MEMBRANE DEFICITS AND OUTCOME IN SCHIZOPHRENIA

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Approximately 40 percent of schizophrenic patients have poor outcomes. Although mechanisms that underlie such outcomes are not known, decreased erythrocyte content of a key membrane essential fatty acid (EFA) - arachidonic acid (AA) - has been associated with poor outcome (prominent negative and persistent positive symptoms). AA is a key component of neuronal membrane phospholipids, and is critical to normal neuronal functioning. Increasing AA (by supplementation) is associated with improvement in negative symptoms and generally less severe symptoms, suggesting that clinical outcome parallels AA levels, and more critically, that the levels are modifiable. Previous studies have focused on patients with poor outcome. Since outcome is often determined early, one critical question is whether low membrane AA early in the course of illness is associated with later poor outcome. Another key issue is whether the peripheral membrane abnormalities seen in chronic schizophrenic patients, and hypothesized to be present early in illness, are associated with defects in brain phospholipid metabolism, as determined by 31P magnetic resonance spectroscopy (MRS). To examine these questions, 40 first-episode schizophrenic patients and 40 age- and sex-matched normal subjects will be studied prospectively with repeated assessments. Relations between AA levels and outcome at 2 years follow-up will be examined. Contemporaneous to peripheral membrane determinations, MRS chemical shift imaging will be used to examine brain phospholipid metabolism. This will provide a unique opportunity to investigate simultaneously central and peripheral membrane biochemistry, and relations to clinical measures. Further, putative factors that may contribute to low membrane AA (increased phospholipase A2 and decreased AA incorporation) and its functional consequences (hyperactivity of the phosphoinositide signaling system) will be examined. If findings from these studies show that a membrane defect exists early in the course of illness (suggested by our pilot data of decreased erythrocyte AA in first-episode schizophrenia), and is associated with unfavorable clinical outcome, then the possibility of specific early interventions such as EFA supplementation can be considered. Also, the study will shed light on the significance of peripheral membrane dynamics to central membrane phospholipid metabolism over the early course of illness.