Genetic evidence for repurposing immunomodulatory drugs for major depressive disorder

Introduction

Major depressive disorder (MDD) is a clinically heterogeneous condition, and converging evidence indicates that inflammatory and immune mechanisms are involved in a subset of patients. Treatments for MDD remain ineffective for many patients, with a substantial proportion failing to achieve remission with current first-line therapies. Notably, treatment-resistant depression appears to disproportionately affect individuals with elevated inflammatory markers. Together, this suggests that anti-inflammatory or immunomodulatory drugs may be promising candidates for repurposing in MDD. However, prior clinical studies have examined only a subset of these compounds and have yielded mixed results.

Aims

We aimed to use genetic data to systematically evaluate immunomodulatory drug targets for evidence of causal effects on MDD risk, identify compounds with repurposing potential based on predicted therapeutic direction, and assess whether these effects differ across individual depressive symptoms.

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 datasets of protein or gene transcript levels (pQTLs and eQTLs) in blood and six brain regions, capturing peripheral and central inflammatory processes. Genetic instruments comprised single-nucleotide polymorphisms (SNPs) and small insertion/deletions (INDELs) within protein-encoding gene regions corresponding to drug targets. As outcomes, we used summary statistics from genome-wide association studies of MDD from the Psychiatric Genomics Consortium (Ncases = 412,305, Ncontrols = 1,588,397), and eight individual depressive symptoms. We prioritised targets based on significant associations in ≥2 exposure panels, robustness across MR models, and no strong evidence for distinct causal variants in colocalisation analysis. We subsequently prioritised compounds based on their mechanism of action and predicted therapeutic direction.

Results

We identified 72 unique drug targets significantly associated with MDD in at least one exposure panel after FDR correction. Among these, 20 met prioritisation criteria for genetic robustness. After integrating therapeutic direction data for their corresponding compounds, we prioritised 13 drug targets (C1S, CRBN, CUL4A, DPEP1, FCGRT, FKBP1A, HRH1, IL1RL2, IMPDH1, MMP7, POLE2, PRIM1, and S1PR4) associated with MDD risk (ORs = 0.99-1.29, psFDR ≤ 0.047). These are targeted by 43 compounds – mostly inhibitory – including doxycycline, sutimlimab, and pomalidomide, which may have therapeutic benefits for MDD. Most genetically supported targets demonstrated heterogeneous effects across depressive symptoms. The number of significant targets for each symptom ranged between 25 (suicidal ideation and appetite) and 34 (sleep problems). Among the prioritised targets, three showed directionally 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 several immunomodulatory drugs for MDD. The heterogeneity of effects across depressive symptoms suggests that distinct 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.

References

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