Longitudinal peripheral DNA methylation remodeling following ketamine-assisted psychotherapy in major depressive disorder.
6 affiliations
- 1Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
- 2School of Psychology, Faculty of Social Sciences, University of Ottawa, Ottawa, ON, Canada.
- 3University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada.
- 4Field Trip Health Canada, Ottawa, ON, Canada.
- 5Psychedelia-Stiftung, Berlin, Germany.
- 6Klinik für Akut- und Notfallmedizin, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Brandenburg Theodor Fontane, Neuruppin, Germany.
Abstract
Ketamine produces rapid antidepressant effects, but the molecular processes associated with their persistence remain poorly defined in humans. We examined longitudinal DNA methylation changes in 10 adults with major depressive disorder undergoing ketamine-assisted psychotherapy using two pre-treatment assessments (T1, T2) and one post-treatment assessment (T3). Participants received three sessions of intranasal racemic ketamine within a structured psychotherapy protocol. Buccal DNA methylation was measured using the Illumina MethylationEPIC v2.0 BeadChip. Depressive symptoms improved markedly following treatment, with mean Beck Depression Inventory-II scores declining from the severe to the mild range (p < .001). Of 802,595 CpG loci evaluated, 20,770 met the nominal T3-versus-T2 screening criterion. Sequential filtering for methylation-change magnitude and movement relative to pre-treatment fluctuation identified 962 retained CpG loci, including 517 retained gene-annotated loci. A supplementary linear mixed-effects analysis modeled repeated measurements within participants across the 603 preselected gene-annotated magnitude-filtered loci; because these loci were selected using the same contrast and cohort, this analysis was not treated as independent confirmation. Exploratory enrichment analysis of this 603-locus set identified NOTCH1-related Reactome terms driven by NOTCH1, DLL1, and ADAM17. Within the retained signature, multiple core and adjacent Notch-related components formed a coherent signaling module spanning ligand, receptor processing, transcriptional regulation, and pathway cross-talk. These findings identify a structured peripheral methylation signature associated with ketamine-assisted psychotherapy. They do not establish brain-specific pathway activation or causality, but provide a longitudinal basis for investigating regulatory adaptations accompanying clinical improvement.
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BibTeX
@article{nepton2026longitudinal,
title = {{Longitudinal peripheral DNA methylation remodeling following ketamine-assisted psychotherapy in major depressive disorder.}},
author = {Arghavan Nepton and Sonya C Faber and Zachary Kaminsky and Mario Nucci and Hesam Farahani and Monnica T Williams and Sergio R Perez Rosal},
journal = {Epigenetics},
year = {2026},
month = oct,
doi = {10.1080/15592294.2026.2731659},
url = {https://europepmc.org/article/MED/42879530},
note = {CC BY},
}
RIS
TY - JOUR
TI - Longitudinal peripheral DNA methylation remodeling following ketamine-assisted psychotherapy in major depressive disorder.
AU - Arghavan Nepton
AU - Sonya C Faber
AU - Zachary Kaminsky
AU - Mario Nucci
AU - Hesam Farahani
AU - Monnica T Williams
AU - Sergio R Perez Rosal
PY - 2026
DA - 2026/10/15
JO - Epigenetics
DO - 10.1080/15592294.2026.2731659
UR - https://europepmc.org/article/MED/42879530
AB - Ketamine produces rapid antidepressant effects, but the molecular processes associated with their persistence remain poorly defined in humans. We examined longitudinal DNA methylation changes in 10 adults with major depressive disorder undergoing ketamine-assisted psychotherapy using two pre-treatment assessments (T1, T2) and one post-treatment assessment (T3). Participants received three sessions of intranasal racemic ketamine within a structured psychotherapy protocol. Buccal DNA methylation was measured using the Illumina MethylationEPIC v2.0 BeadChip. Depressive symptoms improved markedly following treatment, with mean Beck Depression Inventory-II scores declining from the severe to the mild range (p < .001). Of 802,595 CpG loci evaluated, 20,770 met the nominal T3-versus-T2 screening criterion. Sequential filtering for methylation-change magnitude and movement relative to pre-treatment fluctuation identified 962 retained CpG loci, including 517 retained gene-annotated loci. A supplementary linear mixed-effects analysis modeled repeated measurements within participants across the 603 preselected gene-annotated magnitude-filtered loci; because these loci were selected using the same contrast and cohort, this analysis was not treated as independent confirmation. Exploratory enrichment analysis of this 603-locus set identified NOTCH1-related Reactome terms driven by NOTCH1, DLL1, and ADAM17. Within the retained signature, multiple core and adjacent Notch-related components formed a coherent signaling module spanning ligand, receptor processing, transcriptional regulation, and pathway cross-talk. These findings identify a structured peripheral methylation signature associated with ketamine-assisted psychotherapy. They do not establish brain-specific pathway activation or causality, but provide a longitudinal basis for investigating regulatory adaptations accompanying clinical improvement.
SN - 1559-2294
SN - 1559-2308
ER -