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GENETIC PROFILING can now help select the most effective medications or rule out the riskiest ones for certain conditions—similar to how some use it to select the best diet for weight loss or general health. It may be most worthwhile for people looking for a drug that works well without debilitating side effects.
Pharmacogenetic or pharmacogenomic (PGx) testing exists for some 200 medications to date, including 40 neuropsychiatric medications, with findings often included in FDA labeling. But PGx testing is currently considered essential—reimbursable—for only a handful of drugs.
Unlike genetic testing to help diagnose disease or potential risk of disease, PGx testing can find responses to particular medications. It falls under the umbrella of precision medicine.
Why PGx Testing
Pharmacogenetic testing is standard of care, for example, in the treatment of inflammatory bowel disease. For patients who are “slow metabolizers” (specific IBD drugs stay in their bloodstream longer), prescribing these drugs can have side effects of a “severely depressed immune system and life-threatening infections,” writes Shannon Manzi, director of pharmacogenomic services at Boston Children’s Hospital.
Codeine, on the other hand, is dangerous for fast metabolizers because its effects depend on the body turning the drug into a morphine derivative. For fast metabolizers, that allows morphine metabolites to reach dangerously high levels in the bloodstream. After causing the deaths of four children, the FDA warned physicians to prescribe alternative medications.
“The ultimate goal is to really take out the guesswork,” writes Andrea Gaediqk, head of the PGx Lab at Children’s Mercy Hospital in Kansas City. Determining whether an individual falls at either extreme of the spectrum on the speed of metabolizing a certain drug can guide prescriptions of different dosages or different drugs altogether. “It is mostly patients with these extreme metabolizer phenotypes that benefit from drug dosing that is different than usual.”
At Children’s Mercy Hospital, PGx testing is usually done in retrospect —in the GOLDILOKS clinic—when patients have tried a long list of drugs without success or with challenging side effects.
Codeine, however, is also a prime example of the limitations of PGx testing. Because of the drug’s potential dangers and also because alternative drugs exist for the same applications, large-scale, expensive experiments assessing its effects on different genotypes are considered more difficult and less worthwhile.
What seems like the biggest hurdle to widespread use of PGx testing, though, is the large number of variables that affect an individual’s response to a particular medication, including age, gender, diet, environment, whether someone is a smoker or is pregnant, other medical problems and “most importantly the other medications you are taking (including over-the counter medications and herbal supplements),” writes Manzi.
Some genes strongly affect how medication works, while in other cases, different variables are more influential. Using the analogy of a pie to demonstrate the influences of genetics on a specific drug’s metabolism, Manzi estimates that PGx makes up to 90% of the pie for some medications, while for others it’s “only a tiny sliver.”
Gene Testing and Antidepressants
Treating mental illness in particular relies on a combination of medication, psychotherapy and self-care activities (diet, sleep and exercise) that play a role in mood and how the body responds to medication. Still, psychiatry is an area with “many current applications for pharmacogenetics,” write University of Cincinnati psychiatry professor Melissa Delbello and PGx specialist Olivia Bentley in Pharmacy Times.
“We are tantalizingly close to being able to [use PGx testing] to determine whether patients are more or less likely to respond to a specific antidepressant class,” according to Delbello and Bentley. Fluoxetine was one of the first individual drugs found to be affected by PGx variants. And tricyclic antidepressants, prescribed less often since the development of SSRIs —because the latter generally have fewer side effects—can work well for certain patients with certain conditions, and that can be determined using PGx testing.
Yet another problem with PGx testing is that most genes influence how the body metabolizes not just one class of medications, but many others as well—with different and sometimes opposing effects. For the future, the goal might be preemptive testing of an array of different drugs, so that when a medical condition arises, the risks and benefits are already known. But for aspirin and many OTC paint relievers, PGx testing has not yet been developed.
The Problems
A related downside of PGx occurs when the same genetic variant is related to more than just drug effects. For some cholesterol-lowering statins, genetic variants of the ApoE gene affect the drug response but also influence the risk for Alzheimer’s Disease. In this case, the effect of the variant on the drug response is minimal compared to potential problems for patients who learn their ApoE profile.
Turnaround time for testing is an obstacle in cases where medication is required quickly. Also, most tests are given for only one drug at a time, so that more testing is necessary to add other medications at the same time or in the future. When medical centers and others offer PGx profiling (the price ranges from $250 to $500), it is reimbursed only for specific drugs when the FDA “requires” testing.
An alternative is pre-emptive testing, either for one drug or to provide individual profiles covering many drugs. The Inova MediMap Plus analyzes 25 genes that influence responses to medications in 13 drug categories, including anesthesia, cardiovascular, infection, pain, gastrointestinal and psychotropic. The price depends on how many are tested.
For pre-emptive profiling of either one drug or many, as well as for genetic profiling for disease prediction or diagnosis, a major problem is that ongoing research into different effects of genetic variants means that the profiles can change over time. However, there is currently no efficient way to communicate updates to doctors or patients. “The system is completely chaotic,” Baylor clinical geneticist Sharon Plon told the New York Times.
—Mary Carpenter
Every Tuesday in this space, well-being editor Mary Carpenter reports on health news we can use.
