Responding to Parental Requests for Commercially Available Pharmacogenomic Testing
David Camenisch, MD
PAL Consultant
Increasingly, parents are requesting pharmacogenomic (PGX) testing based on the impression that this will help identify the best medication for their child. Motivations include both a desire to find the most effective medicine and also to avoid unpleasant and/or unsafe side effects. These requests are understandable based on the messaging from the major commercial players. From the Genomind website, “PGx test assesses your genes to help your clinician make smarter, more personalized treatment decisions.” From Genesight, “The results of the test can inform your doctor about genes that may impact how you metabolize or respond to certain medications commonly prescribed to treat depression, anxiety, ADHD and other mental health conditions.” These are laudable if not lofty promises that contain qualifiers, and the commercial players may be over selling the product based on an inherent conflict of interest. My hope is that this information will be a useful update on the state of the science to help you navigate this issue with your patients and families.
PGX testing is most requested to help make decisions regarding antidepressants, stimulants and atypical antipsychotics. It is important to remember that what is known about the pharmacogenomic factors that impact an individual’s response (therapeutic benefits and side effects) to commonly used psychiatric medications is substantially different between the classes and in some cases, between drugs within the same class. A very common request from a parent is for PGX testing to determine whether methylphenidate or amphetamine class stimulants would be better for their child. This concern is usually driven by fear of a bad outcome based on personal experience or circulating horror story. Currently, PGX testing, whether commercial or non-commercial, cannot answer this question. The second most common scenario is a request for PGX testing to help identify the best anti-depressant, typically among the SSRIs, but increasingly the conversation includes SNRIs (venlafaxine, duloxetine). This conversation is usually prompted by the understandable desire for a parent to see their child get better sooner and not suffer through multiple trials. Here too, the science is not there. While some information exists regarding the underlying genetic factors that may impact metabolism of certain antidepressants, this is very different from predicting a clinical response and, also, the likelihood of side effects. Parents cannot be faulted for coming to us with these questions. The desire to avoid harm is certainly understandable and is our mandate as physicians. The mandate to first do no harm is one of the primary reasons early on that many physicians were reluctant to pursue commercially available PGX testing. There was (and still is) the very real possibility that results will be used in a way that is counter-therapeutic and potentially harmful by ruling out potentially helpful medications based on unsound science. The situation is changing but it is changing slowly. Inappropriate use of PGX testing can shorten an already limited number of evidence-based medications options.
In responding to parent questions, it can be helpful to be familiar with the limitations of currently available commercial tests. Commercially available tests are combinatorial testing protocols which stratify medications into groups based on multiple genes. The testing protocols that determine how medications are batched are proprietary and a lack of transparency has been one of the issues with clinical acceptance. Other issues with commercially available tests that are limiting wider acceptance include claims that they can predict which medications will be effective, a sparse but evolving evidence base regarding the significance of the different gene – drug pairs, limited research specific to pediatric populations and the failure to take into consideration developmental factors that impact pharmacokinetically relevant enzymes. For example, CYP2C19 and CYP2D6 levels very considerably depending on age. NIH-CPIC currently recommends dose adjustments for citalopram, escitalopram and sertraline based on CYP2C19 metabolizer status and atomoxetine based on CYP2D6 status. Along these lines, one common drug-drug interaction to be aware of is the impact of fluoxetine on atomoxetine levels due to CYP2D6 interactions. The reality, however, is that most specialists are not routinely or even frequently pursuing PGX testing. Barriers include keeping up with the evidence base, monitoring the different recommendations and then also accessing appropriate-use protocols which are usually limited to academic institutions and major medical centers. Logistical issues, approval from insurance providers and access to geneticists who often must approve testing in many institutions renders the timeline for PGX testing incompatible with clinical practice.
Because of an evolving (though hotly debated) evidence base, the decision whether to pursue PGX testing is increasingly nuanced. Familiarity with the tests and evidence base will be key to appropriate use in the future. This is the case for both commercial and noncommercial tests.
Both the National Institute of Health (NIH) supported Clinical Pharmacogenetics Implementation Consortium (CPIC; www.cpicgx.org/) and the FDA (www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling) are actively involved in trying to keep physicians up-to-date and provide useful information to consumers. CPIC provides transparent, regularly updated and evidence-based evaluations of pharmacogenetic data. The FDA has started to incorporate pharmacogenetic information to guide dosing and assess risk when genes are identified that may increase the risk of hypersensitivity reactions. This is the case for citalopram, aripiprazole, atomoxetine, carbamazepine, and oxcarbazepine. The American Academy of Child and Adolescent Psychiatry (AACAP) guidelines are the most simplistic and by some accounts have failed to keep up with the growing body of research that supports PGX testing in certain situations. The AACAP guidelines for Clinical Use of Pharmacogenetics Tests in Prescribing Psychotropic Medications recommends that "clinicians avoid using pharmacogenetics testing to select psychotropic medications in children and adolescents.” For many, this is the most appropriate guidance given the state of the science.
It is very clear that none involved in this debate advocate for selecting medication solely based on pharmacogenetics. It is also clear that individual circumstances and the available evidence base must form the basis of clinical decision making. Increasingly, both commercial and non-commercial PGX testing are gaining relevance and creeping into the office with greater frequency. Without sufficient familiarity, the results from the commercially available tests may be misinterpreted. For these reasons is it helpful to be aware of the shifting landscape so that you can seek out the information and support you need to make the best decisions for your patients.
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Dr. Douglas Russell joined the PAL team in March of 2017. He received his medical degree from Jefferson Medical College and completed both his psychiatry residency and child psychiatry fellowship training at UCLA. Prior to medical school he worked as a radio producer at KUSC fm, a classical public radio station in Los Angeles. He received his BA in music from Wesleyan University. He is always willing to chat about music! If you would rather talk shop, his clinical interests include ADHD and other neurodevelopmental disorders, integrated/collaborative care, and prevention/health promotion. In addition to his work at PAL, Dr. Russell also works in the Seattle Children’s PEARL clinic and supervises child and adolescent psychiatry fellows in our training clinic.
