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，但未充分使用，特别是在非裔美国人人群中。基线或治疗期间的低绝对神经元计数（ANC）（ANC降至1500 mm 3阈值以下，目前要求停用氯氮平）是AA患者使用氯氮平的重要障碍。我们的试点工作发现，停药氯氮平（特别是中性粒细胞减少症）在AA患者是白人的两倍以上。近年来，AA中的良性种族中立（BEN）现象引起了人们的关注。BEN常见于低ANC的AA，但与粒细胞缺乏症或感染的风险增加无关。白色血细胞（WBC）和ANC计数的正常范围是用白人样本建立的，美国的氯氮平指南不允许ANC的较低波动。不幸的是，较低的波动经常见于BEN患者，需要停用氯氮平。我们的试点工作表明，AA BEN患者可能会成功地治疗氯氮平，尽管低ANC（现行指南外），没有更大的粒细胞缺乏症的风险。我们迄今为止的工作，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精神分裂症患者的氯氮平治疗，并首次评估Duffy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100-120人，撒哈拉以南尼日利亚人群130-150人），以检查使用的安全性和粒细胞缺乏症的风险。我们的研究将评估ANC每周两次，持续3个月前和每周6个月后开始氯氮平。我们还计划评估WBC和ANC的波动模式（平均水平，受试者标准差内，轻度、中度或重度中性粒细胞减少症的频率和持续时间，以及需要对极低ANC启动额外监测）。

 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.