Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics

A study uncovered a novel neuroimmune mechanism explaining how rapid-acting antidepressants, including ketamine and psychedelics, alleviate treatment-resistant depression.

This study proposes that ketamine and serotonergic psychedelics (such as psilocybin and LSD) share a common downstream mechanism despite acting on different receptors. The authors found that these drugs converge on neuroimmune signaling pathways, particularly those involving the cytokines IL-15 and IL-7, which may contribute to their rapid antidepressant effects.

Key findings

• Ketamine, psilocybin, and LSD showed convergent molecular responses, despite acting through different primary receptors, suggesting a shared downstream mechanism for rapid antidepressant effects.

• A common neuroimmune signaling network was identified, with IL-15 emerging as a central regulatory hub linking immune activity to neural function. IL-15 (Interleukin-15) is a cytokine—a signaling protein that regulates communication between immune cells. Traditionally, it has been studied for its role in immunity, but growing evidence suggests it also influences brain function, neuroinflammation, and neural plasticity.

  In this paper, IL-15 is important because it emerged as one of the central neuroimmune signals shared by ketamine and psychedelics, making it a candidate biomarker and potential regulator of rapid antidepressant responses.

• Overlapping transcriptomic and proteomic signatures were observed across ketamine and psychedelic treatments, supporting convergence on shared biological pathways.

• Ketamine responders had distinct baseline immune profiles, including lower IL-15 pathway activity and altered B-cell–related signaling, which shifted after treatment.

• IL-7 levels were associated with brain gamma oscillations measured by MEG, and these relationships changed following ketamine, suggesting a link between immune signaling and brain network activity.

• Cytokine ratios (rather than single cytokines) more accurately predicted antidepressant response, highlighting the importance of immune network balance.

• Evidence of B-cell and immune cell pathway modulation suggests adaptive immune processes may contribute to rapid antidepressant responses.

• Adenosine-related signaling pathways were also implicated as a potential shared downstream mechanism, although this finding requires further validation.

• The findings support a model in which neuroimmune signaling interacts with established neuroplasticity pathways (e.g., glutamate, BDNF, mTOR) rather than replacing them.

• The identified neuroimmune signatures may serve as biomarkers to predict response to ketamine or future rapid-acting antidepressants.

Rather than acting solely through neurotransmitters like glutamate or serotonin, Ketamine and psychedelics appear to converge on shared neuroimmune signaling pathways that are associated with rapid antidepressant responses and may interact with established neuroplasticity mechanisms such as glutamate, BDNF, and mTOR signaling. The work suggests that immune signaling is an important component of rapid antidepressant mechanisms, although further studies are needed to establish whether these immune changes are causal rather than simply associated with clinical improvement.

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.

Jones, G.H., Gilbert, J.R., Johnston, J.N. et al. Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics. Mol Psychiatry (2026). Read Paper

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