Advertisement

Clinical Drug Investigation

, Volume 19, Issue 4, pp 283–292 | Cite as

Risperidone Drug Monitoring

A Useful Clinical Tool?
  • Pascal Odou
  • J. C. Levron
  • M. Luyckx
  • C. Brunet
  • Hugues Robert
Clinical Pharmacodynamics

Abstract

Background: Risperidone is an atypical antipsychotic drug that has been marketed in France since 1996. Therapeutic failures have been observed with risperidone.

Objective: To investigate whether interactions with the cytochrome P450 (CYP) isoenzymes implicated in risperidone metabolism could explain these treatment failures.

Design and Setting: This was a retrospective study of clinical and drug monitoring data from 50 patients treated by five psychiatrists in northern France.

Methods: The concentration of active drug (risperidone + 9-hydroxy-risperidone) in serum was evaluated by high performance liquid chromatography and radio receptor assay. Clinical efficacy was assessed by the global improvement (CGI2) item of the Clinical Global Impression rating scale.

Results: Statistical analysis revealed a significant increase in efficacy when the serum concentration of active drug was between 25 and 150 μg/L compared with when it was out of this range. Carbamazepine, a CYP3A4 inducer, dramatically decreased the concentration of the active moiety of risperidone; on the contrary, CYP3A4 inhibitors (alprazolam and valproic acid) increased the concentration of active drug. The metabolism of risperidone by CYP3A4 did not lead to the formation of metabolite(s) with anti-D2 dopaminergic activity. Drugs interacting with CYP2D6 altered the risperidone/9-hydroxy-risperidone ratio but did not change the total amount of active drug.

Conclusions: We have established a therapeutic range for risperidone. CYP3A4 is a major pathway for risperidone metabolism. Consideration of these factors in clinical practice should lead to improved outcomes for patients treated with risperidone.

Keywords

High Performance Liquid Chromatography Carbamazepine Clozapine Risperidone Brief Psychiatric Rate Scale 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We express our gratitude to the Janssen Research Foundation for the gift of risperidone and its active metabolite, and for their technical assistance. We thank A. Robinet-Willekens for her help in the translation of the article into English.

References

  1. 1.
    Leysen JE, Janssen PMF, Schotte A, et al. Interaction of anti-psychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors. Psychopharmacology 1993; 112: S40–S54PubMedCrossRefGoogle Scholar
  2. 2.
    Ereshefsky L, Lacombe S. Pharmacological profile of risperidone. Can J Psychiatry 1993; 38Suppl. 3: S80–8PubMedGoogle Scholar
  3. 3.
    Borison RL. Risperidone: pharmacokinetics. J Clin Psychiatry Monogr 1994; 14(3): 253–5Google Scholar
  4. 4.
    Heykants J, Huang M-L, Mannens G, et al. The pharmacokinetics of risperidone in humans: a summary. Clin Psychiatry 1994; 55Suppl. 5: 13–7Google Scholar
  5. 5.
    Mannens G, Huang ML, Meudermans W, et al. Absorption, metabolism and excretion of risperidone in humans. Drug Metab Dispos 1993; 21(6): 1134–40PubMedGoogle Scholar
  6. 6.
    Ereshefsky L. Pharmacokinetics and drug interactions: update for new antipsychotics. J Clin Psychiatry 1996; 57Suppl. 11: 12–25PubMedGoogle Scholar
  7. 7.
    Van Peer A, Meuldermans W, Woestenborghs R, et al. Clinical pharmacokinetics of risperidone. In: Kane JM, Möller HJ, Awouters F, editors. Serotonin in antipsychotic treatment: mechanisms and clinical practice. New York; Marcel Dekker, 1996: 277–91Google Scholar
  8. 8.
    Barges-Bertocchio MH, Pupeschi G, Levron JC, et al. Carbama-zepine (CBZ) induces the metabolism of risperidone, a novel antipsychotic. Proceedings of the Fifth European ISSX Meeting; 1993 Sep 26–29: Vol. 3, no. 186: 186Google Scholar
  9. 9.
    Lane HY, Chang WH. Risperidone-carbamazepine interactions: is cytochrome P450 3A involved? J Clin Psychiatry 1998; 59(8): 430–1PubMedCrossRefGoogle Scholar
  10. 10.
    De Leon J, Bork J. Risperidone and cytochrome P450 3A. J Clin Psychiatry 1997; 58: 450PubMedCrossRefGoogle Scholar
  11. 11.
    Chong SA, Tan CH, Lee EL, et al. Augmentation of risperidone with valproic acid. J Clin Psychiatry 1998; 59(8): 430–1PubMedCrossRefGoogle Scholar
  12. 12.
    Guy W. ECDEU Assessment Manual for Psychopharmacology: Publication ADM 76-338, Rockville, (MD): US Department of Health, Education and Welfare, 1976: 217–22Google Scholar
  13. 13.
    Woestenborghs R, Lorreyne W, Van Rompaey F, et al. Determination of risperidone and 9-hydroxyrisperidone in plasma, urine and animal tissues by high-performance liquid chromatography. J Chromatogr 1992 December; 583(2): 223–30PubMedCrossRefGoogle Scholar
  14. 14.
    Odou P, Vaiva G, Luyckx M, et al. Neuroleptics monitoring relation between antipsychotic efficiency and radioreceptor assay concentrations. Eur J Clin Pharmacol 1996; 50: 357–63PubMedCrossRefGoogle Scholar
  15. 15.
    Bertchy G, Vandel S, Jounet JM, et al. Interaction valpromide-amytriptilline: augmentation de l’amitrytilline et de la nortriptylline par le valpromide. Encéphale 1990; 16: 43–5Google Scholar
  16. 16.
    Nemeroff CB, De Vane CL, Pollock BG. Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996 March; 153(3): 311–20PubMedGoogle Scholar
  17. 17.
    Ring BJ, Binkley SN, Vandenbranden M, et al. In vitro interaction of the antipsychotic agent olanzapine with human cytochromes P450 CYP2C9, CYP2C19, CYP2D6 and CYP3A. Br J Clin Pharmacol 1996 March; 41(3): 181–6PubMedCrossRefGoogle Scholar
  18. 18.
    Yeates RA, Scharpf F, Laufen H, et al. Screening for cytochrome P450 3 A in man: studies with midazolam and nefidipine. J Pharm Pharmacol 1996 Sept; 48(9): 933–4PubMedCrossRefGoogle Scholar
  19. 19.
    Koley AP, Robinson RC, Markowitz A, et al. Drug-drug interactions: effect of quinidine on nifedipine binding to human cytochrome P450 3A4. Biochem Pharmacol 1997 Feb 21; 53(4): 455–60PubMedCrossRefGoogle Scholar
  20. 20.
    Fischer V, Vogels B, Maurer G, et al. The antipsychotic clozapine is metabolized by the polymorphic human microsomal and recombinant cytochrome P450 2D6. J Pharmacol Exp Ther 1992 Mar; 260(3): 1355–60PubMedGoogle Scholar
  21. 21.
    Linnet K., Olesen OV. Metabolism of clozapine by cDNA-expressed human cytochrome P450 enzymes. Drug Metab Dispos 1997 Dec; 25(12): 1379–82PubMedGoogle Scholar
  22. 22.
    Aravagiri M, Marder SR, Wirshing D, et al. Plasma concentrations of risperidone and its 9 hydroxy metabolite and their relationship to dose in schizophrenic patients: simultaneous determination by a high performance liquid chromatography with electrochemical detection. Pharmacopsychiatry 1998; 31: 102–9PubMedCrossRefGoogle Scholar
  23. 23.
    Darby JK, Pasta DJ, Elfand L, et al. Risperidone dose and blood level variability: accumulation effects and interindividual and intraindividual variability in the non responder patient in the clinical practice setting. J Clin Psychopharmacol 1997; 17(6): 478–84PubMedCrossRefGoogle Scholar
  24. 24.
    Bondolfi G, Baumann P, Dufours H. Treatment resistant schizophreny: clinical experience with new antipsychotics. Eur Neuropharmacol 1996; 6(2): 521–5Google Scholar
  25. 25.
    Perry PJ, Miller DD, Arndt SV, et al. Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry 1991; 148: 231–5PubMedGoogle Scholar
  26. 26.
    Pikar D, Owen RR, Litman RE, et al. Clinical and biologic response to clozapine in patients with schizophrenia. Arch Gen Psychiatry 1992; 49: 345–53CrossRefGoogle Scholar
  27. 27.
    Odou P, Frimat B, Fontaine B, et al. Determination of clozapine in serum by receptor assay versus high performance liquid chromatography: possible detection of hydroxy-metabolites. J Clin Pharm Ther 1996; 21: 337–42PubMedCrossRefGoogle Scholar
  28. 28.
    Davis JM, Ericksen SE, Hurt S, et al. Haloperidol plasma levels and clinical response: basic concepts and clinical data. Psychopharmacol Bull 1985; 21: 48–51PubMedGoogle Scholar
  29. 29.
    Mavroïdis ML, Kanter DR, Hirschowitz J. Plasma haloperidol levels and clinical response: confounding variables. Psychopharmacol Bull 1985; 21: 61–5Google Scholar
  30. 30.
    Smith RC, Vroulis G, Shvartsburg A, et al. RBC and plasma haloperidol and clinical response in schizophrenia. Am J Psychiatry 1982; 139: 1054–6PubMedGoogle Scholar
  31. 31.
    Van Putten T, Marder SR, Mintz J, et al. Haloperidol plasma levels and clinical response: a therapeutic window relationship. Am J Psychiatry 1992: 500-5Google Scholar
  32. 32.
    Miller DD, Hershey LA, Duffy JP. Serum haloperidol concentrations and clinical response in acute psychosis. Drug Intell Clin Pharm 1983; 17: 445Google Scholar
  33. 33.
    Dalh SG. Plasma level monitoring of antipsychotic drugs. Clinical utility. Clin Pharmacokinet 1986; 11: 36–61CrossRefGoogle Scholar
  34. 34.
    Balant-Giorgia AE, Gex-Fabry M, Genet C, et al. Therapeutic drug monitoring of risperidone using a new, rapid HPLC method: reappraisal of interindividual variability factors. Ther Drug Monit 1999; 21: 105–15CrossRefGoogle Scholar
  35. 35.
    Fang J, Bourin M, Baker GB. Metabolism of risperidone to 9 hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. Naunyn Schmiedebergs Arch Pharmacol 1999 Feb; 359(2): 147–51PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  • Pascal Odou
    • 1
    • 2
  • J. C. Levron
    • 3
  • M. Luyckx
    • 4
  • C. Brunet
    • 4
  • Hugues Robert
    • 1
    • 2
  1. 1.Service PharmacieEPSM Lille MétropoleArmentièresFrance
  2. 2.Laboratoire de Biopharmacie et Pharmacie Clinique.Faculté des Sciences Pharmaceutiques et BiologiquesLilleFrance
  3. 3.Janssen Research FoundationVal de ReuilFrance
  4. 4.Laboratoire de Pharmacie Clinique, Pharmacocinétique et Pharmacologie.Faculté des Sciences Pharmaceutiques et BiologiquesLilleFrance

Personalised recommendations