Association of Low-Normal Free T4 Levels With Future Major Depression Development

CONTEXT: Hyperthyroidism and overt and subclinical hypothyroidism are associated with major depression; however, the association of major depression across the spectrum of thyroid function within the normal range is unknown. OBJECTIVE: We investigated whether higher or lower levels of free thyroxine (T4) and thyrotropin (TSH) within the normal range are associated with major depression. METHODS: This was a retrospective cohort study of 66 960 participants with normal thyroid function who visited for health checkups (St. Luke's International Hospital, 2005-2018). The primary outcome was the development of major depression during the follow-up period. Participants were divided into 3 equal groups based on baseline free T4 or TSH values (low-, middle-, or high-normal), and the incidence of major depression was compared using the Cox proportional hazard model after adjusting for potential covariates. RESULTS: During the median follow-up of 1883 days, 1363 (2.0%) patients developed major depression. The low-normal free T4 group had a significantly higher risk of major depression (adjusted HR 1.15; 95% CI, 1.01-1.31), but not the high-normal free T4 group or TSH groups. The association between low-normal free T4 and the development of major depression was maintained, rather more obvious, upon exclusion of participants whose thyroid hormone levels became abnormal during follow-up compared with data from all participants (adjusted HR 1.24; 95% CI, 1.07-1.43). CONCLUSION: In this cohort, low-normal free T4 was associated with an increased risk of future major depression, even if subsequent hormone levels were maintained within the normal range. The magnitude of the impact of low-normal free T4 was relatively mild.