Serum prolactin levels,plasma risperidone levels,polymorphism of cytochrome P450 2D6 and clinical response in patients with schizophrenia

Abstract

The object of this study is to assess 1) the relationship between plasma antipsychotic drug concentration, serum prolactin levels and the clinical efficacy of risperidone, 2) the relationship between the CYP2D6 polymorphisms and metabolizing of risperidone and 3) the role of 9-hydroxyrisperidone in elevating prolactin levels. One-hundred and eighteen Chinese schizophrenia patients (40 males, 78 females, age 15—60 years) were given risperidone at dosages ranging from 2—8 mg/day for 8 weeks. Clinical efficacy was determined using the Brief Psychiatric Rating Scores (BPRS). Serum prolactin levels were assayed before and after the 8 week treatment and plasma risperidone and 9-hydroxyrisperidone levels were also measured at the end of the 8-week treatment. The results showed there was no significant correlation between the concentration of active moiety and clinical response. Risperidone treatment significantly increased serum prolactin levels. Furthermore, changes of prolactin levels were not correlated with the clinical response. For the risperidone/ 9-hydroxyrisperidone ratio, there was a statistically significant difference among the CYP2D6*1/*1, *1/*10, *10/*10 genotypes (Kruskal—Wallis test, p = 0.012). No significant differences were found in the concentration of 9-hydroxyrisperidone and active moiety among the genotypes. In addition, the concentration of 9-hydroxyrisperidone was not significantly correlated with the increase of serum prolactin. In conclusion, our study has, for the first time, produced evidence that in Chinese schizophrenic patients, the metabolism of risperidone is dependent on CYP2D6. Neither changes in serum prolactin levels nor plasma concentration of active moiety were significantly correlated with clinical efficacy of risperidone. 9-hydroxyrisperidone may not play a predominant role in elevating serum prolactin level.

Keywords

schizophrenia CYP2D6 clinical response prolactin risperidone 9-hydroxyrisperidone

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References

Bondolfi G. , Dufour H. , Patris M. , May J.P. , Billeter U. , Eap C.B. , Baumann P. (1998) Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group. Am J Psychiatry 155: 499—504

Chou J.C. , Douyon R. , Czobor P. , Volavka J. , Cooper T.B. (1998) Change in plasma prolactin and clinical response to haloperidol in schizophrenia and schizoaffective disorder. Psychiatry Res 81: 51—55

Chouinard G. , Arnott W. Clinical review of risperidone (1993) Can J Psychiatry 38(Suppl 3): S89—S95

David S.R. , Taylor C.C. , Kinon B.J. , Breier A. (2000) The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia. Clin Ther 22: 1085—1096

Douglas A.M. , Atchison B.A. , Somogyi A.A. , Drummer O.H. (1994) Interpretation of a simple PCR analysis of the CYP2D6(A) and CYP2D6(B) null alleles associated with the debrisoquine/sparteine genetic polymorphism. Pharmacogenetics 4: 154—158

Fang J. , Bourin M. , Baker G.B. (1999) Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. Naunyn Schmiedebergs Arch Pharmacol 359: 147—151

Heim M. , Meyer U.A. (1990) Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet 336: 529—532

Hersberger M. , Marti-Jaun J. , Rentsch K. , Hanseler E. (2000) Rapid detection of the CYP2D6*3, CYP2D6*4 and CYP2D6*6 alleles by tetra-primer PCR and of the CYP2D6*5 allele by multiplex long PCR . Clin Chem 46: 1072—1077

Huang M.L. , Van Peer A. , Woestenborghs R. , De Coster R. , Heykants J. , Jansen A.A. , Zylicz Z. , Visscher H.W. , Jonkman J.H. (1993) Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 54: 257—268

10.

Kapur S. , Roy P. , Daskalakis J. , Remington G. , Zipursky R. (2001) Increased dopamine d(2) receptor occupancy and elevated prolactin level associated with addition of haloperidol to clozapine . Am J Psychiatry 158: 311—314

11.

Knegtering R. , Baselmans P. , Castelein S. , Bosker F. , Bruggeman R. , Van den Bosch R.J. (2005) Predominant role of the 9-hydroxy metabolite of risperidone in elevating blood prolactin levels. Am J Psychiatry 162: 1010—1012

12.

Lee B.H. , Kim Y.K. (2006) The relationship between prolactin response and clinical efficacy of risperidone in acute psychotic inpatients. Prog Neuropsychopharmacol Biol Psychiatry 30: 658—662

13.

Lee H.S. , Tan C.H. , Khoo Y.M. , Chee K.T. , Wong K.E. , Chong S.A. , Mahendran R. , Yap J.L. , Low B.L. , Choo C.H. , Chan A. ( 1999) Serum concentrations and clinical effects of risperidone in schizophrenic patients in Singapore—a preliminary report. Br J Clin Pharmacol 47: 460—461

14.

Leysen J.E. , Gommeren W. , Eens A. , De Chaffoy D.C. , Stoof J.C. , Janssen P.A. (1998) Biochemical profile of risperidone, a new antipsychotic . J Pharmacol Exp Ther 247: 661—670

15.

Markianos M. , Hatzimanolis J. , Lykouras L. (1999) Gonadal axis hormones in male schizophrenic patients during treatment with haloperidol and after switch to risperidone. Psychopharmacology (Berl) 143: 270—272

16.

Matsubara Y. , Ohnuma T. , Shibata N. , Takahashi T. , Arai H. ( 2002) Plasma concentration of risperidone showed a correlation with daily dose, but not with age nor cytochrome P-450 2D6 gene polymorphisms in Japanese schizophrenics. Psychogeriatrics 2: 284—288

17.

Mauri M.C. , Laini V. , Boscati L. , Rudelli R. , Salvi V. , Orlandi R. , Papa P. ( 2001) Long-term treatment of chronic schizophrenia with risperidone: a study with plasma levels. Eur Psychiatry 16: 57—63

18.

Meltzer H.Y. , Busch D.A. , Fang V.S. (1983) Serum neuroleptic and prolactin levels in schizophrenic patients and clinical response. Psychiatry Res 9: 271—283

19.

Mihara K. , KondoT. , Yasui-Furukori N. , Suzuki A. , Ishida M. , Ono S. , Kubota T. , Iga T. , Takarada Y. , De Vries R. , Kaneko S. (2003) Effects of various CYP2D6 genotypes on the steady-state plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone , in Japanese patients with schizophrenia. Ther Drug Monit 25: 287—293

20.

Olesen O.V. , Linnet K. (1997) Simplified high-performance liquid chromatographic method of determination of risperidone and 9-hydroxyrisperidone in serum from patients comedicated with other psychotropic drugs. J Chromatogr B 698: 209—216

21.

Olesen O.V. , Licht R.W. , Thomsen E. , Bruun T. , Viftrup J.E. , Linnet K. (1998) Serum concentrations and side effects in psychiatric patients during risperidone therapy. Ther Drug Monit 20: 380—384

22.

Overall J.E. , Gorham D.R. (1962) The brief psychiatric rating scale. Psychol Rep 10: 799—812

23.

Roh H.K. , Dahl M.L. , Johansson I. , Ingelman-Sundberg M. , Cha Y.N. , Bertilsson L. (1996) Debrisoquine and S-mephenytoin hydroxylation phenotypes and genotypes in a Korean population. Pharmacogenetics 6: 441—447

24.

Roh H.K. , Kim C.E. , Chung W.G. , Park C.S. , Svensson J.O. , Bertilsson L. (2001) Risperidone metabolism in relation to CYP2D6*10 allele in Korean schizophrenic patients. Eur J Clin Pharmacol 57: 671—675

25.

Shingo K. , Reiji Y. , Koji S. , Chima M. , Makiko G. , Kyoko K. , Yasuhisa Y. , Nobuhisa U. , Osamu O. , Jun N. ( 2005) Prediction of response to risperidone treatment with respect to plasma concentrations of risperidone, catecholamine metabolites, and polymorphism of cytochrome P450 2D6. Int Clin Psychopharmacol 20: 71—78

26.

Scordo M.G. , Spina E. , Facciola G. , Avenoso A. , Johansson I. , Dahl M.L. (1999) Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone. Psychopharmacology (Berl) 147: 300—305

27.

Spina E. , Avenoso A. , Facciola G. , Salemi M. , Scordo M.G. , Ancione M. , Madia A.G. , Perucca E. (2001) Relationship between plasma risperidone and 9-hydroxyrisperidone concentrations and clinical response in patients with schizophrenia. Psychopharmacology (Berl) 153: 238—243

28.

van Beijsterveldt L.E. , Geerts R.J. , Leysen J.E. , Megens A.A. , Van den Eynde H.M. , Meuldermans W.E. , Heykants J.J. (1994) Regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat. Psychopharmacology (Berl) 114: 53—62

29.

Van Putten T , Marder S.R. , Mintz J. (1991) Serum prolactin as a correlate of clinical response to haloperidol. J Clin Psychopharmacol 11: 357—361

30.

Xie H.G. , Kim R.B. , Wood A.J. , Stein C.M. (2001) Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol 41: 815—850

31.

Yasui-Furukori N. , Mihara K. , Kondo T. , Kubota T. , Iga T. , Takarada Y. , De Vries R. , Kaneko S. , Tateishi T. (2003) Effects of CYP2D6 genotypes on plasma concentrations of risperidone and enantiomers of 9-hydroxyrisperidone in Japanese patients with schizophrenia. J Clin Pharmacol 43: 122—127

32.

Zhang X.Y. , Zhou D.F. , Yuan C.L. , Zhang P.Y. , Wu G.Y. , Shen Y.C. (2002) Risperidone-induced increase in serum prolactin is correlated with positive symptom improvement in chronic schizophrenia. Psychiatry Res 109: 297—302