Over the past five years, Sally struggled with depression, and despite trying various treatments, none seemed to benefit her. Recently, she visited a new psychiatrist who conducted a saliva swab for pharmacogenetic testing during her initial consultation. By combining Sally’s medication history and the pharmacogenetic test results, the psychiatrist discovered that several previously prescribed medications likely never reached therapeutic levels in her body, resulting in treatment failures. Sally’s new doctor then prescribed a medication tailored to her unique genetic makeup, providing her with the best chance for successful treatment. This personalized approach considered Sally’s individual characteristics, including her genetic information.
A patient’s unique genetic makeup plays a role in their response to medications
Throughout our years of experience in both clinical trials and practice, we’ve observed that patients respond differently to medications. Some may experience adverse reactions while others don’t, or a drug may be more effective for certain individuals than others. It’s uncommon for a drug to be universally safe and effective; in fact, response rates for many drugs are only about 50-75% based on data from numerous clinical trials spanning decades. In the past, these varying responses were attributed to factors such as age, sex, comorbidities, health status and lifestyle choices like smoking, alcohol and diet. However, today, we recognize that a patient’s unique genetic makeup also plays a significant role in their response to medications, alongside these other factors.
Precision medicine, a growing field
Pharmacogenomics and pharmacogenetics—often used interchangeably—involve studying how genes influence the body’s response to medications. Pharmacogenomics examines how your DNA or RNA impacts your reaction to drugs, which can determine whether you will experience adverse effects, find a drug beneficial or see little to no effect at all. In contrast, pharmacogenetics focuses on a limited number of genes to characterize individual responses to specific drugs or therapeutic classes.
In this article, we will use the abbreviation PGx to refer to this growing field of individualized or personalized medicine. PGx aims to identify the right medication for you, predict your response to one or several medications, determine the optimal dosage and assess the likelihood of serious side effects, but it does have some limitations.
Applications in current practice
The traditional approach of cycling through various medications until finding one that works can be risky and inefficient. In fact, certain conditions require immediate effective treatment to prevent rapid deterioration or even death. Given that over 90% of individuals possess DNA variants that could influence their response to medications, precision medicine using PGx testing can serve as a powerful tool for appropriate medication selection. Currently, PGx testing is used to enhance patient care and optimize medication choice and dosage across clinical areas such as psychiatry, pain management, cardiology, neurology, rheumatology, dermatology and cancer treatment.
Example in psychiatry
Four cytochrome P450 enzymes (CYP2D6, CYP3A4, CYP2C19, and CYP1A2) break down more than three-quarters of psychotropic medications and many other medications as well. One of the most critical is CYP2D6, which plays a prominent role in the metabolism of many antidepressants, antipsychotics, and psychostimulants. In addition, there is this very high genetic variability in CYP2D6 expression among patients.
A one-time saliva test can determine how well a patient metabolizes medications utilizing the CYP2D6 pathway. Results reveal if the patient is an “extensive” metabolizer (typical response), a “poor” metabolizer (risk for toxicity and adverse events), or an “ultrarapid” metabolizer (failure to reach therapeutic levels even at standard doses).
Let’s go back to Sally. Sally’s saliva test revealed she is an ultrarapid metabolizer for CYP2D6, meaning she should avoid medications primarily using this pathway for metabolism, such as paroxetine (Paxil), amitriptyline (Elavil), and nortriptyline (Pamelor), as they would not be effective at normal dosages.
Limitations in PGx Testing
While PGx testing is a forward-step in precision medicine, there are limitations to the practical application of PGx testing in clinical settings. For instance, a single test cannot determine patient response to all medications, meaning multiple tests might be necessary depending on the potential treatments and the patient’s individual traits. Moreover, PGx tests are not available for all medications, restricting their use to certain drugs. While there are PGx panels that test multiple genes to understand how a patient may respond to and metabolize specific medications, their scope remains limited.
Provider concerns: According to published literature, the most significant barrier to the clinical implementation of PGx testing is its high cost. Other obstacles include a lack of PGx education for healthcare providers and a scarcity of clinical PGx experts in practice. The most pressing concern reported is the absence of actionable guidelines for drug selection and dosing using PGx. For successful integration of PGx testing into routine clinical practice, an efficient process to order tests and interpret and report the results to clinicians and patients is essential. Multiple companies and some academic institutions offer testing, interpretation and clinical recommendations as part of their service offerings, simplifying the process for providers.
Technology limitations: Over a dozen companies currently offer PGx testing, but a single test cannot determine responses to all medications. PGx panels testing multiple genes can help, but the genes tested, and variants screened vary among companies, leading to discrepancies in interpretations and potential clinical impacts. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published guidance for using PGx test results in clinical practice to promote consistency in the market. Although not obligated to follow CPIC guidelines, genetic testing companies adopting these standards could minimize variability and promote greater adoption of PGx tests in clinical practice by standardizing variant testing and interpretation.
Precision medicine is here to stay, with individualized treatments proven to enhance patient outcomes. PGx offers prescribers valuable assistance in selecting the optimal medication for each patient and situation. Nonetheless, technological advancements and standard provider guidance are needed to seamlessly integrate these tools into conventional clinical practice. Embracing this emerging area of medicine presents a promising opportunity for the industry.