Document Type

Article

Publication Date

3-2026

Identifier

DOI: 10.1111/cts.70525

Abstract

Risperidone, an atypical antipsychotic, is increasingly prescribed in pediatric patients with psychiatric disorders. It is primarily metabolized by CYP2D6 to 9-hydroxyrisperidone, an active metabolite associated with a higher risk of adverse effects. The CYP2D6*17 and *29 alleles are prevalent in individuals of African ancestry and less studied than variants found in European ancestry individuals. This knowledge gap contributes to differences in health outcomes in individuals of non-European origin. The primary objective of this study is to replicate recently identified risperidone-specific activity for the CYP2D6*17 and *29 alleles. During psychiatric hospitalization, CYP2D6 was genotyped as part of routine care. Remnant plasma specimens were analyzed for risperidone and 9-hydroxyrisperidone by tandem liquid chromatography mass spectrometry in 161 patients administered risperidone. The log-transformed metabolite-to-parent ratio was used to estimate CYP2D6 enzymatic activity. The effect of each CYP2D6 allele on activity was assessed with linear regression that included strong CYP2D6 inhibitor use. Patients were predominantly white, non-Hispanic youth, ages 5-18 years old (mean 12.5 years), and 26.7% were prescribed concomitant CYP2D6 inhibitors. The frequency of *17 and *29 alleles were 15.5% and 8.3%, respectively, among Black patients (n = 42). After accounting for CYP2D6 inhibitors in the model, the activity of the *17 allele was > 4-fold that of the *1 allele (p = 0.006) and the *29 allele was 10% that of the *1 allele (p = 0.021), comparable to alleles with no function. The *17 allele confers greater metabolic activity for risperidone than reflected in current pharmacogenetic guidelines. Using existing activity scores may underestimate metabolism in *17 carriers and overestimate it in *29 carriers. Incorporating substrate-specific activity scores and dosing recommendations would support improved dosing.

Journal Title

Clin Transl Sci

Volume

19

Issue

3

First Page

70525

Last Page

70525

MeSH Keywords

Humans; Cytochrome P-450 CYP2D6; Child; Risperidone; Adolescent; Male; Female; Child, Preschool; Alleles; Antipsychotic Agents; Genotype; Cytochrome P-450 CYP2D6 Inhibitors; Paliperidone Palmitate; Mental Disorders

PubMed ID

41845570

Keywords

CYP; mental health; pharmacogenetics; psychiatric

Comments

Grants and funding

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Publisher's Link: https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.70525

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