A systematic review and meta-analysis of nitric oxide-associated arginine metabolites in schizophrenia.

There is increasing interest in the pathophysiological role of arginine metabolism in schizophrenia, particularly in relation to the modulation of the endogenous messenger nitric oxide (NO). The assessment of specific arginine metabolites that, unlike NO, are stable can provide useful insights into NO regulatory enzymes such as isoform 1 of dimethylarginine dimethylaminohydrolase (DDAH1) and arginase. We investigated the role of arginine metabolomics in schizophrenia by conducting a systematic review and meta-analysis of the circulating concentrations of arginine metabolites associated with DDAH1, arginase, and NO synthesis [arginine, citrulline, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), dimethylamine, and ornithine] in this patient group. We searched PubMed, Scopus, and Web of Science from inception to the 31^st of May 2023 for studies investigating arginine metabolites in patients with schizophrenia and healthy controls. The JBI Critical Appraisal Checklist for analytical studies and GRADE were used to assess the risk of bias and the certainty of evidence, respectively (PROSPERO registration number: CRD42023433000). Twenty-one studies were identified for analysis. There were no significant between-group differences in arginine, citrulline, and SDMA. By contrast, patients with schizophrenia had significantly higher ADMA (DDAH1 substrate, standard mean difference, SMD = 1.23, 95% CI 0.86-1.61, p < 0.001; moderate certainty of evidence), dimethylamine (DDAH1 product, SMD = 0.47, 95% CI 0.24-0.70, p < 0.001; very low certainty of evidence), and ornithine concentrations (arginase product, SMD = 0.32, 95% CI 0.16-0.49, p < 0.001; low certainty of evidence). In subgroup analysis, the pooled SMD for ornithine was significantly different in studies of untreated, but not treated, patients. Our study suggests that DDAH1 and arginase are dysregulated in schizophrenia. Further studies are warranted to investigate the expression/activity of these enzymes in the brain of patients with schizophrenia and the effects of targeted treatments.