Exploring the potential impact of TNF-α inhibition on major depressive disorder risk: Insights from a prospective cohort and genetic evidence.

BACKGROUND

A growing body of evidence suggests that inflammatory dysregulation contributes causally to major depressive disorder (MDD) in a subset of individuals. Tumour necrosis factor-α (TNF-α), a key cytokine linking peripheral inflammation and neural dysfunction, may represent a modifiable target for immunomodulatory intervention.

OBJECTIVE

To evaluate whether genetically proxied for TNF-α inhibition (TNFAIs) is associated with a lower risk of MDD and to determine whether this relationship is consistent across inflammatory and clinical contexts.

METHODS

We combined drug-target two-sample Mendelian randomisation (MR) with a large prospective cohort analysis. Genetic proxies for TNFAIs were defined using TNF-locus variants associated with reduced circulating C-reactive protein (CRP) and leukocyte counts. MR analyses used summary statistics from the Psychiatric Genomics Consortium and genome-wide association studies of MDD and depressive symptoms. Validation was performed in 421,062 UK Biobank participants, where a TNFAI genetic score was tested for association with incident MDD using multivariable Cox models. Subgroup analyses were stratified by sex, age, baseline inflammation, antidepressant use and traumatic event.

RESULTS

Genetically proxied TNFAIs were associated with a reduced risk of MDD (OR = 0.88, 95% CI = 0.83-0.92, P = 1.20E-06) and potential improvements in depressed mood, weight loss, hypersomnia, and suicidal thoughts, but a higher likelihood of insomnia (P < 0.05/12). In the UK Biobank, TNFAI genetic score-indicating stronger genetically proxied TNFAIs-was consistently associated with lower incident MDD (HR = 0.95, 95% CI = 0.92-0.98, P = 0.002). These associations remained directionally consistent across all subgroups without significant interactions, suggesting a robust and generalisable protective effect.

CONCLUSIONS

Integrating genetic and longitudinal evidence, our findings support TNF-mediated inflammation as a causal and modifiable pathway in MDD. TNFAIs may represent a promising strategy to reduce MDD risk across diverse clinical and inflammatory contexts.