Beyond Trial and Error: A Nurse Practitioner's Perspective on Pharmacogenetic Testing
Written by: Emma Winson MScN, Nurse Practitioner
Have you ever heard someone say, "Ibuprofen does not work for me, I can only take naproxen"?
We readily accept that two people can have very different experiences with the same medication. So why are we surprised when the same thing happens with antidepressants?
Maybe your anxiety improved, but your libido disappeared.
Maybe your OCD improved, but you gained 30 pounds.
Maybe you took your antidepressant, experienced all of the side effects, and seemingly none of the effect.
As a prescriber, I do not think effective mental health treatment should require simply accepting intolerable side effects when other reasonable options may exist.
If you have ever wondered why a medication seemed to work beautifully for someone else but poorly for you, you are asking an excellent question. There are many possible reasons, and one of them may be how your body metabolizes that medication.
Have you heard of pharmacogenetic testing? It is often called PGx testing.
Pharmacogenetic testing looks at genetic variations that can influence how an individual responds to certain medications. Some of the best-established examples involve drug-metabolizing enzymes such as CYP2D6, CYP2C19 and CYP2B6. Genetic differences affecting these enzymes can sometimes influence medication exposure and, depending on the medication, may contribute to differences in dosing, effectiveness, or tolerability [1].
People can have normal, increased, decreased or little functional activity of particular drug-metabolizing enzymes. Importantly, not every gene included on every commercial PGx panel has the same level of clinical evidence behind it. For example, current guidance supports using certain results to help inform prescribing for several antidepressants, while evidence for some other commonly tested pharmacodynamic genes is not sufficient to support their routine use in antidepressant prescribing [1, 2].
In other words, PGx is useful information, but it is not a crystal ball.
It cannot predict with certainty which medication will work for you. What it can do is provide another piece of information that may help with medication selection, dosing decisions, or identifying medications that deserve additional consideration because of a particular gene-drug interaction.
When I was first introduced to PGx more than a decade ago, I was working as a Primary Care Provider treating anxiety, depression, PTSD, ADHD, insomnia, and other mental health concerns.
At the time, PGx testing was generally presented to me as something to consider after a patient had already experienced multiple medication failures. That made intuitive sense. If someone had tried several antidepressants unsuccessfully, perhaps genetic information could help us better understand what had happened and inform what we tried next.
Access was also more difficult. Testing was expensive for many patients, coverage was limited, and the options available to me generally required a requisition from a Nurse Practitioner or Physician.
I viewed it as a specialized tool for particularly complicated situations.
My perspective has changed considerably.
As PGx testing became more accessible, I had more opportunities to review reports and then follow patients through subsequent treatment. After reviewing well over one hundred PGx reports in clinical practice, I have learned to appreciate that the information could be useful earlier in the treatment journey as well.
A PGx result has to be interpreted in context. Diagnosis, symptoms, previous treatment response, side effects, concurrent medications, drug interactions, medical conditions, family history, patient priorities, cost, and other clinical factors still matter.
PGx simply adds another data point.
There is also a growing body of research evaluating whether PGx-guided antidepressant prescribing improves clinical outcomes. Several systematic reviews and meta-analyses have found modest improvements in response or remission among adults with major depressive disorder receiving PGx-guided treatment compared with usual care. At the same time, results have varied among studies and among different testing panels [3,4].
I use PGx testing as one tool when I am considering medications that have clinically relevant pharmacogenetic information. Much of my experience has been in mental health, but actionable gene-drug relationships also exist for medications used in areas such as pain management and cardiovascular care.
What I am trying to reduce is avoidable trial and error.
Patients sometimes hear me refer to "medication roulette." I do not mean that clinicians are literally choosing medications randomly. Evidence-based prescribing considers a long list of important factors. The problem is that even when we make a thoughtful choice, we cannot perfectly predict how an individual patient will respond.
That uncertainty matters to the person taking the medication.
This is your ability to get out of bed, work, parent their children, maintain relationships, think clearly, sleep, have sex and enjoy their life.
Each unsuccessful trial may mean several more weeks of persistent symptoms, adverse effects, dose adjustments, tapering, switching, and then waiting again to see what happens.
People can also become discouraged very quickly!
I have cared for patients who avoided medical treatment of their mental health for years, finally gathered the courage to try medication, experienced unexpected side effects or little benefit, and became extremely reluctant to try another one.
For an anxious patient, one difficult experience can reinforce exactly what they were afraid of in the first place.
Sometimes I feel as though I have one opportunity to establish enough trust for that person to be willing to try again.
I want to choose thoughtfully.
One patient case has stayed with me over the years.
A patient I cared for had previously tried more than five antidepressants. The medication they were taking when I met them was contributing to weight gain and brain fog, as well as the dreaded brain zaps when a dose was even slightly delayed, while providing relatively little improvement in her depression.
Her PGx report identified several gene-drug considerations that were relevant to medications she had previously taken and failed. It also highlighted a couple options that were more likely to be compatible with her drug metabolsm.
We reviewed the results alongside her treatment history, symptoms, other medications, preferences and the usual clinical considerations involved in selecting an antidepressant.
The first medication we selected after that review was well tolerated and clinically helpful for her.
That was one patient's experience. It does not mean another person with the same report will have the same outcome, and it does not establish that PGx was the sole reason the medication worked. Ancedotally, I will say, this story repeats itself frequently in my practice.
What these experiences show me is how valuable it can be to have another objective piece of information available while making a complicated treatment decision.
Another benefit I have seen clinically is validation.
Patients with long and complicated medication histories sometimes begin questioning their own experiences. They may wonder whether a medication really caused the side effect they noticed, whether they somehow "failed" treatment, or whether their body simply reacts differently from everyone else's.
Sometimes a PGx result provides useful context for an unexpected medication response.
I no longer think PGx should only enter the conversation after someone has accumulated a long list of unsuccessful medication trials.
For someone starting an antidepressant for the first time, it may be reasonable to discuss whether testing would provide useful information before treatment begins. For another patient, proceeding directly with standard evidence-based treatment may make much more sense. In cases where we do not have PGx testing results to reference, I opt towards prescribing mental health treatments that generally skirt metabolic differences; medications that repeatedly emerge as reasonable choices across a range of metabolic profiles.
That decision should be individualized too.
Helping someone arrive at an effective, tolerable treatment sooner may have a meaningful impact for their ability to function and work, and that this is one reason PGx has attracted attention from employers and insurers. There has also been interest in PGx from Canadian insurers and disability programs. Sun Life uses pharmacogenomic testing within disability management and has described the potential for earlier testing to support faster recovery and return to work. Manulife has similarly incorporated pharmacogenetic testing into benefits programming and has reported potential reductions in absenteeism and disability duration based on its program experience. [5,6]
I want you feeling better... yesterday!
I look for every useful piece of information available so that my patients and I can make the most informed decision we can together.
If you are considering PGx testing, look beyond the colourful report.
Find out which genes and medications are included. Ask how the company's recommendations are developed. Review its privacy and data-retention practices. Ask whether the report distinguishes between gene-drug relationships supported by established clinical guidelines and findings for which evidence is more limited.
If you do not have a healthcare provider comfortable interpreting PGx results, find out whether qualified clinical interpretation is available by the company offering the testing.
Cost and insurance coverage also vary. Check directly with your insurer to determine whether PGx testing is included under your plan, health spending account, wellness benefit or another category of coverage. Testing providers may also have different financial-assistance policies.
Most importantly, understand what the test cannot do: Pharmacogenetic testing cannot guarantee which medication will work. It cannot account for every factor influencing medication response. It cannot replace a comprehensive clinical assessment with your super awesome Nurse Practitioner. And it cannot replace thoughtful follow-up with a healthcare provider. PGx testing one component of personalized medicine.
Medicine evolves, our understanding evolves, and as healthcare providers we have a responsibility to evolve with it.
When it comes to treating anxiety, depression, ADHD, and other conditions that profoundly affect quality of life, every helpful piece of information matters. When clinically relevant genetic information can add something useful to a medication decision, I think it is worth talking about.
PGx testing may provide a map on a complicated journey. Use every tool you can find with a mental health provider who puts your time, goals, and best health first.
This blog is for general educational purposes only. Pharmacogenetic testing has important limitations and does not predict or guarantee an individual's response to medication. Test results should be interpreted alongside an individualized clinical assessment, medication history, concurrent medications, medical conditions, and other relevant factors by a qualified healthcare provider.
References
Bousman CA, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. Clinical Pharmacology & Therapeutics. 2023;114(1):51-68. doi:10.1002/cpt.2903. This is particularly useful because it supports the metabolism discussion while also explicitly identifying limits of some commonly tested genes. https://pmc.ncbi.nlm.nih.gov/articles/PMC10564324/
Lam RW, Kennedy SH, Adams C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults. Canadian Journal of Psychiatry. 2024;69(9):641-687. doi:10.1177/07067437241245384. https://journals.sagepub.com/doi/10.1177/07067437241245384
Brown LC, et al. Pharmacogenomic Testing and Depressive Symptom Remission: A Systematic Review and Meta-Analysis of Prospective, Controlled Clinical Trials. Clinical Pharmacology & Therapeutics. 2022;112(6):1303-1317. doi:10.1002/cpt.2748. The analysis found a modest improvement in remission overall while also identifying heterogeneity among tests and studies. https://pmc.ncbi.nlm.nih.gov/articles/PMC9827897/
Canadian Agency for Drugs and Technologies in Health. Pharmacogenomic Testing in Depression: A 2021 Update. CADTH, 2022. This is worth including precisely because it is more cautious than some of the later meta-analyses, finding mixed evidence and important study limitations. https://www.ncbi.nlm.nih.gov/books/NBK595363/
Sun Life. From Pilot to Launch: Closing the Gaps Around Access to Mental Health Care. Sun Life reported that earlier PGx testing in its disability pilot was associated with faster return to work and shorter claims, while its more recent materials continue to describe PGx as part of its strategy for supporting recovery and return to work.https://www.sunlife.ca/content/dam/sunlife/regional/canada/documents/gb/from-pilot-to-launch-oh9004.pdf
Manulife. Personalized Medicine for Better Care. Manulife describes its pharmacogenetic program as having the potential to reduce trial and error, absenteeism and disability duration based on its pilot experience. https://www.manulife.ca/business/news/group-benefits-news/personalized-medicine.html
