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Clinical Trial
. 2025 Jan:123:177-184.
doi: 10.1016/j.bbi.2024.09.005. Epub 2024 Sep 4.

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

Marion Leboyer  1 , Marianne Foiselle  2 , Nicolas Tchitchek  3 , Ryad Tamouza  2 , Roberta Lorenzon  4 , Jean-Romain Richard  2 , Raphaele Arrouasse  5 , Philippe Le Corvoisier  5 , Katia Le Dudal  5 , Eric Vicaut  6 , Pierre Ellul  3 , Michelle Rosenzwajg  4 , David Klatzmann  7
Affiliations
Clinical Trial

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

Marion Leboyer et al. Brain Behav Immun. 2025 Jan.

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-2LD) 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-2LD in patients with bipolar depression. Patients received a placebo or IL-2LD (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-2LD 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-2LD. Baseline clinical and biological characteristics were balanced between groups. The primary evaluation criterion was met, with IL-2LD 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-2LD 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-2LD as an adjunct treatment of major mood disorders.

Keywords: Biotherapy; Cytokine; Immunotherapy; Neuroinflammation; Psychiatric Diseases; Tolerance.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MR, RL and DK are inventors for patent applications related to the therapeutic use of IL-2(LD), which belongs to their academic institutions and has been licensed to ILTOO Pharma. MR and DK hold shares in ILTOO Pharma. No other potential conflicts of interest relevant to this article were reported.

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