Research identifies common neuroimmune signatures in rapid-acting antidepressants

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. 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.” 

Gregory Jones, M.D., Assistant Professor of Psychiatry, The University of Texas MD Anderson Cancer Center 

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.