Systemic Inflammation Mediates the Association between Thyroid Hormone Sensitivity and Depressive Symptoms in Euthyroid Population: Findings from NHANES

INTRODUCTION: The relationship between thyroid function and depression remains unclear in euthyroid individuals. This study investigated the association between central thyroid hormone sensitivity (CTHS) and depression, and explored whether systemic inflammation mediated this relationship. METHODS: This cross-sectional analysis included 6,728 adults from the National Health and Nutrition Examination Survey 2007-2012. Depression was defined as a Patient Health Questionnaire score of ≥10. CTHS was assessed using four indices: thyroid-stimulating hormone index (TSHI), thyrotropin thyroxine resistance index (TT4RI), thyroid feedback quantile-based index (TFQI), and parametric TFQI (PTFQI). Multivariable logistic regression, generalized additive models, and mediation analysis were performed. RESULTS: Participants with depression exhibited significantly lower CTHS across all four indices (all p < 0.05). Generalized additive models revealed nonlinear associations between CTHS and depression. In quartile-based analyses, the strongest inverse associations were observed at the 3rd quartile for TSHI (adjusted OR 0.648, 95% CI: 0.497-0.845), TFQI (adjusted OR 0.646, 95% CI: 0.494-0.844), and PTFQI (adjusted OR 0.707, 95% CI: 0.543-0.920), while the 2nd quartile of TT4RI showed the strongest association (adjusted OR 0.623, 95% CI: 0.480-0.809). CTHS was most consistently associated with anhedonia among depressive symptoms. Mediation analysis revealed that C-reactive protein (CRP) partially mediated the relationship between PTFQI and depression (proportion mediated: 6.3%, p = 0.004). CONCLUSION: CTHS is nonlinearly associated with depression in euthyroid adults, with CRP partially mediating this relationship. These findings highlight the potential role of neuroendocrine-immune interactions in depression and suggest that the indices of CTHS may capture clinically relevant variations missed by conventional thyroid function tests.