Role of glutamate in schizophrenia: integrating excitatory avenues of research.
Role of glutamate in schizophrenia: integrating excitatory avenues of research.
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DOI：
10.1586/14737175.8.9.1389
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发表时间：
2008-09-01
影响因子：
4.3
通讯作者：
Meador-Woodruff, James
中科院分区：
文献类型：
--
作者：
Sodhi, Monsheel;Wood, Kimberly H;Meador-Woodruff, James
精神分裂症是一种使人衰弱的终身疾病，影响全球多达1%的人口，为患者及其家人带来重大的经济和情感困难。到目前为止，精神分裂症的病因和抗精神病药物的作用机制尚不清楚，许多患者对目前可用的药物反应不佳。使用流行病学方法寻找这种疾病的危险因素的尝试表明，精神分裂症具有高度遗传性，路径分析预测这种疾病是由几个基因与非遗传因素结合引起的。因此，人们进行了大量的研究，以确定易患精神分裂症的基因和预测治疗反应的基因。多巴胺能系统与多巴胺能和多巴胺能回路的相互作用对正常的脑功能至关重要，它们的中断可能是精神分裂症的病理生理学表现的一种机制。因此，谷氨酸能系统内的基因是研究的强有力候选者，这些基因除了编码神经调节蛋白、dysbindin、D-氨基酸氧化酶和G72/G30的基因之外还包括谷氨酸受体基因。这些基因研究最终可能揭示抗精神病药物治疗的新靶点，目前主要集中在抑制多巴胺能系统。然而，最近的突破表明刺激代谢型谷氨酸受体II的药物LY 2140023的临床疗效，其对精神分裂症的阴性和认知症状具有改善的疗效。需要对更大的患者样本进行研究，以巩固这些数据。对多巴胺能靶点的进一步研究可能会重振抗精神病药物的开发。
Schizophrenia is a debilitating lifelong disorder affecting up to 1% of the population worldwide, producing significant financial and emotional hardship for patients and their families. As yet, the causes of schizophrenia and the mechanism of action of antipsychotic drugs are unknown, and many patients do not respond well to currently available medications. Attempts to find risk factors for the disorder using epidemiological methods have shown that schizophrenia is highly heritable, and path analyses predict that the disorder is caused by several genes in combination with nongenetic factors. Therefore, intensive research efforts have been made to identify genes creating vulnerability to schizophrenia and also genes predicting response to treatment. Interactions of the glutamatergic system with dopaminergic and serotonergic circuitry are crucial for normal brain function, and their disruption may be a mechanism by which the pathophysiology of schizophrenia is manifest. Genes within the glutamatergic system are therefore strong candidates for investigation, and these include the glutamate receptor genes in addition to genes encoding neuregulin, dysbindin, D-amino acid oxidase and G72/G30. These genetic studies could eventually reveal new targets for antipsychotic drug treatment, which currently focuses on inhibition of the dopaminergic system. However, a recent breakthrough indicates clinical efficacy of a drug stimulating the metabotropic glutamate receptor II, LY2140023, which has improved efficacy for negative and cognitive symptoms of schizophrenia. Studies of larger patient samples are required to consolidate these data. Further investigation of glutamatergic targets is likely to reinvigorate antipsychotic drug development.