UC San Diego

Abstract Background: The presence and severity of attenuated-psychosis symptoms define a clinical high risk (CHR) population at elevated risk for psychotic disorders. The NAPLS project is a prospective study of mechanisms contributing to psychosis vulnerability in persons at CHR. Here we investigated a hypothesized role for the highly-integrated immune and redox systems in the development of psychosis. Methods: We examined expression of 143 plasma analytes from a subgroup of the NAPLS2 cohort, including 32 CHR with subsequent psychosis conversion, 40 CHR followed for 2 years without psychosis, and 35 unaffected subjects. We used a Luminex platform with analytes chosen to reflect immune, redox, hormonal, and metabolic system status, including many analytes previously associated with schizophrenia and psychosis risk. We applied correlation network analysis to discover potentially co-regulated networks associated with later development of psychosis. Results: Several robust (r > .75) and highly significant (P < .0001 after correction for multiple testing) correlation networks were found in all groups, including a network involving IL3, IL5, IL7, and IL13, and a network involving CCL5, BDNF, TSH, and PDGF. There were significantly fewer nodes in CHR-converters compared with CHR-nonconverters and unaffected subjects. In unaffected subjects, plasminogen activator inhibitor-1 (PAI-1) was highly correlated with matrix metallopeptidases (MMP) 7, 9 and 10 and CD40LG, this network was absent in CHR subjects, and in CHR-converters PAI-1 was robustly and significantly correlated with TIMP1, CCL13, and TIMP1. Conclusion: A pattern of robust and highly significant correlation networks in plasma analytes suggests shared regulatory mechanisms for the inter-correlated analytes. The lower number of correlated analytes in CHR subjects who converted to psychosis suggest a shift in regulation, as does the change in the correlation network involving PAI-1. PAI-1 is of interest given studies linking schizophrenia with reduced tissue plasminogen activator (tPA) and increases in negative regulators of tPA, including activation of both PAI-1and TIMP1 with oxidative stress. In addition, a recent study links toxoplasmosis infection and schizophrenia risk to a pathway involving PAI-1 and TIMP1. Patricio O’Donnell, Pfizer Inc.