Cross-sectional and transcriptomic analysis finds a bidirectional link between hypothyroidism and depression, highlighting shared redox and interferon-γ pathways under levothyroxine therapy.
Key Points
To investigate the bidirectional association between thyroid dysfunction and depressive symptoms, evaluate the effect of levothyroxine replacement therapy, and identify shared underlying molecular mechanisms.
Analyzed epidemiological associations between thyroid laboratory markers and depressive symptoms (PHQ-9 score ≥ 5) using the 2007–2012 National Health and Nutrition Examination Surveys (NHANES).
Conducted comparative transcriptomic, functional enrichment (GO/KEGG), and protein-protein interaction network analyses using GEO datasets (GSE251778, GSE103305) from levothyroxine-treated hypothyroid and major depressive disorder cohorts.
Participants receiving thyroid hormone replacement therapy had a significantly higher risk of depressive symptoms compared to euthyroid controls (OR = 1.328; 95% CI: 1.115–1.582; P = 0.002), whereas untreated individuals with elevated TSH did not (OR = 0.893; 95% CI: 0.589–1.356; P = 0.597).
Multivariable adjustment comparing treated versus untreated hypothyroid patients revealed a marginally significant difference in depressive symptom risk (OR = 1.486; 95% CI: 0.956–2.311; P = 0.078).
Transcriptomic analysis identified 17 shared differentially expressed genes enriched in oxidoreductase activity and reactive oxygen species pathways, with IFNG identified as the central core gene.