Pharmacogenetic Testing Options Relevant to Psychiatry in Canada: Options de tests pharmacogénétiques pertinents en psychiatrie au Canada

Abdullah Al Maruf; Mikayla Fan; Paul D Arnold; Daniel J Müller; Katherine J Aitchison; Chad A Bousman

doi:10.1177/0706743720904820

. 2020 Feb 17;65(8):521–530. doi: 10.1177/0706743720904820

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Pharmacogenetic Testing Options Relevant to Psychiatry in Canada: Options de tests pharmacogénétiques pertinents en psychiatrie au Canada

Abdullah Al Maruf ^1,², Mikayla Fan ³, Paul D Arnold ^1,^2,⁴, Daniel J Müller ^5,⁶, Katherine J Aitchison ^7,⁸, Chad A Bousman ^1,^2,^4,^9,^10,^✉

PMCID: PMC7492886 PMID: 32064906

Abstract

Objective:

To identify and assess pharmacogenetic testing options relevant to psychiatry in Canada.

Method:

Searches of published literature, websites, and Standard Council of Canada’s Laboratory Directory were conducted to identify pharmacogenetic tests available in Canada. Identified tests were assessed on 8 key questions related to analytical validity, accessibility, test ordering, delivery of test results, turnaround time, cost, clinical trial evidence, and gene/allele content.

Results:

A total of 13 pharmacogenetic tests relevant to psychiatry in Canada were identified. All tests were highly accessible, and most were conducted in accredited laboratories. Both direct-to-consumer and clinician-gated testing were identified, with turnaround times and cost ranging from 2 to 40 days and CAD$199 to CAD$2310, respectively. Two tests were supported by randomized controlled trials. All tests met minimum gene and allele panel recommendations for psychiatry, but no 2 panels were identical. No test was unequivocally superior to all other tests.

Conclusions:

Pharmacogenetic testing in Canada is readily available but highly variable in terms of ordering procedures, delivery of results, turnaround times, cost, and gene/allele content. As such, it is important for psychiatrists and other health-care providers to understand the differences between the available tests to ensure appropriate selection and implementation within their practice.

Keywords: pharmacogenetic testing, implementation, antidepressant testing tools, psychiatry, Canada

Introduction

Pharmacogenetics is the study of how genetic variation affects response to pharmacologically active agents (e.g., medications). Aligned with the aims of precision health, pharmacogenetics provides an approach for addressing variability in drug efficacy and tolerability via identification and tailoring of treatment for an individual based on their genetic information. Globally, pharmacogenetic testing is now being routinely implemented in a growing number of medical centers and health systems,^1,2 and numerous commercial laboratories are offering clinical pharmacogenetic testing.^3,4 In Canada, institutions such as the Hospital for Sick Children, BC Children’s Hospital, University of Montreal, Western University, the Centre for Addictions and Mental Health,⁵ and the Universities of Calgary and Alberta have research programs that offer pharmacogenetic testing. However, these research programs are limited to individuals with specific medical conditions or taking specific medications and are not equipped to offer pharmacogenetic testing at the population level. As such, several Canadian clinical laboratories as well as community-based pharmacies in collaboration with pharmacogenetic testing companies are providing pharmacogenetic testing services that are available to the entire population.⁶

Despite these early examples of pharmacogenetic testing implementation, the majority of clinicians have yet to use this testing in their practice. It has been estimated that only 6% of U.S. psychiatrists reported ordering a pharmacogenetic test in the past 6 months,⁷ a percentage that is presumably similar or perhaps less among Canadian psychiatrists. The reasons for this modest adoption of pharmacogenetic testing varies among psychiatrists, but broadly speaking, there are 2 main groups: (1) those who have heard or read that testing in psychiatry is not ready for “primetime” and (2) those who would like to incorporate testing into their practice but are unsure what options are available and which of these options are most suitable for their practice. For those in the former group, we refer you to recent evaluations of pharmacogenetic testing in psychiatry^8,9 and also encourage you to review the pharmacogenetic-based prescribing guidelines relevant to psychiatry.^10–15 Herein, we have focused our attention on assisting the latter group of psychiatrists as well as other providers (e.g., primary care physicians, pharmacists) of mental health care. Specifically, we have identified and critically evaluated pharmacogenetic testing options available in Canada and relevant to prescribing in psychiatry. We paid particular attention to the most frequently expressed concerns from clinicians about pharmacogenetic testing such as test ordering, delivery and interpretation of results, test content, turnaround time, and cost.

Methods

Pharmacogenetic Test Identification

Pharmacogenetic tests were identified following a 4-step process. In Step 1, we searched Google, Google Scholar, Medline, Embase, and PsychINFO up to May 30, 2019, using the search terms: pharmacogenetic, pharmacogenomics, gene, genetic, test, commercial, tool, psychiatry, mental health, medication, dose, Canadian, and Canada with no language restrictions. We also searched the Standard Council of Canada’s Laboratory Directory using the terms: pharmacogenetic, pharmacogenomic, gene, and genetic. In Step 2, identified tests were screened to determine whether they could be ordered by someone residing in Canada, either via a health care provider or direct-to-consumer. In Step 3, tests were further assessed for their relevance to psychiatry. A test was retained if it included at least 1 gene that, according to the Pharmacogenomics Knowledgebase (PharmGKB),¹⁶ had evidence suggesting an association with response to medications prescribed in psychiatry. In Step 4, we collected or obtained the gene/allele panels, laboratory certifications, retail prices, and turnaround times for each test from the manufacturers’ websites. In cases where information was not publicly available, we requested the missing information directly from the manufacturer. If after 2 attempts to contact a manufacturer, information related to gene content was not provided, we excluded their test from further analysis.

Evaluation of Pharmacogenetic Tests

For each of the tests with adequate information available, we asked 8 critical questions aligned with our recently proposed pharmacogenetic test selection guideline for clinicians¹⁷: (1) Is the testing performed in a laboratory with Clinical Laboratory Improvement Amendments (CLIA) certification, College of American Pathologists (CAP) accreditation or equivalent? (2) Is the test available in all provinces and territories? (3) Can patients order the test without the involvement of a health-care provider? (4) Are testing results delivered directly to patients? (5) How long does it take to receive the test results (turnaround time)? (6) How much does the testing cost? (7) Is there randomized controlled trial (RCT) evidence supporting clinical use? and (8) Does the test panel include the minimum recommended gene/variant content for psychiatry?¹⁸

The first 6 questions were answered using information found on the manufacturers’ websites or via direct correspondence with the manufacturers. Question 7 was addressed by searching the published literature, and to answer Question 8, gene and allele content from each of the selected tests were compared to the minimum recommended gene and allele panel for psychiatry.¹⁸ The minimum panel consists of 16 alleles within 5 genes (CYP2C9, CYP2C19, CYP2D6, HLA-A, HLA-B) that are linked to pharmacogenetic-based prescribing guidelines for antidepressants (i.e., amitriptyline, citalopram, clomipramine, desipramine, doxepin, escitalopram, imipramine, fluvoxamine, nortriptyline, paroxetine, sertraline, trimipramine, venlafaxine),^10,11 antipsychotics (i.e., aripiprazole, haloperidol, zuclopenthixol),¹³ anticonvulsants (i.e., carbamazepine, oxcarbazepine, phenytoin),^14,15 or the attention-deficit hyperactivity disorder (ADHD) medication, atomoxetine.¹² Genes tested that were not part of the minimum recommended panel were assessed separately using PharmGKB¹⁶ and the Clinical Pharmacogenetics Implementation Consortium (CPIC)¹⁹ to determine what evidence (e.g., guidelines, drug labels) was available to support the testing of these genes in psychiatry and general clinical practice.

Results

Our search identified 13 pharmacogenetic tests relevant to psychiatry that were available in Canada as of May 30, 2019 (Table 1). Comparisons of each test on the 8 key testing selection questions are summarized in Table 2. Nine (69%) of the tests were performed in a CLIA-certified or CAP-accredited laboratory, 2 (15%) had pending applications, and the status of another 2 (15%) could not be determined. All tests were available in all provinces and territories. Five (38%) of the tests could be ordered by and the results delivered directly to patients without the involvement of a health-care provider. Among the 8 tests requiring involvement of a health-care provider for ordering, only 1 provided the test results directly to patients without consultation from a health-care provider. The time from receipt of a patient’s sample by the testing laboratory to the final reporting of results ranged from 2 to 40 business days and the retail cost for each test ranged from CA$199 to CA$2310 (median = CA$499). Only 2 of the tests assessed had peer-reviewed RCT results supporting their use in clinical practice.

Table 1.

Pharmacogenetic Tests Relevant to Medications Prescribed in Psychiatry Available in Canada.

Test Name	Test Provider (Location)	Manufacturer (Location)	Lab Name (Location)	Genes Included
BiogeniQ Kit: All Pharma Profiles	BiogeniQ Inc. (Brossard, Canada)	BiogeniQ Inc. (Brossard, Canada)	BiogeniQ Inc. (Brossard, Canada)	CESI, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, LPHN3, OPMR1, POR, SLCO1B1, TH, VKORC1
Color Extended	Color Genomics (Burlingame, USA)	Color Genomics (Burlingame, USA)	Color Genomics (Burlingame, USA)	CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, CYP4F2, DPYD, F5, IFNL3, NUDT15, SLCO1B1, TPMT, VKORC1
Genecept® Assay	Dynacare (Brampton, Canada)	Genomind (King of Prussia, USA)	Genomind (King of Prussia, USA)	ABCB1, ADRA2A, ANK3, BDNF, CACNA1C, COMT, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, DRD2, GRIK1, HLA-A,HLA-B, HTR2A, HTR2C, MC4 R, MTHFR, OPRM1, SLC6A4, UGT1A4, UGT2B15
GeneSight® Psychotropic Test	Assurex Health, Inc., a subsidiary of Myriad Genetics, Inc. (Salt Lake City, USA)	Assurex Health, Inc., a subsidiary of Myriad Genetics, Inc. (Salt Lake City, USA)	Assurex Health Inc. (Mason, USA)	CYP1A2, CYP2C9, CYP2C19, CYP2B6, CYP3A4, CYP2D6, HLA-A, HLA-B, HTR2A, OPRM1, SLC6A4, UGT1A4, UGT2B15
MatchMyMeds™ Drug Compatibility Test	DNALabs Canada Inc. (Toronto, Canada)	DNALabs Canada Inc. (Toronto, Canada)	DNA Labs Canada (Toronto, Canada)	CYP2C19, CYP2C9, CYP2D6, CYP3A5, F5, SLCO1B1, VKORC1
myDNA Medication Test Kit (Multi)	RxOME Pharmacogenomics Canada Inc. (Vancouver, Canada)	MyDNA Inc. (South Yarra, Australia)	MyDNA/Australian Clinical Labs (South Yarra, Australia)	CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, OPRM1, SLCO1B1, VKORC1
Neuropharmagen® Core	InSource Diagnostics (Monrovia, USA)	AB Biotics (Barcelona, Spain)	InSource Diagnostics (Monrovia, USA)	ABCB1, AKT1, AL157359, BDNF, CES1, COMT, CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, DDIT4, EPHX1, FCHSD1, GRIK2, GRIK4, HLA-A, HTR2A, HTR2C, LPHN3, OPRM1, RPTOR, SLC6A4, UGT2B15
Pharmacogenetic Testing Service	PurePharm Inc./Central Medical Pharmacy (Toronto, Ontario)	PurePharm Inc./Central Medical Pharmacy (Toronto, Ontario)	Not Known	CYP2D6, CYP2C19, CYP2C9
Pharmacogenomic (Pharmacogenetic) Test	Institute for Genomics and Molecular Diagnostics - CEN4GEN® (Edmonton, Canada)	Institute for Genomics and Molecular Diagnostics - CEN4GEN® (Edmonton, Canada)	Not Known	Not Known
Pillcheck™	GeneYouIn Inc. (Toronto, Canada)	GeneYouIn Inc. (Toronto, Canada)	Dynacare (Laval, Canada)	ADRB2, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, DYPD, F2, F5, IFNL3, NUDT15, OPRM1, SLCO1B1, TPMT, UGT1A1, VKORC1
RightMed® Pharmacogenetic Test / Personamed®	ProZed Pharmacy Solutions (North Bay, Canada) and Apollo Clinical Pharmacy (Edmonton, Canada)	OneOme, LLC (Minneapolis, USA)	OneOme, LLC (Minneapolis, USA)	COMT, CYP1A2, CYP2B6, CYP2C cluster, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP4F2, DPYD, DRD2, F2, F5, GRIK4, HLA-A, HLA-B, HTR2C, HTR2A, IFNL4, NUDT15, OPRM1, SLC6A4, SLCO1B1, TPMT, UGT1A1, VKORC1
RxReport™: General Drugs Test	Personalized Prescribing Inc. (Toronto, Canada)	Personalized Prescribing Inc. (Toronto, Canada)	BiogeniQ (Brossard, Canada)	ABCB1, ADRA2A, ADRB1, ADRB2, APOE, BDNF, CACNA1C, CNR1, CNRNB2, COMT, CSMD1, COQ2, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, DRD2, DRD4, F5, FAAH, FKBP5, GNB3, GRIA1, GRIK4, HLA-B, HSPG2, HTR1A, HTR1B, HTR2A, HTR2C, MC4 R, MTHFR, NEDD4 L, OPRD1, OPRM1, POLG, PRKCA, RGS4, SACM1 L, SCN1A, SCN2A, SLCO1B1, SLC6A2, SLC6A4, TPH1, TPH2, TPMT, UGT1A4, UGT2B15, VKORC1, YEATS4, ZNF804A
TreatGx^Plus	GenXys Health Care Systems (Vancouver, Canada)	GenXys Health Care Systems (Vancouver, Canada)	LifeLabs Genetics (Etobicoke, Canada)	ABCG2, ADD1, ADRB2, ANKK1, COX1(PTGS1), CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP2A6, CYP3A5, DYPD, F2, F5, FKBP5, GNB3, GRIK4, HLA-A, HLA-B, HTR2A, HTR2C, IFNL3, KCNIP4, MC4R, MT-RNR1, NUDT15, OPRM1, PRKCA, SLCO1B1, TCF7L2, TNF, TPMT, VKORC1, YEATS4

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Note. 23andMe’s recently announced pharmacogenetic test was not included in this review because it was not available in Canada as of May 30, 2019. Underlined genes have an actionable guideline and/or an actionable drug label relevant to psychiatric medications.

Table 2.

Comparison of Pharmacogenetic Testing Available in Canada on Key Test Selection Questions.

Test Name [Test Provider]	Is Test Performed in a CLIA/CAP (Equivalent)-certified Lab?	Is the Test Available in All Provinces and Territories?	Can Patients Order the Test without a HCP?	Are Results Delivered Directly to Patients?	Turnaround Time (Business Days)	Cost^a	Is there RCT Evidence Supporting Clinical Use?	Does Test Include Minimum Recommended Gene/alleles in Psychiatry?^b
BiogeniQ Kit - All Pharma Profiles [BiogeniQ Inc.]	Pending	Yes	Yes	Yes	5 to 10 days	CA$485	No	No
Color Extended [Color Genomics]	Yes	Yes	Yes	Yes	∼20 days for 2D6/2C19 (others within 6 months)	US$317	No	No
Genecept® Assay [Dynacare]	Yes	Yes	No	No	6 to 8 days	CA$495	No^c	Yes
GeneSight® Psychotropic Test [Assurex Health, Inc.]	Yes	Yes	No	No	2 days	US$1750	Yes	Yes
MatchMyMeds™ Drug Compatibility Test [DNA Canada Labs Inc.]	Yes	Yes	Yes	Yes	10 days	CA$399	No	No
myDNA Medication Test Kit (Multi) [RxOME Pharmacogenomics Canada Inc.]	Yes	Yes	No	No	10 to 15 days	CA$199	No	No
Neuropharmagen® Core [InSource Diagnostics]	Yes	Yes	No	No	5 days	US$400	Yes	No
Pharmacogenetic Testing Service [PurePharm Inc.]	Uncertain	Yes	No	No	5 days	CA$899	No	Uncertain
Pharmacogenomic (Pharmacogenetic) Testing [CEN4GEN]	Uncertain	Yes	No	No	20 to 40 days	CA$840	No	Uncertain
Pillcheck™ [GeneYouIn Inc.]	Yes	Yes	Yes	Yes	5 to 15 days	CA$499	No	No
RightMed® Pharmacogenetic Test [OneOme, LLC]	Yes	Yes	No	No	10 to 15 days	US$349	No	Yes
RxReport™ – General Drugs Test [Personalized Prescribing Inc.]	Pending	Yes	Yes	Yes	7 to 10 days	CA$499	No	No
TreatGxPlus [GenXys Health Care Systems]	Yes	Yes	No	Yes	7 to 10 days	CA$499	No	Yes

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^a Prices may not include applicable taxes or shipping. CLIA, Clinical Laboratory Improvement Amendments; CAP, College of American Pathologists; HCP, Health care provider; RCT, randomized controlled trial.

^b Minimum psychiatry gene/allele panel includes CYP2C9 (*2, *3), CYP2C19 (*2, *3, *17), CYP2D6 (*3, *4, *5, *6, *10, *17, *41, *1xN, *2xN), HLA-A (*31:01), HLA-B (*15:02).

^c This test does not have RCT evidence but was supported by an unblinded prospective trial.

Evaluation of the gene content across test manufacturers showed that testing panels included between 3 and 55 genes, with a total of 87 genes represented on 1 or more of the panels. Among these 87 genes, 17% (n = 15) were associated with an actionable guideline or drug label, but only 7% (n = 6: CYP2C9, CYP2C19, CYP2D6, HLA-A, HLA-B, and POLG) were associated with a psychiatric medication (Figure 1). More than half (61%, n = 53) of the genes, however, were assigned CPIC Levels A or B (prescribing action recommended) or PharmGKB Level 1 or 2 (moderate-high evidence), but only 40% (n = 21) of these genes were relevant to psychiatry (Table S1). Furthermore, only 4 (33%) test panels included all of the minimum recommended genes and alleles relevant to psychiatry although all tests met recommendations for CYP2C19, CYP2C9, and CYP2D6 (Figure 2A). That said, examination of the full CYP2C19, CYP2C9, and CYP2D6 allele content across tests showed notable variation in the alleles beyond the minimum recommended panel (Figure 2B to D and Table S2). Additionally, the HLA-A*31:01 and HLA-B*15:02 alleles were only included by 6 of the identified tests, and only 4 tests included both.

Figure 1. — Genes included on pharmacogenetic testing panels in Canada. Gray = no actionable guidelines or drug labels for the gene. Black = presence of an actionable guideline or drug label for the gene in relation to a psychiatric medication only. White = presence of an actionable guideline or drug label for the gene in relation to a nonpsychiatric medication only. Striped = presence of an actionable guideline or drug label for the gene in relation to both psychiatric and nonpsychiatric medications. *ABCB1* = ATP-binding cassette, subfamily B, member 1; *ABCC1* = ATP-binding cassette, subfamily C, member 1; *ABCG2* = ATP-binding cassette, superfamily G, member 2; *ADD1* = aryloxyalkanoate dioxygenase 1; *ADRA2A* = adrenoceptor alpha 2A; *ADRB1* = adrenoceptor Beta 1; *ADRB2* = adrenoceptor Beta 2; *AKT1* = v-akt murine thymoma viral oncogene homolog 1; *ALI157359 =* long intervening non-coding RNA region AL157359; *ANK3* = ankyrin 3; *ANKK1* = ankyrin repeat and kinase domain containing 1; *APOE* = apolipoprotein E; *BDNF* = brain-derived neurotrophic factor; *CACNA1C* = calcium channel, voltage-dependent, L type, alpha 1C subunit; *CACNA1C* = calcium voltage-gated channel subunit alpha 1; *CESI* = carboxylesterase 1; *CHRNB2* = cholinergic receptor nicotinic beta 2 subunit; *CNR1* = cannabinoid receptor 1; *COMT* = catechol-O-methyltransferase; *COQ2* = coenzyme Q2; *COX1* = cytochrome c oxidase I; *CSMD1* = CUB and sushi multiple domains 1; *CYP1A2* = cytochrome P450, family 1, subfamily A, polypeptide 2; *CYP1A6* = cytochrome P450, family 1, subfamily A, polypeptide 6; *CYP2B6* = cytochrome P450, family 2, subfamily B, polypeptide 6; *CYP2C8* = cytochrome P450, family 2, subfamily C, polypeptide 8; *CYP2C9* = cytochrome P450, family 2, subfamily C, polypeptide 9; *CYP2C19* = cytochrome P450, family 2, subfamily C, polypeptide 19; *CYP2D6* = cytochrome P450, family 2, subfamily D, polypeptide 6; *CYP3A4* = cytochrome P450, family 3, subfamily A, polypeptide 4; *CYP3A5* = cytochrome P450, family 3, subfamily A, polypeptide 5; *CYP4F2* = cytochrome P450, family 4, subfamily F, member 2; *DDIT4* = DNA-damage-inducible transcript 4; *DPYD* = dihydropyrimidine dehydrogenase; *DRD2* = dopamine receptor D2; *DRD3* = dopamine receptor D3; *DRD4* = dopamine receptor D4; *EPHX1* = epoxide hydrolase 1; F2 = coagulation factor II; *F5 =* coagulation factor V; *FAAH =* fatty acid amide hydrolase; *FCHSD1* = FCH and double SH3 domains 1; *GNB3* = Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3; *GRIA1* = glutamate ionotropic receptor, AMPA type, subunit 1; *GRIK1* = glutamate ionotropic receptor, kainate type, subunit 1; *GRIK2* = glutamate ionotropic receptor, kainate type, subunit 2; *GRIK4* = glutamate ionotropic receptor, kainate type, subunit 2; *HLA-A* = major histocompatibility complex, class I, A; *HLA-B* = major histocompatibility complex, class I, B; HSPG2 = heparan sulfate proteoglycan 2; *HTR1A* = 5-hydroxytryptamine receptor 1A; *HTR1B* = 5-hydroxytryptamine receptor 1B; *HTR2A* = serotonin receptor 2A; *HTR2C* = serotonin receptor 2C; *IFNL3* = interferon, lambda 3; *KCNIP4 =* potassium voltage-gated channel interacting protein 4; *LPHN3* = latrophilin 3; *MC4R* = melanocortin-4-receptor gene; *MTHFR* = methylenetetrahydrofolate reductase; *MT-RNR1* = mitochondrially encoded 12S ribosomal RNA; *NEFM* = neurofilament medium; *NEDD4L* = NEDD4 like E3 ubiquitin protein ligase; *NUDT15* = nudix hydrolase 15; *OPRD1* = opioid receptor, delta 1; *OPRM1* = opioid receptor, mu 1; *PRKCA* = protein kinase C alpha; *POLG* = DNA polymerase gamma; *POR* = cytochrome P450 oxidoreductase; *RGS4* = regulator of G Protein signaling 4; *RPTOR* = regulatory associated protein of MTOR, complex 1; *SACM1L* = SAC1 like phosphatidylinositide phosphatase; *SCN1A* = sodium voltage-gated channel, alpha subunit 1; *SCN2A* = sodium voltage-gated channel alpha subunit 2; *SLC6A2* = solute carrier family 6, member 2 (serotonin transporter); *SLC6A4*, solute carrier family 6, member 4 (serotonin transporter); *SLCO1B1* = solute carrier organic anion transporter family, member 1B1; *TCF7L2* = transcription factor 7 like 2; *TNF* = tumor necrosis factor; TH = tyrosine hydroxylase; *TPH1* = tryptophan hydroxylase 1; *TPH2* = tryptophan hydroxylase 2; *TPMT* = thiopurine S-methyltransferase; *UGT1A1* = UDP glucuronosyltransferase 1 family, polypeptide A1; *UGT1A4* = UDP glucuronosyltransferase 1 family, polypeptide A4; *UGT2B15* = UDP glucuronosyltransferase 2 family, polypeptide B15; *VKORC1* = vitamin K epoxide reductase complex, subunit 1; *YEATS4* = YEATS domain containing 4; *ZNF804A* = zinc finger protein 804A.

Figure 2. — Summary of (A) minimum psychiatry panel, (B) *CYP2C19*, (C) *CYP2C9*, and (D) *CYP2D6* allelic coverage among the tests evaluated. Total number of tests included was 11. Tests offered by CEN4GEN and PurePharm were excluded because the alleles tested were not made available upon request. Dup = duplication.

Discussion

Our results suggest that pharmacogenetic testing in Canada is readily available but highly variable in terms of ordering procedures, results delivery, turnaround times, cost, and gene/allele content. Our results did not unequivocally point to a single test being superior to all other tests and as such, it is important for psychiatrists and other health-care providers to understand the differences between the available tests to ensure appropriate selection and implementation within their practice.

Aligned with our previously published decision tree for the selection of pharmacogenetic tests,¹⁷ one of the first criteria to consider is whether the test is performed in a regulated clinical laboratory with high-quality standards. We found that most tests are performed in a CLIA-certified or CAP-accredited (or equivalent independent third party) laboratory, which reasonably ensures a high level of analytical validity. However, we were unable to verify the accreditation status of 2 laboratories (PurePharm Inc. and CEN4GEN) and another laboratory (BiogeniQ Inc.) that provided testing for 2 independent manufacturers had a pending accreditation. Importantly, accreditation does not guarantee high clinical utility as this will depend largely on the context in which the test is being implemented. Although an evaluation of clinical utility is beyond the scope of this review, expert groups such as the International Society of Psychiatric Genetics have stated the current evidence suggests pharmacogenetic testing “would likely be most beneficial for individuals who have experienced an inadequate response or adverse reaction to a previous antidepressant or antipsychotic trial.”²⁰

Assuming the laboratory is accredited, the next step is to determine whether a test includes the necessary genes to assist in guiding the selection and dosing of medications you commonly prescribe. In the case of psychiatry, this typically includes antidepressants, antipsychotics, anxiolytics, anticonvulsants (mood stabilizers), and ADHD medications. To date, there are no pharmacogenetic-based prescribing guidelines for anxiolytics, but the FDA drug labels for clobazam and diazepam implicate CYP2C19 genetic variation in the clearance of both drugs. On the other hand, there are prescribing guidelines associated with 13 antidepressants (i.e., amitriptyline, citalopram, clomipramine, desipramine, doxepin, escitalopram, fluvoxamine, imipramine, nortriptyline, paroxetine, sertraline, trimipramine, and venlafaxine), 4 antipsychotics (i.e., aripiprazole, haloperidol, pimozide, and zuclopenthixol), 3 anticonvulsants (i.e., carbamazepine, oxcarbazepine, and phenytoin), and the ADHD medication, atomoxetine.^10–15 These guidelines involve 1 or more of 5 genes, CYP2C9, CYP2C19, CYP2D6, HLA-A, and HLA-B. We found that all of the tests we evaluated included CYP2C9, CYP2C19, and CYP2D6, which allows for implementation of all the guidelines linked to antidepressants, antipsychotics, and atomoxetine.²¹ However, about half of the tests would not be able to facilitate the use of available anticonvulsant guidelines due to the absence of HLA-A or HLA-B on their panels. The absence of 1 or both HLA genes on current panels can be partially explained by the availability and reimbursement of testing for these genes by several provincial laboratories and health-care systems. This coupled with the fact that the 3 drugs (i.e., carbamazepine, oxcarbazepine, and phenytoin) relevant to these 2 HLA genes are not commonly used in psychiatry suggests the absence of these genes on a testing panel may be of minimal concern.

Related and equally important to the gene content of each testing panel is the allele content. One cannot assume that 2 tests with the same gene content will test for the same alleles within those genes. Previous²² as well as our current evaluations of CYP2C9, CYP2C19, and CYP2D6 allele content across testing panels highlights this point. Although we found that all of the testing panels included the minimum recommended set of alleles for these 3 genes, we also found notable variation in the number of additional alleles included on the evaluated testing panels. We have previously shown that this variation can lead to differences in genotype calls, phenotype assignments (e.g., metabolizer status), and medication selection and dosing recommendations.²³ For example, the CYP2D6*36 (no function) allele has yet to be reported among individuals of European descent but is relatively common among individuals of Asian background (1.5%, range: 0.0% to 16.4%).^24,25 This is noteworthy given that individuals of Asian background represent 17.7% of the Canadian population.²⁶ However, only one-third of the test panels we evaluated include *36. Exclusion of *36 could inadvertently assign some Asians as normal or intermediate metabolizers instead of poor metabolizers, which could in turn have significant implications for medication selection and dosing recommendations. Notably, scenarios such as this are not confined to Asians. In fact, all patients of non-European backgrounds are at greater risk of false negative pharmacogenetic testing results (i.e., being incorrectly assigned as a normal metabolizer) due to our limited understanding of pharmacogenetic variation in these populations. As such, health-care providers serving patients of non-European background should pay particular attention to the alleles being tested and be cautious with results suggesting normal metabolism (i.e., a genotype of *1/*1).

Given the variability in gene and allele content observed between tests, it is also worth considering any evidence available that supports the use of a particular test in clinical practice. Double-blinded RCTs are commonly regarded as the gold standard for evaluating efficacy of an intervention despite reasonable arguments in favor of using evidence derived from unblinded, open-label, or retrospective trials when evaluating pharmacogenetic testing.²⁷ To date, few pharmacogenetic tests have been evaluated in RCTs,⁹ and only 2 tests available in Canada have this level of evidence.^28–30 Importantly, these RCTs were conducted by the manufacturers and were restricted to individuals with major depressive disorder that had failed to respond or had experienced adverse effects in previous antidepressant trials. Although, open-label and retrospective trials of tests available in Canada have provided support for pharmacogenetic testing in anxiety and bipolar disorders.^31,32 Nevertheless, potential biases and the generalizability of trial findings should be noted when considering this evidence.

The final considerations relate to the practical aspects of pharmacogenetic testing (i.e., test ordering, delivery of results, turnaround times, and cost). As we summarized in Table 2, these aspects do differ across tests and represent some of the most frequently perceived barriers to implementing pharmacogenetic testing. Beginning with the process of ordering and delivery of testing results, we found 2 approaches used by test providers in Canada: direct-to-consumer and clinician-gated. The direct-to-consumer approach does not require the involvement of a health-care provider to order the test or receive test results, whereas the clinician-gated approach requires varying degrees of participation from a health-care provider. Debate is ongoing, and consensus has not been reached on which model appropriately balances ethical and legal issues with an individual’s right to their health information. However, there is a sense of strong agreement that the involvement of a health-care provider is essential for proper interpretation and implementation of pharmacogenetic testing results and that risks are not negligible if results are provided to consumers/patients in the absence of a health-care provider. Ideally, ordering and interpretation of pharmacogenetic testing should employ a shared decision-making approach that includes health-care providers (psychiatrists, pharmacists, genetic counselors) and the patient.³³ However, the implementation of this approach is challenged by insufficient knowledge about pharmacogenetics among health-care providers as well as the infrastructure (e.g., integrated electronic medical records) needed to better facilitate this approach. To address these challenges, initiatives such as the electronic medical records and genomics project (https://emerge-network.org/projects-2/ehr-integration) and exemplar programs for boosting pharmacogenetic knowledge among health-care providers are underway.³⁴ In addition, all test manufacturers provide interpretative reports with recommendations to assist with implementation of test results.²² These interpretations and recommendations, however, can vary from test to test due to differences in the decision algorithms each manufacturer employs. Unfortunately, decision algorithms are typically proprietary, and as such, it is often a challenge to figure out how manufacturers arrive at their recommendations. This is particularly the case for manufacturers that employ a combinatorial approach in which variation in several genes are combined in a proprietary fashion to make a recommendation for a particular medication. Although this combinatorial approach is more closely aligned with how medications are processed and act on the body, most of the current prescribing guidelines (e.g., CPIC, drug labels) are based on single gene by medication interactions. As such, a manufacturer employing a combinatorial approach should provide evidence, preferably an RCT, demonstrating clinical utility of their decision algorithm. If such evidence is not available, caution should be taken when interpreting or implementing their medication selection and dosing recommendations. That said, even when evidence of clinical utility is available, pharmacogenetic testing should not be used without careful consideration of other factors. Currently available pharmacogenetic tests and their associated decision algorithms do not account for demographic factors (e.g., age, sex), clinical characteristics (e.g., body mass index, liver and renal function), and concomitant use of inhibitors or inducers of drug metabolizing enzymes that have known impacts on drug exposure and therapeutic outcomes.^35–38 Thus, pharmacogenetic testing results must be interpreted alongside this information prior to making therapeutic recommendations.

Another feasibility concern is the turnaround time of pharmacogenetic testing. This is a particularly relevant issue in psychiatry, where acute clinical presentations often require prompt pharmacological treatment. In these cases, most tests available in Canada will not be suitable, given current turnaround times exceed 5 business days. However, with the advent of rapid genotype testing methods and point-of-care testing devices, this current barrier could be temporary.³⁹ While we await the evolution of this technology, the implementation of pharmacogenetics will need to adapt to current turnaround times. This means in urgent clinical scenarios, the use of pharmacogenetic testing to guide initial medication selection and dosing will not be possible. However, testing in these situations could assist with medication adjustments or help guide planning of future treatment. The adoption of preemptive genotyping and integration of testing results into electronic medical records could also alleviate this feasibility concern.

Lastly and arguably, the biggest perceived barrier to pharmacogenetic testing implementation in Canada is the monetary cost of testing. Currently, pharmacogenetic testing in Canada is not covered by health insurance plans. However, many employer-based health-spending accounts list pharmacogenetic testing as an eligible expense and several insurers (i.e., Sun Life Financial, Great-West Life Assurance Co., Manulife Financial Corp.) are piloting the use of pharmacogenetic testing among individuals with a mental health–related disability claim,⁴⁰ indicating reimbursement for testing might be available in the future. Nevertheless, for the majority of people currently residing in Canada, the cost of testing will be an out-of-pocket expense. Our review showed that this would amount to a median cost of CA$499 or about half (45%) of an average Canadian’s weekly wage.⁴¹ As such, the current cost of pharmacogenetic testing has the potential to contribute to health disparities although test manufacturers have attempted to address this concern by offering payment plans and in some cases fee reductions. However, this is not a sustainable approach for addressing the current high cost of testing, and as such, other models of pharmacogenetic testing delivery should be explored to ensure an equitable, efficient, and fiscally sound solution in Canada.

In conclusion, the availability of pharmacogenetic testing and its use for guiding the selection and dosing of psychotropic medications is readily available in Canada. Given the exponential growth in the evidence base and favorable perceptions of pharmacogenetic testing among clinicians, patients, and the general public,^42–44 there is good reason to anticipate increases in both the supply of and demand for testing in the future. As such, psychiatrists and other health-care providers will undoubtably be tasked with deciding which test, if any, best suits the needs of their patients and clinical practice. It is our hope that our critical review and evaluation assists in this decision-making process and allows for thoughtful and evidence-informed implementation of pharmacogenetic testing in psychiatry throughout Canada.

Supplemental Material

Supplemental Material, Table_S1_FINAL - Pharmacogenetic Testing Options Relevant to Psychiatry in Canada: Options de tests pharmacogénétiques pertinents en psychiatrie au Canada

Click here for additional data file.^{(334KB, pdf)}

Supplemental Material, Table_S1_FINAL for Pharmacogenetic Testing Options Relevant to Psychiatry in Canada: Options de tests pharmacogénétiques pertinents en psychiatrie au Canada by Abdullah Al Maruf, Mikayla Fan, Paul D. Arnold, Daniel J. Müller, Katherine J. Aitchison and Chad A. Bousman in The Canadian Journal of Psychiatry

Supplemental Material, Table_S2_FINAL - Pharmacogenetic Testing Options Relevant to Psychiatry in Canada: Options de tests pharmacogénétiques pertinents en psychiatrie au Canada

Click here for additional data file.^{(336.4KB, pdf)}

Supplemental Material, Table_S2_FINAL for Pharmacogenetic Testing Options Relevant to Psychiatry in Canada: Options de tests pharmacogénétiques pertinents en psychiatrie au Canada by Abdullah Al Maruf, Mikayla Fan, Paul D. Arnold, Daniel J. Müller, Katherine J. Aitchison and Chad A. Bousman in The Canadian Journal of Psychiatry

Footnotes

Authors’ Note: Data are available upon request.

Declaration of Conflicting Interests: AAM, DJM, and CB are members of the Clinical Pharmacogenomics Implementation Consortium. CB is supported by the Cumming School of Medicine at the University of Calgary and the Alberta Children’s Hospital Research Institute. MF declares no conflicts. PDA holds the Alberta Innovates Translational Health Chair in Child and Youth Mental Health. KA has acted in a consulting capacity for companies including Roche Diagnostics, Bristol-Myers Squibb and Otsuka Pharmaceuticals Ltd, Otsuka Canada Pharmaceuticals Inc., Lundbeck, and HLS Therapeutics. She has also received research support from companies including Bristol-Myers Squibb and Otsuka Pharmaceuticals, Johnson and Johnson Research and Development, Jannsen Inc. Canada, and Roche Molecular Systems. DJM is coinvestigator in 2 pharmacogenetic studies where genetic test kits were provided as in-kind contribution by Assurex Health (Myriad Neuroscience) to evaluate feasibility of pharmacogenetic testing in clinical practice and potential benefits of pharmacogenetic testing compared to treatment as usual. DJM have not received any payments or received any equity, stocks, or options from this company or any other pharmacogenetic companies. DJM is coinvestigator in 2 filed genetic patents assessing risk for antipsychotic-induced weight gain. CB has received material support from Assurex Health (Myriad Neuroscience), CNSDose, Genomind, and AB-Biotics for research purposes and has ongoing research collaborations with MyDNA but does not have equity, stocks, or options in these companies or any other pharmacogenetic companies. CB, DJM and KA are members of the Genetic Testing Committee of the International Society of Psychiatric Genetics.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD: Chad A. Bousman, MPH, PhD Inline graphic https://orcid.org/0000-0001-6303-8696

Supplemental Material: Supplemental material for this article is available online.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Material, Table_S1_FINAL - Pharmacogenetic Testing Options Relevant to Psychiatry in Canada: Options de tests pharmacogénétiques pertinents en psychiatrie au Canada

Click here for additional data file.^{(334KB, pdf)}

Supplemental Material, Table_S2_FINAL - Pharmacogenetic Testing Options Relevant to Psychiatry in Canada: Options de tests pharmacogénétiques pertinents en psychiatrie au Canada

Click here for additional data file.^{(336.4KB, pdf)}

[bibr1-0706743720904820] 1. Dunnenberger HM, Crews KR, Hoffman JM, et al. Preemptive clinical pharmacogenetics implementation: current programs in five US medical centers. Annu Rev Pharmacol Toxicol. 2015;55(1):89–106. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr2-0706743720904820] 2. Volpi S, Bult CJ, Chisholm RL, et al. Research directions in the clinical implementation of pharmacogenomics: an overview of US programs and projects. Clin Pharmacol Ther. 2018;103(5):778–786. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr3-0706743720904820] 3. Bousman CA, Forbes M, Jayaram M, et al. Antidepressant prescribing in the precision medicine era: a prescriber’s primer on pharmacogenetic tools. BMC Psychiatry. 2017;17(1):60. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr4-0706743720904820] 4. Haga SB, Kantor A. Horizon scan of clinical laboratories offering pharmacogenetic testing. Health Aff. 2018;37(5):717–723. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr5-0706743720904820] 5. Müller DJ, Kekin I, Kao ACC, Brandl EJ. Towards the implementation of CYP2D6 and CYP2C19 genotypes in clinical practice: update and report from a pharmacogenetic service clinic. Int Rev Psychiatry. 2013;25(5):554–571. [DOI] [PubMed] [Google Scholar]

[bibr6-0706743720904820] 6. Cohn I, Cohn RD, Ito S. Professional opportunity for pharmacists to integrate pharmacogenomics in medication therapy. Can Pharm J (Ott). 2018;151(3):167–169. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr7-0706743720904820] 7. Salm M, Abbate K, Appelbaum P, et al. Use of genetic tests among neurologists and psychiatrists: knowledge, attitudes, behaviors, and needs for training. J Genet Couns. 2014;23(2):156–163. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr8-0706743720904820] 8. Rosenblat JD, Lee Y, McIntyre RS. The effect of pharmacogenomic testing on response and remission rates in the acute treatment of major depressive disorder: a meta-analysis. J Affect Disord. 2018;241:484–491. [DOI] [PubMed] [Google Scholar]

[bibr9-0706743720904820] 9. Bousman CA, Arandjelovic K, Mancuso SG, Eyre HA, Dunlop BW. Pharmacogenetic tests and depressive symptom remission: a meta-analysis of randomized controlled trials. Pharmacogenomics. 2019;20(1):37–47. [DOI] [PubMed] [Google Scholar]

[bibr10-0706743720904820] 10. Hicks J, Bishop J, Sangkuhl K, et al. Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther 2015;98(2):127–134. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr11-0706743720904820] 11. Hicks J, Sangkuhl K, Swen J, et al. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther. 2017;102(1):37–44. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr12-0706743720904820] 12. Brown JT, Bishop JR, Sangkuhl K, et al. Clinical pharmacogenetics implementation consortium guideline for cytochrome P450 (CYP) 2D6 genotype and atomoxetine therapy. Clin Pharmacol Ther. 2019;106(1):94–102. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr13-0706743720904820] 13. Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte—an update of guidelines. Clin Pharmacol Ther. 2011;89(5):662–673. [DOI] [PubMed] [Google Scholar]

[bibr14-0706743720904820] 14. 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] [PMC free article] [PubMed] [Google Scholar]

[bibr15-0706743720904820] 15. Caudle KE, Rettie AE, Whirl-Carrillo M, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing. Clin Pharmacol Ther. 2014;96(5):542–548. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr16-0706743720904820] 16. Whirl-Carrillo M, McDonagh EM, Hebert JM, et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012;92(4):414–417. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr17-0706743720904820] 17. Bousman CA, Zierhut H, Müller DJ. Navigating the labyrinth of pharmacogenetic testing: a guide to test selection. Clin Pharmacol Ther. 2019;106(2):309–312. [DOI] [PubMed] [Google Scholar]

[bibr18-0706743720904820] 18. Bousman C, Maruf AA, Müller DJ. Towards the integration of pharmacogenetics in psychiatry. Curr Opin Psychiatry. 2018;32(1):1. [DOI] [PubMed] [Google Scholar]

[bibr19-0706743720904820] 19. Relling MV, Klein TE. CPIC: Clinical pharmacogenetics implementation consortium of the pharmacogenomics research network. Clin Pharmacol Ther. 2011;89(3):464–467. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr20-0706743720904820] 20. Genetic Testing Statement | ISPG - International Society of Psychiatric Genetics [accessed 2019 Aug 8] https://ispg.net/genetic-testing-statement/.

[bibr21-0706743720904820] 21. Fan M, Bousman C. Commercial pharmacogenetic tests in psychiatry: do they facilitate the implementation of pharmacogenetic dosing guidelines? Pharmacopsychiatry. 2019. doi: 10.1055/a-0863-4692. [DOI] [PubMed] [Google Scholar]

[bibr22-0706743720904820] 22. Bousman CA, Jaksa P, Pantelis C. Systematic evaluation of commercial pharmacogenetic testing in psychiatry. Pharmacogenet Genomics. 2017;27(11):387–393. [DOI] [PubMed] [Google Scholar]

[bibr23-0706743720904820] 23. Bousman CA, Dunlop BW. Genotype, phenotype, and medication recommendation agreement among commercial pharmacogenetic-based decision support tools. Pharmacogenomics J. 2018;18(5):613–622. [DOI] [PubMed] [Google Scholar]

[bibr24-0706743720904820] 24. Del Tredici AL, Malhotra A, Dedek M, et al. Frequency of CYP2D6 alleles including structural variants in the United States. Front Pharmacol. 2018;9:305. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr25-0706743720904820] 25. Gaedigk A, Sangkuhl K, Whirl-Carrillo M, Klein T, Leeder JS. Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med. 2017;19(1):69–76. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr26-0706743720904820] 26. Census Profile, 2016 Census: Canada [Country] and Canada [Country]. [accessed 2019 Aug 8] https://www12.statcan.gc.ca/census-recensement/2016/dp-pd/prof/details/page.cfm?&Geo1=PR&Code1=01&Geo2=&Code2=&SearchText=Canada&SearchType=Begins&SearchPR=01&B1=All&TABID=1&type=0.

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PERMALINK

Pharmacogenetic Testing Options Relevant to Psychiatry in Canada: Options de tests pharmacogénétiques pertinents en psychiatrie au Canada

Abdullah Al Maruf, M.Pharm, PhD

Mikayla Fan

Paul D Arnold, MD, PhD, FRCPC

Daniel J Müller, MD, PhD

Katherine J Aitchison, BA(Hons), MA(Oxon) BM BCh, PhD, FRCPsych

Chad A Bousman, MPH, PhD