In this study, we examined the relationships between plasma concentrations of risperidone and 9-hydroxyrisperidone and polymorphisms of CYP3A4. All 130 schizophrenia patients (45 men, 85 women, age 15—60 years) who met DSM-IV criteria were given risperidone for 8 weeks. Clinical efficacy was determined using the Positive and Negative Syndrome Scale (PANSS). CYP3A4*1G was found to be associated with the change in total PANSS scores (Kruskal—Wallis test, P = 0.021), which was not significant on adjusting for multiple testing. Our study has, for the first time, conducted a genetic association study of the CYP3A4 gene with risperidone response. Further studies on larger groups and on the effects of the longer term risperidone treatment are needed to confirm these results.
Ahmadi, KR, Weale, ME, Xue, ZY, Soranzo, N., Yarnall, DP, Briley, JD, et al. (2005) A single-nucleotide polymorphism tagging set for human drug metabolism and transport. Nat Genet37: 84-89.
2.
Csernansky, JG, Mahmoud, R., Brenner, R. ( 2002) A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med346: 16-22.
3.
Davis, JM, Matalon, L., Watanabe, MD, Blake, L., Metalon, L. ( 1994) Depot antipsychotic drugs: place in therapy. Drugs47: 741-773.
4.
de Leon, J. ( 2007) The crucial role of the therapeutic window in understanding the clinical relevance of the poor versus the ultra-rapid metabolizer phenotypes in subjects taking drugs metabolized by CYP2D6 or CYP2C19. J Clin Psychopharmacol27: 241-245.
5.
de Leon, J., Susce, MT, Pan, RM, Fairchild, M., Koch, WH, Wedlund, PJ ( 2005) The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry66: 15-27.
6.
DeVane, CL, Nemeroff, CB ( 2001) An evaluation of risperidone drug interactions. J Clin Psychopharmacol21: 408-416.
7.
Fang, J., Bourin, M., Baker, GB ( 1999) Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. Naunyn Schmiedebergs Arch Pharmacol359: 147-151.
8.
Faul, F., Erdfelder, E., Lang, AG, Buchner, A. ( 2007) G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods39: 175-191.
9.
Flaum, M., Amador, X., Gorman, J., Bracha, HS, Edell, W., McGlashan, T., et al. (1997) DSM-IV Sourcebook. Washington, DC: American Psychiatric Association.
10.
Fukushima-Uesaka, H., Saito, Y., Watanabe, H., Shiseki, K., Saeki, M., Nakamura, T., et al. (2004) Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population. Hum Mutat23: 100.
11.
Huang, ML, Van Peer, A., Woestenborghs, R., De Coster, R., Heykants, J., Jansen, AA, et al. (1993) Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther54: 257-268.
12.
Du, J., Xing, Q., Xu, L., Xu, M., Shu, A., Shi, Y., et al. (2006) Systematic screening for polymorphisms in the CYP3A4 gene in a Chinese population. Pharmacogenomics7: 831-841.
13.
Kane, JM ( 1996) Schizophrenia. N Engl J Med334: 34-41.
14.
Kay, SR, Fiszbein, A., Opler, LA ( 1987) The positive and negative syndrome scale (PANSS) for schizophrenia . Schizophr Bull13: 261-276.
15.
Leucht, S., Barnes, TR, Kissling, W., Engel, RR, Correll, C., Kane, JM ( 2003) Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry160: 1209-1222.
16.
Lieberman, JA ( 1996) Atypical antipsychotic drugs as a first-line treatment of schizophrenia: a rationale and hypothesis. J Clin Psychiatry57 (Suppl. 11): 68-71.
17.
Mannens, G., Huang, ML, Meuldermans, W., Hendrickx, J., Woestenborghs, R., Heykants, J. ( 1993) Absorption, metabolism, and excretion of risperidone in humans. Drug Metab Dispos21: 1134-1141.
18.
Mauri, MC, Laini, V., Boscati, L., Rudelli, R., Salvi, V., Orlandi, R., et al. (2001) Long-term treatment of chronic schizophrenia with risperidone: a study with plasma levels. Eur Psychiatry16: 57-63.
19.
Megens, AA, Awouters, FH, Schotte, A., Meert, TF, Dugovic, C., Niemegeers, CJ, et al. (1994) Survey on the pharmacodynamics of the new antipsychotic risperidone. Psychopharmacology ( Berl) 114: 9-23.
20.
Olesen, OV, Licht, RW, Thomsen, E., Bruun, T., Viftrup, JE, Linnet, K. ( 1998) Serum concentrations and side effects in psychiatric patients during risperidone therapy. Ther Drug Monit20: 380-384.
21.
Robinson, D., Woerner, MG, Alvir, JM, Bilder, R., Goldman, R., Geisler, S., et al. (1999) Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry56: 241-247.
22.
Schotte, A., Janssen, PF, Gommeren, W., Luyten, WH, Van Gompel, P., Lesage, AS, et al. (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl) 124: 57-73.
23.
Schulz, SC, Findling, RL, Wise, A., Friedman, L., Kenny, J. ( 1998) Child and adolescent schizophrenia. Psychiatr Clin North Am21: 43-56.
24.
Stephens, M., Scheet, P. ( 2005) Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet76: 449-462.
25.
Stephens, M., Smith, NJ, Donnelly, P. ( 2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet68: 978-989.
26.
van Beijsterveldt, LE, Geerts, RJ, Leysen, JE, Megens, AA, Van den Eynde, HM, Meuldermans, WE, et al. (1994) Regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat. Psychopharmacology (Berl) 114: 53-62.
27.
Wang, L., Yu, L., Zhang, AP, Fang, C., Du, J., Gu, NF, et al. (2007) Serum prolactin levels, plasma risperidone levels, polymorphism of cytochrome P450 2D6 and clinical response in patients with schizophrenia. J Psychopharmacol21: 837-842.
28.
Yasui-Furukori, N., Hidestrand, M., Spina, E., Facciola, G., Scordo, MG, Tybring, G. ( 2001) Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes. Drug Metab Dispos29: 1263-1268.
