While the utilization of clinical genotyping to determine drug response and dosage has been anticipated for many years, the actual utilization of screening for atypical drug metabolizers has only recently become a reality. The key factor making this innovation possible has been the development of low-cost, high-throughput genotyping that can accurately establish the precise genotype of key drug metabolizing enzymes (DME). In the very near future, more complex methodologies to ascertain the influence of both DME genes and genes that code for key drug targets will be available. However, today it is possible to improve the likelihood of a positive therapeutic outcome as well as minimize adverse drug effects for select children and adolescents who are being treated for depression.
At this point in the development of psychiatric pharmacogenomics, the most frequently screened DME gene is cytochrome P450 (CYP) 2D6. Genotyping of the 2D6 gene is available through most large reference laboratories. For example, clinical testing of the 2D6 genotype was initiated at the Mayo Clinic in February 2003.
One important consideration in pharmacogenomic clinical genotyping is the accuracy and comprehensiveness of the assessment. The 2D6 gene is highly variable, having 180 reported variants. The vast majority of these variants are extremely rare, but there are 11 different alleles that occur in significant numbers of patients throughout the world.
This gene is located on the long arm of the 22nd chromosome in an area that is referred to as a "hot spot." It is a hot spot because there is an increased probability for the occurrence of "uneven crossovers" at this location, and as a consequence, there has been an accumulation of multiple copies of this gene on this chromosome. The wide variation in the 2D6 gene demonstrates that the protein product is not a critical enzyme required for survival.
In white populations, 11 polymorphisms account for about 99% of the allelic frequency. Table 1 lists the most common alleles, as well as estimates of their population frequency. While these estimates are generally true for most U.S. white communities, there are a number of interesting exceptions where specific polymorphisms have accumulated in homogeneous ethnic populations.
In order to use genotypic data clinically, a practical systematic method of categorizing genotypes has been developed. Essentially, there are four broad categories. The first category is normal or "extensive" metabolizers. These individuals have two effective copies of the 2D6 gene. The second category is "intermediate" metabolizers, which describes individuals who have one effective copy of the 2D6 gene and one defective copy. The third category is "poor" metabolizers, which describes those individuals who have two defective copies of the gene. Finally, there are individuals who are categorized as ultrarapid metabolizers who have three or more effective copies of the gene due to uneven crossovers during meiosis.