Human leukocyte antigen typing, response to neuroleptics, and clozapine-induced agranulocytosis in jewish Israeli schizophrenic patients

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.

MeSH terms

  • Adolescent
  • Adult
  • Agranulocytosis / chemically induced*
  • Agranulocytosis / immunology
  • Antipsychotic Agents / adverse effects*
  • Antipsychotic Agents / pharmacology*
  • Antipsychotic Agents / therapeutic use
  • Clozapine / adverse effects*
  • Clozapine / pharmacology
  • Clozapine / therapeutic use
  • Female
  • HLA Antigens / classification*
  • HLA Antigens / immunology
  • Humans
  • Israel
  • Jews / psychology*
  • Male
  • Middle Aged
  • Phenotype
  • Risk Factors
  • Schizophrenia / drug therapy*
  • Schizophrenia / ethnology


  • Antipsychotic Agents
  • HLA Antigens
  • Clozapine