1. ¹Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Berlin, Germany
2. ²Department of Pharmacology, Institute of Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany
3. ³Department of Gerontopsychiatry, Center for Psychiatry, Weinsberg, Germany

Correspondence: Dr M Dettling, Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Benjamin Franklin, Eschenallee 3, Berlin 14050, Germany. E-mail: michael.dettling@charite.de

Received 13 March 2006; Revised 10 August 2006; Accepted 21 August 2006; Published online 17 October 2006.

Abstract

Clozapine-induced agranulocytosis (CA) is still among the least understood adverse drug reactions in psychopharmacology. In particular, its genetic background is far from being clarified. Within the framework of a case–control study, we performed human leukocyte antigen (HLA) genotyping and haplotype analyses in 42 non-Jewish Caucasian schizophrenic patients (N=42) suffering from CA and 75 non-Jewish Caucasian schizophrenic patients treated with clozapine without developing CA. While controlling for age (P<0.0001) and sex (P=0.835), testing of the alleles from both HLA-loci resulted in borderline results for Cw2 (P=0.085, odds ratio (OR)=0.36, 95% confidence interval (CI): 0.08–1.23), Cw7 (P=0.058, OR=2.0, 95% CI: 0.87–4.63) and DRB5^*0201 (P=0.005, adjusted OR=22.15). For haplotype analysis, we obtained significant association results with CA for the two-locus haplotypes HLA-Cw-B (P=0.022) and HLA-DRB5-DRB4 (P=0.050), and for the three-locus haplotype HLA-Cw-B-DRB5 (P=0.030). The complex nature of CA implies that many genes might play a role, but currently, only HLA associations with CA are identified as clinically relevant.