- Discuss pharmacogenomic implications as it relates to psychiatric illness.
- Outline how pharmacogenomics relates to response to a variety of drugs used in the treatment of various psychiatric diseases.
- Review the use of pharmacogenomic testing as it relates to the treatment of various psychiatric diseases.
It is now possible to use genetic testing to minimize adverse responses to psychiatric medications and to increase the probability of identifying medications that will be more likely to provide a therapeutic response for an individual patient.1 It has been known for many years that variations in drug-metabolizing enzymegenes (DME genes), such as the cytochrome P450 2D6 gene (CYP2D6), are associated with differential pharmacokinetic profiles for psychotropic medications.2 While individual clinical laboratories began testing for drug-metabolizing genes before 2004, the FDA approval of the AmpliChip developed by Roche Diagnostics was a landmark event that facilitated the utilization of clinical genotyping in a greatly expanded number of clinical settings.3
Variations in the DME genes have been shown to alter the responses of patients to psychotropic medications. Specifically, the cytochrome P450 family of genes has been studied extensively. Five of the many cytochrome P450 genes that are particularly relevant for the management of psychotropic medications will be reviewed.
The Cytochrome P450 2D6 Gene
The CYP2D6 was the first DME gene that was widely tested to identify poor metabolizers. Additionally, the identification of ultrarapid metabolizers of 2D6 substrate medications has proven to be clinically useful. There are more than 70 medications that are currently metabolized by the 2D6 enzyme. Many of these drugs are widely used psychotropic medications.
CYP2D6 is located on the 22nd chromosome and codes for the CYP2D6 enzyme. It is highly variable and there are currently more than 100 formally recognized variants. These CYP2D6 allelic variants have been classified as being upregulated, normal, deficient, or completely inactive. A variety of methodologies for predicting 2D6 phenotypes based on CYP2D6 genotypes have been suggested. However, the most widely used methodologies for phenotype specification are designed to identify patients as having one of four metabolic capacities. These categories are usually labeled as poor, intermediate, extensive (i.e., normal), and ultrarapid.
There is considerable variability in the allele frequency of 2D6 gene variants based on the ancestral origin of a population. For example, the completely inactive *3 allele is essentially found only in European populations. Similarly, the deficient *17 allele is primarily found in sub-Saharan Africa populations. Yet another example is the *10 allele, which is the most common allele found in Japanese populations.4
The results of pharmacogenomic testing provide an estimate of a metabolic capacity phenotype. However, a more active genotype can produce a CYP2D6 enzyme that is subsequently inhibited as a consequence of a drug interaction. Strong inhibition of patients who have one or even two normal CYP2D6 alleles can result in decreased metabolic capacity. However, poor metabolizers ...