TOPLINE:

In patients with autoimmune hypothyroidism, the initiation of liothyronine (LT3) in combination with levothyroxine (LT4) therapy was associated with an increased risk of developing any psychiatric morbidity, particularly affective or anxiety morbidity.

METHODOLOGY:

• Researchers in Sweden conducted a retrospective population-based cohort study to evaluate the association between exposure to LT3 plus LT4 therapy and the risk of developing psychiatric morbidity in adults with autoimmune hypothyroidism.
• They included 184,266 patients with autoimmune hypothyroidism (median age, 47 years; 77.8% women) who newly initiated thyroid hormone replacement therapy and did not have prior psychiatric morbidity.
• Of these patients, 5346 were exposed to LT3 plus LT4 (median age, 41 years; 88.5% women) and 178,920 remained on LT4 alone (median age, 48 years; 78.4% women). The median follow-up duration was 2.7 years among patients exposed to LT3 plus LT4 and 3.8 years among those exposed to LT4.
• The primary outcome was the development of any psychiatric morbidity, and the secondary outcomes were affective or anxiety morbidity and psychotic morbidity.

TAKEAWAY:

• Patients who were exposed to LT3 plus LT4 had a 43% higher risk for any psychiatric morbidity than those who were exposed to LT4 only (adjusted hazard ratio [aHR], 1.43; P < .001).
• The risks for affective or anxiety morbidity (aHR, 1.44; P <.001) and psychotic morbidity (aHR, 1.46; P = .0067) were also significantly higher among patients exposed to LT3 plus LT4 than among those exposed to LT4.
• The associations were consistent for any psychiatric morbidity and affective or anxiety morbidity in both sexes and in patients younger than 75 years, with aHRs ranging from 1.38 to 1.56 and from 1.38 to 1.67 for any psychiatric morbidity and affective or anxiety morbidity, respectively (P < .05 for all).
• Among patients who were exposed to LT3 plus LT4, women (aHR, 1.42; P = .024) and patients younger than 30 years (aHR, 1.91; P = .012) had a higher risk for psychotic morbidity.

IN PRACTICE:

"The observed associations may reflect underlying vulnerability among patients who are prescribed LT3, including the possibility that LT3 may be initiated in response to emerging symptoms of poor mental well-being rather than being causally related to psychiatric morbidity," the authors wrote.

SOURCE:

The study was led by Fredric Hedberg, MD, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. It was published online on May 7, 2026, in the Journal of the Endocrine Society.

LIMITATIONS:

The use of a retrospective design limited causal inference and may have introduced residual confounding. The study lacked data on laboratory measurements, prescribed doses, and duration of LT3 exposure as well as detailed information on socioeconomic factors, treatment decisions, and comorbidities. Surveillance bias and protopathic bias could not be excluded, potentially affecting observed associations.

DISCLOSURES:

This study received support from the Region Stockholm Drug and Therapeutic Committee and the Lisa and Johan Grönberg Foundation. The authors declared having no competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.