Risperidone is metabolized by cytochrome P4502D6 (CYP2D6) to its active metabolite, 9- hydroxyrisperidone. CYP2D6 genes encoding this enzyme are polymorphically expressed and most of the variants result in decreased substrate metabolism. The influence of CYP2D6*10 polymorphism on risperidone and 9-hydroxyrisperidone plasma levels, metabolic ratio and dose adjusted active moiety in Indian Schizophrenic patients were assessed. Also, the prevalence of CYP2D6*10 in normal healthy volunteers residing in Maharashtra were determined. The study was initiated following Institutional Ethics Committee approval and written informed consent from participants. Seventy two schizophrenic patients and One hundred and eleven healthy volunteers were genotyped for CYP2D6*10 by PCR-RFLP method. Risperidone and 9-hydroxyrisperidonelevels were estimated in patients by HPLC. Clinical assessment of patients was done using PANSS score. Genotype frequencies were calculated using Hardy-Weinberg equilibrium. Differences in (corrected dose) C/Ds plasma drug, Metabolic Ratio, PANSS score between different genotypes was analyzed using one way ANOVA for normally distributed data and KruskalWallis test in case of non-normally distributed. Pearson’s correlation was used to examine the relationship between drug levels and dosage. Frequency of T allele observed was 16% in controls and 19% in schizophrenic patients. Poor Metabolizers had significantly higher levels of risperidone C/D and Metabolic Ratio than homozygous Extensive Metabolizers and Intermediate metabolizers. No statistically significant correlation was found between PANSS score and plasma levels. A strong correlation was however observed between the drug levels and administered dose. Our findings suggest that CYP2D6 may be a useful determinant of risperidone & 9-OH-risperidone drug levels and their Metabolic Ratio.

Keywords: CYP2D6; Genotype-Phenotype Correlation; Indian Population; Risperidone; 9-OH Risperidone; Schizophrenia.