Identifying novel metabolites in children with attention-deficit hyperactivity disorder through metabolome profiling

Metabolomics research offers promising potential for identifying key metabolites and exploring the pathophysiological underpinnings of attention-deficit hyperactivity disorder (ADHD). However, serum metabolomics in ADHD remains largely uncharted. Our study aimed to search for metabolomic biomarkers in children with ADHD. 70 drug-naïve children diagnosed with ADHD according to DSM-5 criteria and 70 sex-, age-, IQ-matched healthy controls were recruited from the National Taiwan University Hospital. All participants were assessed for clinical and ADHD symptoms using the Clinical Global Impression Severity (CGI-S) and ADHD Rating Scale-IV (ADHDRS-IV), respectively. Serum-based metabolomic profiles were obtained through liquid chromatography-mass spectrometry. We performed the Wilcoxon test for univariate analysis, the orthogonal partial least squares discriminant analysis (OPLS-DA) for multivariate analysis, and Spearman correlation analyses for the associations between identified metabolites and clinical and ADHD measures. In our study, 156 metabolites were identified in peripheral blood samples using an untargeted metabolomics approach, among which cholic acid, homoveratric acid, inosine, and nicotinuric acid were significantly different between ADHD and controls. Children with ADHD had upregulated cholic acid and homoveratric acid levels and downregulated inosine and nicotinuric acid levels compared to controls. Notably, the upregulated metabolites positively correlated, and the downregulated metabolites negatively correlated with CGI-S and ADHDRS-IV scores. These metabolites and their mechanisms suggested that the pathophysiology of ADHD might involve connections between the gut-brain axis, oxidative stress, dopaminergic pathway, and purine salvage pathway. Our findings of four novel metabolite-behavior relationships in children with ADHD enhanced our understanding of the potential pathways underlying the pathophysiological mechanisms of ADHD.