Association of treatment-resistant schizophrenia with the G2677A/T and C3435T polymorphisms in the ATP-binding cassette subfamily B member 1 gene

Abstract

Approximately 20-25% of all schizophrenic patients are resistant to, or are intolerant of, repeated attempts at treatment with a number of antipsychotic agents from different chemical classes. This form of the disease is generally known as 'treatment-resistant schizophrenia (TRS)' (Cohen and Buchanan, 1997). The observation that a broad range of antipsychotics is ineffective against TRS raises the possibility that a common pharmacokinetic process, such as absorption or distribution, is involved. Consequently, the focus of the study was P-glycoprotein (PGP), a membrane protein that functions as a multi-drug efflux pump. We therefore hypothesized that the ATP-binding cassette subfamily B member 1 (ABCB1) gene, which encodes PGP, is associated with the poor drug response in TRS patients or the occurrence of side effects of antipsychotics.To validate this hypothesis, a statistical analysis of the frequency of the G2677A/T and C3435T single nucleotide polymorphisms (SNPs) in ABCB1 was conducted between 16 TRS patients and 84 non-TRS patients, who were divided using the criteria established by Kane et al. (1988). In addition, the occurrence of major side effects of antipsychotics, including extrapyramidal symptoms, postural hypotension, dysuria, and constipation, were also assessed by clinical charts. The assessments were performed by two trained psychiatrists who were blind to all genotypic data. The genotype of each individual at the ABCB1 locus was determined by polymerase chain reaction restriction fragment-length polymorphism assays as described previously (Cascorbi et al., 2001). Differences in allele frequency were compared between populations with use of the Fisher's exact test. A P value of less than 0.05 was considered to indicate statistical significance. No significant differences in characteristics, including age, sex or subtype distributions, were observed between TRS and non-TRS individuals. The allelic frequencies of G2677A/T were 0.47 for the wild type versus 0.17/0.36 for the variants. Likewise, the frequencies for C3435T were 0.57 versus 0.43. These frequencies are similar to those from previous reports on Japanese individuals (Sakaeda et al., 2002). The allelic frequencies of G2677A/T and C3435T did not differ significantly between TRS and non-TRS individuals (P = 0.44, odds ratio = 0.73, 95% confidence interval 0.34-1.56; P = 0.56, odds ratio = 0.76, 95% confidence interval 0.35-1.67, respectively). Furthermore, there were no significant differences in allele frequencies that could be ascribed to the occurrences of side effects.To our knowledge, this report is the first study that demonstrates the impact of ABCB1 SNPs on the clinical antipsychotic response for schizophrenia. Recent in-vitro reports demonstrated that most antipsychotics show varying degrees of affinity for PGP, and that the penetration of atypical antipsychotics into the brain is also influenced by PGP activity, denoting the significance of PGP function or expression for the effectiveness of neurotropics. In particular, PGP at the b...

Effects of typical and atypical antipsychotic drugs on gene expression profiles in the liver of schizophrenia subjects

“…ABC proteins transport various molecules across extra- and intra-cellular membranes and are expressed in liver tissue. Polymorphisms in the ABC gene are associated with treatment resistance in schizophrenia and response to the atypical AP drug risperidone in schizophrenia [ 56 , 57 ]. These studies suggest that the ABC genes may play a role in responses to different APs in schizophrenia.…”

Pharmacogenetics of Antipsychotics

“…Polymorphisms in the encoding gene MDR1 (synonymous with ABCB1, ATPbinding cassette, subfamily B [MDR/transporter associated with antigen processing], member 1 gene) have been investigated in several studies. Although there are negative findings, 54,55 some positive findings exist for the G2677T/A and C3435T polymorphisms. Contradictory results have been reported, with studies showing better treatment response of T allele carriers of both polymorphisms, 56 while others reported worse response in the T allele carriers of C3435T.…”

MDR1 Gene Polymorphism in Japanese Patients with Schizophrenia and Mood Disorders Including Depression

“…In our previous study, MDR1 2677GϾA,T and 3435 CϾT were examined in the relation with drug-resistant schizophrenia. 31) Although no difference in the polymorphisms for the exon between patients with and without drug-resistance, the impact of promoter region remained unclear. MDR1 polymorphisms for promoter region may provide the modified drug response of P-gp substrates in psychiatric disorders, especially in mood disorders with lower frequency of mutated alleles on Ϫ1517 TϾC and Ϫ129 TϾC.…”