Bidirectional association between thyroid dysfunction and depressive symptoms: the role of levothyroxine therapy and shared molecular mechanisms

Background The association between thyroid dysfunction, thyroid hormone replacement therapy, and depression remains inconsistent. This study investigated the bidirectional risk association between thyroid dysfunction and depressive symptoms, focusing on the effect of thyroid hormone therapy on depressive symptoms, and exploring the shared molecular basis between hypothyroidism treated with levothyroxine and depression at the genetic level. Methods Part one utilized 2007–2012 National Health and Nutrition Examination Surveys (NHANES) data to analyze associations between thyroid profiles and depressive symptoms. Part two compared molecular expression profiles between levothyroxine-treated hypothyroid patients and major depressive disorder patients using GEO datasets (GSE251778, GSE103305). Results Part one revealed a bidirectional association between depressive symptoms and hypothyroidism: patients with decreased interest, appetite changes, or feelings of worthlessness/failure were more likely to have hypothyroidism, while hypothyroidism was associated with an increased risk of depressive symptoms in general (PHQ-9 score ≥ 5). Compared with those with normal thyroid function, participants receiving thyroid hormone replacement therapy had a significantly higher risk of PHQ-9 score ≥ 5 (OR = 1.328; 95% CI: 1.115–1.582; P = 0.002), whereas untreated patients with elevated TSH did not (OR = 0.893; 95% CI: 0.589–1.356; P = 0.597). After adjusting for confounders, the difference in depressive symptoms risk between the treated and untreated groups was of marginal significance (OR = 1.486, 95% CI: 0.956–2.311; P = 0.078). Part two identified 17 common differentially expressed genes (DEGs) between levothyroxine-treated hypothyroid patients and major depressive disorder patients by intersecting their respective DEGs with controls. GO enrichment analysis revealed significant terms such as ‘oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor’ and ‘oxidoreductase activity, acting on NAD(P)H’. KEGG enrichment analysis revealed pathways related to antigen processing and presentation, chemical carcinogenesis-reactive oxygen species, and the cytoskeleton in muscle cells. PPI network analysis revealed that IFNG is the core gene. Conclusions This study confirmed the bidirectional association between thyroid disorders and depressive symptoms. The results also suggest that levothyroxine replacement therapy may be associated with an increased risk of depressive symptoms in hypothyroid patients. Potential molecular mechanisms involved an imbalance in redox homeostasis and abnormal interferon-γ signalling pathways. These findings provide new insights into the pathophysiological mechanisms linking thyroid dysfunction and depression and may offer clues for future therapeutic strategies.