McNamara Robert K, Able Jessica A, Jandacek Ronald, Rider Therese, Tso Patrick
Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0559, United States.
Schizophr Res. 2009 Feb;107(2-3):150-7. doi: 10.1016/j.schres.2008.09.027. Epub 2008 Nov 7.
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.
先前的临床研究表明，非典型抗精神病药物的长期治疗可增加精神分裂症（SZ）患者红细胞和死后前额叶皮质（PFC）中ω-3脂肪酸的含量。然而，由于人体组织磷脂中ω-3脂肪酸的含量可能受到多种外部变量的影响，因此对这种假定的作用机制进行明确评估需要动物模型。在本研究中，我们确定了非典型抗精神病药物利培酮（RISP，3.0mg/kg/d）长期治疗对食用含或不含膳食ω-3脂肪酸前体α-亚麻酸（ALA，18:3n-3）饮食的大鼠红细胞和PFC中ω-3脂肪酸含量的影响。长期RISP治疗导致血浆中RISP和9-OH-RISP浓度达到治疗相关水平（18±2.6ng/ml），并显著增加了食用ALA+饮食的大鼠红细胞中二十二碳六烯酸（DHA，22:6n-3，增加22%；p=0.0003）和二十二碳五烯酸（22:5n-3，增加18%；p=0.01）的含量，以及PFC中DHA的含量（增加7%；p=0.03）。相比之下，长期RISP治疗并未改变食用ALA-饮食大鼠红细胞或PFC中ω-3脂肪酸的含量。长期RISP治疗未改变红细胞或PFC中花生四烯酸（AA，20:4n-6）的含量。这些数据表明，长期RISP治疗可显著增强ALA-DHA的生物合成，并优先增加外周和中枢膜中ω-3脂肪酸的含量。增强的ω-3脂肪酸生物合成和膜成分代表了一种新的作用机制，这可能部分有助于RISP治疗SZ的疗效。
