Conference Coverage

Psychiatric pharmacogenomics not ‘ready for prime time’


 

EXPERT ANALYSIS FROM THE PSYCHOPHARMACOLOGY UPDATE INSTITUTE

– Pharmacogenomics testing for guiding drug choices in psychiatric disease is “not completely ready for prime time,” based on a critical review of published guidelines and expert opinions on the use of those tests, according to Erika L. Nurmi, MD, PhD.

It is important to understand the limitations of such tests because many patients or family members are asking clinicians to be guided by the results of tests they have ordered on their own, said Dr. Nurmi, a researcher and clinician at the UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles.

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Actively involved in conducting pharmacogenomics studies, Dr. Nurmi described herself as a strong believer in the underlying science. But “I just think we are a long way off from using it right,” she said.

Published guidelines and expert opinions based on objective data support these conclusions, she said. Dr. Nurmi suggested that an algorithm proposed by the Mayo Clinic might be the most practical option for those who do not have a strong interest already in this field.

“Basically, what it says is if you do not have the testing in hand, don’t order it. If you have the testing in hand when a poor metabolizer of CYP2D6 or CYP2C19 has been identified, switch to a med that is not metabolized by those enzymes. That’s it,” Dr. Nurmi reported at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

The guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) were only modestly more detailed. Only a moderate level of evidence supported most recommendations, she said, and these were labeled optional. The exception regarded treating ultrafast metabolizers of CYP2D6 who are taking paroxetine: In these, the use of a drug metabolized by a different enzyme was strongly recommended.

Similar recommendations in the CPIC guidelines were made for fluoxetine, fluvoxamine, and sertraline. In patients on citalopram or escitalopram, ultrafast metabolizers of CYP2C19 are considered candidates for a non-CYP2C19 drug. If they are poor metabolizers, the CPIC guidelines recommended a non-CYP2C19 drug or reducing the starting dose by 50%.

However, in all of these cases, pharmacogenomics testing is best reserved for patients who have had an inadequate response to therapy or, in the case of poor metabolizers, have had unacceptable adverse events.

Of the limitations Dr. Nurmi outlined for pharmacogenomics testing, one of the most important is that these tests typically focus on a single genetic variant. According to Dr. Nurmi, the problem with a single variant is that “our bodies are more complex.” She said she believes that genetic information for drug selection will not be useful until testing is able to synthesize information from multiple genetic variants and place this in context with confounders such as age and exposure to other substances, such as hormones, caffeine, or grapefruit juice.

This complexity is likely to be mastered eventually, Dr. Nurmi said, but patients now have unrealistic expectations. For their part, clinicians need to develop an understanding of the limitations of these tests in order to provide informed counsel. As pharmacogenomics testing is being marketed directly to consumers with inflated claims about its value, clinicians often must defend their decision to use or not use this information.

“Commercially available products combine variants of widely discrepant validity using proprietary, undisclosed algorithms into sweeping treatment recommendations,” said Dr. Nurmi, who noted that she has found some of her own data misappropriated to make claims. Often, the companies that develop the tests have conducted the validation studies without any replication by independent investigators. She noted that many studies have been declared positive on the basis of secondary outcomes after the primary outcome was negative.

“There are very few positive prospective, randomized, double-blind trials,” Dr. Nurmi said. Even when such trials have been conducted, they typically are not designed to show a clinically meaningful outcome.

By attempting to look at a single or a limited number of variants in which to guide choice of medication in psychiatric disease, pharmacogenomics testing is being “vastly oversimplified,” Dr. Nurmi said. Although she said she believes this field is enormously promising and that medical records for each patient eventually will contain the genome sequence, she emphasized that, at this time, pharmacogenomics testing has a very limited role to play for the management of psychiatric diseases.

Dr. Nurmi reported she had no financial relationships relevant to this topic.

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