CYP2D6 Genetic Polymorphisms and Risperidone Pharmacokinetics: A Systematic Review and Meta-analysis

Lusi Zhang, Sarah Jane Brown, Yuting Shan, Adam M. Lee, Josiah D. Allen, Seenae Eum, Jose de Leon, Jeffrey R. Bishop

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


BACKGROUND: Risperidone is a second-generation antipsychotic drug metabolized to an active metabolite, 9-hydroxyrisperidone, primarily by cytochrome P450 (CYP) 2D6 and to a lesser extent by CYP3A4. The extent to which drug metabolism genetics impacts risperidone and 9-hydroxyrisperidone exposure has not been clarified.

OBJECTIVE: A systematic review and meta-analysis evaluated the impact of genetically defined CYP2D6 function on risperidone pharmacokinetics applying a standardized genotype-phenotype translation system.

METHODS: A comprehensive electronic database search identified studies reporting relationships between genetically determined CYP2D6 metabolism and risperidone pharmacokinetic properties. The exposure of risperidone or active moiety (risperidone + 9-hydroxyrisperidone) was measured by dose-adjusted steady-state serum or plasma concentration or area under the concentration-time curve as primary outcomes. Subjects were assigned to CYP2D6 poor metabolizer, intermediate metabolizer, normal metabolizer, or ultrarapid metabolizer groups using a standardized genotype-phenotype translation method. Effect sizes between groups were pooled and stratified by single or multiple dosing regimens.

RESULTS: A total of 15 studies involving 2125 adult subjects were included in the meta-analysis. Following multiple-dose oral administration, compared with CYP2D6 normal metabolizers, the risperidone dose-adjusted steady-state serum/plasma concentration was 2.35-fold higher in intermediate metabolizers (95% confidence interval [CI] 1.77-3.13, p<0.0001) and 6.20-fold higher in poor metabolizers (95% CI 5.05-7.62, p<0.0001); the active moiety dose-adjusted steady-state concentration was 1.18-fold higher in intermediate metabolizers (95% CI 1.11-1.25, p<0.0001) and 1.44-fold higher in poor metabolizers (95% CI 1.23-1.69, p<0.0001). Higher area under the concentration-time curve of risperidone and active moiety was also found in single-dose studies.

CONCLUSION: Genetically defined impaired CYP2D6 activity is associated with increased exposure of both risperidone and risperidone + 9-hydroxyrisperidone in adults receiving oral formulations. Additional studies are needed to quantify the clinical impact of these relationships.

Original languageEnglish (US)
Pages (from-to)632-647
Number of pages16
Issue number7
StatePublished - Jul 1 2020

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© 2020 Pharmacotherapy Publications, Inc.


  • CYP2D6
  • meta-analysis
  • pharmacogenetics
  • pharmacokinetics
  • risperidone


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