Histidine Metabolic Pathway Contributes to Clozapine-Induced Sialorrhea Based on Nontargeted Metabolomics

Abstract

<b><i>Introduction:</i></b> Clozapine-induced sialorrhea (CIS) is one of the most common side effects of clozapine use, while the mechanism remains unclear. <b><i>Methods:</i></b> A total of 51 schizophrenia patients taking clozapine were selected. Among them, 32 had sialorrhea, and 19 had no sialorrhea. Saliva metabolites were identified using ultra-high-performance liquid chromatography-MS/MS (UHPLC-MS/MS), and the differences in saliva metabolites in each group were analyzed through qualitatively searching HMDB, KEGG, and self-built databases, combined with multivariate statistics. After further evaluation by receiver-operating characteristic curve (ROC) analysis, the screened differential metabolites were enriched and topologically analyzed. <b><i>Results:</i></b> The biomarkers potentially related to CIS included 37 differential metabolites involving 17 metabolic pathways, mainly histidine metabolism (<i>p</i> < 0.05, impact = 0.50), pyrimidine metabolism (<i>p</i> < 0.05, impact = 0.08), and β-alanine metabolism (<i>p</i> < 0.05, impact = 0.06). <b><i>Conclusion:</i></b> Our study indicates that histidine metabolic pathway may contribute to the mechanism of CIS.