Landmarks of pharmacogenomics and some considerations for clinical practice

PGx history

The history of PGx can be traced back to 500 BCE, when Pythagoras discovered that eating fava beans was fatal for some individuals but nourishing for others, and that the beans could be used to treat constipation. ⁵ The next major discovery in the advent of PGx was by Archibald Garrod, who hypothesized that the ingestion of substances affects genes at the molecular level, and that specific enzymes are required for detoxification. According to Garrod, the lack of these enzymes led to metabolic disorders and potential fatality. ⁶ By the 1940s and 1950s, scientists had begun to observe and report a range of atypical responses to medications. During World War II, some soldiers, after being administered antimalarial drugs, developed a range of adverse side effects, including anemia. It was later found that these soldiers were deficient in the enzyme glucose 6-dehydrogenase.^5,6 Within the same period, the anesthesia drug succinylcholine was found to prolong paralysis and induce fatal reactions in some individuals with a mutated genetic variant linked to the absence of the enzyme butyrylcholinesterase. ⁶ Nevertheless, it was not until the late 1950s that Friedrich Vogel coined the term ‘pharmacogenetics.’ During this period, the single most important contribution that propelled genetic studies in the 20th century was the discovery of the double helical structure of DNA by James Watson and Francis Crick. Later, the term ‘pharmacogenomics’ became official during the launch of the Human Genome Project in 1990, and, once human DNA mapping was completed in 2003, the field of PGx began to grow.^7,8

PGx and modern medicine

The study of PGx led to the birth of a booming biotechnology industry that continues to identify new cures and therapeutic treatments for diseases. Nonetheless, pharmaceutical companies face high costs in producing and marketing these drugs. ⁹ Collaboration between pharmaceutical companies and other biotechnology entities has become a necessity in the search for affordable and effective treatments. This research has resulted in considerable advancement in the fields of medicine and nursing, and has helped elucidate how genes interact with medications to open new pathways in identifying genotypes and phenotypes suitable for specific medications. Research has broadened practitioners’ understanding of psychotropic medications and how to minimize adverse drug reactions, negating the need for traditional trial-and-error in psychiatric care. Figure 1 provides a mind map of the development of PGx.

PGx has affected several fields of medicine. Although we are witnessing a resistance to the adoption of PGx in psychiatric medicine, the United States Food and Drug Administration (FDA) has approved roughly 40 psychotropic biomarkers, along with guidelines for the improvement of patient care. Health care providers’ major concerns were risks and insurance reimbursement. Public and private insurance companies currently reimburse for PGx testing. The out-of-pocket cost of the PGx panel test is currently US $300 without insurance. ¹⁰ The quantity of biomarkers per PGx test order is not standardized; however, many genetic agencies offer PGx testing beyond the scope approved by the FDA. Some genetic companies cover only the biomarkers approved by the FDA (mostly pharmacokinetic biomarkers), while others cover pharmacokinetic and pharmacodynamic biomarkers.

It is also equally important for providers and consumers to be wary of genetic companies marketing PGx testing without FDA approval. Interested parties are encouraged to research the authenticity of the genetics laboratory agency, and its approval by the FDA, before subscribing to its services. In the world of health care, consumers are dying to find the best antidote for their problems on the market. Companies like Theranos, and executives like Elizabeth Holmes, will continue to emerge, so providers should thoroughly examine company claims and verify their authenticity with regulating authorities. The FDA’s recent warning letter to Inova Genomics Laboratory for claims of PGx testing that have not been verified is a reminder that providers cannot be naïve about PGx marketing claims. ¹¹

Prior to ordering PGx testing, consider the following questions: Have previous psychotropic drugs failed to stabilize the patient’s condition? Has the patient become noncompliant with therapeutic treatment due to the adverse side effects of psychotropic drugs? Have the patient’s symptoms failed to respond to the approved class of psychotropic drugs for the condition after 6 months of treatment? Does the patient’s family history show serious adverse responses, such as serotonin syndrome or neuroleptic malignant syndrome, to psychotropic drugs? A positive answer to these questions justifies ordering PGx testing for insurance reimbursement. Health care professionals should also consider using FDA-approved label biomarkers and guidelines (Table 1) to justify whether the medications fall into certain categories. ¹²

Physicians should educate patients on PGx testing, and allow patients to make informed decisions. Brochures on the importance of PGx testing for treatment-resistant depression, ADHD, bipolar disorder, and other mood disorders are useful educational resources. Educational tools can also focus on the ability to prevent harm. Having a panel of PGx test results from a patient is the most effective way to stop trial and error, thereby avoiding harm beforehand. When the patient agrees to PGx testing for his or her condition, physicians or their staff should call to verify the patient’s insurance coverage for the testing, and inform the patient of costs if the patient’s insurance does not cover the test. By calling, or getting verification from insurance company websites, physicians will avoid undue financial burden on patients. For example, a review of the Tricare website shows that the agency covers specific genetic testing deemed medically necessary, but it does not indicate whether PGx testing for psychotropic drugs is covered. ¹⁰ Lastly, physicians should consider inviting a PGx testing company to their practice setting to provide education on PGx.

Practical PGx resources

In addition to the FDA-approved biomarkers and guidelines, the following resources may be relevant to any provider who intends to incorporate PGx testing into his or her practice. None of these resources provide a guide on whether to order a test or not, but two of the sites have information about current genetic testing and how to use them to improve the outcome of medication treatment.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) is used by many medical professionals. ¹⁴ CPIC substantiates its guidelines with published clinical studies, and uses graded levels of evidence to show how phenotypes are assigned to genotypes. CPIC has more robust and relevant information for the clinical application of psychotropic drugs than the FDA guidelines. For instance, CPIC includes the consideration of CYP2D6 and CYP2C19, whereas the FDA guidelines focus on only CY2D6 for amitriptyline. The CPIC website provides information on drug biomarkers for novice providers to evaluate evidence for themselves. PharmGKB is a subsidiary website of CPIC. ¹⁵ PharmGKB publishes clinical guidelines for each drug, and provides recommendations for genotype dosing. The Pharmacogenomics Research Network (PGRN) is a website with open membership for providers, researchers, graduates, and postdoctoral students, and offers interested individuals the opportunity to learn about, and contribute to, PGx research. ¹³

Considerations for PGx clinical use

The FDA has approved roughly 40 psychotropic medications for biomarker labeling. The caveat regarding these approved labels is that few psychiatric practitioners use them to make clinical decisions for patients. A nationwide survey of their awareness and utilization of FDA-approved labels among 10,303 physicians revealed that approximately 41% of physicians use FDA-approved biomarkers labels to inform PGx test decision-making and improve medication management. The field of oncology, with the highest rate of early adopters, has more FDA-approved biomarkers for PGx testing than any other field. However, psychiatrists (with the second largest number of approved FDA biomarkers) have not fully embraced PGx testing in clinical practice.^16,17

In addition, consistent with Parker and Satkoske, ¹⁸ the FDA acknowledges that one key limitation of these labels is that the efficacy of PGx has not been established with minority populations. ¹² Moreover, due to the history of the United States government conducting unethical medical experimentation under the guise of clinical trials and treatment with these populations, ¹⁸ such efficacy testing is likely to be a sensitive issue. This will undoubtedly contribute to the slow adoption of PGx among minority groups. Although this assertion is controversial, it is a platform from which the medical community can design education that focuses on the benefits of genetic testing for minority populations. The provision of appropriate educational programs highlighting the safety of PGx testing, and its utilization in minority communities, is essential to bridging this gap. The Perera laboratory, along with other scientists, aim to bring precision medicine to underserved populations. ¹⁹ Already, some inroads are leading to an increase in data and the accurate dosing of medications such as warfarin and tacrolimus for underserved populations.^19,20 These discoveries attest to the different alleles in minority populations, which makes it significant for providers to learn about and utilize PGx-guided treatment, and move away from a one-size-fits-all medical approach.

FDA-approved biomarkers require providers to understand certain basic concepts in pharmacology in order to utilize PGx-guided treatment. Phenoconversion is a genotypic conversion of an EM to a phenotypic PM. Phenoconversion occurs as a result of substrates, inhibitors, and inducers changing the expected outcome of a drug prescribed based on PGX testing. ²¹ Some of these FDA-approved drugs for PGx biomarkers are more susceptible to phenoconversion than others. In addition, interference from other drugs or illicit substances, such as cigarettes, may elicit phenoconversion. ²² Usually, substances that function as inhibitors or substrates can facilitate the therapeutic or adverse effects of another drug metabolized by that isozyme, but inducers decrease the function of that drug’s metabolism. These factors pose a major challenge to providers in the application of PGx-guided treatment. Table 2 shows a compilation of some common cytochrome P450 enzymes with their substrates, inducers, and inhibitors.^22,23

PGx-guided treatment could be used to minimize the opioid epidemic; however, it would be imperative for providers to understand the mechanisms of prodrugs such as tramadol and codeine if the patient is identified as a PM. In most cases, PMs accumulate metabolites of the medication, and in the case of prodrugs, the accumulation of metabolites may be 80% of the inactive drug, while the remaining drug is rendered ineffective. ²¹ A typical example of this type of phenomenon is seen in codeine, which has a complex biological activity. The prodrugs morphine and metabolite 6-glucuronide become ineffective in PMs. For instance, Koren and colleagues provides several examples of the importance of understanding prodrug mechanisms in PMs. ²⁴ The report a baby who died from breastfeeding because the mother was prescribed codeine postpartum to treat episiotomy pain. A 2-year-old boy underwent an adenotonsillectomy to treat sleep apnea and was prescribed codeine and acetaminophen to reduce the pain, but he died on the second evening. A 5-year-old boy underwent a bilateral myringotomy tube placement and an adenotonsillectomy and was prescribed codeine/acetaminophen, and he died the following day. ²⁴ This is a significant series of anecdotal cases in which PGx-guided treatment could have prevented the sudden death due to morphine overdose in each case.

A review of codeine-related deaths from 1965 to 2015 revealed the deaths of approximately 21 children, all below the age of 12, and 64 severe respiratory distress cases. The reports relate only to cases submitted to the FDA, leaving room for concern. ²⁵ The FDA and the American Academy of Pediatrics cautioned against the use of codeine and tramadol, but a recent study shows that roughly 1 in 20 children is still prescribed codeine after surgery. The understanding and utilization of PGx-guided treatment will identify ultra-rapid metabolizers and PMs of codeine and tramadol.

Although tramadol and eteplirsen are not psychotropic drugs, these medications were selected as among the approved FDA biomarker drugs because they represent some of the most common medications for patients diagnosed with a mental illness and other medical comorbidities. These medications, and others, present the potential to inhibit or induce CYP450, even for patients who may be prescribed drugs they can normally metabolize through PGx-guided treatment. Another basic concept and emerging area in the field of psychiatric clinical practice is methylenetetrahydrofolate reductase (MHTFR) polymorphisms and homocysteine. Numerous studies associate the MTHFR variant and abnormal homocysteine levels to neurocognitive disorders and the exacerbation of other mental illnesses.^26–28 Folate and other B vitamins are essential elements in the modulation of neurotransmitters. A patient with MTHFR polymorphism may not respond to psychotropic drugs, even though the patient may be an EM of that drug. Ensuring that the patient is not folate-deficient will positively impact the patient’s response to the drug in the brain. For patients with MTHFR, serum folate levels may be within reference range, and may reduce vitamin B12. Based on current literature, these patients might benefit from the ingestion of methylcobalamin and methylfolate. ²⁷ The promotion of adequate vegetable consumption is essential for the therapeutic effect of psychotropic drugs for most patients, but for some, methylcobalamin and methylfolate may be needed for their psychotropic drugs to work. ²⁷

The hypotheses and theories of genetic interaction with the ingestion of substances span centuries of anecdotal evidence, from individuals to small communities of scientists. At 28 years after completion of the Human Genome Project, the ability to exploit a double helix at the bedside of medicine is still not realized in practice in several other specialties. Psychiatric mental health nurse practitioners must embrace the opportunity to utilize this new tool beyond prescribing for diagnostic and preventative measures. A late-adopter attitude toward the use of PGx testing is safe but does not innovate or advance genomics for diagnostic, preventive, and treatment of mental illness.