Summary: New research from The University of Texas MD Anderson Cancer Center reveals a shared neuroimmune mechanism that helps explain how rapid-acting antidepressants—such as ketamine and serotonergic psychedelics—can quickly reduce symptoms in treatment-resistant depression. The study identifies blood-based immune markers, including interleukin-15 (IL-15), interleukin-7 (IL-7) and B-cell signaling pathways, that align with changes in brain activity and predict clinical response.
Although ketamine and psychedelics act on different primary brain receptors, the investigators found that their downstream effects converge on the same immune-to-brain signaling pathways. These conserved pathways were demonstrated across laboratory models, cell-based systems and clinical samples, offering a promising route toward blood tests that could guide treatment selection and improve outcomes for people with difficult-to-treat depression.
Key Facts
- Convergent neuroimmune axis: Rapid-acting antidepressants with different receptor targets—such as NMDA receptor antagonists (ketamine) and serotonergic psychedelics (psilocybin, LSD)—converge on common immune signaling pathways that influence brain function.
- Baseline immune predictors of response: Patients who responded to ketamine in the clinical dataset had distinct pre-treatment immune signatures: lower IL-15 pathway activity combined with higher B-cell signaling compared with non-responders.
- Biological reversal with successful treatment: Clinical responders experienced normalization of those baseline immune differences after ketamine, with IL-7 and IL-15 balance shifting alongside measurable changes in brain electrical activity.
- Blood-to-brain biomarker alignment: Immune-related gene and protein changes detected in blood samples tracked with electrophysiological shifts in the brain, supporting peripheral blood measures as practical proxies for central neuroimmune function.
- Clinical relevance in complex populations: This neuroimmune framework may improve identification and treatment of severe, treatment-resistant depression in medically complex patients, including those undergoing cancer care.
Source: MD Anderson
In a new study, researchers at The University of Texas MD Anderson Cancer Center probed how rapid-acting antidepressants produce fast clinical benefit and which patients are most likely to respond. The study, published in Molecular Psychiatry and co-led by Gregory Jones, M.D., assistant professor of Psychiatry, shows that different fast-acting therapies converge on shared immune-to-brain signaling pathways.
The team integrated multiple experimental approaches, including cerebrospinal fluid (CSF) proteomics, induced pluripotent stem cell (iPSC) neuron transcriptomics treated with ketamine, its metabolite (2R,6R)-hydroxynorketamine, LSD or psilocybin, and multimodal clinical measures from people with treatment-resistant depression (TRD) and healthy volunteers. Across these methods, immune pathways—especially signals centered on IL-15, IL-7 and related B-cell activity—emerged as conserved mediators linked to rapid antidepressant effects.
“Ketamine and psychedelics affect the brain in different ways subjectively, but our findings suggest they ultimately engage some of the same neuroimmune pathways,” said Gregory Jones. By combining blood-based molecular data with brain electrophysiology, the team was able to map how peripheral immune signals relate to neural circuits that change with successful treatment.
What are rapid-acting antidepressants and how are they used?
Treatment-resistant depression refers to major depressive episodes that fail to improve after multiple standard treatments, including conventional antidepressant medications and psychotherapy. Rapid-acting treatments such as intravenous ketamine and single-dose psychedelic therapies (psilocybin, LSD in research settings) can produce striking symptom relief in some patients within hours to days. However, clinicians lack reliable biomarkers to predict who will benefit. Identifying blood and brain signatures associated with rapid response could enable more precise, time-efficient care and help investigators develop longer-lasting therapies.
What did the researchers find?
The investigators found concordant immune changes across experimental systems and clinical measurements. Key observations include:
- CSF and iPSC neuron analyses pointed to conserved immune pathways, with IL-15 and monocyte chemoattractant protein-1 (MCP-1) identified as regulatory hubs.
- In whole blood transcriptomics, ketamine responders had lower IL-15 signaling and higher B-cell pathway activity at baseline; both measures shifted toward normalization after effective treatment.
- At the protein level, plasma IL-7—an important driver of B-cell biology—correlated with baseline magnetoencephalography (MEG) gamma power across participants and showed particularly strong associations in TRD patients within subcortical regions.
- Following ketamine, the relationship between IL-7 and gamma power inverted in TRD participants, which coincided with widespread reductions in gamma activity across default-mode network regions.
- Mixed-effects models showed that cytokine ratios involving IL-7 and IL-15 predicted antidepressant response or non-response, supporting the concept that rebalancing the IL-7/IL-15 axis contributes to therapeutic benefit.
What’s next?
These findings are exploratory and require validation in larger, prospective clinical trials. Key next steps include testing whether pre-treatment measurements of IL-7, IL-15 and related B-cell markers can reliably predict response to ketamine or psychedelic-assisted therapy, and whether therapies that directly target these immune pathways can enhance or prolong antidepressant effects. Larger studies will also clarify how these biomarkers perform across diverse patient populations and clinical settings.
Funding: The research received partial funding from the National Institutes of Health. For a full list of contributing authors, disclosures and funding details, see the published paper in Molecular Psychiatry.
Key Questions Answered
A: Although ketamine primarily antagonizes NMDA receptors and psychedelics act on serotonin receptors (notably 5-HT2A), both classes activate downstream signaling cascades that converge on a shared neuroimmune pathway. That pathway modulates communication between immune cells (including B cells and interleukins like IL-7 and IL-15) and central neural circuits, contributing to rapid symptom relief.
A: The study highlights interleukin-15 (IL-15), interleukin-7 (IL-7) and downstream B-cell signaling markers. Responders to ketamine showed lower IL-15 activity and higher baseline B-cell signaling, both of which shifted after successful treatment.
A: If validated prospectively, simple blood tests measuring IL-7, IL-15 and B-cell markers could help clinicians predict who will benefit from rapid-acting antidepressants, allowing more personalized and efficient treatment plans for people with difficult-to-treat depression.
Editorial Notes
- This article was edited by a Neuroscience News editor.
- The underlying journal paper was reviewed in full by the reporting team.
- Additional clinical and scientific context was added by staff editors.
About this research summary
Author: Aubrey Bloom
Source: M. D. Anderson Cancer Center
Contact: Aubrey Bloom – M. D. Anderson
Image credit: Neuroscience News
Original research: Open access. Title: “Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics” by Gregory H. Jones et al., published in Molecular Psychiatry. DOI: 10.1038/s41380-026-03777-z
Abstract (summary)
Despite acting at distinct receptor targets, ketamine and serotonergic psychedelics produce rapid clinical responses and share downstream biological signatures that implicate common molecular mediators. This study combined CSF proteomics from healthy volunteers who received intravenous ketamine with transcriptomic analyses of iPSC-derived neurons treated with ketamine, its metabolite, LSD or psilocybin, plus multimodal clinical measures including blood transcriptomics, MEG and plasma cytokines from TRD patients and healthy volunteers who received ketamine or placebo. Conserved immune pathways were identified across systems, with IL-15 and MCP-1 emerging as key regulatory hubs. In whole blood, ketamine responders showed decreased IL-15 and elevated B-cell signaling at baseline that reversed after treatment. Plasma IL-7 correlated with baseline MEG gamma power and the IL-7–gamma relationship shifted after ketamine alongside network-wide reductions in gamma activity. Mixed-effects models indicated that cytokine ratios tied to IL-7/IL-15 signaling predicted response and non-response, suggesting that restoring balance within this immune axis may underpin therapeutic efficacy. ClinicalTrials.gov identifiers: NCT00088699; NCT02484456.