Potential mechanism of metabolic syndrome related cognitive impairment: Mediation effect of thyroid-stimulating hormone in schizophrenia patients

To investigate the correlation between thyroid hormone levels and cognitive function in schizophrenia (SCZ) patients with metabolic syndrome (MetS), as well as the mediating role of thyroid hormones in the relationship between MetS-related indicators and cognitive function.

A cross-sectional trial was conducted on 120 SCZ inpatients and outpatients (40 cases of MetS and 80 cases of non-MetS) and 80 healthy controls admitted in the Chongqing Mental Health Center from August 2023 to December 2024. Thyroid function indicators [Thyroid-stimulating hormone TSH), triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), and free thyroxine (FT4)], MetS-related parameters [blood glucose, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and waist circumference], Positive and Negative Syndrome Scale (PANSS) score, and Montreal Cognitive Assessment (MoCA) scores were collected. One-way ANOVA or Kruskal-Wallis rank sum test was applied to analyze the differences among the 3 groups, and LSD test or Bonferroni correction was performed for post hoc analysis. Pearson correlation analysis was conducted to assess the relationship between thyroid hormone levels and metabolic parameters as well as cognitive/clinical scale scores (MoCA, PANSS) in the MetS group.

The MetS group exhibited significantly lower FT4 level (P<0.05) and MoCA score (P=0.001), but higher TSH level (P<0.05) and PANSS negative symptom score (P<0.001) when compared to the non-MetS group. Correlation analysis indicated that in the MetS group, TSH level was positively correlated with TG (r=0.672, P<0.001) and PANSS negative symptom score (r=0.458, P<0.05), and negatively with HDL-C (r=-0.377, P=0.017) and MoCA score (r=-0.667, P<0.001); FT4 level was positively correlated with MoCA score(r=0.534, P<0.001). In the non-MetS group, TSH level was positively correlated with PANSS negative symptom score (r=0.267, P=0.017) and negatively with HDL-C (r=-0.236, P=0.036), T3 was positively with waist circumference (r=0.268,P=0.017). No correlation was observed in FT4 level with HDL-C (r=-0.207, P=0.067) or MoCA score (r=0.216, P=0.055). Mediation analysis revealed that TSH partially mediated the association between TG and MoCA score, with a mediation effect accounting for 29. 91% of the total effect. The mediating effect was not significant in the non-MetS group.

Abnormal elevation of TSH may serve as a critical link between MetS and cognitive impairment in SCZ patients, which providing novel insights into the mechanisms underlying cognitive dysfunction in the patients.