It is our hypothesis that a genetic basis reflected by MHC markers underlies pharmacologic response (both antipsychotic in the case of classical neuroleptic drugs and hematologic in the case of Clozapine) in patients with schizophrenia. Our application proposes a two arm study of immunogenetic mechanisms and pharmacologic response in schizophrenia. Specifically, we will examine the association between MHC markers, in particular, HLA-A1 and neuroleptic treatment response in patients with schizophrenia, since a decrease frequency of the HLA-A1 antigen was found in schizophrenics who were refractory to neuroleptic treatment. In a previous study, we reported an increase in HLA-A1 and a decrease in HLA-A2 in patients responsive to neuroleptic treatment. In other experiments, we will determine the therapeutic and supratherapeutic neuroleptic doses using lymphocytes from HLA-A1 positive versus negative patients to test the preferential effect of neuroleptics using an """"""""in vitro"""""""" T cell activation model. The second arm of the proposal is based on an association that was found between the HLA B38 DR4 DQw3 haplotype (DRB1*0402 and DQB1*0302 alleles) and vulnerability to develop Clozapine-induced agranulocytosis among treatment refractory Jewish patients. In addition, among non-Jewish agranulocytosis patients, an increase in HLA-DR2 , DQw1 antigens has been found. We will confirm that the MHC susceptibility haplotype (B38, DR4, DQw3) predisposes Jewish patients to develop agranulocytosis following Clozapine treatment. Also, we will determine the specific alleles by PCR-RFLP and PCR-SSO methods for DR4, Dqw3 and DR2, Dqw1 involved in Clozapine-induced agranulocytosis susceptibility in order to provide a more reliable screening test for neuroleptic resistant individuals undergoing Clozapine treatment in order to minimize the risk of such complication. It is likely that a common MHC class II allele is responsible for agranulocytosis susceptibility between these two groups. However, the possibility of a second gene, yet to be discovered, and in linkage disequilibrium with MHC alleles and responsible for agranulocytosis susceptibility can not be eliminated at this moment.
