The CYP2D6 Poor Metabolizer Phenotype May Be Associated With Risperidone Adverse Drug Reactions and Discontinuation

Jose de Leon, M.D.; Margaret T. Susce, R.N., M.L.T.; Run-Mei Pan, B.Sc.; Maureen Fairchild, Ph.D.; Walter H. Koch, Ph.D.; and Peter J. Wedlund, Ph.D.

Objective: The cytochrome P450 2D6 (CYP2D6) enzyme metabolizes risperidone. CYP2D6 poor metabolizers have no CYP2D6 activity (7% of whites and 1%-2% of other races). This study tested whether the CYP2D6 poor metabolizer phenotype was associated with adverse drug reactions (ADRs) and discontinuation due to ADRs.

Method: Adult inpatients and outpatients were recruited from July 2000 to March 2003 including (1) 325 who were stabilized on risperidone therapy and classified as either expressing moderate-to-marked ADRs (22%, 73/325) or not (78%, 252/325) and (2) 212 who discontinued risperidone and were classified as discontinued due to ADRs (38%, 81/212) or for other reasons (62%, 131/212). Genetic tests were performed by allele-specific polymerase chain reaction and/or by the AmpliChip CYP450 microarray system for up to 34 separate CYP2D6 alleles. Two logistic regression models with dependent variables (moderate-to-marked ADRs while taking risperidone and risperidone discontinuation due to ADRs) were evaluated with respect to the CYP2D6 phenotype.

Results: The odds ratios (ORs) and 95% confidence intervals (CIs) for the CYP2D6 poor metabolizer phenotype in the univariate analyses and after correcting for clinical variables were (1) OR = 3.1 (CI = 1.4 to 7.0) and 3.4 (CI = 1.5 to 8.0) for moderate-to-marked ADRs on risperidone and (2) OR = 3.0 (CI = 0.85 to 10.6) and 6.0 (CI = 1.4 to 25.4) for discontinuation due to ADRs.

Conclusions: The CYP2D6 poor metabolizer phenotype appears to be associated with risperidone ADRs and discontinuation due to ADRs; however, this finding requires further study in larger patient populations. The CYP3A5 and p-glycoprotein exon 21 and 26 genotypes were not significantly associated with risperidone response.

(J Clin Psychiatry 2005;66:15-27)

Received April 28, 2004; accepted Sept. 2, 2004. From the University of Kentucky Mental Health Research Center at Eastern State Hospital and University of Kentucky Colleges of Medicine and Pharmacy, Lexington (Drs. de Leon and Wedlund, Ms. Susce, and Ms. Pan); and Roche Molecular Systems, Inc., Alameda, Calif. (Drs. Fairchild and Koch).

This study was supported by several sources: a research-initiated grant from the Eli Lilly Research Foundation (to Dr. de Leon; 24% of direct costs), a National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Award ( to Dr. de Leon, 11% of direct costs), internal funding (37% of direct costs), and by Roche Molecular Systems, Inc., which provided free genotyping and laboratory supplies (equivalent to 28% of direct costs).

In the past 2 years, Dr. de Leon has received grant/research support from NARSAD, Eli Lilly, and Roche Molecular Systems and has served on the speakers or advisory boards of Bristol-Myers Squibb, AstraZeneca, and Eli Lilly. Drs. Fairchild and Koch are employees of and Dr. Wedlund has served as a consultant for Roche Molecular Systems, Inc.

Roche Molecular Systems, Inc., markets the AmpliChip CYP450 microarray system, which detects CYP2D6 and CYP2C19 gene variations. Francisco J. Diaz, Ph.D. (Department of Statistics, Universidad Nacional, Medellin, Colombia), calculated interrater reliability analysis. Tom Cooper, M.A. (Nathan Kline Institute, Orangeburg, N.Y., and New York University School of Medicine, New York, N.Y.), supervised laboratory analysis for plasma risperidone concentrations.

Corresponding author and reprints: Jose de Leon, M.D., University of Kentucky Mental Health Research Center at Eastern State Hospital, 627 West Fourth St., Lexington, KY 40508 (e-mail: jdeleon@uky.edu).