Genes: Does One Size Fit All?

As seen in the Consultant Connection August 2014 Issue
 Amy Fox, PharmD Candidate, Ohio Northern University
What is Genetic Testing?
One of the newest technologies being looked at for medical purposes is genetic testing. A big push for genetic testing is to help personalize medications for patients. In general, medications are currently prescribed based on the “average” patient. This means that a medication should work the same for one patient just as it does another. It can be thought of as a “one size fits all” method. Prescribing centered on genetic testing is aiming to individualize drug therapy based on patient specific genes. One of the most significant highlights of genetic testing is looking at cytochrome P450 (CYP) enzyme metabolism. Many drugs are metabolized by CYP enzymes from the liver. Differences in genetic make-up can effect how CYP enzymes work, and not everyone will metabolize the drugs the same way. Because of this, it may not be appropriate to use a “one size fits all” method, but rather a more personalized approach.
Genetic Testing for Antipsychotic Drug Therapy
Genetic testing is now being looked at for antipsychotic drug therapy. Antipsychotic drug side effects can be serious and are usually present when too high of a dose is given. Side effects may include extrapyramidal symptoms, a prolonged QT interval, dyslipidemia, postural hypotension, sedation, seizures, sexual dysfunction, diabetes, and/or weight gain. Currently, antipsychotic drug regimens are done by trial and error. To start an antipsychotic medication, many prescribers use the motto of “start low and go slow.” This means starting out at a low dose and titrating up to effect or until side effects are seen. Medications are used based off of the “average” patient. Genetic testing helps to determine if the patient will need a lower than normal dose to avoid side effects of the drug, or they may need a higher dose to achieve therapeutic success if his or her metabolism of the drug is faster. This can help get to the correct dose faster by giving the prescriber an idea of where to start dosing, which in turn is of clinical benefit to the patient.
What’s the Importance?
Most antipsychotics are metabolized by the CYP2D6 enzyme. Some of these include aripiprazole, haloperidol, and risperidone. Based on genetics, different alleles account for differences in CYP enzymes. There are four different categories one can fit into in regards to CYP2D6: poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultrarapid metabolizers. Poor metabolizers are those with little or no CYP2D6 function. This means it takes poor metabolizers longer to metabolize a drug, which will increase the drug’s half-life. By increasing the half-life, the drug will remain in the body longer and this could lead to a greater chance for the side effects mentioned before. Intermediate metabolizers have some CYP2D6 functioning, but are still not considered “normal.” Extensive metabolizers are classified as normal functioning of CYP2D6. This is the category where most individuals fall. Ultrarapid metabolizers have an increased functioning of the CYP2D6 enzyme. This means the drug will be metabolized faster than normal, which shortens the half-life of the drug. It also may lead to a failure in therapeutic success due to under-treatment. Genetic testing helps identify the patients that may need a dosage reduction to avoid side effects such as poor metabolizers. On the other hand, it helps identify ultrarapid metabolizers that may need an increased dosing frequency to achieve the goal of treatment.
What does the Future Hold?
Although this sounds very convincing, some studies have been showing conflicting data. Genetics may have a part in personalizing antipsychotic medication for individuals, but there seems to be other factors that also have an influence. Many antipsychotics are metabolized by more than one CYP enzyme, which may account for inconclusive data results. Also, the receptors that the drugs bind to could have genetic variation and be considered a factor. Overall, genes are not a “one size fits all,” and medication prescribing may become more personalized with genetic testing in the future.
De Leon J. Pharmacogenomics: The promise of personalized medicine for CNS disorders. Neuropsychopharmacology. 2009. 34:159-172.
Kirchheiner J, et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry. 2004; 9:442-473.
Malhotra A, et al. Pharmacogenetics in psychiatry: translating research into clinical practice. Mol Psychiatry. 2012; 17(8): 7600-769.
PharmGKB. Clinical PGx: CYP2D6. Accessed 2014 Jun 26. Retrieved from: http://www.pharmgkb.org/gene/PA128#tabview=tab0&subtab=31.


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