A recent study found that rapid-acting antidepressants like ketamine and psychedelics may relieve depression by regulating specific immune system pathways in the body and brain. The research suggests that rebalancing a precise set of immune signaling molecules can predict how well a patient will respond to treatment. These findings were published in the journal Molecular Psychiatry.
Standard antidepressants often take weeks to relieve symptoms of major depressive disorder. In contrast, compounds such as ketamine and psilocybin act within hours, providing rapid relief for patients with treatment-resistant depression. Despite their rapid effects, these therapies present unique challenges.
Ketamine’s benefits often fade within a few weeks, requiring repeated treatments. Meanwhile, therapies involving psychedelics require extensive clinical supervision and psychological support. Researchers want to understand the exact biological mechanisms that make these drugs work so quickly, hoping to develop new therapies without these drawbacks.
Ketamine and psychedelics target entirely different receptors in the brain. Ketamine blocks a receptor called NMDA, while classic psychedelics like psilocybin and LSD stimulate a specific serotonin receptor. Because both classes of drugs produce rapid antidepressant effects, researchers suspect they eventually activate the same downstream molecular pathways inside the cells.
Clinical depression is associated with chronic, low-grade inflammation throughout the body. Fast-acting antidepressants also activate a cellular pathway known as mTOR, which controls both structural changes in the brain and immune cell metabolism. A team of scientists led by Gregory H. Jones, a researcher at the National Institute of Mental Health and The University of Texas MD Anderson Cancer Center, set out to identify these shared biological responses.
The researchers first examined lab-grown human brain cells, known as induced pluripotent stem cells. These are adult cells that have been reprogrammed into an embryonic-like state and then coaxed into becoming brain cells. The team treated these specialized cells with either ketamine, a ketamine byproduct called HNK, LSD, or psilocybin.
After treating the cells, the scientists analyzed which genes were turned on or off by each drug. To see if these genetic changes matched biological activity in humans, the researchers compared the cell data with spinal fluid samples. These samples were previously collected from healthy volunteers who had received intravenous ketamine.
By comparing the two datasets, the team found 103 proteins that were altered by ketamine in the spinal fluid and also changed by at least one of the drugs in the lab-grown cells. Very few of these proteins were exclusive to ketamine and its byproduct; 86 percent were also altered by at least one of the psychedelics. When the team mapped how these proteins interact, they discovered two distinct functional modules.
The primary module was a highly connected network centered around immune system signaling. Two immune molecules, interleukin-15 and monocyte chemoattractant protein-1, emerged as central hubs in this network. Interleukin-15 helps regulate the body’s defense cells, while monocyte chemoattractant protein-1 directs immune cells to areas of inflammation.
A secondary module contained proteins related to insulin signaling and the brain’s ability to rewire its connections. This dual structure suggested that immune signaling might direct the broader brain changes caused by these fast-acting drugs.
To test whether these immune signals apply to real-world depression treatment, the researchers analyzed data from a clinical trial. The trial included 39 participants with treatment-resistant depression and 25 healthy volunteers. Each person received a single intravenous dose of ketamine or a placebo.
The research team looked at gene expression in the participants’ blood before and after treatment. Before receiving ketamine, patients who eventually responded well to the drug showed lower interleukin-15 activity than those who did not respond. These responders also showed higher activity in signaling pathways for B-cells, a type of white blood cell that produces antibodies.
Four hours after the ketamine infusion, this pattern reversed in the responders. Their interleukin-15 activity increased, while their B-cell signaling decreased. The researchers used computational tools to estimate changes in specific blood cell types, finding that proportions of natural killer T-cells also shifted after treatment.
Next, the researchers measured the actual levels of immune proteins circulating in the participants’ blood plasma. They focused on a molecule called interleukin-7, which acts as a primary driver of B-cell development. They compared these interleukin-7 levels to brain wave activity measured by magnetoencephalography, a highly sensitive neuroimaging technique.
The team looked specifically at gamma power, a measure of high-frequency brain wave activity that often changes in response to rapid-acting antidepressants. Before treatment, higher levels of circulating interleukin-7 strongly correlated with higher gamma brain wave power in patients with depression. This relationship was particularly strong in deep brain regions like the thalamus and striatum.
Following the ketamine treatment, this relationship inverted. Higher interleukin-7 levels became associated with reduced gamma power in a collection of brain regions called the default mode network. The default mode network is typically active when a person is resting or wandering in thought, and it is often hyperactive in depressed patients.
The team also looked at the ratio of different immune molecules to see if they could predict treatment success. They found that a higher starting ratio of monocyte chemoattractant protein-1 to interleukin-7 predicted a worse response to ketamine. Conversely, a higher ratio of two other immune proteins, interleukin-4 and interferon-gamma, predicted a better antidepressant response.
The researchers noted several limitations to their work. The lab-grown brain cells were derived entirely from female donors, and the spinal fluid samples came exclusively from healthy volunteers. This demographic limitation means the results might not fully represent how these drugs affect the broader population or people with clinical depression.
The data collection in the human trial also featured mismatched timing across different biological measurements. Blood samples were drawn four hours after the ketamine infusion, while brain imaging occurred six to nine hours post-infusion. This difference in timing could complicate how the immune and brain wave changes relate to each other over time.
The findings are primarily exploratory and serve to generate hypotheses for future testing. Larger, independent studies will be necessary to confirm if modulating these specific immune pathways can reliably treat depression. Direct validation in human subjects could eventually lead to therapies that mimic the rapid effects of ketamine without the associated side effects.
The study, “Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics,” was authored 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, and Carlos A. Zarate Jr.