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.