A new study suggests rapid-acting antidepressants such as ketamine and psychedelics may relieve depression by rebalancing specific immune system pathways in the body and brain, with the ability to predict treatment response. The findings, published in Molecular Psychiatry, come from a collaboration led by Gregory H. Jones of the National Institute of Mental Health and The University of Texas MD Anderson Cancer Center.
Standard antidepressants often take weeks to ease symptoms, whereas compounds like ketamine and psilocybin can provide rapid relief for those with treatment‑resistant depression. Yet these therapies pose challenges, including the need for repeated dosing and extensive clinical supervision during psychedelic‑assisted treatment.
Researchers note that ketamine and psychedelics act on entirely different receptors in the brain—ketamine blocks NMDA receptors while classic psychedelics target a serotonin receptor—but they suspect both classes may activate the same downstream molecular pathways over time.
Clinical depression is linked with chronic, low‑grade inflammation, and fast‑acting antidepressants are known to engage a cellular pathway called mTOR, which governs brain structural changes and immune cell metabolism. The study set out to identify shared biological responses that might underpin these rapid effects.
To explore this, the team treated lab‑grown human brain cells, derived from induced pluripotent stem cells, with ketamine, a ketamine byproduct (HNK), LSD, or psilocybin. They then analysed which genes were switched on or off by each drug.
For real‑world context, the researchers compared these cellular changes with spinal fluid samples from healthy volunteers who had received intravenous ketamine. By aligning the two data sets, they sought clues about how the cellular responses relate to human biology.
They identified 103 proteins that were altered by ketamine in the spinal fluid and by at least one psychedelic in the cell models, with 86 per cent of these also affected by the psychedelics. When the team mapped how these proteins interact, they uncovered two distinct functional modules.
The primary module formed a highly connected network centred on immune system signalling, with interleukin‑15 and monocyte chemoattractant protein‑1 (MCP‑1) emerging as central hubs. Interleukin‑15 helps regulate defence cells, while MCP‑1 directs immune cells to sites of inflammation.
A secondary module consisted of proteins linked to insulin signalling and the brain’s ability to reconfigure its connections, suggesting the immune signalling pathway could steer the broader brain changes induced by fast‑acting drugs.
To gauge relevance to actual treatment, the researchers turned to a clinical trial involving 39 participants with treatment‑resistant depression and 25 healthy volunteers. Each participant received a single intravenous dose of ketamine or a placebo, with comprehensive blood and brain activity monitoring.
Before treatment, those who would later respond to ketamine showed lower interleukin‑15 activity than non‑responders, and they also exhibited higher activity in signaling pathways related to B‑cells. Four hours after infusion, this pattern reversed in responders: interleukin‑15 activity rose while B‑cell signalling decreased, with further indications of shifts in natural killer T‑cell proportions.
In a parallel assessment, the team measured circulating interleukin‑7, a driver of B‑cell development, and compared it with brain activity measured by magnetoencephalography. They found that higher pre‑treatment interleukin‑7 levels correlated with higher gamma power, particularly in deep brain regions such as the thalamus and striatum, among those with depression.
Post‑ketamine, the relationship inverted: higher interleukin‑7 levels tended to accompany lower gamma power within the brain’s default mode network, a area typically more active at rest and often overactive in depression.
The researchers also noted that certain baseline ratios of immune molecules could forecast treatment outcome. A higher starting MCP‑1 to interleukin‑7 ratio predicted a poorer response to ketamine, while a higher ratio of interleukin‑4 to interferon‑gamma predicted a better response.
Limitations were acknowledged. The lab‑grown brain cells used in the experiments were derived from female donors, and the spinal fluid samples came from healthy volunteers, potentially affecting generalisability to a broader patient population. Additionally, there was a timing mismatch in the human trial: blood samples were collected four hours after ketamine, while brain imaging occurred six to nine hours post‑infusion, which could complicate linking immune changes to neural activity.
Researchers describe the findings as exploratory, emphasising the need for larger, independent studies to confirm whether modulating these specific immune pathways could reliably treat depression and pave the way for therapies that replicate the rapid benefits of ketamine without its side effects.
The study, “Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics,” lists Gregory H. Jones and colleagues, including Jessica R. Gilbert, Jenessa N. Johnston, Nirmala Akula, Anton Schulmann, and many others, as contributing authors.
