A biomarker study links immune signaling (IL-7/IL-15) and brain gamma-wave activity to ketamine response in TRD.
A new study combining spinal fluid protein analysis, lab-grown neurons, blood gene activity, and brain imaging has pinpointed 2 immune proteins, interleukin (IL)-15 and monocyte chemoattractant protein-1 (MCP-1), as a shared signal behind the rapid antidepressant effects of ketamine and serotonergic psychedelics in patients with
“Our findings suggest that therapeutic efficacy involves restoring IL-15/IL-7 balance, leading to downstream effects on B-cell homeostasis and neuronal activity,” wrote Gregory H. Jones, MD, from The University of Texas MD Anderson Cancer Center, and colleagues.
Ketamine works fast, producing a response in roughly 40% to 50% of patients with TRD, but relapse typically occurs within a median of 18 days.2,3,4 Psilocybin-assisted therapy also works, but it requires heavy staff and resource support and is difficult to test in blinded trials.5,6 Ketamine and psychedelics act on different receptors, yet trigger similar downstream biology, prompting investigators to search for the molecular link behind rapid antidepressant response.
Using this multiomic approach, investigators grew cortical neurons from stem cells taken from 5 patients with TRD and 5 healthy volunteers, all females, and then exposed the neurons for 24 hours to ketamine, its metabolite (2R,6R)-hydroxynorketamine (HNK), lysergic acid diethylamide (LSD), or psilocybin.¹ The neurons' response to all 4 drugs was highly similar (r = 0.70-0.88; P <2×10⁻¹⁶). Investigators then compared these changes with serial spinal fluid protein data collected from 9 healthy volunteers after a single ketamine infusion (0.5 mg/kg).¹
The overlap identified 103 proteins changed in spinal fluid after ketamine and also altered in the lab-grown neurons by ≥ 1 rapid-acting antidepressant. Most of these (86%) also changed after a serotonergic psychedelic and not just ketamine, pointing to a shared biological pathway rather than a ketamine-specific effect. The overlapping proteins clustered mainly around immune signaling, led by IL-15 and MCP-1, alongside a smaller group tied to insulin signaling and synaptic plasticity.
The team then studied blood and brain data from a completed crossover trial of 39 patients with TRD and 25 healthy volunteers, each of whom received both a ketamine infusion (0.5 mg/kg) and a placebo infusion on separate visits.¹ In a subset of 27 participants, blood samples underwent RNA sequencing before and after ketamine to measure immune gene activity. Patients who went on to respond to ketamine (a 50% or greater drop in depression severity by 24 hours) had lower IL-15 activity and higher B-cell activity beforehand than non-responders, and both patterns reversed after the infusion.
Before treatment, higher blood IL-7 levels went along with higher brain gamma-wave activity on MEG scans (P <.05), a pattern seen only in patients with TRD and strongest in the thalamus, insula, and striatum, regions tied to emotion and reward processing. After ketamine, the relationship reversed: higher IL-7 now went along with lower gamma activity in the brain's default-mode network, a circuit tied to rumination and low mood.
A simple blood-marker ratio also predicted the outcome. Patients with a higher baseline ratio of MCP-1 to IL-7 tended to respond worse to ketamine than placebo (P <.001), while those with a higher ratio of IL-4 to interferon gamma (IFN-γ) tended to respond better (P <.001). Both patterns held up across the 3-day study period and did not change after accounting for other inflammatory conditions or anti-inflammatory medication use.
(2R,6R)-HNK, a ketamine metabolite without dissociative adverse events, is already in phase 2 trials, and LSD (DT120) is in phase 3 trials for major depressive disorder.7,8 Both are newer rapid-acting antidepressants moving through the pipeline. The investigators describe the immune findings as hypothesis-generating and say larger, prospective studies are needed before any of them guide clinical decisions.
“This study broadly identified clinically relevant biomarkers and novel therapeutic targets, underscoring the importance and benefit of multimodal approaches to reverse engineering the mechanism of action underlying [rapid-acting antidepressants],” investigators wrote.
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