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JAMA Jul 2022Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial... (Comparative Study)
Comparative Study Randomized Controlled Trial
Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial.
IMPORTANCE
Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment.
OBJECTIVE
To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes.
DESIGN, SETTING, AND PARTICIPANTS
A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications.
INTERVENTIONS
Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978).
MAIN OUTCOMES AND MEASURES
The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters.
RESULTS
Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45).
CONCLUSIONS AND RELEVANCE
Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03170362.
Topics: Antidepressive Agents; Clinical Decision-Making; Depressive Disorder, Major; Drug Interactions; Female; Humans; Inappropriate Prescribing; Male; Middle Aged; Pharmacogenetics; Pharmacogenomic Testing; Remission Induction; Treatment Outcome; United States; United States Department of Veterans Affairs
PubMed: 35819423
DOI: 10.1001/jama.2022.9805 -
Genes Jun 2020Pharmacogenomics is one of the emerging approaches to precision medicine, tailoring drug selection and dosing to the patient's genetic features. In recent years, several...
Pharmacogenomics is one of the emerging approaches to precision medicine, tailoring drug selection and dosing to the patient's genetic features. In recent years, several pharmacogenetic guidelines have been published by international scientific consortia, but the uptake in clinical practice is still poor. Many coordinated international efforts are ongoing in order to overcome the existing barriers to pharmacogenomic implementation. On the other hand, existing validated pharmacogenomic markers can explain only a minor part of the observed clinical variability in the therapeutic outcome. New investigational approaches are warranted, including the study of the pharmacogenomic role of the immune system genetics and of previously neglected rare genetic variants, reported to account for a large part of the inter-individual variability in drug metabolism. In this Special Issue, we collected a series of articles covering many aspects of pharmacogenomics. These include clinical implementation of pharmacogenomics in clinical practice, development of tools or infrastractures to support this process, research of new pharmacogenomics markers to increase drug efficacy and safety, and the impact of rare genetic variants in pharmacogenomics.
Topics: Biomarkers; Humans; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine
PubMed: 32580376
DOI: 10.3390/genes11060679 -
Genes Sep 2021This Special Issue includes 15 peer-reviewed articles for publication by experts in Prader-Willi syndrome (PWS) and their reflective area of interest impacting this rare...
This Special Issue includes 15 peer-reviewed articles for publication by experts in Prader-Willi syndrome (PWS) and their reflective area of interest impacting this rare disorder [...].
Topics: Databases, Genetic; Genetic Association Studies; Humans; Pharmacogenomic Testing; Phenotype; Prader-Willi Syndrome; Rare Diseases
PubMed: 34573411
DOI: 10.3390/genes12091429 -
International Journal of Molecular... Oct 2020Epilepsy, a neurological disease characterized by recurrent seizures, is highly heterogeneous in nature. Based on the prevalence, epilepsy is classified into two types:... (Review)
Review
Epilepsy, a neurological disease characterized by recurrent seizures, is highly heterogeneous in nature. Based on the prevalence, epilepsy is classified into two types: common and rare epilepsies. Common epilepsies affecting nearly 95% people with epilepsy, comprise generalized epilepsy which encompass idiopathic generalized epilepsy like childhood absence epilepsy, juvenile myoclonic epilepsy, juvenile absence epilepsy and epilepsy with generalized tonic-clonic seizure on awakening and focal epilepsy like temporal lobe epilepsy and cryptogenic focal epilepsy. In 70% of the epilepsy cases, genetic factors are responsible either as single genetic variant in rare epilepsies or multiple genetic variants acting along with different environmental factors as in common epilepsies. Genetic testing and precision treatment have been developed for a few rare epilepsies and is lacking for common epilepsies due to their complex nature of inheritance. Precision medicine for common epilepsies require a panoramic approach that incorporates polygenic background and other non-genetic factors like microbiome, diet, age at disease onset, optimal time for treatment and other lifestyle factors which influence seizure threshold. This review aims to comprehensively present a state-of-art review of all the genes and their genetic variants that are associated with all common epilepsy subtypes. It also encompasses the basis of these genes in the epileptogenesis. Here, we discussed the current status of the common epilepsy genetics and address the clinical application so far on evidence-based markers in prognosis, diagnosis, and treatment management. In addition, we assessed the diagnostic predictability of a few genetic markers used for disease risk prediction in individuals. A combination of deeper endo-phenotyping including pharmaco-response data, electro-clinical imaging, and other clinical measurements along with genetics may be used to diagnose common epilepsies and this marks a step ahead in precision medicine in common epilepsies management.
Topics: DNA Copy Number Variations; Epilepsy; Epilepsy, Absence; Epilepsy, Generalized; Genetic Markers; Humans; Pharmacogenomic Testing; Precision Medicine; Prognosis; Seizures; Time Factors
PubMed: 33096746
DOI: 10.3390/ijms21207784 -
Clinical Pharmacology and Therapeutics Oct 2021Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and... (Review)
Review
Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and methadone). Polymorphisms in CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes that have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol-O-methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1, and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone, and methadone, and for OPRM1 and COMT for clinical use.
Topics: Analgesics, Opioid; Catechol O-Methyltransferase; Cytochrome P-450 CYP2D6; Genotype; Humans; Pain; Pharmacogenomic Testing; Pharmacogenomic Variants; Receptors, Opioid, mu
PubMed: 33387367
DOI: 10.1002/cpt.2149 -
JACC. Cardiovascular Interventions Aug 2019Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y receptor inhibitor is the standard treatment for patients undergoing percutaneous coronary intervention. The... (Review)
Review
Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y receptor inhibitor is the standard treatment for patients undergoing percutaneous coronary intervention. The availability of different P2Y receptor inhibitors (clopidogrel, prasugrel, ticagrelor) with varying levels of potency has enabled physicians to contemplate individualized treatment regimens, which may include escalation or de-escalation of P2Y-inhibiting therapy. Indeed, individualized and alternative DAPT strategies may be chosen according to the clinical setting (stable coronary artery disease vs. acute coronary syndrome), the stage of the disease (early- vs. long-term treatment), and patient risk for ischemic and bleeding complications. A tailored DAPT approach may be potentially guided by platelet function testing (PFT) or genetic testing. Although the routine use of PFT or genetic testing in percutaneous coronary intervention-treated patients is not recommended, recent data have led to an update in guideline recommendations that allow considering selective use of PFT for DAPT de-escalation. However, guidelines do not expand on when to implement the selective use of such assays into decision making for personalized treatment approaches. Therefore, an international expert consensus group of key leaders from North America, Asia, and Europe with expertise in the field of antiplatelet treatment was convened. This document updates 2 prior consensus papers on this topic and summarizes the contemporary updated expert consensus recommendations for the selective use of PFT or genotyping in patients undergoing percutaneous coronary intervention.
Topics: Blood Platelets; Clinical Decision-Making; Consensus; Coronary Thrombosis; Cytochrome P-450 CYP2C9; Dual Anti-Platelet Therapy; Hemorrhage; Humans; Patient Selection; Percutaneous Coronary Intervention; Pharmacogenomic Testing; Pharmacogenomic Variants; Platelet Aggregation Inhibitors; Platelet Function Tests; Precision Medicine; Predictive Value of Tests; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Risk Factors; Treatment Outcome
PubMed: 31202949
DOI: 10.1016/j.jcin.2019.03.034 -
Clinical Pharmacology and Therapeutics Aug 2020Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used analgesics due to their lack of addictive potential. However, NSAIDs have the potential to... (Meta-Analysis)
Meta-Analysis
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used analgesics due to their lack of addictive potential. However, NSAIDs have the potential to cause serious gastrointestinal, renal, and cardiovascular adverse events. CYP2C9 polymorphisms influence metabolism and clearance of several drugs in this class, thereby affecting drug exposure and potentially safety. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for NSAIDs based on CYP2C9 genotype (updates at www.cpicpgx.org).
Topics: Anti-Inflammatory Agents, Non-Steroidal; Clinical Decision-Making; Consensus; Cytochrome P-450 CYP2C9; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Genotype; Humans; Pharmacogenetics; Pharmacogenomic Testing; Pharmacogenomic Variants; Phenotype; Predictive Value of Tests; Risk Assessment; Risk Factors
PubMed: 32189324
DOI: 10.1002/cpt.1830 -
Nature Communications Apr 2019Genome-wide association studies (GWASs) of medication use may contribute to understanding of disease etiology, could generate new leads relevant for drug discovery and...
Genome-wide association studies (GWASs) of medication use may contribute to understanding of disease etiology, could generate new leads relevant for drug discovery and can be used to quantify future risk of medication taking. Here, we conduct GWASs of self-reported medication use from 23 medication categories in approximately 320,000 individuals from the UK Biobank. A total of 505 independent genetic loci that meet stringent criteria (P < 10/23) for statistical significance are identified. We investigate the implications of these GWAS findings in relation to biological mechanism, potential drug target identification and genetic risk stratification of disease. Amongst the medication-associated genes are 16 known therapeutic-effect target genes for medications from 9 categories. Two of the medication classes studied are for disorders that have not previously been subject to large GWAS (hypothyroidism and gastro-oesophageal reflux disease).
Topics: Aged; Biological Specimen Banks; Cardiovascular Diseases; Databases, Factual; Drug Utilization; Female; Gastrointestinal Diseases; Genetic Loci; Genome, Human; Genome-Wide Association Study; Humans; Male; Mental Disorders; Middle Aged; Musculoskeletal Diseases; Pharmacogenomic Testing; Prescription Drugs; Self Administration; Self Report; United Kingdom
PubMed: 31015401
DOI: 10.1038/s41467-019-09572-5 -
Current Problems in Pediatric and... Feb 2018Significant advances have been made in the application of pharmacogenomic testing for the treatment of patients with psychiatric disorders. Over the past decade, a... (Review)
Review
Significant advances have been made in the application of pharmacogenomic testing for the treatment of patients with psychiatric disorders. Over the past decade, a number of studies have evaluated the utility of pharmacogenomic testing in pediatric patients with psychiatric disorders. The evidence base for pharmacogenomic testing in youth with depressive and anxiety disorders as well as attention/deficit hyperactivity disorder (ADHD) is reviewed in this article. General pharmacogenomic principles are summarized and functional polymorphisms in P450 enzymes (and associated metabolizer phenotypes), the serotonin transporter promoter polymorphisms, serotonin 2A receptor genes (e.g., HT2AR) and catecholamine pathway genes (e.g., COMT) are reviewed. These commonly tested pharmacogenomic markers are discussed with regard to studies of drug levels, efficacy and side effects. The translation of pharmacogenomics to individualized/precision medicine in pediatric patients with ADHD, anxiety and depressive disorders has accelerated; however, its application remains challenging given that there are numerous divergent pathways between medication/medication dose and clinical response and side effects. Nonetheless, by leveraging variations in individual genes that may be relevant to medication metabolism or medication target engagement, pharmacogenomic testing may have a role in predicting treatment response, side effects and medication selection in youth with ADHD, depressive and anxiety disorders.
Topics: Adolescent; Adolescent Psychiatry; Antidepressive Agents, Second-Generation; Anxiety Disorders; Attention Deficit Disorder with Hyperactivity; Catechol O-Methyltransferase; Child; Child Psychiatry; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 Enzyme System; Depressive Disorder; Humans; Pharmacogenetics; Pharmacogenomic Testing; Receptor, Serotonin, 5-HT2A; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors
PubMed: 29325731
DOI: 10.1016/j.cppeds.2017.12.003 -
Genes Mar 2021Since the term "pharmacogenetics" was first published in the late 1950s by Friedrich Vogel, the field has evolved into genome-wide association studies identifying novel...
Since the term "pharmacogenetics" was first published in the late 1950s by Friedrich Vogel, the field has evolved into genome-wide association studies identifying novel variants associated with drug response phenotypes, international societies and consortia dedicated to pharmacogenomic research and clinical implementation, clinical practice guidelines, and the increasing availability of pharmacogenomic tests for healthcare providers in both hospital and primary care [...].
Topics: Genome-Wide Association Study; Humans; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine
PubMed: 33801919
DOI: 10.3390/genes12030393