Low-dose interleukin-2 in patients with bipolar depression: a phase 2 randomised double-blind placebo-controlled trial

Abstract Immune abnormalities including an insufficiency of regulatory T cells (Treg) and increased blood-based inflammatory markers have been observed in bipolar disorders (BD), particularly during depression. As Tregs are pivotal to control inflammation, Treg stimulation by low-dose IL-2 (IL-2 LD ) could have a therapeutic impact on bipolar depression. We performed a randomized, double-blind, placebo-controlled (2 active: 1 placebo) proof-of-concept trial of add-on IL-2 LD in patients with bipolar depression. Patients received a placebo or IL-2 LD (1MIU) once a day for 5 days, and then once a week for 4 weeks starting on week 2. The primary objective was to demonstrate a biological Treg response to IL-2 LD assessed by fold increase in Treg percentage of CD4+ cells from baseline to day 5. Secondary objectives included safety assessment and mood improvement throughout the study period. This trial is registered with ClinicalTrials.gov, number NCT04133233 . Fourteen patients with bipolar depression were included, with 4 receiving placebo and 10 IL-2 LD . Baseline clinical and biological characteristics were balanced between groups. The primary evaluation criterion was met, with IL-2 LD expanding 1.17 [95% CI 1.01-1.34] vs 1.01 [95% CI 0.90 - 1.12] (p=0.0421) and activating Tregs. Secondary evaluation criteria were also met with significant improvements of depressive symptoms and global functioning from day-15 onwards in the IL-2 LD treated patients. The treatment was well-tolerated, with no serious adverse events related to treatment. This proof-of-concept trial shows that stimulating Tregs in patients with bipolar depression is safe and associated with clinical improvements. This supports a pathophysiological role of inflammation in BD and warrants pursuing the evaluation of IL-2 LD as an adjunct treatment of major mood disorders.