Homeostatic Imbalance of Purine Catabolism in First- Episode Neuroleptic-Naı̈ve Patients with Schizophrenia

Background: Purine catabolism may be an unappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. Accumulating evidence suggests a pivotal role of oxidative stress in schizophrenia pathology. Methodology/Principal Findings: Using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system, we compared 6 purine metabolites simultaneously in plasma between first-episode neuroleptic-naı̈ve patients with schizophrenia (FENNS, n = 25) and healthy controls (HC, n = 30), as well as between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. Significantly higher levels of xanthosine (Xant) and lower levels of guanine (G) were seen in both patient groups compared to HC subjects. Moreover, the ratios of G/guanosine (Gr), uric acid (UA)/Gr, and UA/Xant were significantly lower, whereas the ratio of Xant/G was significantly higher in FENNS-BL than in HC. Such changes remained in FENNS-4w with exception that the ratio of UA/Gr was normalized. All 3 groups had significant correlations between G and UA, and Xan and hypoxanthine (Hx). By contrast, correlations of UA with each of Xan and Hx, and the correlation of Xan with Gr were all quite significant for the HC but not for the FENNS. Finally, correlations of Gr with each of UA and G were significant for both HC and FENNS-BL but not for the FENNS-4w. Conclusions/Significance: During purine catabolism, both conversions of Gr to G and of Xant to Xan are reversible. Decreased ratios of product to precursor suggested a shift favorable to Xant production from Xan, resulting in decreased UA levels in the FENNS. Specifically, the reduced UA/Gr ratio was nearly normalized after 4 weeks of antipsychotic treatment. In addition, there are tightly correlated precursor and product relationships within purine pathways; although some of these correlations persist across disease or medication status, others appear to be lost among FENNS. Taken together, these results suggest that the potential for steady formation of antioxidant UA from purine catabolism is altered early in the course of illness. Citation: Yao JK, Dougherty GG Jr., Reddy RD, Keshavan MS, Montrose DM, et al. (2010) Homeostatic Imbalance of Purine Catabolism in First-Episode Neuroleptic-Naı̈ve Patients with Schizophrenia. PLoS ONE 5(3): e9508. doi:10.1371/journal.pone.0009508 Editor: Kenji Hashimoto, Chiba University Center for Forensic Mental Health, Japan Received November 27, 2009; Accepted January 27, 2010; Published March 3, 2010 This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Funding: This material is based upon work supported in part by the grants from the Department of Veterans Affairs (VA), Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research & Development [Merit Reviews (JKY) and Senior Research Career Scientist Award (JKY)], VA Pittsburgh Healthcare System (JKY, GGD, RDR), National Institute of Health [MH58141 (JKY), MH64118 (RDR), MH45203 (MSK), R24 GM078233 (RKD), c UL1 RR024153 and NIH/NCRR/GCRC Grant M01 RR00056], Metabolomics Research Network (RKD); Stanley Medical Research Institute (RKD), and National Alliance for Research on Schizophrenia and Affective Disorders (RKD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]