Sex-specific differences in the relationship between thyroid hormones and neurocognition in schizophrenia: A large-scale cross-sectional study

Background: Sex differences in thyroid hormones, cognitive function, and psychiatric symptoms in schizophrenia remain underexplored. The study aimed to investigate the cross-sectional relationships between thyroid hormone levels, cognitive impairments, and clinical symptoms in people with chronic schizophrenia, with a focus on sex differences.

Methods: We included 1007 people with schizophrenia (602 males and 405 females), and 326 healthy controls (193 males and 133 females). Cognitive function and psychiatric symptoms were assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Positive and Negative Syndrome Scale (PANSS), respectively. Blood samples were collected to measure serum total thyroxine (TT4), total triiodothyronine (TT3), thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3). Analysis of variance (ANOVA) and two-way ANOVA were used to compare clinical characteristics and sex differences. Pearson correlation and hierarchical linear regression were conducted to assess the relationships between thyroid hormone levels, cognitive impairments, and clinical symptoms.

Results: People with schizophrenia exhibited lower levels of thyroid hormones compared to the healthy control group (both P < 0.01). Male patients had higher TT3 and FT3 levels than female patients (both P < 0.01). The cognitive scores of the healthy controls were generally higher than those of people with schizophrenia (P < 0.001). Additionally, there were significant sex differences in visuospatial/constructive abilities and language (both P < 0.01) among people with schizophrenia, with males scoring higher than females. The linear regression found that in the cognitive domain, TT4 was negatively associated with Visuospatial/Constructive abilities and RBANS total scores in male patients (both P < 0.05), whereas TT4 was positively associated with these abilities and attention in female patients (all P < 0.05). Additionally, in male patients, TT3 was negatively associated with most of PANSS scale (all P < 0.05). In female, TT3 was only negatively associated with the PANSS Negative scale (P < 0.05).

Conclusion: Sex differences exist in thyroid hormone T3 levels in people with schizophrenia. The association between thyroid hormones and cognitive performance varies by sex in chronic schizophrenia.