The Ethnopharmacology of Atypical Antipsychotics

Since the risk of antipsychotic-induced adverse events is often related to plasma drug concentrations, factors that influence the metabolic transformation of these agents can substantially influence this risk. The cytochrome P450 (CYP) enzyme system, particularly CYP2D6, is very important for the metabolism of many typical and atypical antipsychotic agents. However, there is substantial ethnic/racial pharmacogenetic variability in the phenotypic (ie, metabolic rate) or genotypic (ie, presence of functional or nonfunctional alleles) expression of these enzyme systems. Caucasians have a bimodal distribution of CYP2D6 enzyme activity, with individuals classified either as extensive or poor metabolizers. In contrast, while there are few poor metabolizers among people of Asian descent, a substantial proportion of this population exhibits an intermediate rate of metabolism. African American populations also have a substantial number of intermediate metabolizers, and about the same number of poor metabolizers as Caucasians. Mexican Americans may have a slightly higher metabolic rate than other ethnic groups. Numerous studies have demonstrated that CYP2D6 metabolic status influences the clearance of conventional and atypical antipsychotics. African Americans and Asians, with CYP2D6 phenotypes or genotypes indicative of poor metabolizers, frequently exhibit significantly higher plasma drug concentrations and longer half-lives compared to extensive metabolizers. Importantly, this increased drug exposure is associated with an increased risk of extrapyramidal symptoms. Data on metabolic polymorphism of antipsychotics are lacking among African Americans. There are also some data suggesting that genetic polymorphism can influence the risk of antipsychotic-induced weight gain. These findings highlight the need to consider race/ethnicity when prescribing, dosing, and monitoring antipsychotic agents. CNS Spectr. 2005; 10(3 Suppl 2):6-12