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.

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.