Energy metabolism dysregulation in schizophrenia with non-thyroidal illness syndrome: Roles of citric acid and Tyrosol-4-sulfate.

BACKGROUND

Non-Thyroidal Illness Syndrome (NTIS) is frequently observed in schizophrenia and is traditionally regarded as a peripheral endocrine disturbance. However, whether NTIS reflects a distinct metabolic phenotype linked to central energy dysregulation in schizophrenia remains unclear. We hypothesized that NTIS in schizophrenia reflects a distinct metabolic state characterized by disrupted energy metabolism, which may be linked to specific symptom dimensions.

METHODS

A total of 185 patients with schizophrenia were enrolled and classified into NTIS and non-NTIS groups based on standard thyroid hormone criteria. Untargeted metabolomic profiling was performed using ultra-high-performance liquid chromatography high-resolution mass spectrometry. Differential metabolites were identified using Orthogonal-Partial-Least Squares-Discriminant-Analysis and Receiver Operating Characteristic curve analysis, followed by pathway enrichment analyses and regression analyses to examine associations with clinical symptoms.

RESULTS

A total of 29 differential metabolites were screened (Variable Importance in Projection > 2, P - correction < 0.05), primarily related to amino acids and organic acids. Pathway enrichment analysis revealed significant perturbations in 10 metabolic pathways, with the TCA cycle (citrate cycle) (impact = 0.261, P < 0.0001). Two metabolites, Citric acid (AUC = 0.701, P < 0.05) and Tyrosol-4-sulfate (AUC = 0.703, P < 0.05) demonstrated good discriminative performance for NTIS status. These 2 metabolites were positively associated with the Visuospatial/Constructional dimension and negatively associated with positive symptoms in the NTIS group.

CONCLUSIONS

Schizophrenia patients with NTIS display a distinct metabolic phenotype marked by TCA cycle dysregulation. Citric acid and tyrosol-4-sulfate may serve as metabolic indicators linking thyroid dysfunction to cognitive, psychotic symptoms.