Genetic evidence for repurposing immunomodulatory drugs for major depressive disorder

Abstract Objective To identify immunomodulatory drug targets with genetic evidence in major depressive disorder (MDD), probe symptom-level heterogeneity in their effects, and identify drug repurposing opportunities. Methods We used cis -Mendelian randomisation to evaluate the targets of 204 immunomodulatory compounds, including immunosuppressants, cytokine inhibitors, and anti-infectives. As exposures, we selected genetic instruments from nine genome-wide association studies (GWASs) of protein or gene transcript levels in blood and six brain regions, capturing peripheral and central inflammatory processes. As outcomes, we used summary statistics from GWASs of MDD and eight individual depressive symptoms. We prioritised targets based on consistency across tissues and robustness of Mendelian randomisation estimates, and prioritised compounds based on predicted therapeutic effects. Results We prioritised 13 drug targets (C1S, CRBN, CUL4A, DEPE1, FCGRT, FKBP1A, HRH1, IL1RL2, IMPDH1, MMP7, POLE2, PRIM1, and S1PR4) associated with MDD risk. These are targeted by 46 compounds – mostly inhibitory – including doxycycline, sutimlimab, and pomalidomide, which may have therapeutic benefits for MDD. In symptom-level analyses, most targets showed heterogeneity across symptoms. Among prioritised targets, three showed consistent effects across more than half the symptoms, while the remainder showed symptom-specific or opposing effects between symptoms. Conclusion We provide genetic evidence supporting the repurposing of immunomodulatory drugs for MDD, including compounds acting on novel therapeutic targets. Effects differ across depressive symptoms, suggesting that symptoms respond to different drug mechanisms. These findings highlight the importance of considering individual symptoms, rather than MDD as a unitary condition, when developing treatments with a broad spectrum of action or targeting specific symptom profiles.