Interindividual and cross-ethnic variations
As early as the 1950s, substantial cross-ethnic and interindividual variations in psychotropic responses had been identified. Such variations have remained mostly obscure, however, because many of the reports were published in nonclinical journals.1,2,4,5 Pharmacogenetics as a discipline has its origin in observations of severe adverse effects, which vary dramatically across ethnic groups.1,6 Subsequently, when major enzymes (such as a number of the cytochrome P-450 isozymes) that are responsible for the metabolism of psychotropic and other medications were identified, it became clear that there are substantial ethnic variations in enzyme activity.
More recently, studies aimed at identifying genetic determinants of disease susceptibility, temperament, and behavioral traits have led to the discovery of genetic variations that affect psychotropic responses. The gene that encodes the serotonin (5-HT) transporter and the enzyme catechol-O-methyltransferase serve as the most prominent examples. Since almost all of the alleles that affect the activity of such genes are unevenly distributed across ethnic groups, subsequent human genomic studies have been compelled to take ethnicity and race into serious consideration.12
Genetic variations
Cytochrome P-450 2D6 (CYP2D6) may represent the best clinically significant example of ethnic variations at the genetic level. Since CYP2D6 participates in the metabolism of close to 50% of the drugs currently on the market, genotypic and phenotypic variations of the enzyme often lead to major differences in the concentration of the drugs in the blood and the brain. The result is a remarkable divergence in therapeutic responses and propensity for adverse effects.1,2,12,13
CYP2D6 has more than 50 distinct variant alleles that lead to the production of enzymes with divergent activities and that effectively divide patients into 4 groups:
• Poor metabolizers have 2 defective genes and the complete absence of CYP2D6
• Slow metabolizers have variant genes that are less effective in producing the enzyme
• Extensive metabolizers have 2 functional “wild-type” genes
• Ultra-rapid metabolizers have more than 2 copies of the gene and excessive production of the enzyme
As is true with the majority of the genes that have been studied, these CYP2D6 genotype groups are highly unevenly distributed across ethnic and racial groups. Although the majority of whites of European ancestry are extensive metabolizers, 5% to 9% are poor metabolizers because of the existence of a specific allele labeled as CYP2D6*4.
By contrast, up to 70% of patients with East Asian ancestry carry another distinct allele (CYP2D6*10) that produces a less effective form of the enzyme, which makes many of them slow metabolizers. African Americans and sub-Saharan Africans also are more likely to be slow metabolizers because of yet another specific allele (CYP2D6*17) commonly seen only in those of sub-Saharan African origin (20% to 40%). Ultra-rapid metabolizers are highly prevalent among Ethiopians (29%), Arabs (19%), Ethiopian and Sephardic Jews (18% and 13%, respectively), and people from southern Spain (5%), but they are relatively rare (less than 1%) in other populations.15-19
