Molecular psychiatryJul 28, 2026

Shared brain-immune signaling linked to fast antidepressant effects of ketamine and psychedelics

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Aug 3, 2026

Abstract

Cytokine levels, particularly interleukin-7 (IL-7), are associated with the antidepressant response to ketamine treatment.

Shared biomarkers of rapid antidepressant response were identified in both cerebrospinal fluid and induced pluripotent stem cells.
Key immune pathways involving IL-15 and monocyte chemoattractant protein-1 (MCP-1) were conserved across different biological samples.
Ketamine responders exhibited lower IL-15 and increased B-cell signaling pathways at baseline, which changed after treatment.
Plasma levels of IL-7 correlated significantly with baseline brain activity as measured by magnetoencephalography.
The relationship between IL-7 and brain activity inverted after ketamine treatment, indicating a shift in response.
Cytokine ratios related to IL-7 and IL-15 signaling were predictive of both treatment response and non-response.

Simplified

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 p_FDR < 0.05). The association was most pronounced in the TRD participants across subcortical regions (diagnosis x IL-7 p_FDR < 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 p_clc < 0.05). In mixed-effects models, cytokine ratios linked to IL-7/IL-15 signaling predicted antidepressant response (IL-4/interferon gamma (IFN-γ) p_FDR < 0.041) and non-response (MCP-1/IL-7 p_FDR < 0.009), suggesting that rebalancing within the IL-7/IL-15 axis may contribute to therapeutic efficacy. Clinicaltrials.gov identifier: NCT00088699; NCT02484456.