Pharmacogenomics is gaining support in mental health and polypharmacy, where the data make a strong case for improvements in clinical and economic outcomes.
Ten years ago, clinicians called on the medical community and pharmaceutical industry to invest fully in precision and personalized medicine, pronouncing it time to put an end to the era of trial-and-error drug selection.1 At that time, excitement was building around the applications for pharmacogenomics (PGx) and its promise to help take the guessing game out of prescribing drugs.
Fast forward to today: many patients are still on a prescription drug that is ineffective or toxic for them, despite advances in science and technology that can be used to help assess medication efficacy and optimize drug selection and dosing for each individual.2,3 Even more disturbing, more than 2 million adverse drug reactions occur in the United States each year, and up to 100,000 of those reactions prove to be fatal.4 Although not all these medication misadventures can be prevented, a recent clinical trial showed that using PGx testing reduced adverse events (AEs) by 30%.3
As a national clinical laboratory, Quest Diagnostics provides one of the most comprehensive PGx test panels available. We developed our polypharmacy panel to provide guidance across multiple indications, including mental health, pain management, oncology, neurology, and cardiology.
The array is designed to genotype blood, buccal, and saliva samples for 44 different genes and hundreds of alleles that can affect medication dosages and response. Quest does not provide medication guidance or provide clinical annotation on our reports; however, the results can be integrated with clinical decision support systems (CDSS) and electronic health records (EHR) that are able to provide medication-specific information. Clinicians and pharmacists who are best positioned to use the PGx data then have the information they need to prescribe the optimal treatment for each individual.
Mental health therapy may be one of the most compelling areas for use of PGx, as there is solid data showing it can help improve clinical outcomes and drive cost savings.25–28 But even today, patients beginning psychiatric care must often go through a trial-and-error period to find the medication that is the best match. This trial-and-error period can lead to low medication adherence, a delay in the patient’s response to treatment, and higher health care costs, especially if the patient is experiencing AEs and is not responding to the medication.
With PGx testing, clinicians are armed with 2 new pieces of information to guide prescribing: first, pharmacokinetic phenotypes, or metabolism genes that determine how well an individual breaks down medications; and second, pharmacodynamics, or how the body biologically responds to a medication. Combining PGx results with other factors such as the patient’s overall health, the nature of their illness, demographics, family history, diet, and experience with other medications in the past may help the clinician determine a more effective treatment plan.
As a result, the patient may experience improved medication efficacy and reduced AEs, leading to a better clinical outcome and a more satisfactory patient journey—as well as potential savings for the medical practice and health system overall.
For example, take one of the most commonly prescribed classes of mental health medications: antidepressants. Data show patients with major depressive disorder are more likely to respond to antidepressant therapy and have improved remission rates if the medication prescribed is informed by PGx.8
In a study of outpatients with treatment-resistant depression, patients who switched from medications with significant gene-drug interactions showed greater improvements and fewer AEs than those who stayed on them.5 In addition, cost-effectiveness modeling predicts almost $4000 in direct and indirect total medical cost savings annually per patient with PGx-guided medication management for depression.9
Another area in which PGx is gaining traction is with patients who take multiple medications, which is often called polypharmacy. PGx can help decrease the number of medications a patient receives and replace medications that aren’t working with ones that can. PGx testing can also help reduce the risk of dangerous drug interactions. One large study in Europe showed PGx testing reduced AEs by 30%.3
Improved medication efficacy and efficiency due to PGx testing can also lead to cost savings. When the Kentucky Teachers’ Retirement Association adopted a comprehensive medication management program for its Medicare Advantage patients—including a pharmacist review of PGx and other patient-related factors—the program achieved a reduction of nearly $7000 per patient in direct medical charges, for a total of approximately $37 million in savings across 5288 participants.10
One thing to keep in mind is that the criterion for polypharmacy is not well defined. Is it a patient on more than 1 medication or 20 medicines? I use the operational definition of more than 5 medications, but the medical community needs a standardized definition to help guide clinical care.
Another critical point to make is the importance of pharmacists in the review of PGx results, especially with polypharmacy patients. Clinicians are experts in their fields and pharmacists are experts in medications.
EHRs and clinical decision support tools can guide clinicians to the medication or dose that may be better for the patient based on genetics, but they don’t take the place of pharmacists. When you have a complicated patient on multiple medications and PGx information is available, the pharmacist can help look at drug-drug and drug-drug-gene interactions to provide guidance on doses and medications.10
Pharmacists in health-system settings are often a key part of clinical care teams helping to implement PGx. We are also starting to see community pharmacists become more involved in reviewing PGx information.
Because pharmacists are on the frontlines of care and are often the most accessible health care providers, they will play an increasingly important role answering patients’ questions on PGx and helping to educate both patients and providers on the value and use of PGx testing.
As PGx testing becomes more widely available, patients will increasingly become advocates for their own health care and request testing or, if they already have results, ask clinicians to use that information to help guide treatment. Patients have demonstrated that they want to know what their genes indicate.11,12 These savvy consumers will be the ones who end up making PGx portable and usable for their providers.
Over time, we’ll see providers start asking patients whether they’ve had PGx testing done in the past. And although EHRs with interruptive alerts can be the bane of providers’ existence, alerts will serve as helpful reminders on when to order PGx testing. We will also see increased use of PGx to determine which patients may be genetically able to respond to medication for enrollment in clinical trials.
Use of PGx testing in mental health is also likely to increase alongside the rise of virtual care. At Quest, we have seen an uptick in home sample collection as part of telehealth.
PGx can play a role supplementing telehealth, which by its nature presents challenges with physically evaluating patients. PGx testing can minimize medication AEs, giving a clinician greater confidence to prescribe that treatment and then monitor the patient via virtual visits.
As PGx testing is increasingly used in tandem with telehealth, it can also help minimize access gaps in care, particularly gaps in access to mental health care. Historically, primary care providers (PCPs) have referred patients to psychiatrists for mental health evaluation.
A drop off in care often occurs when a second visit is required—particularly an in-person visit. Some patients have limited means to travel to onsite visits, and many simply don’t want the hassle of another appointment.
Patients’ preferences for fewer health care appointments along with other factors, including a rise in mental health diagnoses and ongoing clinician shortages, have led to PCPs becoming increasingly involved in their patients’ mental health care.13 In fact, most prescriptions for antidepressants are written by PCPs, indicating that they, not psychiatrists, are the providers most often treating depression in the community.14,15
With PGx information, PCPs may feel more comfortable prescribing psychiatric medications knowing patients may be less likely to have AEs, medications are more likely to be effective, and patients are more likely to remain adherent.
Education is one of the main barriers to overcome to increase the adoption of PGx testing. Many health care professionals and clinicians aren’t aware of PGx or are aware but do not see the potential value or need for testing, even though their patients or those patients' caregivers (including parents and guardians) may request testing.
Changing provider behaviors and attitudes is difficult, and some providers discount the benefits of PGx testing because it’s not included in clinical guidelines. In the next 5 years, we hope to see a larger number of providers and health systems using PGx testing as guidelines are updated and we become better able to define which genes are clinically relevant. Other factors inhibiting provider adoption include long turnaround times to results and results that aren’t easily actionable.
While we can continue to pave a path forward for PGx testing through provider education, addressing the other big challenge will be more difficult. Providers and patients both want to know: who pays for it?
Most commercial payers want more data demonstrating improvements in clinical and economic outcomes before they grant coverage, though Medicare reimbursement is improving.16,17
Still, thanks to grassroots efforts and patient advocacy, we are starting to see payers cover PGx testing for some patients.18 Single-gene tests tend to have better reimbursement than panel-based tests, as payers are not convinced they should cover the full cost of what’s seen as a once-in-a-lifetime test.19 PGx panel-based testing is primarily reimbursed for mental health reasons.17
Because widespread reimbursement is not likely in the near-term, one of the ways we can alleviate payer constraints is by engaging employers to provide PGx as a benefit to their employees. Quest recently performed an IRB-approved pilot study analyzing medication management with PGx among our own employees.
For this project, Quest provided the laboratory services and transferred the results to Coriell Life Sciences where pharmacists integrated the PGx information, clinical decision support information, and patient-specific factors to perform comprehensive medication management. Pharmacists then recommended actions such as discontinuing a medication or initiating a new medication for almost 86% of employees who completed the program.20 With programs such as the Kentucky Teachers’ Retirement Association demonstrating the potential economic benefits of medication management with PGx, we may expect similar opportunities to reduce health care costs in an employee population.
For now, reactive PGx testing is likely to continue gaining support in mental health and polypharmacy, where there is strong clinical and economic data. The data demonstrating the clinical utility of pre-emptive, panel-based testing is not yet as strong, but continues to grow and could be especially helpful in primary care settings where a clinician may be prescribing their patient a wide range of medications over a period of years. Although implementing PGx can be challenging, barriers can be overcome with advances in technology, continued education, and collaboration across the clinical community—bringing us a step closer to realizing the full potential of genetics to improve medication use and, in turn, health outcomes.
About the Author
Raymond Lorenz, PharmD, BCPP, director of medical science liaison, neurology and pharmacogenomics, Quest Diagnostics.
1. Seigel CA. The era of trial and error medicine needs to be over. Published November 7, 2014. Accessed April 17, 2023. https://www.kevinmd.com/2014/11/era-trial-error-medicine-needs.html
2. Brown LC, Stanton JD, Bharthi K, Maruf AA, Müller DJ, Bousman CA. Pharmacogenomic Testing and Depressive Symptom Remission: A Systematic Review and Meta‐Analysis of Prospective, Controlled Clinical Trials. Clin Pharmacol Ther. Published online 2022. doi:10.1002/cpt.2748
3. Swen JJ, Wouden CH van der, Manson LE, et al. A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study. Lancet. 2023;401(10374):347-356. doi:10.1016/s0140-6736(22)01841-4
4. Administration F and D. Preventable Adverse Drug Reactions: A Focus on Drug Interactions. Published March 6, 2018. Accessed April 17, 2023. https://www.fda.gov/drugs/drug-interactions-labeling/preventable-adverse-drug-reactions-focus-drug-interactions
5. Greden JF, Parikh SV, Rothschild AJ, et al. Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study. J Psychiatr Res. 2019;111:59-67. doi:10.1016/j.jpsychires.2019.01.003
6. Brown LC, Lorenz RA, Li J, Dechairo BM. Economic Utility: Combinatorial Pharmacogenomics and Medication Cost Savings for Mental Health Care in a Primary Care Setting. Clin Ther. 2017;39(3):592-602.e1. doi:10.1016/j.clinthera.2017.01.022
7. Winner JG, Carhart JM, Altar CA, et al. Combinatorial pharmacogenomic guidance for psychiatric medications reduces overall pharmacy costs in a 1 year prospective evaluation. Curr Med Res Opin. 2015;31(9):1633-1643. doi:10.1185/03007995.2015.1063483
8. Bradley P, Shiekh M, Mehra V, et al. Improved efficacy with targeted pharmacogenetic-guided treatment of patients with depression and anxiety: A randomized clinical trial demonstrating clinical utility. J Psychiatr Res. 2018;96:100-107. doi:10.1016/j.jpsychires.2017.09.024
9. Maciel A, Cullors A, Lukowiak AA, Garces J. Estimating cost savings of pharmacogenetic testing for depression in real-world clinical settings. Neuropsych Dis Treat. 2018;14:225-230. doi:10.2147/ndt.s145046
10. Jarvis JP, Peter AP, Keogh M, et al. Real-World Impact of a Pharmacogenomics-Enriched Comprehensive Medication Management Program. J Personalized Medicine. 2022;12(3):421. doi:10.3390/jpm12030421
11. Gawronski BE, Cicali EJ, McDonough CW, Cottler LB, Duarte JD. Exploring perceptions, knowledge, and attitudes regarding pharmacogenetic testing in the medically underserved. Frontiers Genetics. 2023;13:1085994. doi:10.3389/fgene.2022.1085994
12. Orth T. DNA tests: Many Americans report surprises and new connections. Published February 25, 2022. Accessed April 17, 2023. https://today.yougov.com/topics/society/articles-reports/2022/02/24/dna-tests-many-americans-report-surprises-and-new-
13. Rotenstein LS, Edwards ST, Landon BE. Adult Primary Care Physician Visits Increasingly Address Mental Health Concerns. Health Aff. 2023;42(2):163-171. doi:10.1377/hlthaff.2022.00705
14. Wang PS, Demler O, Olfson M, Pincus HA, Wells KB, Kessler RC. Changing Profiles of Service Sectors Used for Mental Health Care in the United States. Am J Psychiat. 2006;163(7):1187-1198. doi:10.1176/ajp.2006.163.7.1187
15. Gray GV, Brody DS, Johnson D. The Evolution of Behavioral Primary Care. Prof Psychology Res Pract. 2005;36(2):123-129. doi:10.1037/0735-7028.36.2.123
16. Keeling NJ, Rosenthal MM, West-Strum D, Patel AS, Haidar CE, Hoffman JM. Preemptive pharmacogenetic testing: exploring the knowledge and perspectives of US payers. Genet Med. 2019;21(5):1224-1232. doi:10.1038/gim.2017.181
17. Service C for M and M. Local coverage determination (LCD): MolDX: pharmacogenomics testing (L38294). Published July 26, 2020. Accessed April 17, 2023. https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?LCDId=38294&;ver=16
18. Empey PE, Pratt VM, Hoffman JM, Caudle KE, Klein TE. Expanding evidence leads to new pharmacogenomics payer coverage. Genet Med. 2021;23(5):830-832. doi:10.1038/s41436-021-01117-w
19. Anderson HD, Crooks KR, Kao DP, Aquilante CL. The landscape of pharmacogenetic testing in a US managed care population. Genet Med. 2020;22(7):1247-1253. doi:10.1038/s41436-020-0788-3
20. Keogh M, Fragala MS, Peter AP, Lorenz RA, Goldberg SE, Shaman JA. Early insights from a pharmacogenomic-enriched comprehensive medication management program implementation in an adult employee population. J Occup Environ Medicine. 2022;Publish Ahead of Print. doi:10.1097/jom.0000000000002705
21. FDA. Table of Pharmacogenomic Biomarkers in Drug Labeling. Published online 2020. https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling
22. Beunk L, Nijenhuis M, Soree B, et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. Eur J Hum Genet. Published online 2023:1-8. doi:10.1038/s41431-023-01347-3
23. Phillips EJ, Sukasem C, Whirl‐Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Clin Pharmacol Ther. 2018;103(4):574-581. doi:10.1002/cpt.1004
24. DPWG. DPWG Recommendations for carbamazepine and oxcarbazepine. Accessed April 27, 2023. https://api.pharmgkb.org/v1/download/file/attachment/DPWG_May_2021.pdf
25. Bousman CA, Stevenson JM, Ramsey LB, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. Clin Pharmacol Ther. Published online 2023. doi:10.1002/cpt.2903
26. Brouwer JMJL, Nijenhuis M, Soree B, et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2C19 and CYP2D6 and SSRIs. Eur J Hum Genet. 2022;30(10):1114-1120. doi:10.1038/s41431-021-01004-7
27. Karnes JH, Rettie AE, Somogyi AA, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA‐B Genotypes and Phenytoin Dosing: 2020 Update. Clin Pharmacol Ther. 2021;109(2):302-309. doi:10.1002/cpt.2008