Biomarker and Safety Study of Clozapine in Benign Ethnic Neutropenia

 描述(由申请人提供)：氯氮平是治疗精神分裂症最有效的抗精神病药物，但它的使用不足，特别是在非裔美国人群体中。低绝对中性粒细胞计数(ANC)，无论是基线还是在治疗期间(ANC下降到1500mm3的阈值以下，目前要求停用氯氮平)是AA患者使用氯氮平的一个重要障碍。我们的试点工作发现，再生障碍性贫血患者停用氯氮平(特别是中性粒细胞减少症)的比例是高加索患者的两倍以上。近年来，良性中性粒细胞减少症(BEN)在AAS中的现象引起了人们的关注。BEN在ANC低的再障患者中常见，但与粒细胞缺乏症或感染的风险增加无关。白细胞(WBC)和中性粒细胞(ANC)计数的标准范围是用高加索样本建立的，美国的氯氮平指南不允许ANC的较低波动。不幸的是，患有BEN的患者波动较小，需要停用氯氮平。我们的试点工作表明，尽管ANC较低(不在当前指南之外)，AA BEN患者仍可以成功地使用氯氮平治疗，并且不会有更大的粒细胞缺乏症风险。我们到目前为止的工作，如果得到更大规模研究的支持，表明氯氮平可以安全地用于BEN患者，改善AA精神分裂症患者获得氯氮平治疗的机会，并首次评估达菲抗原受体趋化因子(DARC)基因与BEN和ANC水平的关系。我们的目标是在250名黑人患者中安全使用氯氮平(美国为100-120人，尼日利亚亚萨哈拉人为130-150人)，以检查使用的安全性和粒细胞缺乏症的风险。我们的研究将在氯氮平治疗前3个月每周两次评估ANC，在氯氮平治疗后6个月每周评估一次ANC。我们还计划评估患有BEN的精神病患者WBC和ANC的波动模式(受试者S.D.内的平均水平，轻度、中度或重度中性粒细胞减少的频率和持续时间，以及启动对极低ANC的额外监测的要求)。

 DESCRIPTION (provided by applicant): Clozapine is the most effective antipsychotic for the treatment of schizophrenia however it is underused particularly in the African American population. Low Absolute Neutrophil Counts (ANC), either baseline or during treatment (a drop in ANC below the threshold of 1500 mm3 currently mandates clozapine discontinuation) is a significant barrier to clozapine use in AA patients. Our pilot work finds that discontinuation of clozapine (particularly for neutropenia) in AA patients is over twice that in Caucasians. Recently the phenomenon of Benign Ethnic Neutropenia (BEN) in AAs has gained attention. BEN is frequent in AA with low ANCs, but is NOT associated with an increased risk for agranulocytosis or infection. Normative ranges for white blood cell (WBC) and ANC counts were established with Caucasian samples and clozapine guidelines in the US do not permit lower fluctuations of ANC. Unfortunately, lower fluctuations are often seen in persons with BEN, requiring clozapine discontinuation. Our pilot work has shown that AA BEN patients may be successfully treated with clozapine despite low ANC (outside current guidelines) with no greater risk of agranulocytosis. Our work to date, if supported by a larger study, suggests that clozapine could be safely used in people with BEN, improving access to clozapine treatment for AA patients with schizophrenia as well as evaluation for the first time the Duffy Antigen Receptor Chemokine (DARC) gene in relation to BEN and ANC levels. We aim to safely use clozapine in 250 black patients (100-120 in US and 130-150 in a SubSaharan Nigerian population) to examine the safety of use and the risk of agranulocytosis. Our study will evaluate ANC twice weekly for 3 months prior and weekly 6 months after clozapine initiation. We also plan to evaluate the fluctuating patterns of WBC and ANC (mean levels, within subject s.d., frequency and duration of mild, moderate or severe neutropenia, and requirement for initiation of extra monitoring for very low ANC) in psychotic patients with BEN.