A pilot study on risperidone metabolism: the role of cytochromes P450 2D6 and 3A

J Clin Psychiatry. 1999 Jul;60(7):469-76.


Background: The limited available information on plasma risperidone levels shows a stable relationship between daily doses of risperidone and total plasma concentration (risperidone plus its active metabolite 9-hydroxyrisperidone). The ratio between risperidone and 9-hydroxyrisperidone characterizes cytochrome P450 2D6 (CYP2D6) status. According to the manufacturer, the CYP2D6 genotype or drugs that influence CYP2D6 or other cytochrome P450 isoenzyme activity are not expected to be clinically significant. One case report suggests that CYP3A participates in the metabolism of risperidone.

Method: A case series of 13 risperidone patients (the initial case and 12 new cases) who were genotyped for CYP2D6 were followed, and another 20 risperidone patients from a case-control study for the CYP2D6 genotype were reviewed.

Results: The CYP2D6 poor metabolizers, who are enzyme deficient (2/13 in the case series and 3/20 in the case-control study), did not appear to tolerate risperidone well. Drugs affecting CYP3A, in particular powerful inducers and inhibitors, resulted in at least a 2-fold decrease or increase in plasma risperidone levels.

Conclusion: The anecdotal nature of this study is clearly a limitation. Drugs influencing CYP3A and CYP2D6 metabolic activity may significantly affect risperidone levels. Thus, plasma level monitoring of risperidone in a clinical setting may be useful, especially if patients are taking multiple medications or a CYP2D6 deficiency is suspected. New prospective studies under more controlled conditions are needed to verify these hypotheses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antipsychotic Agents / metabolism*
  • Antipsychotic Agents / pharmacokinetics
  • Antipsychotic Agents / therapeutic use
  • Aryl Hydrocarbon Hydroxylases*
  • Case-Control Studies
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2D6 / physiology*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Cytochrome P-450 Enzyme System / physiology*
  • Female
  • Genotype
  • Humans
  • Isoxazoles / blood
  • Male
  • Mental Disorders / drug therapy
  • Mental Disorders / genetics
  • Mental Disorders / metabolism
  • Middle Aged
  • Oxidoreductases, N-Demethylating / genetics
  • Oxidoreductases, N-Demethylating / metabolism
  • Oxidoreductases, N-Demethylating / physiology*
  • Paliperidone Palmitate
  • Pilot Projects
  • Pyrimidines / blood
  • Risperidone / metabolism*
  • Risperidone / pharmacokinetics
  • Risperidone / therapeutic use


  • Antipsychotic Agents
  • Isoxazoles
  • Pyrimidines
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • Risperidone
  • Paliperidone Palmitate