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R ESEARCH R EPORT
Polymorphisms of the ABCB1 gene are associated with the therapeutic response to risperidone in Chinese schizophrenia patients Qinghe Xing1,2, Rui Gao1,2, Huafang Li3, Guoyin Feng3, Mingqing Xu1,2, Shiwei Duan1,2, Junwei Meng1,2, Aiping Zhang1,2, Shengying Qin1,2 & Lin He2,4† †Author
for correspondence Center, Shanghai Jiao Tong University, Shanghai 200030, PR China 2Institute for Nutritional Sciences, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China 3Shanghai Institute of Mental Health, Shanghai 200030, PR China 4Shanghai Jiao Tong University, Bio-X Center, Hao Ran Building, 1954 Hua Shan Road, Shanghai 200030; or Institute for Nutritional Sciences, SIBS, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, China China Tel.: +86 216 282 2491; Fax: +86 216 282 2491; E-mail:
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Keywords: ABCB1, polymorphism, response, risperidone
P-glycoprotein, a product of the ATP-binding cassette B1 (ABCB1) gene, plays an important role in absorption and distribution of drugs. The brain entry of risperidone and 9-OH-risperidone is greatly limited by P-glycoprotein, which implies that the functional polymorphisms of ABCB1 in humans may be a factor contributing to the variability in response to risperidone. The present study was therefore designed to examine whether polymorphisms of the ABCB1 gene are related to therapeutic response. For this purpose, 130 Chinese schizophrenia patients undergoing risperidone treatment were recruited. Plasma drug concentrations were monitored and clinical symptoms were evaluated using the Brief Psychiatric Rating Scale (BPRS) before and 8 weeks after the treatment. Association tests between genotypes and percentage improvement in total BPRS scores were performed using analyses of variance. Our results show that genotyping C1236T may help to predict the efficacy of risperidone treatment on the basis that patients with the TT genotype showed greater improvement than those with other genotypes on the overall BPRS (F = 3.967, p = 0.021), while other polymorphisms, including rs13233308, G2677T/A and C3435T polymorphism, did not show any association with the response to risperidone. These results showed suggestive evidence that genetic variation in the ABCB1 gene may influence the individual response to risperidone.
P-glycoprotein, which is encoded by the ABCB1 gene, is a 130 kDa transporter protein that is abundantly distributed in the apical part of the brain capillary endothelial cells forming the tight junctions of the blood–brain barrier. Modulation of the efflux function of P-glycoprotein in the blood–brain barrier may affect the penetration of its substrates into the CNS [1–4]. Therefore, interindividual variability of P-glycoprotein function in the brain may contribute to this variability of clinical response to neuropsychiatric agents [5]. Risperidone is one of the most commonly used novel antipsychotic drugs. It has many clinical advantages over classic neuroleptics, including a lower incidence of extrapyramidal symptoms (EPS); a more frequent clinically-significant improvement; a lower risk of relapse; and a favorable effect on both positive and negative symptoms [6–8]. As with all antipsychotics, there are wide individual differences in response to risperidone, both regarding therapeutic effects and adverse effects. This interindividual variability in response to risperidone imposes some limitations with respect to the therapeutic use of the drug. In particular, the selection of both initial and final doses of risperidone for individual patients becomes difficult, as the same dose of
10.2217/14622416.7.7.987 © 2006 Future Medicine Ltd ISSN 1462-2416
risperidone may produce markedly different reactions, efficacious or adverse, in different patients [9]. It is therefore important to determine the sources of interindividual variation in clinical response and to predict such response before treatment with risperidone begins. Compared with other psychotropic drugs, risperidone is quite a polar compound, whose transmembrane transport is more dependent on transporters. Risperidone and its major metabolite, 9-OH-risperidone, are good substrates of P-glycoprotein, with relatively high affinity (Km values for risperidone and 9-OH-risperidone were 26.3 ± 5.5 mM and 149.6 ± 29.7 mM, respectively) and high capacity (Vmax for risperidone and 9-OH-risperidone were 71.4 ± 3.2 and 67.0 ± 4.3 nmol phosphate released/mg protein/min, respectively) [10–11]. The brain concentrations of risperidone and 9-OH-risperidone in abcb1 knockout mice were markedly higher (13.1and 29.4-fold respectively, p
