CLOZAPINE INDUCED AGRANULOCYTOSIS IN SCHIZOPHRENIA

氯氮平是一种独特的，非典型的抗精神病药物， 治疗难治性精神分裂症的疗效。 随机 研究表明，它上级传统的治疗方法， disorder. 然而，氯氮平的使用受到了1.6%的限制， 发生危及生命的粒细胞缺乏症。 很多时候， 发生粒细胞缺乏症的患者有有意义的反应， 精神病复发的症状 其用于 美国要求每周进行血液监测，因为没有 粒细胞缺乏症发展的预测试验。 本研究旨在探讨氯氮平诱导的抗精神分裂症的可能机制。 精神分裂症患者的粒细胞缺乏症 毒性和免疫性 将探索机制。 将特别强调 氯氮平代谢物作为直接抑制骨的药物， 骨髓和作为免疫原性化合物。 由于持续时间较长， 粒细胞缺乏症和严重的骨髓抑制可能是一种 直接毒性或免疫造血前体。 这项小额赠款提案的具体目标是：1。以确定 氯氮平或其代谢物是否对正常人骨具有细胞毒性 前体2.在血清中寻找细胞毒抗体， 攻击造血前体，并确定抗体是否 依赖于氯氮平，代谢物或补体。3.测量 拟定的毒性代谢物和/或抗 从受影响的患者恢复后采集的造血前体 氯氮平引起的粒细胞缺乏症4.测量血浆中潜在的 有毒代谢物，以确定高水平是否与骨 骨髓抑制 这些数据可能有助于解开氯氮平的机制 诱导的粒细胞缺乏症，可以确定一个预测性的实验室检查， 识别高风险患者，并可能使药物更成功地 给精神分裂症患者服用

Clozapine is a unique, atypical antipsychotic dibenzoxazebine with unusual efficacy in treating patients with refractory schizophrenia. Randomized studies have shown it to be superior to conventional treatment of this disorder. The use of clozapine, however, has been limited by a 1.6% incidence of life-threatening agranulocytosis. Many times patients who develop agranulocytosis have had meaningful responses and once withdrawn from clozapine experience dramatic psychiatric relapses. Its use in the United States requires weekly blood monitoring, because there exists no predictive tests for the development of agranulocytosis. This proposal will evaluate potential mechanisms of clozapine induced agranulocytosis in patients with schizophrenia. Both toxic and immunologic mechanisms will be explored. Specific emphasis will be placed on the role of clozapine metabolites both as agents which directly suppress the bone marrow and as immunogenic compounds. Due to the prolonged duration of agranulocytosis and the severe marrow suppression there may be either a direct toxic or immune hematopoietic precursors. The specific aims for this small grant proposal are: 1. To determine whether clozapine or its metabolites are cytotoxic to normal human bone precursors. 2. To search for a cytotoxic antibody in the serum which attacks hematopoietic precursors and identify whether the antibody is dependent on clozapine, a metabolite or complement. 3. To measure the toxicity of the proposed toxic metabolite and/or antibody against hematopoietic precursors taken from affected patients after recovery from clozapine-induced agranulocytosis. 4. To measure plasma levels of potential toxic metabolites to determine whether high levels are associated with bone marrow suppression. This data may help unravel the mechanism of clozapine induced agranulocytosis, may identify a predictive laboratory test to identify high risk patients, and may allow the drug to be more successfully administered to patients with schizophrenia.