Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, United States of America.
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, United States of America.
Schizophr Res. 2024 Jun;268:312-322. doi: 10.1016/j.schres.2023.08.002. Epub 2023 Aug 24.
Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but it is markedly underutilized, particularly in the US Black population, partly because of concern over clozapine-associated low absolute neutrophil count (ANC). People of African descent have a lower normative ANC range than the White population, which is associated with a specific "ACKR1-null" ("Duffy null") CC genotype (SNP rs2814778) on the ACKR1 gene, termed benign ethnic neutropenia (BEN). The range of ANC variability and safety of clozapine have not been established in people with BEN or examined prospectively in people of African descent.
We completed a multisite, 6-month, prospective, open-label clinical trial of clozapine treatment in people of African descent with schizophrenia spectrum disorders for whom clozapine was clinically indicated, with or without the ACKR1-null genotype. We examined clozapine safety and weekly ANC during clozapine treatment and evaluated ANC variability by ACKR1-null genotype, sex, study site, and clozapine dosing using repeated measures analysis of covariance. Genotype was assayed using TaqMan® technology.
We enrolled 274 participants, of whom 227 (82.8 %) completed 6 months of clozapine treatment. There was one case of severe neutropenia (<500 cells/mm) (0.36 %) over 1467.6 person-months of clozapine exposure. This participant recovered without sequelae after discontinuation of clozapine. Of the 249 participants with known genotypes, 199 (79.9 %) had the ACKR1-null genotype. Neutropenia (<1500 cells/mm) occurred significantly more often in the ACKR1-null group (33 % [65/199]) than in those with the T allele (6 % (3/50); p < 0.001). Fourteen (5 %) patients discontinued due to adverse events. Rates of infection and fever were low and sialorrhea was the commonest side effect (N = 187, 68 %).
To our knowledge, this is the largest prospective clozapine trial in people of African descent. Severe neutropenia was rare, despite the high prevalence (80 %) of the ACKR1-null genotype. Our findings suggest that clozapine can be used safely in Black patients including those with BEN.
氯氮平是治疗抵抗性精神分裂症最有效的抗精神病药物，但它的使用率明显较低，尤其是在美国黑人中，部分原因是担心氯氮平相关的绝对中性粒细胞计数（ANC）降低。非洲裔人群的正常 ANC 范围低于白人群体，这与 ACKR1 基因上特定的“ACKR1-缺失”（“Duffy 缺失”）CC 基因型（SNP rs2814778）有关，称为良性种族中性粒细胞减少症（BEN）。BEN 人群中氯氮平的 ANC 变异性范围和安全性尚未确定，也没有前瞻性地在非洲裔人群中进行研究。
我们完成了一项多中心、6 个月、前瞻性、开放标签的氯氮平治疗精神分裂症谱系障碍的临床试验，纳入了临床需要氯氮平治疗且存在或不存在 ACKR1-缺失基因型的非洲裔人群。我们在氯氮平治疗期间检查了氯氮平的安全性和每周 ANC，并通过重复测量协方差分析评估了 ANC 变异性与 ACKR1-缺失基因型、性别、研究地点和氯氮平剂量的关系。基因型使用 TaqMan®技术进行检测。
我们共纳入了 274 名参与者，其中 227 名（82.8%）完成了 6 个月的氯氮平治疗。在 1467.6 人月的氯氮平暴露中，有 1 例（0.36%）出现严重中性粒细胞减少症（<500 个细胞/mm）。该参与者在停用氯氮平后无后遗症恢复。在已知基因型的 249 名参与者中，199 名（79.9%）为 ACKR1-缺失基因型。中性粒细胞减少症（<1500 个细胞/mm）在 ACKR1-缺失组中更常见（33%[65/199]），而在 T 等位基因组中为 6%（3/50）（p<0.001）。因不良事件，有 14 名（5%）患者停药。感染和发热的发生率较低，流涎是最常见的副作用（N=187，68%）。
据我们所知，这是最大的针对非洲裔人群的前瞻性氯氮平试验。尽管 ACKR1-缺失基因型的患病率很高（80%），但严重中性粒细胞减少症仍很少见。我们的研究结果表明，氯氮平可安全用于包括 BEN 患者在内的黑人患者。
