Clinical Utility Of Pharmacogenetic Testing Research Articles

Assessing Clinical Utility ofPharmacogenetic Testing inthe Military Health System.

Response to medications can differ widely among individual patients. Adverse drug reactions can lead to serious morbidity and mortality. Pharmacogenetic (PGx) testing can predict responses to medications and increased risks of adverse events where the genetic basis is understood. Several published manuscripts suggest positive impacts of systematic preemptive PGx testing. However, few studies have been conducted on PGx implementation in the Military Health System (MHS). A cross-sectional study of adult beneficiaries in a primary care clinic at a large military treatment facility was conducted in 2022. Participants underwent PGx genotyping of CYP2C19 and CYP2D6 genes at the Defense Health Agency Genetics Reference Laboratory. Participant medication lists were compared to the current Clinical Pharmacogenetic Implementation Consortium (CPIC) PGx gene-drug guidelines to assess potential actionability of these results. Genotyping of CYP2C19 and CYP2D6 in 165 MHS beneficiaries (mean age: 65 years) revealed that 81.2% of participants had at least one abnormal PGx finding. Among those with an abnormal PGx result, 65% were taking a medication listed on the CPIC website with an association with the particular gene in which the finding was identified. In addition, 78% of all of the participants in the study were taking at least one medication that is metabolized by CYP2C19 or CYP2D6 with associated CPIC guidelines. Pharmacogenetic testing for CYP2C19 and CYP2D6 identified a substantial proportion of MHS patients at a single center who could benefit from evaluation of current medication regimens based on the CPIC guidelines. Individualized medical management may be warranted to a greater degree than previously recognized based on the findings given possible differences in medication metabolism. Many MHS beneficiaries already take medications metabolized by CYP2C19 and CYP2D6, and a substantial proportion may be at risk for preventable adverse events for medications metabolized by these enzymes. While preliminary, a large number of actionable polymorphisms among a relatively small set of individuals taking at-risk medications suggest that implementing PGx testing in clinical practice may be beneficial in the MHS with appropriate clinical infrastructure.

Pharmacogenetics of Antipsychotic Treatment in Schizophrenia.

Antipsychotics are the mainstay treatment for schizophrenia. There is large variability between individuals in their response to antipsychotics, both in efficacy and adverse effects of treatment. While the source of interindividual variability in antipsychotic response is not completely understood, genetics is a major contributing factor. The identification of pharmacogenetic markers that predict antipsychotic efficacy and adverse reactions is a growing area of research and holds the potential to replace the current trial-and-error approach to treatment selection in schizophrenia with a personalized medicine approach.In this chapter, we provide an overview of the current state of pharmacogenetics in schizophrenia treatment. The most promising pharmacogenetic findings are presented for both antipsychotic response and commonly studied adverse reactions. The application of pharmacogenetics to schizophrenia treatment is discussed, with an emphasis on the clinical utility of pharmacogenetic testing and directions for future research.

A prospective study to determine the clinical utility of pharmacogenetic testing of veterans with treatment-resistant depression.

Pharmacotherapies for depression are often ineffective and treatment-resistant depression (TRD) is common across bipolar disorder (BD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). Patient genetic information can be used to predict treatment outcomes. Prospective studies indicate that pharmacogenetic (PGX) tests have utility in the treatment of depression. However, few studies have examined the utility of PGX in other diagnoses typified by depression, or in veterans, a cohort with high rates of medical comorbidity, social stress, and suicide. To determine the efficacy of genetically guided pharmacological treatment of TRD. We conducted an 8-week, prospective, multisite, single-blind study in 182 veterans with TRD including patients with BD, MDD, and PTSD. Subjects were randomly assigned to PGX-guided treatment in which the clinician incorporated PGX information into decision-making, or treatment as usual (TAU). Overall, the PGX group improved marginally faster compared to TAU, but the difference was not statistically significant. Secondary analyses revealed that only PTSD patients showed a potential benefit from PGX testing. Patients predicted by PGX testing to have moderate levels of genetic risk showed a significant benefit from the PGX-guided treatment, whereas other risk groups demonstrated no benefit. Clinicians generally found the PGX test was useful, particularly in more depressed patients and/or those with more warnings for significant or serious adverse outcomes. Clinicians more often used the results to select a drug, but only rarely to adjust dosing. The data reveal possible group differences in the utility of PGX testing in veterans with TRD.ClinicalTrials.gov Identifier: NCT04469322.

How Can Drug Metabolism and Transporter Genetics Inform Psychotropic Prescribing?

Many genetic variants in drug metabolizing enzymes and transporters have been shown to be relevant for treating psychiatric disorders. Associations are strong enough to feature on drug labels and for prescribing guidelines based on such data. A range of commercial tests are available; however, there is variability in included genetic variants, methodology, and interpretation. We herein provide relevant background for understanding clinical associations with specific variants, other factors that are relevant to consider when interpreting such data (such as age, gender, drug–drug interactions), and summarize the data relevant to clinical utility of pharmacogenetic testing in psychiatry and the available prescribing guidelines. We also highlight areas for future research focus in this field.

Clinical utility of pharmacogenetic testing in the treatment of bipolar disorder of Chinese patients.

Aim: The purpose of this study was to evaluate the clinical utility of pharmacogenetic (PGx) testing in the treatment of bipolar disorder in the Chinese population. Patients & methods: Compare efficacy and side effects, measured by the Clinical Global Impression Efficacy Index scale (CGI-EI), of PGx-guided treatment (n=100) to that of the traditional treatment (n=100). Results: Compared with the traditional treatment, PGx-guided treatment reduced the number of medications used for patients, also achieving better efficacy at 4, 8 and 12weeks. In the analysis of side effects, the PGx-guided group significantly reduced the side effects. Conclusion: Our study suggests that PGx testing results-guided treatment is superior to the traditional treatment of bipolar disorder in the Chinese population.

Physicians' Attitudes and Ethical Obligations to Pharmacogenetic Testing.

IntroductionDespite the increased utilization of pharmacogenetic (PGt) testing to guide drug therapy, little is known about the ethical challenges posed by the use of these genetic tools.MethodsThis cross-sectional study aimed to address ethical issues related to ancillary genetic information, consent forms, and potential confidentiality breaches from physicians’ perspectives. A questionnaire was administered to all practicing physicians working in KAUH. ResultsAlmost 49% and 65% of physicians were willing to recommend PGt testing for adult and pediatric patients, respectively. The findings showed that physicians attitudes towards the clinical utility of PGt testing became more preceptive. The majority (73.7%) indicated that PGt testing should not be treated as other routine laboratory tests. The finding also focused on potential conflicts regarding ancillary genetic information, in which 78.8% indicated that they would like to preserve the confidentiality and privacy of the patients and only 14.4% of physicians did not feel obligated to let patients know about any future risk that might be uncovered using PGt testing. The findings showed that collecting both verbal and written consents was imperative prior to testing. Seriousness and predictability of the diseases were reported to be legitimate circumstances that allow disclosure of genetic information.DiscussionUnless the field of PGt testing addresses the ethical challenges that might be encountered during PGt treatment, these issues might influence its acceptance in routine clinical settings. Establishing a minimal set of ethical standards may help emphasize the role of physicians and thus facilitate the implementation of PGt tests.

Clinical Utility of Pharmacogenetic Testing and a Clinical Decision Support Tool to Enhance the Identification of Drug Therapy Problems Through Medication Therapy Management in Polypharmacy Patients.

In polypharmacy patients, medication therapy management (MTM) services provide a comprehensive review of current medications and future treatment goals. Pharmacogenetics (PGx) may further optimize the identification of potential drug therapy problems (DTPs); however, the clinical utility of PGx information with a clinical decision support tool (CDST) in an MTM setting in identifying DTPs has not been systematically assessed. To assess the clinical utility of an MTM service enhanced by pharmacogenetic test results and a clinical decision support tool. This study was a post hoc analysis of the data obtained from an open-label, randomized, observational trial. Polypharmacy patients eligible for MTM service were randomly assigned to 3 intervention arms: standard MTM (SMTM), MTM incorporating CDST (CMTM), and CMTM further enhanced by PGx test results of CYP450 and VKORC1 enzymes (PGxMTM). Allocation for this post hoc analysis was based on patient adherence to the research protocol and completion of a PGx test. The number of DTPs per patient was compared across the 3 arms using analysis of variance. In addition, the frequency of serious DTPs as a categorical variable (grade 3 or above vs. lower grade) was compared across the 3 arms between PGx driven and non-PGx driven DTP recommendations. Statistical significance was tested using the chi-square test. The level of agreement between the DTP seriousness and the acceptance made by prescribers was presented as Cohen's kappa coefficient. Numbers of patients after cohort reallocation based on completion of PGx testing were 104, 180, and 58 for the SMTM, CMTM, and PGxMTM arms, respectively. On average, 3.08 DTPs were identified for each patient, which was nearly identical across all 3 arms. Blinded clinical pharmacists considered seriousness (grade 3 or 4) in 31% of the PGx-related DTPs in comparison with 4.9% of the non-PGx DTPs (P < 0.001). The more serious (i.e., grade 3 or above) DTP recommendations were more likely to be accepted by prescribers with the odds ratios of 1.95 (P = 0.05) and 2.39 (P = 0.15), when the analysis was performed for all DTPs and DTPs from the PGxMTM arm only, respectively. MTM enhanced by PGx testing and the clinical decision support tool did not increase the number of DTPs identified. However, PGx testing and the decision support software helps pharmacists determine more serious DTPs, and resulting subsequent recommendations were more readily accepted by a prescriber. Future study of the patient safety outcomes and overall health care costs associated with the utility of the decision support is warranted. No funding was received for conducting the post hoc analysis presented in this study. Magness is employed by Magellan Health, which received funding from Genelex for costs to administrate the medication management program. The open-label randomized trial was sponsored by Genelex (Clinicaltrials.gov ID number NCT02428660). PGx tests were provided and laboratory analysis was performed by Genelex. Valerie Baron is an employee of YouScript, which created the clinical decision support tool used in this study and formerly was part of Genelex. The other authors have nothing to disclose.

Patient characteristics driving clinical utility in psychiatric pharmacogenetics: a reanalysis from the AB-GEN multicentric trial

Clinical utility of commercial multi-gene pharmacogenetic tests in depression is starting to be studied with some promising results on efficacy and tolerability. Among the next steps is the definition of the patient profile that is most likely to benefit from testing. Here we present a reanalysis of data from the AB-GEN randomized clinical trial showing that clinical utility of pharmacogenetic testing can be markedly influenced by patient characteristics such as age, baseline severity and duration of current depressive episode.Trial registration ClinicalTrials.gov NCT02529462.

Clinical utility of pharmacogenetic testing in children and adolescents with severe mental disorders

This is a retrospective cohort study of 20 children and adolescents to evaluate the clinical utility of a pharmacogenetic decision support tool. Twenty children and adolescents underwent pharmacogenetic testing between June 2014 and May 2017. All children and adolescents were evaluated at Puerta de Hierro University Hospital-Majadahonda (Madrid, Spain). We report the proportion of patients achieving clinical improvement, amelioration of side effects, and changes in number of drugs. Data normality was assessed with the Shapiro–Wilk test, and changes of pre- and post-pharmacogenetic testing were analyzed with the Wilcoxon test for paired samples. A two-sided p value threshold of 0.05 was considered for significance. Pharmacogenetic testing helped to improve the clinical outcome as measured by the Clinical Global Impressions (CGI) Scale in virtually all children (95%; 19 out of 20 children). The CGI improvement (CGI-I) was 2 (0.79) (range 1–4), 2.1 (0.56) (range 1–3), and 1.9 (0.99) (range 1–4) in foster and non-foster care children, respectively. Pharmacogenetic testing also helped to reduce the number of children using polypharmacy (from 65 to 45%), the mean number of drugs per children (from 3.3 to 2.4 drugs, p = 0.017), and self-reported relevant side effects (p = 0.006). Pharmacogenetic testing helped to improve the clinical outcome, and to reduce polypharmacy and the number of drugs used in children and adolescents with severe mental disorders. More evidence using robust (i.e., clinical trials) independent studies is required to properly determine the clinical utility and cost-effectiveness of pharmacogenetic testing tools in children and adolescents with mental disorders.

Evidence required to demonstrate clinical utility of pharmacogenetic testing: the debate continues.

Pharmacogenetics is an area of research that has potential to greatly benefit patients. However, the routine use of diagnostic pharmacogenetic testing to inform treatment decisions is limited. Here we discuss the determination of clinical utility of pharmacogenetic testing and the level of evidence required to support translation into clinical practice.

Pharmacogenetics of antipsychotic treatment in schizophrenia.

Antipsychotics are the mainstay treatment for schizophrenia. There is large variability between individuals in their response to antipsychotics, both in efficacy and adverse effects of treatment. While the source of interindividual variability in antipsychotic response is not completely understood, genetics is a major contributing factor. The identification of pharmacogenetic markers that predict antipsychotic efficacy and adverse reactions is a growing area of research, and holds the potential to replace the current trial-and-error approach to treatment selection in schizophrenia with a personalized medicine approach.In this chapter, we provide an overview of the current state of pharmacogenetics in schizophrenia treatment. The most promising pharmacogenetic findings are presented for both antipsychotic response and commonly studied adverse reactions. The application of pharmacogenetics to schizophrenia treatment is discussed, with an emphasis on the clinical utility of pharmacogenetic testing and directions for future research.

A Massive Open Online Course on Pharmacogenomics: Not Just Disruptive Innovation but a Possible Solution

In 2005, Latif stated “there is significant opportu­ nity to deliver pharmacogenetics and pharmaco­ genomics educational content via internet­based instruction” [1]. Internet­based instruction is not a new concept and has probably been adopted, in part, at most US colleges/schools of pharmacy. Curricula courses may provide an electronic course syllabus, have didactic lectures recorded and then ‘podcasted’, or have utilized online dis­ cussion forums between faculty and students. Recently, there has been significant attention and proliferation of massive online open courses (MOOCs). The general intent of a MOOC is to provide an open access, distance­learning model, aiming for large­scale interactive par­ ticipation. Instructional design approaches of MOOCs include peer­review, group collabora­ tion and automated feedback by way of quizzes and exams [101]. In the last year, major MOOC developments have occurred, including increased acceptance by public and private higher educa­ tion institutions, the ability to obtain course credit, and the abundance of content in areas including science, engineering, mathematics, humanities and economics [102]. Creating a MOOC on pharmacogenomics, through col­ laboration with several US colleges/schools of pharmacy known for their expertise in this field, has the potential to solve the challenges of inadequate depth of instruction and the lack of resources for recruiting and/or training faculty in pharmacogenomics. Pharmacogenomic/pharmacogenetic instruc­ tion in US colleges/schools of pharmacy has increased over the last several years [2,3]. The majority of colleges/schools provide 10–30 hours of didactic teaching focusing on basic genetic concepts and terminology, genetic variability impacting drug response, and clinical utility of pharmacogenetic testing [3]. In addition, there are numerous reports of several colleges/schools of

Predictive Ability of Direct-to-Consumer Pharmacogenetic Testing: When is Lack of Evidence Really lack of Evidence?

For several years personal genome tests have been offered directly to consumers via the internet. Based on single genome scans, these direct-toconsumer (DTC) tests predict susceptibility to common multifactorial diseases, such as Type 2 diabetes, coronary heart disease and nonfamilial cancer, inform about predisposition to drug response, report carrier status for monogenic diseases, or provide all of the above. The market is served by a few major players, such as 23andMe and deCODEme, and numerous lesser-known companies such as YouScript, GenePlanet and Theranostics [101–105]. The market for DTC personal genome testing is steadily increasing, even though the evidence on the predictive ability and clinical utility of these tests is limited. The few available studies have shown that predicted risks of multifactorial diseases differed between companies and were sometimes even contradictory for the same individual [1,106], but large-scale studies on the predictive ability are lacking. From prediction studies that investigated genetic risk models based on different but comparable selections of SNPs, we know that the predictive ability of genetic testing for multifactorial diseases is low to moderate, except when one or more SNPs had substantial impact on disease risk [2]. From this indirect evidence it is concluded that the DTC offer of genetic testing for multifactorial diseases is premature. To date, most of the discussion about DTC personal genome tests has focused on the prediction of these multifactorial diseases and less attention has been given to the predictive ability and clinical utility of pharmacogenetic testing. Yet, many companies offer pharmacogenetic testing to inform about the genetic susceptibility to drug response and side effects of treatment [3], such as the efficacy of clopidogrel and the risk

Clinical and Ethical Considerations in Pharmacogenetic Testing

Pharmacogenetic testing for polymorphisms affecting drug response and metabolism is now clinically available, and its use in psychiatry is expected to become more widespread. Currently, few clinical and ethical standards exist for the use of these new tests. As a step toward building consensus about testing, we assessed the attitudes and practices of psychiatrists at 3 academic departments of psychiatry where pharmacogenetic testing is clinically available. We hypothesized that testing would be used primarily in treatment-resistant illness and that clinicians would believe such tests carried little risk. Residents and faculty at 3 departments of psychiatry considered to be "early adopters" of pharmacogenetic testing were invited during the academic year 2006-2007 to complete an Internet-based survey, including questions regarding clinical practices and opinions about testing utility, risks, and necessary safeguards. The 75 respondents had ordered pharmacogenetic testing a mean of 20.86 times in the previous 12 months. Testing was judged most useful in cases of treatment-resistant depression and medication intolerance. There was a lack of consensus about the risks of testing, particularly the risk of secondary information about disease susceptibility. Respondents endorsed the use of several safeguards, including confidentiality, pretest and posttest counseling, and informed consent, but consensus about other safeguards was lacking. Women and those who had not ordered testing in the prior year were more concerned about risks and need for safeguards than were men and those who had recently ordered testing. Physicians at early adopting departments of psychiatry endorsed the clinical utility of pharmacogenetic testing and the use of some patient safeguards, but showed a lack of consensus about other safeguards and risks.

Pharmacogenetics of antiretroviral therapy: genetic variation of response and toxicity.

The application of a pharmacogenetic approach to antiretroviral drug therapy represents a significant challenge, as treatment involves multiple drugs and drug classes with the potential for significant variability in drug-host, as well as drug-drug, interactions. However, despite this inherent complexity, considerable gains have been made in understanding how genetic factors influence the efficacy and toxicity of HIV therapy. In this review the available evidence regarding genetic variation in drug disposition will be examined, including the potential for relatively polymorphic drug-metabolizing enzymes (e.g., cytochrome P450 isoforms) and drug transporters (e.g., P-glycoprotein) to influence the disposition of HIV protease inhibitor and non-nucleoside reverse transcriptase inhibitor drugs. In addition, the role of genetic variation in determining the immune response to drug-specific antigens will be considered as a potentially significant determinant of susceptibility to idiosyncratic drug reactions (e.g., major histocompatibility complex alleles associated with abacavir hypersensitivity). The current and potential clinical utility of pharmacogenetic testing in HIV management will also be emphasized.