Meged S, Stein D, Sitrota P, Melamed Y, Elizur A, Shmuelian I, Gazit E
Abarbanel Mental Health Center, Bat-Yam, Israel.
Int Clin Psychopharmacol. 1999 Sep;14(5):305-12.
The atypical antipsychotic agent clozapine is known to be effective in schizophrenic patients refractory to other medications; however, it induces agranulocytosis in approximately 1-2%. In Jews, this complication is associated with the haplotype HLA B38,DR4,DQ3. The aim of the present study was to determine which human leukocyte antigen (HLA) antigens are involved in clozapine-induced agranulocytosis. We performed HLA typing in 88 Jewish Israeli schizophrenic patients and in 127 ethnically matched healthy individuals. Thirty-eight patients responsive to standard antipsychotic medications were treated with haloperidol, and 50 refractory patients received clozapine. A trend was noted for elevated rates of HLA B38 among control individuals and clozapine-treated patients of Ashkenazi origin compared to individuals of non-Ashkenazi origin, but the findings failed to reach statistical significance. No association was found between HLA class I antigens and the response to haloperidol or clozapine. Neutropenia developed in two clozapine-treated patients and agranulocytosis in one. Two of these three patients were of Ashkenazi origin, and both demonstrated the HLA B38 phenotype. Although the findings did not reach a statistical significance because of the small number of patients, they may support an association between clozapine-induced neutropenia/agranulocytosis and Ashkenazi origin and the HLA B38 phenotype. The rate of agranulocytosis in our sample (2%) is similar to the usual cumulative risk of agranulocytosis but in contrast to its high frequency among Jewish American patients. One possible explanation for this difference is the high rate of Ashkenazi patients in the American sample and the preponderance of non-Ashkenazi patients in our population.
非典型抗精神病药物氯氮平已知对其他药物治疗无效的精神分裂症患者有效；然而，它会在约1% - 2%的患者中诱发粒细胞缺乏症。在犹太人中，这种并发症与单倍型HLA B38、DR4、DQ3相关。本研究的目的是确定哪些人类白细胞抗原（HLA）与氯氮平诱发的粒细胞缺乏症有关。我们对88名以色列犹太精神分裂症患者和127名种族匹配的健康个体进行了HLA分型。38名对标准抗精神病药物有反应的患者接受了氟哌啶醇治疗，50名难治性患者接受了氯氮平治疗。与非阿什肯纳兹血统的个体相比，在对照个体以及阿什肯纳兹血统的接受氯氮平治疗的患者中，发现HLA B38的发生率有升高趋势，但该结果未达到统计学显著性。未发现HLA I类抗原与对氟哌啶醇或氯氮平的反应之间存在关联。两名接受氯氮平治疗的患者出现了中性粒细胞减少症，一名出现了粒细胞缺乏症。这三名患者中有两名是阿什肯纳兹血统，且均表现出HLA B38表型。尽管由于患者数量少，研究结果未达到统计学显著性，但它们可能支持氯氮平诱发的中性粒细胞减少症/粒细胞缺乏症与阿什肯纳兹血统及HLA B38表型之间存在关联。我们样本中的粒细胞缺乏症发生率（2%）与通常的粒细胞缺乏症累积风险相似，但与美国犹太患者中的高发生率形成对比。对此差异的一种可能解释是美国样本中阿什肯纳兹患者的比例高，而我们的人群中非阿什肯纳兹患者占多数。
