The Effect of Ketamine on the Immune System in Patients with Treatment-Resistant Depression

In people with treatment-resistant depression, a single intravenous dose of ketamine (0.5 mg/kg) produces rapid, temporary shifts in immune markers. Within 4 hours, total T cells and certain helper T-cell subsets increased, while by 24 hours, activated T cells declined and the ratio of helper to cytotoxic T cells decreased. Blood levels of the anti-inflammatory cytokine IL-10 rose, while the pro-inflammatory cytokines IL-6 and IL-8 fell—IL-8 remained lower for at least 24 hours. In laboratory experiments, high-dose ketamine boosted the growth of helper T cells from depressed patients and increased secretion of IL-8 and IL-6 from activated immune cells. The sustained drop in IL-8 points to an anti-inflammatory effect and may serve as a biomarker for treatment response.

Study at a glance

Abstract

Treatment-resistant depression (TRD) is associated with immune dysregulation. Ketamine, a rapid-acting antidepressant, may exert effects via immunomodulation. The aim was to examine ketamine’s impact on immune markers in TRD, including T-cell subsets, cytokines, and in vitro T-cell responses. Eighteen TRD inpatients received 0.5 mg/kg iv ketamine. Blood was sampled at baseline, 4 h, and 24 h to analyze T-cell phenotypes (CD28, CD69, CD25, CD95, HLA-DR) and serum cytokines (IL-6, IL-8, IL-10, TNF-α, IL-1β, IL-12p70). In vitro, PBMCs from TRD patients and controls were exposed to low (185 ng/mL) and high (300 ng/mL) ketamine doses. Ketamine induced a transient increase in total T cells and CD4+CD25+ and CD4+CD28+ subsets at 4 h, followed by a reduction in CD4+ and an increase in CD8+ T cells at 24 h, decreasing the CD4+/CD8+ ratio. Activation markers (CD4+CD69+, CD4+HLA-DR+, CD8+CD25+, CD8+HLA-DR+) declined at 24 h. Serum IL-10 increased, IL-6 decreased, and IL-8 levels—initially elevated—showed a sustained reduction. In vitro, high-dose ketamine enhanced the proliferation of TRD CD4+ T cells and dose-dependent IL-8 and IL-6 secretion from activated cells. Ketamine induces rapid, transient immune changes in TRD, including reduced T-cell activation and cytokine modulation. A sustained IL-8 decrease suggests anti-inflammatory effects and potential as a treatment-response biomarker.