Cytochrome P450 2D6 Deficiency and its Clinical Relevance in a Patient Treated with Risperidone

• Introduction
• Case
• Discussion
• References

In contrast to several authors who found hepatic cytochrome P 450 2D6 (CYP2D6) metabolising status to be clinically unimportant in treatment with the CYP2D6 substrate, risperidone, we report on a 17-year-old schizophrenic patient who suffered from severe extrapyramidal side effects (EPS) while being treated with risperidone at 4 mg per day. He was genotyped as a CYP2D6 poor metaboliser (PM). The active moiety of risperidone (sum of risperidone and 9-hydroxyrisperidone) was elevated and increased even further under co-medication with haloperidol and biperiden. We conclude that the PM phenotype for CYP2D6 of this patient had major clinical importance in treatment with risperidone. Most likely metabolic pathways other than CYP2D6 were also involved that are probably inhibited by haloperidol.

Introduction

More than 40 clinically important prescribed drugs, among them many antipsychotics and antidepressants, are metabolised by the hepatic cytochrome P450 2D6 (CYP2D6) [4]. This enzyme exhibits a high interindividual variability due to a genetic polymorphism of the CYP2D6 gene, giving rise to two major phenotypes - poor metabolisers (PMs) and extensive metabolisers (EMs) [9] [3]. 7 - 10 % of Caucasians are PMs with a grossly impaired drug metabolism [7]. The CYP2D6 phenotype is of great clinical importance since PMs will reach higher plasma levels of the parent compound in comparison to EMs under the same dose of medication [4]. Therefore, PMs are at higher risk of developing severe concentration-dependent side effects [12] [2].

The antipsychotic drug, risperidone, is converted to its active metabolite 9-hydroxyrisperidone by CYP2D6. Depending on the metabolic capacity of this enzyme, the ratio of risperidone to 9-hydroxyrisperidone is lower than unity in EMs but greater than unity in PMs [5]. It has been speculated that this does not affect the treatment of schizophrenia since 9-hydroxyrisperidone had been shown to be virtually pharmacodynamically equipotent to risperidone in animal models [8] [14]. Also, another study showed that the active moiety of risperidone (sum of risperidone and 9-hydroxyrisperidone) was unchanged in PMs, as an elevation of risperidone plasma levels was compensated by a similar decrease of 9-hydroxyrisperidone concentration [8]. Thus, the manufacturer concluded that elevated plasma concentrations of risperidone due to comedication-inhibiting CYP2D6 function is of no clinical relevance due to a simultaneous decrease of 9-hydroxyrisperidone [10].

In contrast, we report on a patient who exhibited severe EPS while receiving risperidone at 4 mg per day. To find an explanation for the adverse drug reaction, we analysed the CYP2D6 phenotype by genotyping, and we studied risperidone's kinetics in this patient.

Case

A 17-year-old man with a hebephrenic schizophrenia according to DSM IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) was admitted to a general adolescent psychiatric ward. As the initial treatment with perazine (150 mg/day) provided only minor relief of the symptoms, medication was changed to a monotherapy of risperidone (6 mg/day) after 3 months with initial improvement in the psychotic symptoms. However, the patient began to suffer from severe akathisia, Parkinsonism and drowsiness. Reduction of medication (4 mg of risperidone/day) brought no relief. Analysis of plasma concentrations (4 mg/day of risperidone at steady state) by standard procedures (mass spectroscopy, internal standard; Bioscientia, Ingelheim, Germany) revealed an increased plasma concentration of risperidone and an elevated active moiety. The ratio of risperidone to 9-hydroxyrisperidone) was higher than unity (Table [1]). Renal function was normal.

Eleven days later, blood was taken twice to achieve more precise pharmacokinetic data. Both risperidone levels and active moiety were already elevated at steady state. At the approximate time of peak plasma concentration (t_max) of the active moiety two hours after the intake of risperidone, risperidone levels were increased further, whereas the 9-hydroxyrisperidone level showed no significant change when t_max was reached (Table [1]).

Eight days after haloperidol (6 mg/day) and biperiden (2 mg/day) had initially been given as comedication due to deteriorating psychotic symptoms and side effects, both risperidone and 9-hydroxyrisperidone plasma concentration had increased further (Table [1]). When risperidone was discontinued, the side effects vanished. Finally, after an improvement in the psychotic symptoms, olanzapine administration (7.5 mg/day) was initiated that was tolerated well by the patient. Plasma concentrations of haloperidol (3.4 µg/l) and olanzapine (12 ng/ml) were not elevated.

Genotyping applying long distance- and multiplex-polymerase chain reaction [13] revealed that the patient was homozygous for the most common non-functional CYP2D6*4 allele.

Discussion

Previous studies [8] [11] covering only few poor metabolisers (n = 2; n = 3) showed that the active moiety of risperidone depended to a minor extent, if at all, on the individual's CYP2D6 phenotype. In contrast to the results of former investigations, we found an increased risperidone level but no decrease in levels of 9-hydroxyrisperidone in a patient genotyped as a poor metaboliser. Therefore, the active moiety was much higher than the 28 µg/l expected from a daily dose of 4 mg of risperidone [1].

Another recent study also showed that none of the poor metabolisers included (n = 5) tolerated risperidone well (EPS). Plasma levels of one poor metaboliser not receiving comedication showed an increase in the active moiety [1].

Our patient's side effects could be explained by the increased risperidone levels and the elevated active moiety, which might be caused by an extremely prolonged half-life of risperidone and an unchanged half life of 9-hydroxyrisperidone. The half-life of risperidone in extensive metabolisers (about 2.8 h) extends to up to 21.0 h (± 5 h) in poor metabolisers, while the half life of 9-hydroxyrisperidone seems to be identical (20 - 22 h) in extensive and poor metabolisers [8].

Why haloperidol, another CYP2D6 substrate, should influence risperidone levels in a CYP2D6-deficient individual also begs explanation. One might be that drug-metabolising enzymes other than CYP2D6 are also involved in the metabolism of risperidone. For example, the hepatic cytochrome P450 3A4 (CYP3A4) was shown to be capable of metabolising risperidone to 9-hydroxyrisperidone, albeit on a much smaller scale than CYP2D6 [6]. CYP3A4 also seems to be involved in the metabolism of haloperidol [15]. A competitive or inhibitive interaction could be the hypothetical cause of the raised risperidone levels under haloperidol comedication. An involvement of CYP3A4 in the metabolism of haloperidol could also explain why the plasma concentration of haloperidol was not elevated in this individual. So far, the literature has not provided much data on the effects of biperiden on the hepatic cytochrome system. It is open to debate whether risperidone and 9-hydroxyrisperidone are pharmacodynamically equipotent in humans, as testing has so far been confined to animal models. Future trials should focus on pharmacodynamic and pharmacokinetic aspects of risperidone and 9-hydroxyrisperidone, and more individuals should be examined by therapeutic drug monitoring and genotyping.

References

• 1 Bork J A, Rogers T, Wedlund P J, de Leon J. A pilot study on risperidone metabolism: the role of cytochromes P450 2D6 and 3A.  J Clin Psychiatry. 1999;  60 469-476
  CrossrefPubMedSearch in Google Scholar
• 2 Chen S Q, Chou W H, Blouin R A, Mao Z P, Humphries L L, Meek C. et al . The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: Screening costs and influence on clinical outcomes in psychiatry.  Clin Pharmacol Ther. 1996;  60 (5) 522-534
  CrossrefPubMedSearch in Google Scholar
• 3 Eichelbaum M, Spannbrucker N, Steincke B, Dengler H J. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect.  Eur J Clin Pharmacol. 1979;  16 (3) 183-187
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• 4 Eichelbaum M, Gross A S. The genetic polymorphism of debrisoquine/sparteine metabolism-clinical aspects.  Pharmacol Ther. 1990;  46 (3) 377-394
  CrossrefPubMedSearch in Google Scholar
• 5 Ereshefsky L. Pharmacokinetics and drug interactions: update for new antipsychotics.  J Clin Psychiatry. 1996;  57 (11) 12-25
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• 6 Fang J, Bourin M, Baker G B. Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4.  Naunyn-Schmiedebergs-Arch-Pharmacol. 1999;  359 (2) 147-151
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• 8 Huang M -L, van Peer A, Woestenborghs R, De Coster R, Heykants J, Jansen A AI. et al . Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactine response in healthy subjects.  Clin Pharmacol Ther. 1993;  54 257-268
  PubMedSearch in Google Scholar
• 9 Mahgoub A, Idle J R, Dring L G, Lancaster R, Smith R L. Polymorphic hydroxylation of Debrisoquine in man.  Lancet. 1977;  2 (8038) 584-586
  PubMedSearch in Google Scholar
• 10 Risperdal [package insert]. Neuss, Germany: Janssen-Cilag GmbH 1999
  Search in Google Scholar
• 11 Scordo M G, Spina E, Facciolà G, Avenoso A, Johansson I, Dahl M L. Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone.  Psychopharmacology. 1999;  147 300-305
  CrossrefPubMedSearch in Google Scholar
• 12 Spina E, Gitto C, Avenoso A, Campo G M, Caputi A P, Perucca E. Relationship between plasma desipramine levels, CYP2D6 phenotype and clinical response to desipramine: a prospective study.  Eur J Clin Pharmacol. 1997;  51 (5) 395-398
  CrossrefPubMedSearch in Google Scholar
• 13 Stüven T, Griese E -U, Kroemer H K, Eichelbaum M, Zanger U M. Rapid detection of CYP2D6 null alleles by long distance- and multiplex-polymerase chain reaction.  Pharmacogenetics. 1996;  6 417-421
  PubMedSearch in Google Scholar
• 14 Van Beijsterveldt L EC, Geerts R JF, Leysen J E, Megens A AHP, Van den Eynde H MJ, Meuldermans W EG. et al . The regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat.  Psychopharmacology. 1994;  114 53-62
  PubMedSearch in Google Scholar
• 15 Yasui N, Kondo T, Otani K, Furukori H, Mihara K, Suzuki A. et al . Effects of itraconazole on the steady-state plasma concentrations of haloperidol and its reduced metabolite in schizophrenic patients: in vivo evidence of the involvement of CYP3A4 for haloperidol metabolism.  J Clin Psychopharmacol. 1999;  19 (2) 149-154
  CrossrefPubMedSearch in Google Scholar

Dr. G. Barth

Universitätsklinik für Psychiatrie und Psychotherapie

Osianderstr. 22

72076 Tübingen


Germany

Email: gdbarth@med.uni-tuebingen.de

References

• 1 Bork J A, Rogers T, Wedlund P J, de Leon J. A pilot study on risperidone metabolism: the role of cytochromes P450 2D6 and 3A.  J Clin Psychiatry. 1999;  60 469-476
  CrossrefPubMedSearch in Google Scholar
• 2 Chen S Q, Chou W H, Blouin R A, Mao Z P, Humphries L L, Meek C. et al . The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: Screening costs and influence on clinical outcomes in psychiatry.  Clin Pharmacol Ther. 1996;  60 (5) 522-534
  CrossrefPubMedSearch in Google Scholar
• 3 Eichelbaum M, Spannbrucker N, Steincke B, Dengler H J. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect.  Eur J Clin Pharmacol. 1979;  16 (3) 183-187
  CrossrefPubMedSearch in Google Scholar
• 4 Eichelbaum M, Gross A S. The genetic polymorphism of debrisoquine/sparteine metabolism-clinical aspects.  Pharmacol Ther. 1990;  46 (3) 377-394
  CrossrefPubMedSearch in Google Scholar
• 5 Ereshefsky L. Pharmacokinetics and drug interactions: update for new antipsychotics.  J Clin Psychiatry. 1996;  57 (11) 12-25
  PubMedSearch in Google Scholar
• 6 Fang J, Bourin M, Baker G B. Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4.  Naunyn-Schmiedebergs-Arch-Pharmacol. 1999;  359 (2) 147-151
  PubMedSearch in Google Scholar
• 7 Griese E U, Zanger U M, Brudermanns U, Gaedigk A, Mikus G, Morike K. et al . Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population.  Pharmacogenetics. 1998;  8 (1) 15-26
  PubMedSearch in Google Scholar
• 8 Huang M -L, van Peer A, Woestenborghs R, De Coster R, Heykants J, Jansen A AI. et al . Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactine response in healthy subjects.  Clin Pharmacol Ther. 1993;  54 257-268
  PubMedSearch in Google Scholar
• 9 Mahgoub A, Idle J R, Dring L G, Lancaster R, Smith R L. Polymorphic hydroxylation of Debrisoquine in man.  Lancet. 1977;  2 (8038) 584-586
  PubMedSearch in Google Scholar
• 10 Risperdal [package insert]. Neuss, Germany: Janssen-Cilag GmbH 1999
  Search in Google Scholar
• 11 Scordo M G, Spina E, Facciolà G, Avenoso A, Johansson I, Dahl M L. Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone.  Psychopharmacology. 1999;  147 300-305
  CrossrefPubMedSearch in Google Scholar
• 12 Spina E, Gitto C, Avenoso A, Campo G M, Caputi A P, Perucca E. Relationship between plasma desipramine levels, CYP2D6 phenotype and clinical response to desipramine: a prospective study.  Eur J Clin Pharmacol. 1997;  51 (5) 395-398
  CrossrefPubMedSearch in Google Scholar
• 13 Stüven T, Griese E -U, Kroemer H K, Eichelbaum M, Zanger U M. Rapid detection of CYP2D6 null alleles by long distance- and multiplex-polymerase chain reaction.  Pharmacogenetics. 1996;  6 417-421
  PubMedSearch in Google Scholar
• 14 Van Beijsterveldt L EC, Geerts R JF, Leysen J E, Megens A AHP, Van den Eynde H MJ, Meuldermans W EG. et al . The regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat.  Psychopharmacology. 1994;  114 53-62
  PubMedSearch in Google Scholar
• 15 Yasui N, Kondo T, Otani K, Furukori H, Mihara K, Suzuki A. et al . Effects of itraconazole on the steady-state plasma concentrations of haloperidol and its reduced metabolite in schizophrenic patients: in vivo evidence of the involvement of CYP3A4 for haloperidol metabolism.  J Clin Psychopharmacol. 1999;  19 (2) 149-154
  CrossrefPubMedSearch in Google Scholar

Dr. G. Barth

Universitätsklinik für Psychiatrie und Psychotherapie

Osianderstr. 22

72076 Tübingen


Germany

Email: gdbarth@med.uni-tuebingen.de