Thyroid peroxidase antibodies in bipolar disorder: implications for clinical sub-phenotypes and lithium response

Bipolar disorder (BD) is a heterogeneous psychiatric disorder that is increasingly recognized as having immune-inflammatory pathogenesis. Previous studies have shown thyroid autoimmunity, in particular, thyroid peroxidase antibody (TPO-Ab), is associated with rapid cycling and antidepressant-induced mania in BD. We examined the relationship between TPO-Ab seropositivity and BD clinical sub-phenotypes and lithium response. In this cross-sectional study, adult patients with BD enrolled in the Mayo Clinic BD Biobank were stratified into TPO-Ab positive versus negative groups using all available information (research data and electronic health records). Multivariable logistic regression analyses were conducted to assess associations between TPO-Ab status and clinical sub-phenotypes, including early age at onset, history of psychosis, rapid cycling, suicide attempt, and antidepressant-induced mania. Linear regression was used to examine associations with lithium treatment response (Alda A score). All models were adjusted for age, sex, BMI, and laboratory data source for TPO-Ab values. Among 339 individuals (mean age = 43.8 ± 15.2 years, 61.1% female), 23.9% were TPO-Ab positive. In adjusted models, TPO-Ab positivity was associated with reduced odds of history of psychosis (OR = 0.49, 95% CI 0.27–0.87, p = 0.017) and poorer treatment response to lithium (β = -0.92, 95% CI -1.74 – -0.11, p = 0.026). In exploratory analyses, no significant interactions of TPO-Ab status with age and sex were observed across different sub-phenotypes. Our findings suggest that thyroid autoimmunity is associated with a distinct BD phenotype characterized by less psychosis and a poor response to lithium treatment. Future prospective longitudinal studies should validate these findings in larger cohorts and investigate underlying biological mechanisms by incorporating thyroid function status, thyroid antibody dynamics, and broader autoantibody proteome.