Psychiatric morbidity following liothyronine exposure in autoimmune hypothyroidism: a Swedish nationwide cohort study

Abstract Context Levothyroxine (LT4) is the primary treatment of hypothyroidism. Despite adequate LT4 substitution some patients experience symptoms and the use of adjunct liothyronine (LT3) has increased. Several trials show no clear advantage of LT4 + LT3, and observational studies report conflicting results. Objective We aimed to assess the relationship between initiation of LT3 treatment and psychiatric morbidity in patients with autoimmune hypothyroidism. Methods All adults in Sweden with autoimmune hypothyroidism without prior psychiatric morbidity initiated on thyroid hormone replacement between 2006 and 2020 were included. Data were obtained from the National Patient Register and the National Prescribed Drug Register. The risk of any psychiatric morbidity after LT4 vs LT4 + LT3 therapy was estimated using Cox regression models with multivariable adjustments and LT3 as a time-dependent covariate. Results The total cohort comprised 184 266 individuals. During follow-up, 5346 (2.9%) were exposed to LT3. Median follow-up on LT4 + LT3 was 2.7 years (IQR 1.1-4.4) and 3.8 years (IQR 1.5-7.3) on LT4. Exposure to LT3 was associated with higher risk of any psychiatric morbidity (aHR 1.43, 95% CI 1.34-1.53, P < .001). An association was also found with affective or anxiety morbidity (aHR 1.44, 95% CI 1.35-1.54, P < .001) and with psychotic morbidity (aHR 1.46, 95% CI 1.11-1.92, P = .0067) after multivariable adjustment. Conclusion In autoimmune hypothyroidism LT4 + LT3 treatment was associated with increased risk of psychiatric morbidity. This may reflect a potential LT3 effect or an underlying vulnerability among LT3 users, underscoring the need for further studies to clarify any causal relationship.