Naturalistic pharmacogenetic study of treatment resistance to typical neuroleptics in European-Brazilian schizophrenics.
OBJECTIVE
This study aimed to explore the influence of variation in DRD2, DRD3, CYP2D6, CYP3A4, and CYP3A5 genes on treatment resistance to typical neuroleptics in a Brazilian sample of patients with schizophrenia.


METHODS
One polymorphism at DRD2 gene, five at DRD3, 24 at CYP2D6, nine at CYP3A4 gene, and one at CYP3A5 gene were genotyped in a sample of 186 patients with schizophrenia.


RESULTS
From the nine studied CYP3A4 single nucleotide polymorphisms, only the -392A>G was polymorphic, and significant associations were observed between this single nucleotide polymorphism and efficacy of neuroleptic treatment. Homozygous individuals for the -392A variant [P=0.014, odds ratio (OR)=3.32] were more frequent in the treatment-resistant group, compared with carriers of one copy of the -392G variant. The CYP3A5 low expressor genotype (CYP3A5*3/CYP3A5*3) was found to be associated with refractoriness to neuroleptic treatment (P=0.003, OR=3.16). Among the haplotypes observed in DRD3 gene, the T/A/G/A/C haplotype showed an association with refractoriness to neuroleptics (chi=5.342, P=0.021, OR=1.75). This association showed that carriers of one copy of this haplotype presented intermediate values between noncarriers and homozygous individuals for the haplotype. No association was observed with polymorphisms in DRD2 and CYP2D6 genes. Multiple logistic regression analyses showed that the number of copies of DRD3 T/A/G/A/C haplotype and CYP3A5 low expressor genotype were predictors of refractoriness to neuroleptic after controlling for selected risk factors. CYP3A5*3 individuals carrying at least one copy of the T/A/G/A/C haplotype showed a higher risk to be refractory to neuroleptics than CYP3A5*3 homozygotes+non-T/A/G/A/C carriers (chi=5.533, P=0.019, OR=2.32, 95% confidence interval=1.08-5.02). No significant associations were observed with DRD2 and CYP2D6 polymorphisms.


CONCLUSIONS
Our results suggest a role for CYP3A5 and DRD3 gene variants on refractoriness to neuroleptic treatment in Brazilians with schizophrenia.
Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Fabiana B
FB
Kohlrausch
Clarissa S
CS
Gama
Maria Inês
MI
Lobato
Paulo
P
Belmonte-de-Abreu
Sidia M
SM
Callegari-Jacques
Alejandro
A
Gesteira
Francisco
F
Barros
Angel
A
Carracedo
Mara H
MH
Hutz
D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001938:Brazil; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D017448:Receptors, Dopamine D2 / Q000235:genetics; D050637:Receptors, Dopamine D3 / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics*; D044465:White People / Q000235:genetics*
D014150:Antipsychotic Agents; C493593:DRD3 protein, human; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A