Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics
9 affiliations
- 1Experimental Therapeutics & Pathophysiology Branch, Division of Intramural Research Program, National Institute of Mental Health, Bethesda, MD USA
- 2Department of Psychiatry, The University of Texas MD Anderson Cancer Center, Houston, TX USA
- 3Human Genetics Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD USA
- 4Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, TX USA
- 5Laboratory of Cancer Genetics, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD USA
- 6Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD USA
- 7Translational Immunopsychiatry Unit, National Institute of Mental Health, Bethesda, MD USA
- 8Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX USA
- 9Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX USA
Abstract
Despite distinct receptor targets, both ketamine and serotonergic psychedelics produce a rapid clinical response and share biological signatures that suggest convergence on common downstream molecular mediators. To identify shared biomarkers of rapid antidepressant response, this study integrated CSF proteomics from healthy volunteers (HVs) who received intravenous ketamine with transcriptomic analyses from induced pluripotent stem cells (iPSCs) derived from participants with treatment-resistant depression (TRD) and HVs; iPSCs were treated with ketamine, its metabolite (2 R,6 R)-hydroxynorketamine, lysergic acid diethylamide (LSD), or psilocybin. Multimodal clinical characterization (transcriptomics (n = 16 TRD; 11 HV), magnetoencephalography (MEG) (n = 30 TRD; 25 HV), and plasma cytokines (n = 39 TRD; 25 HV) were also performed on TRD and HV participants who received a single dose of intravenous ketamine (0.5 mg/kg) or placebo. Conserved immune pathways were identified across CSF and iPSC neurons with interleukin-15 (IL)-15 and monocyte chemoattractant protein-1 (MCP-1) emerging as key regulatory hubs. Transcriptomically, in whole blood, ketamine responders exhibited decreased IL-15 and elevated B-cell signaling pathways at baseline that were reversed post-treatment. At the protein level, plasma IL-7 levels (primary B-cell driver) correlated with baseline MEG gamma power, reaching brain-wide significance across all participants (main effect pFDR < 0.05). The association was most pronounced in the TRD participants across subcortical regions (diagnosis x IL-7 pFDR < 10-14). Post-ketamine, the TRD IL-7–gamma relationship inverted, paralleling widespread gamma power reductions throughout default-mode network regions (session x IL-7 pclc < 0.05). In mixed-effects models, cytokine ratios linked to IL-7/IL-15 signaling predicted antidepressant response (IL-4/interferon gamma (IFN-γ) pFDR < 0.041) and non-response (MCP-1/IL-7 pFDR < 0.009), suggesting that rebalancing within the IL-7/IL-15 axis may contribute to therapeutic efficacy. Clinicaltrials.gov identifier: NCT00088699; NCT02484456.
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BibTeX
@article{jones2026convergent,
title = {{Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics}},
author = {Gregory H. Jones and Jessica R. Gilbert and Jenessa N. Johnston and Nirmala Akula and Anton Schulmann and Miranda Arakelian and Shiyong Peng and Peixiong Yuan and Ewurakua A. Winful and Mani Yavi and Brandi Quintanilla and Abdel Elkahloun and Ruin Moaddel and Ioline D. Henter and Dede Greenstein and Rodrigo Machado-Vieira and Christopher M. Bartley and Bashkim Kadriu and Moran Amit and Katy Rezvani and Mark D. Kvarta and Francis J. McMahon and Carlos A. Zarate},
journal = {Molecular Psychiatry},
year = {2026},
month = jul,
doi = {10.1038/s41380-026-03777-z},
url = {https://doi.org/10.1038/s41380-026-03777-z},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics
AU - Gregory H. Jones
AU - Jessica R. Gilbert
AU - Jenessa N. Johnston
AU - Nirmala Akula
AU - Anton Schulmann
AU - Miranda Arakelian
AU - Shiyong Peng
AU - Peixiong Yuan
AU - Ewurakua A. Winful
AU - Mani Yavi
AU - Brandi Quintanilla
AU - Abdel Elkahloun
AU - Ruin Moaddel
AU - Ioline D. Henter
AU - Dede Greenstein
AU - Rodrigo Machado-Vieira
AU - Christopher M. Bartley
AU - Bashkim Kadriu
AU - Moran Amit
AU - Katy Rezvani
AU - Mark D. Kvarta
AU - Francis J. McMahon
AU - Carlos A. Zarate
PY - 2026
DA - 2026/07/28
JO - Molecular Psychiatry
DO - 10.1038/s41380-026-03777-z
UR - https://doi.org/10.1038/s41380-026-03777-z
AB - Despite distinct receptor targets, both ketamine and serotonergic psychedelics produce a rapid clinical response and share biological signatures that suggest convergence on common downstream molecular mediators. To identify shared biomarkers of rapid antidepressant response, this study integrated CSF proteomics from healthy volunteers (HVs) who received intravenous ketamine with transcriptomic analyses from induced pluripotent stem cells (iPSCs) derived from participants with treatment-resistant depression (TRD) and HVs; iPSCs were treated with ketamine, its metabolite (2 R,6 R)-hydroxynorketamine, lysergic acid diethylamide (LSD), or psilocybin. Multimodal clinical characterization (transcriptomics (n = 16 TRD; 11 HV), magnetoencephalography (MEG) (n = 30 TRD; 25 HV), and plasma cytokines (n = 39 TRD; 25 HV) were also performed on TRD and HV participants who received a single dose of intravenous ketamine (0.5 mg/kg) or placebo. Conserved immune pathways were identified across CSF and iPSC neurons with interleukin-15 (IL)-15 and monocyte chemoattractant protein-1 (MCP-1) emerging as key regulatory hubs. Transcriptomically, in whole blood, ketamine responders exhibited decreased IL-15 and elevated B-cell signaling pathways at baseline that were reversed post-treatment. At the protein level, plasma IL-7 levels (primary B-cell driver) correlated with baseline MEG gamma power, reaching brain-wide significance across all participants (main effect pFDR < 0.05). The association was most pronounced in the TRD participants across subcortical regions (diagnosis x IL-7 pFDR < 10-14). Post-ketamine, the TRD IL-7–gamma relationship inverted, paralleling widespread gamma power reductions throughout default-mode network regions (session x IL-7 pclc < 0.05). In mixed-effects models, cytokine ratios linked to IL-7/IL-15 signaling predicted antidepressant response (IL-4/interferon gamma (IFN-γ) pFDR < 0.041) and non-response (MCP-1/IL-7 pFDR < 0.009), suggesting that rebalancing within the IL-7/IL-15 axis may contribute to therapeutic efficacy. Clinicaltrials.gov identifier: NCT00088699; NCT02484456.
SN - 1359-4184
SN - 1476-5578
ER -