For the millions living with treatment-resistant depression, the speed of relief matters as much as its depth. Understanding why ketamine and psychedelics — compounds with entirely different receptor targets — both produce antidepressant effects within hours could unlock a new class of biomarker-guided therapies and reveal the shared biological architecture of rapid mood recovery.
This multimodal investigation integrated cerebrospinal fluid proteomics from healthy volunteers receiving intravenous ketamine with transcriptomic analyses from induced pluripotent stem cells (iPSCs) derived from individuals with treatment-resistant depression. The iPSCs were exposed to ketamine, its active metabolite (2R,6R)-hydroxynorketamine, LSD, and psilocybin — creating a rare cross-compound molecular comparison. Across these distinct chemical entities, two immune proteins emerged as convergent regulatory hubs: interleukin-15 (IL-15) and monocyte chemoattractant protein-1 (MCP-1). At the transcriptomic level, ketamine responders displayed reduced baseline IL-15 expression and elevated B-cell signaling that normalized following treatment. Critically, plasma IL-7 — a primary B-cell growth factor — correlated with baseline magnetoencephalography (MEG) gamma power across the full participant cohort (n up to 64 across modalities), achieving brain-wide statistical significance (pFDR < 0.05).
This work is potentially paradigm-shifting for several reasons. The prevailing narrative around ketamine centers on NMDA receptor antagonism and glutamate surge; serotonergic psychedelics act primarily at 5-HT2A receptors. That both converge on neuroimmune cytokine networks — specifically pathways governing B-cell activity and lymphocyte trafficking — reframes rapid antidepressant action as partly immunological rather than purely synaptic. This aligns with a growing body of evidence implicating neuroinflammation in depression's pathophysiology, but the B-cell and IL-15 angle is underexplored territory. The MEG gamma power correlation with IL-7 is particularly intriguing: gamma oscillations index cortical excitation-inhibition balance, suggesting peripheral immune tone may directly modulate neural circuit function. Key limitations include modest cohort sizes across modalities, the use of iPSC-derived neurons rather than intact human neural circuits, and the study's inability to establish causality between immune shifts and clinical response. Still, the multi-modal convergence across CSF, blood, and brain electrophysiology elevates this beyond incremental progress.