Target Validation of Interleukin-4 Receptor Alpha for Major Depressive Disorder

We propose to validate interleukin-4 receptor alpha (IL-4Rα) as a novel immune target for major depressive disorder (MDD). IL-4Rα is the shared subunit of the IL-4 and IL-13 receptors and modulates the T-helper 2 (Th2) immune pathway. To our knowledge, IL-4Rα has not been investigated in psychiatric drug development, representing a novel mechanism for therapeutic intervention in MDD.Our rationale stems from converging evidence across immunology, psychiatry, and translational biology. Our proteomic analyses show that MDD shares immune signatures involving Th2/Th17 pathways with inflammatory skin disorders, and that the immune signature specific to MDD is reversed by dupilumab, an anti-IL-4Rα monoclonal antibody approved for atopic dermatitis and asthma.We will use dupilumab as a repurposed tool compound in a randomized, double-blind, placebo-controlled trial to evaluate whether IL-4Rα inhibition modulates the MDD immune signature and reduces depressive symptoms. Study outcomes will include peripheral immune changes, depressive symptom improvement, safety, and exploratory behavioral measures.This proposal focuses on a patient group with high unmet need. Given the favorable safety profile and tolerability of dupilumab in real-world populations, this study offers a low-risk, high-impact opportunity to de-risk a novel immune pathway in MDD and enable biomarker-driven development of IL-4Rα-targeted therapeutics in psychiatry.