Summary: A study uncovered a novel neuroimmune mechanism explaining how rapid-acting antidepressants, including ketamine and psychedelics, alleviate treatment-resistant depression.
Despite acting on different initial neural receptors, these distinct fast-acting therapeutics converge on shared immune-to-brain signaling pathways. The research team identified specific immune biomarkers, notably interleukin-15 (IL-15), interleukin-7 (IL-7), and downstream B-cell signaling pathways, in both preclinical models and human clinical trials.
These baseline immune signatures correlated with brain electrical activity and predicted which patients responded to treatment, offering a potential blood-based biomarker profile to guide clinical selection and develop more durable antidepressant therapies.
Key Facts
- Convergent Neuroimmune Axis: Rapid-acting antidepressants with distinct primary receptor targets (e.g., NMDA receptor antagonists like ketamine and serotonergic psychedelics like psilocybin) converge on identical molecular immune pathways between the body and brain.
- Baseline Immune Predictors of Response: Patients who successfully responded to ketamine exhibited characteristic pre-treatment immune profiles: lower baseline IL-15 pathway activity and elevated baseline B-cell signaling compared to non-responders.
- Post-Treatment Biological Reversal: Clinical response to ketamine directly reversed these baseline immune imbalances, normalizing the balance between IL-7 and IL-15 signaling and inducing corresponding shifts in brain electrical activity.
- Blood-to-Brain Biomarker Alignment: Matching immune-related gene and protein changes observed in patient blood samples correlated with shifts in brain electrophysiology, establishing systemic blood signals as viable proxies for central neuroimmune function.
- Oncology-Depression Application: Provides a biological framework to better identify and treat severe depression in complex patient populations, including cancer patients experiencing treatment-resistant psychological distress.
Source: MD Anderson
In a new study, researchers from The University of Texas MD Anderson Cancer Center have uncovered insights that may help explain how rapid-acting antidepressants, such as ketamine and psychedelics, can reduce symptoms in difficult-to-treat depression. The findings may also help identify patients who are most likely to benefit from these treatments.
The study, published in Molecular Psychiatry, was co-led by Gregory Jones, M.D., assistant professor of Psychiatry. The researchers discovered that these therapies work by changing communication signals between the immune system and the brain, suggesting that they share certain neuroimmune pathways, even though they act on different receptors in the brain.
“Ketamine and psychedelics affect the brain in different ways subjectively, but our findings suggest that they eventually end up in some of the same neuroimmune pathways,” Jones said.
“By studying blood signals and brain activity together, researchers can better understand how the body and brain may work in tandem to respond to antidepressants. We hope to be able to use these findings to better treat patients with depression, which is not uncommon in those facing a cancer diagnosis.”
What are rapid-acting antidepressants and how can they be used to treat depression?
Treatment-resistant depression occurs when symptoms do not improve after multiple treatments with traditional antidepressants or talk therapy. Rapid-acting antidepressants, such as ketamine and psilocybin, have demonstrated significant, rapid symptom improvement in some patients with treatment-resistant depression, but it is unclear which patients are more likely to benefit. A deeper understanding of the biological mechanisms driving these responses could help scientists develop more durable and accessible treatments for depression.
What did the researchers learn about rapid-acting antidepressants in this study?
The researchers analyzed the effects of multiple rapid-acting antidepressants in laboratory models as well as in a previous clinical trial. They discovered that several rapid-acting antidepressants trigger a common set of molecular changes related to the immune system in brain cells. They observed matching immune-related changes in patients’ blood along with related shifts in patients’ brain electrical activity after ketamine treatment, suggesting a shared biological pathway that may underlie rapid relief from depression.
Participants who responded to ketamine showed lower IL-15 pathway activity and higher B cell signaling before treatment than nonresponders, both of which reversed after treatment in patients who responded. The results suggest that rapid antidepressant response may involve restoring balance between IL-7 and IL-15, with downstream effects on B cells and brain activity.
What’s next for this research?
The findings are exploratory and need validation in larger, prospective studies. Future research will determine whether IL-15, IL-7 and related biomarkers can predict treatment response before therapy and whether targeting these pathways could improve or extend responses to rapid-acting antidepressants.
Funding: This research was funded in part by the National Institutes of Health. For a full list of collaborating authors, disclosures and funding sources, see the full paper in Molecular Psychiatry.
Key Questions Answered:
A: While ketamine targets NMDA receptors and psychedelics primarily act on serotonin receptors (such as 5-HT2A), both drug classes trigger downstream signaling cascades that converge on a shared neuroimmune pathway. This shared pathway regulates communication between immune cells (like B cells and specific interleukins) and central neural circuits, driving rapid clinical relief.
A: The researchers identified interleukin-15 (IL-15), interleukin-7 (IL-7), and downstream B-cell signaling markers. Specifically, patients who responded to ketamine entered treatment with lower IL-15 activity and higher B-cell signaling, which reversed and normalized following successful treatment.
A: If validated in larger prospective trials, clinicians could use simple blood tests targeting IL-7, IL-15, and B-cell markers to predict which patients will benefit from rapid-acting antidepressants before therapy begins, saving time and tailoring interventions for difficult-to-treat depression.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this depression and psychopharmacology research news
Author: Aubrey Bloom
Source: M. D. Anderson
Contact: Aubrey Bloom – M. D. Anderson
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics” by Gregory H. Jones, Jessica R. Gilbert, Jenessa N. Johnston, Nirmala Akula, Anton Schulmann, Miranda Arakelian, Shiyong Peng, Peixiong Yuan, Ewurakua A. Winful, Mani Yavi, Brandi Quintanilla, Abdel Elkahloun, Ruin Moaddel, Ioline D. Henter, Dede Greenstein, Rodrigo Machado-Vieira, Christopher M. Bartley, Bashkim Kadriu, Moran Amit, Katy Rezvani, Mark D. Kvarta, Francis J. McMahon & Carlos A. Zarate Jr.. Molecular Psychiatry
DOI:10.1038/s41380-026-03777-z
Abstract
Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics
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.
