Chronic risperidone treatment preferentially increases rat erythrocyte and prefrontal cortex omega-3 fatty acid composition: Evidence for augmented biosynthesis

Prior clinical studies suggest that chronic treatment with atypical antipsychotic medications increase erythrocyte and postmortem prefrontal cortex (PFC) omega-3 fatty acid composition in patients with schizophrenia (SZ). However, because human tissue phospholipid omega-3 fatty acid composition is potentially influenced by multiple extraneous variables, definitive evaluation of this putative mechanism of action requires an animal model. In the present study, we determined the effects of chronic treatment with the atypical antipsychotic risperidone (RISP, 3.0 mg/kg/d) on erythrocyte and PFC omega-3 fatty acid composition in rats maintained on a diet with or without the dietary omega-3 fatty acid precursor, alpha-linolenic acid (ALA, 18:3n-3). Chronic RISP treatment resulted in therapeutically-relevant plasma RISP and 9-OH-RISP concentrations (18 ± 2.6 ng/ml), and significantly increased erythrocyte docosahexaenoic acid (DHA, 22:6n-3, + 22%, p = 0.0003) and docosapentaenoic acid (22:5n-3, + 18%, p = 0.01) composition, and increased PFC DHA composition (+ 7%, p = 0.03) in rats maintained on the ALA+ diet. In contrast, chronic RISP did not alter erythrocyte or PFC omega-3 fatty acid composition in rats maintained on the ALA− diet. Chronic RISP treatment did not alter erythrocyte or PFC arachidonic acid (AA, 20:4n-6) composition. These data suggest that chronic RISP treatment significantly augments ALA−DHA biosynthesis, and preferentially increases peripheral and central membrane omega-3 fatty acid composition. Augmented omega-3 fatty acid biosynthesis and membrane composition represents a novel mechanism of action that may contribute in part to the efficacy of RISP in the treatment of SZ.