Precision medicine, a “novel approach to disease prevention and treatment,” is based on “an appreciation of the heterogeneity of disease entities and individual difference in genetic make-up.”1
The role of pharmacogenetics, a central component of precision medicine, has been somewhat controversial, “since use of genetics alone can be construed as stigmatizing or unaffordable to most,” but on the other hand, it may be a “means to better understand issues related to treatment response or lack of, due to specific genetic characteristics and could be a useful tool eventually enabling universal access.”1
“Pharmacogenetics are increasingly being used in medicine, but specifically in 3 main fields: cardiovascular health, cancer, and psychiatry,” according to Chad Bousman, MPH, PhD, assistant professor in the Departments of Medical Genetics, Psychiatry, and Physiology and Pharmacology at the University of Calgary in Canada. “In psychiatry, the majority of pharmacogenetic work is done and implemented with antidepressants, which can be considered the flagship,” he told Psychiatry Advisor.
A substantial number of patients (30% to 50%) do not respond adequately to their first antidepressant trial and only 37.5% achieve remission.2 Even those who respond often fail to remit or tend to relapse, which is a serious concern because remission is the “pathway to recovery from [major depressive disorder] (MDD).”2
Moreover, it can take long periods of time, from several months to several years, of clinical trial and error before an effective, tolerable antidepressant is found for a particular patient.2 During this time, patients are exposed to ineffective medications with potential adverse effects as well as the harmful effects of depression itself.
The reasons for nonresponse to antidepressants may be complex, but it is clear that there are genetic components, Dr Bousman said. “Each individual has a metabolizing status for a given drug, whether normal, rapid, or poor for the enzymes that metabolize the drug, which can be used to inform how the person might respond,” he explained.
The application of pharmacogenetic approaches to antidepressants is therefore designed both to “improve depression remission rates and also reduce adverse effects by identifying genetic markers that can potentially inform more tailored treatment,” he said.
The CYP Enzyme System
Genes are expressed into RNA and transcribed into proteins that interact with psychotropic drugs.3 The cytochrome P450 (CYP) enzyme system is involved in metabolizing a large number of psychiatric medications, including antidepressants, benzodiazepines, and antipsychotics.4
“CYPs are the metabolic factories in the liver and the mucosal surface of the intestinal tract.”4 They can be regarded as the “body’s waste management system for drugs, toxins, and cellular waste products” as well as “cellular highways for drugs.”4
CYP2D6, CYP2C9, and CYP2C19 metabolize approximately 70% of all psychotropic medications.4 It is estimated that 70% of people have a variation in at least one of the main CYP enzymes, leading to abnormal metabolism of medication and accounting for the individual variability that contributes to adverse drug reactions.4
“The pharmacokinetic genes CYP2D6 and CYP2C19 may lead to the administration of a drug at higher or lower doses based on the patient’s metabolism status or phenotype,” Ian McGrane, PharmD, BCPS, BCPP, assistant professor at the University of Montana Skaggs School of Pharmacy in Missoula, told Psychiatry Advisor. “Some antidepressants and antipsychotics have prescribing or dosing recommendations for patients who are poor metabolizers for a certain CYP protein,” he said.
Within the larger CYP450 system, however, only CYP2D6 and CYP2C19 are recommended by guidelines as having clinical utility. For example, the CYP1A2 and CYP3A4/5/7 enzymes are metabolic pathways for some neuropsychiatric medications but their expression and drug metabolism activity are affected by several environmental factors, he noted.
Other genetic tests also have utility, including histocompatibility complex human leukocyte antigen (HLA) allele HLA-B*1502 for carbamazepine and phenytoin, since certain people, especially those of Asian ancestry who have the polymorphism, are at higher risk for Stevens-Johnson syndrome.5 Guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC) support HLA-B*1502 genotyping for this population if they are being considered for treatment with carbamazepine.6
Integrating Pharmacogenetics Into Clinical Practice
Both experts provided practical tips to aid in the often-challenging process of incorporating pharmacogenetic testing into clinical practice. While pharmacogenetic testing “has a role in psychiatric practice, it should not be performed for every patient, since there is very limited outcomes research suggesting the testing will benefit the majority of people” Dr McGrane advised.
Additionally, the resting results should “not be applied toward stable patients who are doing well.” Moreover, “unfortunately, use of pharmacodynamic genes — serotonin/dopamine receptor and transporter genes — is not yet of value in selecting which medications will be more effective,” he noted.
Dr Bousman said that although there is a strong evidence base behind the utility of pharmacogenetic testing in improving outcomes in depression,2,7,8 there are also naysayers. One report concluded that testing was not effective, but the concepts of pharmacogenomics that were applied to the case were done so without being adequately supported by a robust evidence base, he said.9,10 “Just as a clinician wouldn’t give a drug blindly without knowing what it is and how it acts in the body before prescribing, the same is true with pharmacogenetic testing,” he said.
Dr McGrane concurred. “Clinicians should be aware of the pharmacokinetic properties of the medications they are using. Overlooking clinical patient characteristics and drug-drug interactions is common for clinicians who order pharmacogenetic tests.”
Both experts emphasized the importance of consulting clinical guidelines before embarking upon pharmacogenetic testing. Two reliable and extensive sources of information are PharmGKB, which is supported by NIH/NIGMS and managed at Stanford University, and the guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC), which are designed to “help clinicians understand how available genetic test results could be used to optimize drug therapy.”11
Numerous environmental and other factors influence the extent to which particular genes interact, so decisions regarding medication selection must be made with the recognition of the complexity of medication response. “In general, pharmacogenetic tests are only one of a number of factors to consider when choosing or dosing a neuropsychiatric medication,” Dr McGrane pointed out. “Ultimately, they do not guide the prescriber to choose a more effective medication but they may have some impact on what dose of medication should be chosen initially,” he said. Therapeutic drug monitoring is a “method of understanding what the blood concentration of the drug is, which is sometimes helpful in challenging clinical cases,” he suggested.12
Dr Bousman added that while pharmacogenetic testing cannot determine what drug to select, it can often offer guidance regarding what drug might not work. Additionally, environmental factors have a profound impact on the expression of genetic factors, and their importance cannot be overlooked
“One of the strengths of these tools is their use in shared decision-making,” Dr Bousman observed. “The doctor can explain to the patient the concept of genetic testing and use it to explain some of the rationale behind choosing or ruling out a particular drug.”
Choosing a Company to Conduct Testing
Pharmacogenomic testing platforms and laboratory services include those approved by the US Food and Drug Administration, as well as those developed and/or provided in Clinical Laboratory Improvement Amendments-certified laboratories.5 It is important to recognize that “not all testing platforms or services examine the same variants in a given gene and that these differences may be more or less important depending on the ancestry of a particular patient.”5
“There are many commercial companies that have developed these tests, with US-based companies as the main hub, but companies in other countries such as Australia and Canada are following suit, and new companies are springing up all the time,” Dr Bousman observed.
Dr Bousman coauthored a recent literature and internet search of 22 commercial companies offering pharmacogenetic tools to psychiatrists, concluding that the “mere existence of these tools should not be mistaken for evidence of clinical usefulness,” and that their findings suggest that “research on validity, reliability, clinical usefulness, and cost-effectiveness are needed for most of these tools before universal adoption into clinical practice.”13
Keeping Track of a Patient’s Tests
“A major problem is that once a patient has testing done and transfers care to another provider, the results are often lost or not passed on,” Dr McGrane noted. “Health systems need to develop a way of easily identifying where genetic tests are placed in the patient chart,” he recommended, suggesting that the results could be listed similarly to the way a patient’s allergies are listed in the chart. “That way, results will not be lost and can easily be interpreted and not delay patient care,” he said.
- 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.
- Singh AB. Improved antidepressant remission in major depression via a pharmacokinetic pathway polygene pharmacogenetic report. Clin Psychopharmacol Neurosci. 2015;13(2):150-156.
- Arranz MJ, Kapur S. Pharmacogenetics in psychiatry: are we ready for widespread clinical use? Schizophr Bull. 2008;34(6):1130-1144.
- Durham D. Utilizing pharmacogenetics in psychiatry: the time has come. Mol Diagn Ther. 2014;18(2):117-119.
- Drozda K, Müller DJ, Bishop JR. Pharmacogenomic testing for neuropsychiatric drugs: current status of drug labeling, guidelines for using genetic information, and test options. Pharmacotherapy. 2014;34(2):166-184.
- Leckband SG, Kelsoe JR, Dunnenberger HM, et al. Clinical pharmacogenetics implementation consortium guidelines for HLA-B genotype and carbamazepine dosing. Clin Pharmacol Ther. 2013;94(3):324-328.
- Winner JG, Carhart JM, Altar CA, Allen JD, Dechairo BM. A prospective, randomized, double-blind study assessing the clinical impact of integrated pharmacogenomic testing for major depressive disorder. Discov Med. 2013;16(89):219-227.
- 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.
- 9Rahman T, Ash DM, Lauriello J, Rawlani R. Misleading guidance from pharmacogenomic testing. Am J Psychiatry. 2017;174(10):922-924.
- Bousman C, Allen J, Eyre HA. Pharmacogenetic tests in psychiatry. Am J Psychiatry. 2018;175(2):189.
- Caudle KE, Klein TE, Hoffman JM, et al. Incorporation of pharmacogenomics into routine clinical practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline development process. Curr Drug Metab. 2014;15(2):209-217.
- Hiemke C, Bergemann N, Clement HW, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51(1-02):9-62.
- Bousman CA, Hopwood M. Commercial pharmacogenetic-based decision-support tools in psychiatry. Lancet Psychiatry. 2016;3(6):585-590.