Pillcheck webinar: how genetic diversity shapes medication response, and what it means for mental health care

How can our growing knowledge of genetic diversity lead to better health? In this Pillcheck webinar, recorded in 2021, Liz Garman, Customer Solutions Manager at Pillcheck, talks with two experts about personalized medication, with a focus on depression and anxiety:

• Boyko Kabakchiev, PhD, Chief Technology Officer at Pillcheck, who holds a doctorate in human genetics and bioinformatics and specializes in data analysis.
• John Papastergiou, a pharmacist and researcher who was among the first community pharmacists in Canada to set up pharmacogenomics clinics. At the time of the webinar he was an assistant professor at the Leslie Dan Faculty of Pharmacy, University of Toronto, and an adjunct professor at the School of Pharmacy, University of Waterloo.

You can watch the full 15-minute webinar below. A summary of the discussion follows.

What is pharmacogenetics, and how many people does it affect?

Pharmacogenetics (PGx) studies how differences in our genes affect the way we respond to medications. Liz opened the webinar by noting that more than 95% of people carry at least one genetic variation that affects their drug response. Larger studies published since then support this: an analysis of almost 490,000 people in the UK Biobank found that 99.5% of them carry a variant that may lead to an atypical response to at least one medication, and that people of non-European ancestry more often carry variants that reduce enzyme function.

Why isn't the standard dose right for everyone?

Boyko explained that the genetic diversity we inherit from our ancestors affects, among many other things, how well we benefit from medications. Doctors usually choose among several medications for a condition based on a person's age, weight and other factors. But the standard drug and the standard dose are not right for everyone. Depending on how quickly their body breaks down (metabolizes) a medication, which is partly determined by their genes, a person may need a higher or lower dose, or a different drug.

This is why Pillcheck was developed: a clinical-grade DNA test based on the established science of pharmacogenetics. From the start, Pillcheck chose to reflect the diversity of the Canadian population by including genetic variants that are common in the many ancestral backgrounds found in Canada.

Why might prescribers overlook our biological diversity?

Most widely used medications have been around for decades, and Boyko noted that drug development and prescribing practices still carry some "baggage" from the past. He described two main reasons why prescribers might unintentionally overlook biological diversity.

1. Genetic variation is a spectrum, and race is a poor proxy for it

Genetic variation across geographic regions is continuous, like a colour spectrum. Boyko showed how the activity of two key enzymes that process many medications, including most mental health and pain medications, changes gradually across different ancestral groups rather than falling into separate categories. Medical guidelines and algorithms often use race to guide clinical decisions, but race, however it is defined, is a very poor proxy for biology. Ignoring genetics when designing treatment strategies tends to reinforce historical biases.

He also pointed out that when it comes to drug metabolism, two people with similar ancestry can be more different from each other than two people from different backgrounds. The mix of variants in each person's DNA is unique, which is why testing the individual is more informative than relying on ancestry.

2. Clinical trials often did not include diverse populations

Randomized clinical trials are the gold standard for drug development. They compare how well treatments work for the people enrolled and assume the results apply to the "average patient". But if a trial did not include a diverse population, its results may not help choose the best treatment for a real person.

Boyko gave the example of the enzyme CYP3A5. Most people of European ancestry are CYP3A5 poor metabolizers: their bodies make little or no working enzyme. Dosing approaches built mainly on this group can be inaccurate for many people of other ancestries, who more often carry working copies of the gene. The anti-rejection medication tacrolimus, used after organ transplants, is a well-known example. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend that people who express CYP3A5 (normal and intermediate metabolizers) start tacrolimus at 1.5 to 2 times the standard starting dose, because they break the drug down faster and may otherwise take longer to reach target blood levels.

How does Pillcheck account for genetic diversity?

Pillcheck's analysis includes many variants that are less common in people of European ancestry but more common in people of African or Asian ancestry. Rather than relying on population averages that may or may not apply to an individual, Pillcheck provides prescribing recommendations based on each person's own genetic results.

Liz noted that this helps healthcare practitioners take a more holistic view of each person. Pillcheck clients often say their results helped their doctor understand why a medication was not relieving their pain, and that the test helped with their pain management.

Boyko added that the healthcare system and many doctors are not yet fully equipped to use genetic results in routine care. This is partly a technology problem and partly a change in how practitioners are used to working. That is why Pillcheck combines the genetic test with an online medication review by an expert pharmacist.

What did John's first pharmacogenomics study in community pharmacy show?

John explained that pharmacists are well suited to pharmacogenomics because they understand how drugs act in the body (pharmacodynamics) and how the body processes drugs (pharmacokinetics). Before running a randomized trial, his team first asked a simpler question: could community pharmacists offer pharmacogenomic testing, and would they act on the results?

That study, published in 2017, enrolled 100 people in two Toronto community pharmacies using Pillcheck. The most common reasons for testing were a medication that wasn't working (43%) and side effects (33%). Pharmacists identified an average of 1.3 drug therapy problems per person directly related to the genetic results. Their recommendations included changing therapy (60%), adjusting the dose (13%), stopping a drug (4%) and increasing monitoring (22%), across a wide range of medical conditions.

The question that remained, John said, was whether these changes made a real difference to patients. Some doctors told him they would have reached the same decisions eventually without a genetic test.

How was the randomized trial in depression and anxiety designed?

To answer that question, John's team ran a randomized clinical trial in community pharmacies. They chose mental health because there are well-established scales to measure how people are doing over time. John noted that running a randomized trial in a busy community pharmacy, rather than a closed research setting, was much harder than expected.

• People with depression or anxiety were randomly assigned to standard care or to standard care plus Pillcheck pharmacogenetic testing.
• Everyone gave a cheek swab, and patients were kept unaware of which group they were in as much as possible. Only the clinical pharmacist saw the genetic results.
• Pharmacists made appropriate recommendations in both groups. In the testing group, they could also use the genetic results.
• Participants were assessed at the start of the study and after one, three and six months. The main outcome was the PHQ-9 depression questionnaire. Secondary outcomes included the GAD-7 anxiety scale and measures of disability and treatment satisfaction. The published study enrolled 213 people.

What did the trial find?

In a randomized clinical trial in three Canadian community pharmacies, published in 2021, people with depression or anxiety whose antidepressant treatment was guided by Pillcheck had greater improvement in depression, anxiety and disability over six months than those who received standard treatment.

John said the results suggested that people in the testing group reached the right medication faster, and the difference between the groups appeared early in follow-up. People in the standard-care group also improved, which he attributed partly to the extra attention: pharmacists don't usually assess patients with rating scales that often.

He was clear that pharmacogenetics is not a silver bullet. Results are not always black and white, but in many cases they help narrow down the options and guide the decisions that the pharmacist, the doctor and the patient make together. He has also seen this in his own practice across many therapeutic areas beyond mental health, although those areas have not yet been studied in similar trials.

What makes a pharmacogenetic test useful in a diverse community?

John said this is the question he hears most often. Pharmacogenetic tests vary widely in price and content, and it can be hard to tell them apart. His advice to pharmacists and other healthcare providers who use test results to make clinical decisions, especially across many conditions:

• Look for breadth. Choose a test that covers as many relevant genes as possible.
• Look for depth. Choose a test that checks as many variants of each gene as possible. This makes the test more sensitive and its results applicable to a multi-ethnic population like Toronto's.
• Make sure it fits your population. A test designed mainly around one ancestry can miss variants that matter for others.

His take-home message: get the right test, make sure it applies to your population, and make sure it is robust.

What does this mean for employers and benefit plans?

Health benefit plans aim to serve everyone they cover. Because genetic differences in drug response vary across and within ancestries, a pharmacogenetic program that tests a broad range of variants, combined with pharmacist support, can help make medication care more inclusive. Learn more about diversity, equity and inclusion in benefits and about how ancestry affects drug response. Employers, plan sponsors and benefits advisors can find out how to offer Pillcheck on our page for organizations.

How can Pillcheck help?

Pillcheck is a pharmacogenetic test that shows how your genes may affect your response to medications, including many antidepressants and pain medications. Your report is reviewed with you by an expert pharmacist, who can share recommendations with your doctor. Learn more about Pillcheck for mental health and the results of the randomized trial.

Pillcheck testing is performed in CAP- and COLA-accredited clinical genetic laboratories located in Canada. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. The Pillcheck test panel ensures high accuracy for people of non-European and admixed ancestries. Your results last a lifetime, and report updates are free of charge.

Summary

• Nearly everyone carries at least one genetic variant that can affect how they respond to medications.
• Genetic variation in drug metabolism is a spectrum. Race is a poor proxy for it, and people with similar ancestry can differ widely.
• Many dosing approaches were built on studies of mostly European populations, which can make them less accurate for others. CYP3A5 and tacrolimus are a well-known example.
• In a randomized trial in Canadian community pharmacies, people with depression or anxiety whose treatment was guided by Pillcheck improved more over six months than those who received standard treatment.
• A useful pharmacogenetic test covers many genes and many variants, and is designed for a diverse population.

Frequently asked questions

Can my ancestry tell me how I will respond to a medication?

Not reliably. Some genetic variants are more common in certain ancestral groups, but variation is continuous and two people with similar ancestry can metabolize drugs very differently. A pharmacogenetic test looks at your own genes rather than population averages.

Does pharmacogenetic testing guarantee that the first medication will work?

No. Genes are one of several factors, along with age, other medications, health conditions and lifestyle. Pharmacogenetic results help narrow down the options and guide dosing, so your healthcare team can make better-informed decisions.

Who reviews my Pillcheck results?

An expert pharmacist reviews your results and your current medications with you and can share recommendations with your doctor. Any change to your treatment should be made with your prescriber.

Is Pillcheck suitable for people of non-European or mixed ancestry?

Yes. The Pillcheck panel includes variants that are more common in people of non-European ancestry, to provide high accuracy for people of diverse and admixed backgrounds.

References

1. Papastergiou J, Quilty LC, Li W, et al. Pharmacogenomics guided versus standard antidepressant treatment in a community pharmacy setting: a randomized controlled trial. Clin Transl Sci. 2021;14(4):1359-1368. doi:10.1111/cts.12986
2. Papastergiou J, Tolios P, Li W, Li J. The Innovative Canadian Pharmacogenomic Screening Initiative in Community Pharmacy (ICANPIC) study. J Am Pharm Assoc. 2017;57(5):624-629. doi:10.1016/j.japh.2017.05.006
3. McInnes G, Lavertu A, Sangkuhl K, et al. Pharmacogenetics at scale: an analysis of the UK Biobank. Clin Pharmacol Ther. 2021;109(6):1528-1537. doi:10.1002/cpt.2122
4. Birdwell KA, Decker B, Barbarino JM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clin Pharmacol Ther. 2015;98(1):19-24. doi:10.1002/cpt.113