The concept of pharmacogenetics, that is, a link between genetic variations and drug response, is over 70 years old. The first paper on the topic was published in 1957 by Arno G Motulsky. Werner Kalow published the book “Pharmacogenetics. Heredity and the response to drugs” back in 1962. Since then, there has been a tremendous expansion of scientific evidence and well-established pharmacogenetic (PGx) prescribing guidelines. Despite this and the advent of affordable genetic testing, PGx is still underutilized in general clinical practice. While many psychiatrists are now familiar with this technology, other healthcare providers are reluctant to use pharmacogenetic tests to guide the prescribing of antidepressants and other medications. The most common concerns are:

1. Which PGx tests are reliable? – Discrepancies in drug recommendations between various PGx tests render these results unreliable and useless.
2. Drug dose vs drug response – There is little correlation between blood concentration in the blood and how the patient is responding to medication.
3. Cost – Clinicians are uneasy with suggesting PGx tests that may require their patients to pay hundreds of dollars out of pocket.

The discussion below will cover these issues and provide critical points for consideration.

Issue #1: Which pharmacogenetic tests are reliable?

The debate of clinical utility of PGx tests hinges on two fundamental pillars:

a. Test sensitivity. This determines whether the genetic testing panel can detect ethnic-specific mutations and accurately predict altered metabolism. The inclusion of multiple ethnic-specific mutations in the testing panel improves the test’s sensitivity but increases the costs. Hence, cheap genetic tests frequently have low sensitivity.

Reputable PGx testing providers should disclose all the tested mutations to enable clinicians to evaluate whether the genetic panel can be used in ethnically diverse populations.

b. Interpretation of test results. Evaluation of proprietary psychiatry PGx tests demonstrated low concordance of test results for the same patient group. In this evaluation, medication recommendation agreement was the greatest for mood stabilizers (84%), followed by antidepressants (56%), anxiolytics/hypnotics (56%), and antipsychotics (55%). These proprietary psychiatric tests are “Black box” decision-support tools that conceal how pharmacogenetic testing results are translated into clinical recommendations. Despite multiple clinical studies, it is not possible to say which of these tests is more “right”. The European Union’s General Data Protection Regulation requires deconvolution of black box approaches before being used in patient care, and similar legislation is likely to be introduced in Canada.

Other PGx testing providers, including Pillcheck, have adopted transparent interpretation according to the CPIC and other clinical guidelines. By choosing PGx vendors that follow open interpretation, the clinician can easily check if the drug dosing alerts conform to established guidelines.

The International Society of Psychiatric Genetics and other professionals urge clinicians to use PGx testing for guiding antidepressant prescribing based on the CYP2D6 and CYP2C19 genes. Pharmacogenetics is a companion tool, rather than a competitor, to protocol-based care.

Issue #2: Drug dose vs drug response

Indeed, the correlation between drug concentration in the blood and clinical response is far from perfect.  Many patients do not show significant improvement, even while taking high drug doses, and require treatment with multiple antidepressants and antipsychotics. Heterogeneity of mental health conditions requires clinical expertise to enable proper diagnosis and development of an appropriate treatment plan. PGx testing does not predict the perfect medication for the individual patient. Clinical trials with psychiatric PGx tests largely failed to predict which medications are most effective.
Akin to therapeutic monitoring, PGx tests can predict the rate of drug metabolism and clearance. PGx test results should alert the prescribing clinician whether a drug is cleared at a significantly reduced or accelerated rate. Poor drug metabolism is a strong but not perfect predictor of drug toxicity and intolerance. Significantly enhanced drug clearance minimizes the probability of achieving clinical response at regular doses.

The value of therapeutic drug monitoring (TDM) is well recognized. The American Society of Clinical Psychopharmacology (ASCP) and German Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie recommends TDM for antipsychotic drugs with a narrow therapeutic index. Yet, PGx tests can give clinicians insights on the anticipated rate of drug metabolism for hundreds of drugs without the need for repeated blood testing. Standardized PGx tests can inform treatment decisions and optimize safety and efficacy, while TDM is particularly useful for patients with suspected nonadherence.

Issue #3: Test costs

In Canada, most clinical diagnostic tests are covered through provincial health plans. Some blood tests such as PSA require a patient co-pay. Food sensitivity and pharmacogenetic tests are sometimes covered through private health insurance. Many working-age Canadians have coverage for the cost of medications and can use Health Spending Accounts to reimburse PGx test cost. The same payment mechanism was used for CBT. In most cases, PGx testing should only need to be done once, while the results can provide useful insights over a patient’s lifetime.

Many Canadian insurance and disability management providers already utilize PGx-testing as part of medication management programs, along with CBT and other tools. If your patient is on disability leave, s/he can ask the designated case manager to order a PGx test. Pillcheck is used by Canada Life, Morneau Shepell, Medavie Blue Cross, Alberta Blue Cross, Pacific Blue Cross and Manitoba Blue Cross. Case managers can request Pillcheck for your patient directly on the secure Pillcheck Portal. In this situation, the Case Manager’s role is simply to facilitate the test referral and fax the pharmacist’s summary to the claimant’s physician. Case managers receive access only to pharmacist’s recommendations and not the full genetic test report. The Pillcheck Portal ensures compliance with genetic non-discrimination legislation and privacy regulations.

Pharmacogenetic tests support provider-patient communications

Expert clinicians who have extensive pharmacogenetics experience note that test results frequently identify the reasons for past medication intolerability and failure. Understanding why previously prescribed drugs resulted in poor experience (and nonadherence) can help reassure patients that their experience was legitimate and gives them the confidence to try a new medication that is more compatible with their genetics.

Clinicians interested in referring their patients for PGx testing service regularly should consider taking Continuous Education courses on pharmacogenetics. The American Medical Association offers the CME online course ASHP-AMA Pharmacogenomics Virtual Summit Series. The University of Florida also offers a collection of courses, including implementation guides for hospitals.

Primary care physicians can start utilizing pharmacogenetic testing with support from PGx testing providers. Some providers require the use of special software to interpret test results to account for drug-gene-interactions and other clinical factors. The Pillcheck service includes a medication review by a clinical pharmacist who will assess the patient’s medications in the context of his/her drug metabolic profile. A summary will be shared with the referring clinician and the patient. For Pillcheck medication reviews, we partner with the Northwest Telepharmacy group that employs clinical pharmacists across Canada.

Referring clinicians can contact the consulting pharmacist directly to seek additional clarifications – each Pillcheck Pharmacist Letter includes license number, phone number and email.

Summary

• Pharmacogenetic tests are a useful supporting clinical tool that provides insights on anticipated drug metabolism and reduce the risk of side effects.
• PGx testing is particularly useful for drugs with a narrow therapeutic index and patients with a history of poor drug tolerability
• Pillcheck adheres to established CPIC guidelines and drug labels, providing a standardized and transparent interpretation of genetic variations.
• The Pillcheck genetic panel is designed to ensure high sensitivity in an ethnically diverse population.
• Insurance providers may cover the cost of personalized medication management as part of disability care.
• PGx tests can also be reimbursed through workplace benefits
• Medication reviews by clinical pharmacists save clinicians time on the interpretation of pharmacogenetic test results.

If you are interested in referring your patients to Pillcheck, please contact us at [email protected] or 1-877-409-3629.

References

Chad A. Bousman and Boadie W. Dunlop Genotype, phenotype, and medication recommendation agreement among commercial pharmacogenetic-based decision support tools Pharmacogenomics J. 2018 Sep;18(5):613-622.

Chad A. Bousman and Harris A. Eyre “Black box” pharmacogenetic decision-support tools in psychiatry Braz J Psychiatry. 2020 Mar-Apr; 42(2): 113–115.

International Society of Psychiatric Genetics. Genetic Testing Statement. https://ispg.net/genetic-testing-statement

Bousman CA et al., Encountering Pharmacogenetic Test Results in the Psychiatric Clinic Can J Psychiatry . 2022 Feb;67(2):95-100.