Chronic risperidone normalizes elevated pro-inflammatory cytokine and C-reactive protein production in omega-3 fatty acid deficient rats.

Prior clinical and preclinical studies suggest that omega-3 fatty acids negatively regulate pro-inflammatory signaling cascades, and that the atypical antipsychotic risperidone up-regulates omega-3 fatty acid biosynthesis. In the present study, we investigated the effects of chronic (40days) risperidone treatment (3mg/kg/day) on basal pro-inflammatory cytokine (interleukin-6, IL-6; tumor necrosis factor-alpha, TNFα) and C-reactive protein (CRP) production in control and n-3 fatty acid deficient rats. Relationships with erythrocyte polyunsaturated fatty acid composition were determined. Compared with untreated controls, untreated n-3-deficient rats exhibited significantly greater basal IL-6, TNFα, and CRP production. Following chronic risperidone treatment there were trends for greater IL-6, TNFα, and CRP production in controls, but these did not reach significance. In n-3-deficient rats, chronic risperidone normalized elevated IL-6, TNFα, and CRP levels. Erythrocyte arachidonic acid (20:4n-6) composition was positively correlated, and erythrocyte eicosapentenoic (20:5n-3) and docosahexaenoic acid (22:6n-3) inversely correlated, with plasma IL-6, TNFα, and CRP levels in untreated control and n-3-deficient rats, and these associations were not observed among risperidone-treated rats. The adrenic acid (22:4n-6)/arachidonic acid ratio, an index of elongase-mediated arachidonic acid biosynthesis, was reduced by risperidone in controls and elevated in n-3-deficient rats. These preclinical data demonstrate that chronic risperidone treatment normalizes constitutively elevated pro-inflammatory cytokine and CRP production in n-3 fatty acid deficient rats but not in controls, and that the mechanism is dissociable from n-3 fatty acid biosynthesis.