Dopamine D2 receptor blockade is the major basis for the antipsychotic action of typical antipsychotic drugs (AP) and a necessary but not sufficient basis for the antipsychotic action of atypical APs such as clozapine and other multireceptor antagonists which rely, in part, upon 5-HT2A antagonism. Genetic factors affecting the density and/or function of D2 receptors may therefore affect AP response. Objectives This exploratory study investigates the effect of 12 single nucleotide polymorphisms (SNPs) spanning the entire dopamine D2 gene on clozapine response in two distinct schizophrenic populations (Caucasian and Africanâ American) refractory or intolerant to conventional APs. Methods This study included 183 Caucasian and 49 Africanâ American DSM-III-R or DSM-IV schizophrenics. Genotyping was determined by 5prime-exonuclease fluorescence assays. Within each population genotype, allele, allele +/â , and haplotype frequencies were compared between responders and non-responders by X2 tests. Linkage disequilibrium analysis was also performed. Results In the Caucasian sample, no significant associations were found for individual SNP tests; however, two haplotypes were identified as having significant protective effects on treatment outcome. In the Africanâ American sample, individual SNP tests identified the Taq1A, Taq1B, and rs1125394 markers as being predictive of clozapine response. Haplotype analyses identified four protective haplotypes containing these SNPs. In addition, no association between the â 141C Ins/Del site and clozapine response was found in either population. Conclusions Interindividual variability in clozapine response among treatment refractory/intolerant patients is still not fully understood and likely involves multiple factors. This exploratory analysis suggests that the D2 receptor gene may be one such factor.

Dopamine D2 receptor gene variants and quantitative measures of positive and negative symptom response following clozapine treatment / R. Hwang, T. Shinkai, V. Deluca, F. Macciardi, S. Potkin, H.Y. Meltzer, J.L. Kennedy. - In: EUROPEAN NEUROPSYCHOPHARMACOLOGY. - ISSN 0924-977X. - 16:4(2006 May), pp. 248-259. [10.1016/j.euroneuro.2005.09.004]

Dopamine D2 receptor gene variants and quantitative measures of positive and negative symptom response following clozapine treatment

F. Macciardi;
2006

Abstract

Dopamine D2 receptor blockade is the major basis for the antipsychotic action of typical antipsychotic drugs (AP) and a necessary but not sufficient basis for the antipsychotic action of atypical APs such as clozapine and other multireceptor antagonists which rely, in part, upon 5-HT2A antagonism. Genetic factors affecting the density and/or function of D2 receptors may therefore affect AP response. Objectives This exploratory study investigates the effect of 12 single nucleotide polymorphisms (SNPs) spanning the entire dopamine D2 gene on clozapine response in two distinct schizophrenic populations (Caucasian and Africanâ American) refractory or intolerant to conventional APs. Methods This study included 183 Caucasian and 49 Africanâ American DSM-III-R or DSM-IV schizophrenics. Genotyping was determined by 5prime-exonuclease fluorescence assays. Within each population genotype, allele, allele +/â , and haplotype frequencies were compared between responders and non-responders by X2 tests. Linkage disequilibrium analysis was also performed. Results In the Caucasian sample, no significant associations were found for individual SNP tests; however, two haplotypes were identified as having significant protective effects on treatment outcome. In the Africanâ American sample, individual SNP tests identified the Taq1A, Taq1B, and rs1125394 markers as being predictive of clozapine response. Haplotype analyses identified four protective haplotypes containing these SNPs. In addition, no association between the â 141C Ins/Del site and clozapine response was found in either population. Conclusions Interindividual variability in clozapine response among treatment refractory/intolerant patients is still not fully understood and likely involves multiple factors. This exploratory analysis suggests that the D2 receptor gene may be one such factor.
Clozapine - Antipsychotics - Response - Dopamine - D2 - Association - Haplotype - Pharmacogenetics - Gene - Receptor
Settore MED/03 - Genetica Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/15089
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