Project Summary/Abstract This proposal is for a multi-site study that will logically extend the findings of our previously-funded VAMR- CSR&D project Application of Metabolomics in Psychosis and Therapeutic Monitoring. Our central hypothesis is that abnormalities in cell membrane phospholipids represent an important physiological subtype within the etiologically complex syndrome of the schizophrenias. More specifically, we propose that abnormalities involving arachidonic acid and related metabolites (collectively termed eicosanoids) are fundamental to at least one physiological subtype of schizophrenia. Further, we propose that phospholipid-arachidonate-eicosanoid (PAE) signaling abnormalities are responsible for niacin subsensitivity (the reduced sensitivity to the skin flush effect of niacin), which is among the most widely-replicated physiological abnormalities selectively associated with schizophrenia. Specifically, the proposed work will determine the extent to which niacin subsensitivity is a stable and heritable physiological marker of a schizophrenia subtype featuring prominently disordered PAE signaling. Finally, preliminary evidence suggests abnormal niacin response to be a heritable trait, thus we expect that PAE signaling abnormalities will parallel the occurrence of niacin subsensitivity among non- psychotic first-degree relatives (FDR) of affected probands. To examine these questions, 300 neuroleptic- treated clinically stable patients with chronic schizophrenia (CSz), 100 patients with bipolar disorder (BD), and 100 demographically-balanced healthy control (HC) subjects will be studied from the Pittsburgh site. We hypothesize that the niacin-subsensitivity/PAE-disordered endophenotype will be present in approximately 30% of CSz patients - and will be minimally present among BD subjects or normal controls. We expect that niacin subsensitivity will be correlated with defects in PAE signaling pathways, and that a predictive relationship between PAE components and niacin sensitivity can be modeled mathematically. Using within- subjects and repeated-measures design to compare chemical mediators (plasma eicosanoid vasodilators, arachidonic acid and phospholipids) and the niacin flush EC50 values (the 1-methylnicotinate concentration required to elicit a half-maximal flush response) in 90 CSz patients (baseline and 6-month return visit from Portland site), we will demonstrate that niacin subsensitivity, as well as the biochemical and/or genetic mechanisms responsible for it, will persist during the stable phase of the illness. Moreover, we will test the heritability of niacin subsensitivity and plasma levels of eicosanoid vasodilators by comparing 90 FDR and 90 HC subjects (from Portland site). Although experimental evidence is still in its early stages of development, the preponderance of published reports supports the validity of niacin subsensitivity as a schizophrenia endophenotype. The proposed study will better characterize the metabolic and biochemical underpinnings of this novel biomarker. In addition, this is a cost-effective study utilizing existing VA-supported infrastructure (MIRECC) to recruit CSz and BD patients in Pittsburgh site, and VA-funded research development award (Dr. Messamore) to recruit CSz and FDR patients in Portland site at no additional costs. PUBLIC HEALTH RELEVANCE: Project Narrative: Schizophrenia is a leading cause of disability, but its causes are poorly understood. This project will determine whether certain cell membrane components (phospholipids, arachidonic acid, or eicosanoids) are affected in schizophrenia, and if the abnormalities are heritable. Furthermore, such membrane abnormalities may be responsible for reduced sensitivity to the skin flush effect of niacin. The results could lead to improved methods for early detection of the illness, and possibly, new types of treatment.