ArticleJournal of affective disorders2026
Thyroid dysfunction and Research Domain Criteria framework-based depression phenotypes: Insights from a historical longitudinal cohort.
Article in Journal of affective disorders, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundDepression is a clinically heterogeneous disorder, making it difficult to identify its biological underpinnings, including potential links to dysregulation of the hypothalamic-pituitary-thyroid axis, which plays a central role in the pathophysiology of depression. The Research Domain Criteria (RDoC) framework provides a multi-dimensional approach to parsing depressive phenotypes. This study investigates the association between thyroid-stimulating hormone (TSH) abnormalities and depressive symptoms mapped to RDoC domains.
methodsIn a retrospective cohort from 2000 to 2021, adults with euthymic (PHQ-9 < 5) and euthyroid (TSH >0.3-4.2 mIU/L) baseline status and at least two TSH-PHQ-9 paired assessments within six months were included. PHQ-9 items were mapped to four RDoC-aligned domains: Negative Valence-Externalizing, Negative Valence-Internalizing, Arousal/Regulatory (AR) Systems, and Cognitive/Sensorimotor (CS) Systems. Linear mixed-effects models adjusted for covariates were used to assess the association between subsequent TSH dysfunction (low TSH ≤0.3 mIU/L and high TSH >4.2 mIU/L) and domain scores.
resultsAmong 6191 adults (mean age, 50.2 years; 67% female; 92.4% White), abnormal TSH levels are associated with higher AR Systems scores, with higher mean AR scores for low TSH (2.54; 95% CI, 2.38-2.70) and high TSH (2.57; 95% CI, 2.44-2.69) compared with normal TSH (2.40; 95% CI, 2.29-2.50; p ≤ .04). No significant differences were found in other RDoC domains.
conclusionsOur findings support the utility of a biologically informed, dimensional framework in depression research. Elevated AR Systems symptoms in the context of abnormal TSH levels may suggest a possible narrower phenotype, with implications for personalized treatment if validated and further investigation into the thyroid-depression interface.
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