The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation.
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.


METHODS
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.
de Leon
Jose
J
University of Kentucky Mental Health Research Center at Eastern State Hospital, Lexington, KY 40508, USA. jdeleon@uky.edu
Susce
Margaret T
MT
Pan
Run-Mei
RM
Fairchild
Maureen
M
Koch
Walter H
WH
Wedlund
Peter J
PJ
D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001480:Basal Ganglia Diseases / Q000139:chemically induced / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010352:Patient Dropouts; D010597:Pharmacogenetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D018967:Risperidone / Q000009:adverse effects* / Q000493:pharmacokinetics; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
D014150:Antipsychotic Agents; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone