Urinary organic acid levels and their associations with clinical characteristics in patients with schizophrenia

INTRODUCTION: Schizophrenia is a chronic psychiatric disorder characterized by substantial biological and clinical heterogeneity. Beyond classical neurotransmitter-based models, increasing evidence suggests that systemic metabolic alterations may contribute to its pathophysiology. OBJECTIVES: This study aimed to characterize urinary organic acid profiles in patients with schizophrenia and investigate their associations with clinical characteristics and pathway-level metabolic alterations. METHODS: In this cross-sectional study, urinary organic acids were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 55 patients with schizophrenia and 30 age- and sex-matched healthy controls. Organic acid concentrations were normalized to urinary creatinine levels. Clinical severity was evaluated using the Positive and Negative Syndrome Scale and the Clinical Global Impressions-Severity scale. Differential metabolite analysis, subgroup comparisons, principal component analysis, correlation analyses, and pathway enrichment analyses were performed. RESULTS: Patients with schizophrenia demonstrated widespread alterations in urinary organic acid profiles compared with healthy controls, with 40 metabolites remaining significantly different after false discovery rate correction. Subgroup analyses identified additional metabolomic variation according to symptom severity, treatment adherence, family history, and current treatment status. Principal component analysis demonstrated partial separation between patients and controls, whereas subgroup distributions showed substantial overlap. Correlation analyses revealed predominantly weak-to-moderate associations between clinical variables and urinary metabolite concentrations. Pathway enrichment analysis identified propanoate metabolism as the only pathway that remained statistically significant after multiple testing correction, while several additional pathways demonstrated nominal enrichment. CONCLUSION: These findings suggest that schizophrenia is associated with broad alterations in urinary metabolomic profiles and support the possibility that intermediary metabolic pathways may contribute to the biological complexity and heterogeneity of the disorder. Further longitudinal and validation studies are needed to clarify the biological and clinical relevance of these observations.