal cortex, which significantly correlated with antidepressant response to ketamine at 24 h. This is consistent with the hypothesis that ketamine increases sensitivity to unexpected sensory input and restores deficits in sensitivity to prediction error that are hypothesised to underlie depression. However, the lack of repetition suppression evident in the MMN evoked data compared to studies of healthy adults suggests that, at least within the short term, ketamine does not improve deficits in adaptive internal model calibration.
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Ketamine has been shown to increase sensitivity to prediction error in the hours where the antidepressant state emerges.
“Ketamine has indeed been shown to increase sensitivity to prediction error in the hours where the antidepressant state emerges (74).”
From Predictive coding and neurocomputational psychiatry: a mechanistic framework for understanding mental disorders (2026) · cites this paper as [74]
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“In Sumner et al. (2020), ketamine induced higher forward connectivity modulation from the right primary auditory cortex to the right inferior temporal cortex (for deviant stimuli), which was correlated with greater decreases in depressive symptoms.”
InfluentialMartin, J., Nezhad, F. G., Rueda, A., Lee, G. H., Charlton, C. E., Soltanzadeh, M., Ladha, K. S., Krishnan, S., Diaconescu, A. O., & Bhat, V. (2024) · PLoS ONE · doi:10.1371/journal.pone.0308413 · Cited by 2 · see citing works
“Ketamine’s effects on mood have been modeled using dynamic causal modeling (DCM) [25, 26] of event-related potentials (ERPs) under the MMN paradigm [27, 28].”
BackgroundApplication of Anesthetic Agents in Depression
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Daldegan‐Bueno, D., Donegan, C. J., Forsyth, A., Sumner, R. L., Murphy, R. J., Menkes, D. B., Evans, W. J., Hoeh, N. R., Sundram, F., Reynolds, L., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26827380
- Authors
- Sumner, R. L., McMillan, R., Spriggs, M. J., Campbell, D., Malpas, G., Maxwell, E., Deng, C., Hay, J., Ponton, R., Sundram, F., & Muthukumaraswamy, S. D.
- Affiliations
- University of Auckland (NZ)
- Auckland District Health Board (NZ)
- Corresponding author
- Sumner, Rachael L.
- ORCID
- Venue
- European Neuropsychopharmacology
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 38
- Pages
- 73-85
- ISSN
- 0924-977X (ISSN-L)
- OpenAlex
- W3047161913
- Cited by
- 32
- References
- 59
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 11 · 2023: 7 · 2022: 1 · 2021: 6
- FWCI
- 2.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Brain Research New Zealand
- Royal Society of New Zealand
- Auckland Medical Research Foundation
- Health Research Council of New Zealand
- 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, predictive coding, short-term plasticity, dynamic causal modeling, primary auditory cortex, inferior temporal cortex, antidepressant response, auditory deviance detection
- MeSH terms
- Adult, Cerebral Cortex, Major Depressive Disorder, Double-Blind Method, Electroencephalography, Female, Forecasting, Humans, Infusions, Intravenous, Ketamine, Male, Psychiatric Status Rating Scales, Treatment Outcome, Long-Term Potentiation, Cross-Over Studies, Excitatory Amino Acid Antagonists, Young Adult
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