CLOZAPINE INDUCED AGRANULOCYTOSIS IN SCHIZOPHRENIA

氯氮平是一种独特的、非典型的抗精神病药物二苯并恶唑宾，具有不寻常的 治疗难治性精神分裂症的疗效观察。随机化 研究表明，它优于传统的治疗方法。 无序。然而，氯氮平的使用受到了1.6%的限制 危及生命的粒细胞缺乏症的发生率。很多时候，患者 发展成粒细胞缺乏症有有意义的反应，一旦停用 从氯氮平经历戏剧性的精神复发。它的使用在 美国要求每周进行一次血液监测，因为没有 粒细胞缺乏症发生的预测性试验。 该提案将评估氯氮平诱导的潜在机制。 精神分裂症患者的粒细胞缺乏症。既有毒性又有免疫性 我们将探索相关机制。具体的重点将放在角色上 氯氮平的代谢物作为直接抑制骨骼的药物 骨髓和免疫原化合物。由于持续时间延长， 粒细胞缺乏症和严重的骨髓抑制可能是 直接毒性或免疫性造血祖细胞。 这项小额拨款提案的具体目标是：1.确定 氯氮平或其代谢物对正常人骨骼是否有细胞毒性 先驱物。2.在血清中寻找一种细胞毒抗体 攻击造血祖细胞并识别抗体是否 依赖于氯氮平，一种代谢物或补体。3.测量 建议的有毒代谢物和/或抗体的毒性 从患者康复后采集的造血祖细胞 氯氮平所致的粒细胞缺乏症。4.测量血浆潜伏期水平 有毒代谢物以确定高水平是否与骨骼相关 骨髓抑制。这一数据可能有助于解开氯氮平的作用机制。 诱导的粒细胞缺乏症，可以确定一种预测性的实验室测试 识别高危患者，并可能使药物更成功 给精神分裂症患者使用。

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 Many times patients who develop agranulocytosis have had meaningful responses and once withdrawn from clozapine experience dramatic psychiatric relapses.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.