Combination LT3/LT4 Therapy Linked to Higher Psychiatric Risk in Autoimmune Hypothyroidism: Study
Sweden: Researchers have found in a new study that among patients with autoimmune hypothyroidism, adding liothyronine (LT3) to levothyroxine (LT4) therapy was associated with an increased risk of psychiatric disorders, especially affective and anxiety-related morbidity.
The findings are from a large nationwide cohort study conducted in Sweden and published in the Journal of the Endocrine Society, led by Fredric Hedberg and colleagues. The study assessed whether combination thyroid hormone therapy (LT4 plus LT3) is linked to higher rates of psychiatric outcomes compared with standard levothyroxine monotherapy.
Levothyroxine remains the standard treatment for hypothyroidism, but some patients continue to experience symptoms, leading to increasing off-label use of liothyronine despite limited evidence of added benefit. Against this backdrop, the study evaluated potential mental health risks linked to LT3 use in real-world settings.
Using Swedish national registers, researchers analysed 184,266 adults with autoimmune hypothyroidism treated between 2006 and 2020. Patients with prior psychiatric illness were excluded, and treatment exposure was tracked using national databases, with LT3 use assessed as a time-dependent variable.
Key findings:
- During follow-up, 5,346 patients (2.9%) were exposed to LT3 in addition to LT4.
- The median follow-up duration was 2.7 years for the combination therapy group and 3.8 years for the LT4-only group.
- Multivariable Cox regression analysis showed a consistent association between LT3 use and increased psychiatric morbidity.
- Patients on LT4+LT3 therapy had a 43% higher risk of developing any psychiatric disorder compared with LT4 alone.
- The increased risk was observed across affective and anxiety-related disorders.
- A smaller but statistically significant association was also noted for psychotic disorders.
These findings suggest that the addition of liothyronine may be linked to adverse mental health outcomes in patients with autoimmune hypothyroidism. While the results do not confirm a direct causal relationship, they raise important questions about the neuropsychiatric safety profile of combination thyroid hormone therapy.
Several explanations have been proposed, including potential physiological effects of T3 on brain neurotransmission, altered hormone fluctuations, or the possibility that patients selected for LT3 therapy may represent a subgroup with greater baseline symptom burden or vulnerability to psychiatric illness.
The authors emphasize that, despite careful adjustment for confounders, residual bias cannot be fully excluded in observational research. Nonetheless, the large national dataset and long-term follow-up strengthen the robustness of the findings.
Overall, the study highlights the need for careful consideration when prescribing LT3 as an adjunct to LT4 therapy. It also highlights the importance of further prospective research to determine whether the observed association reflects a true biological effect or underlying patient characteristics driving treatment selection.
Reference:
Hedberg, F., Lindh, J. D., Mannheimer, B., Planck, T., Skov, J., Falhammar, H., & Calissendorff, J. Psychiatric Morbidity Following Liothyronine Exposure in Autoimmune Hypothyroidism: A Swedish Nationwide Cohort Study. Journal of the Endocrine Society. https://doi.org/10.1210/jendso/bvag107
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