Pharmacogenomic potential of psychiatric medications and CYP2D6

The ultimate goal in measuring CYP2D6 (or any other CYP450) function or identifying variant alleles is to predict effective therapeutic doses and responses in patients. This is the promise of individualized medicine. By knowing a patient's disposition to drugs, he could be started on appropriate dosing regimens without the extensive trial-and-error period that is common with psychiatric medications. We could also avoid drugs whose metabolism may prove to be problematic, choosing second-line therapies which are metabolized by different, unaffected enzymes. Of course, knowing a genotype is not very useful unless we couple the genotype findings with clinically validated dosing algorithms. Dosing recommendations for PM, EM, IM, and UM patients are beginning to appear in the literature for various classes of drugs but, at present, there are no well-accepted guidelines available. The Food and Drug Administration does encourage the incorporation of pharmacogenomic testing for investigational compounds in the development process. As the notion of PGx becomes more familiar and more clinical trials are completed, evidence-based dosing adjustments should be forthcoming. Although the biochemistry and pharmacology of CYP450 drug metabolism has made huge strides, the application of pharmacogenomics has not yet become commonplace for a number of reasons. Drug metabolism is a complex process, and CYP2D6 may not be the only polymorphic protein involved in a given drug's metabolism. Also, both primary and secondary metabolic pathways exist for drugs, the latter of which may be utilized when other drugs or endogenous compounds occupy the principle pathway. Given the possibility of multiple metabolic pathways, the presence of co-medications, inducers, and inhibitors in the diet and disease changes, predicting drug metabolism in a person remains difficult even when a given CYP450 genotype is obtained. Also there are multiple variants which can be present and consideration must be given as to which variant allele(s) to look for while, at the same time, always considering the cost/benefit ratio of a possible testing algorithm. Despite the numerous uncontrolled variables involved in drug metabolism and the inability for pharmacogenomics to address them all, there remains some promise for CYP2D6 genotyping to at least help physicians hone in on appropriate dose ranges before therapy is initiated or in identifying individuals at metabolic extremes who are at the highest risk for adverse outcomes. Ultimately, if CYP2D6 characterization is shown to be an evidence-based improvement in the practice of psychiatric medicine, laboratorians will need to be prepared for an influx of requests for these tests.