Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics

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 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.