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Journal of Child and Adolescent... Feb 2024The efficacy and tolerability of psychotropic medications can vary significantly among children and adolescents, and some of this variability relates to pharmacogenetic... (Review)
Review
The efficacy and tolerability of psychotropic medications can vary significantly among children and adolescents, and some of this variability relates to pharmacogenetic factors. Pharmacogenetics (PGx) in child and adolescent psychiatry can potentially improve treatment outcomes and minimize adverse drug reactions. This article reviews key pharmacokinetic and pharmacodynamic genes and principles of pharmacogenetic testing and discusses the evidence base for clinical decision-making concerning PGx testing. This article reviews current guidelines from the United States Food and Drug Administration (FDA), the Clinical Pharmacogenetics Implementation Consortium (CPIC), and the Dutch Pharmacogenetics Working Group (DPWG) and explores potential future directions. This review discusses key clinical considerations for clinicians prescribing psychotropic medications in children and adolescents, focusing on antidepressants, antipsychotics, stimulants, norepinephrine reuptake inhibitors, and alpha-2 agonists. Finally, this review synthesizes the practical use of pharmacogenetic testing and clinical decision support systems.
Topics: United States; Child; Humans; Adolescent; Pharmacogenetics; Adolescent Psychiatry; Psychotropic Drugs; Antidepressive Agents; Pharmacogenomic Testing
PubMed: 38377525
DOI: 10.1089/cap.2023.0074 -
Clinical Pharmacology and Therapeutics Jul 2023Over 20% of US Food and Drug Administration (FDA)-approved drugs in the United States are metabolized by the hepatic enzyme cytochrome P450 2D6 (CYP2D6). The gene... (Review)
Review
Over 20% of US Food and Drug Administration (FDA)-approved drugs in the United States are metabolized by the hepatic enzyme cytochrome P450 2D6 (CYP2D6). The gene encoding CYP2D6 is highly polymorphic and genetic variation has been shown to impact drug response for many commonly dispensed drugs including opioids and antidepressants. Thus, it is important to understand an individual's CYP2D6 metabolizer status to optimize treatment outcomes for patients taking medications that are metabolized by this enzyme. Consequently, clinical CYP2D6 pharmacogenetic testing is being implemented by a growing number of health centers. Furthermore, clinical guidelines currently recommend adapting therapeutic regimens based on CYP2D6 genotype-informed phenotype. However, CYP2D6 genetic variation varies considerably across global populations and many allelic variants, or star alleles, are predominantly found in certain ancestral populations. Although CYP2D6 genetic variation has been extensively studied, there is still a paucity of information for many non-European populations. As has been shown for other pharmacogenes in randomized controlled trials, results from European populations cannot simply be extrapolated to other groups and, in some cases, even has the potential to cause harm. Therefore, enhanced inclusion in pharmacogenetic studies is urgently needed to increase ancestral representation, determine the extent of global CYP2D6 genetic variation (e.g., ancestry-specific variants), and determine the clinical impact of this variation on clinical treatment outcome. This review highlights knowledge gaps, challenges, and future directions in CYP2D6 pharmacogenomics through a unique pharmacoequity lens to address health inequities that hamper our ability to optimize drug therapy for improved pharmacological outcomes in diverse populations globally.
Topics: Cytochrome P-450 CYP2D6; Pharmacogenetics; Genotype; Antidepressive Agents; Pharmaceutical Preparations
PubMed: 36924260
DOI: 10.1002/cpt.2890 -
Personalized Medicine Nov 2020The field of pharmacogenetic testing was hailed as one of the early successful clinical applications arising from the personalized (or precision) medicine revolution.... (Review)
Review
The field of pharmacogenetic testing was hailed as one of the early successful clinical applications arising from the personalized (or precision) medicine revolution. Substantial progress has been made to identify genes and genetic variants involved in drug response and establish clinical implementation programs. Yet, drug response is a complex trait and recent work has highlighted the key role played by the gut microbiome. As the study of the gut microbiome and pharmacogenetics converge, it may be possible to generate more precise predictions of drug response and improve health outcomes to treatments. Substantial effort will be needed to understand the dynamic impact of the microbiome and the interplay with host genetics and how to implement expanded pharmacogenetic testing.
Topics: Biomarkers, Pharmacological; Humans; Microbiota; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine
PubMed: 33026284
DOI: 10.2217/pme-2020-0077 -
Pharmacogenomics Jun 2016Recent research highlighted the large extent of rare variants in pharmacogenes and, on this basis, it was estimated that rare variants account for 30-40% of the... (Review)
Review
Recent research highlighted the large extent of rare variants in pharmacogenes and, on this basis, it was estimated that rare variants account for 30-40% of the functional variability in pharmacogenes. It has been proposed that comprehensive next-generation sequencing (NGS)-based sequencing of pharmacogenes could soon be a cost-effective methodology for clinical routine genotyping. Yet, multiple challenges on technical, interpretative and ethical levels need to be overcome to enable the reasonable dissemination of comprehensive pharmacogenetic genotyping, that includes rare genetic variation, into clinical practice. We argue that current pre-emptive pharmacogenetic testing cannot be based on comprehensive approaches but needs to be restricted to validated variants. Rather, comprehensive strategies should only be used for retrospective analyses of patients exhibiting unanticipated drug responses. Thereby, subsequent to computational analyses and functional validations, emerging variants with confirmed functional relevance can be incorporated into candidate genotyping strategies, thus refining and enhancing future pre-emptive genetic testing.
Topics: Genotyping Techniques; High-Throughput Nucleotide Sequencing; Humans; Pharmacogenetics; Phenotype; Retrospective Studies
PubMed: 27248710
DOI: 10.2217/pgs-2016-0023 -
Best Practice & Research. Clinical... Jun 2018The study of how individual genetic differences, known as polymorphisms, change the pharmacokinetics and pharmacodynamics of drugs is called pharmacogenomics. As the... (Review)
Review
The study of how individual genetic differences, known as polymorphisms, change the pharmacokinetics and pharmacodynamics of drugs is called pharmacogenomics. As the field of pharmacogenetics grows and continues to identify genetic polymorphisms, it is promising that the unmet need in this patient population may soon be addressed with personalized drug therapy based on the patient's genetic composition. Although encouraging, pharmacogenomic testing is underutilized in the United States and is often not covered by insurance companies. This manuscript describes the current state of precision medicine as it relates to perioperative care and how preoperative genomic analysis can help improve patient outcomes. This investigation also outlines future directions in this important and evolving field.
Topics: Anesthesia; Humans; Perioperative Care; Pharmacogenetics; Precision Medicine
PubMed: 30322465
DOI: 10.1016/j.bpa.2018.07.001 -
Pharmacogenomics Aug 2018
Topics: Antipsychotic Agents; Cognitive Dysfunction; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide; Schizophrenia
PubMed: 30028229
DOI: 10.2217/pgs-2018-0083 -
Clinical and Experimental Pharmacology... Aug 2019Genetic polymorphisms impact biological responses to drugs. Current pharmacogenomics guidelines formulated by different countries, such as the Clinical Pharmacogenetics... (Review)
Review
Genetic polymorphisms impact biological responses to drugs. Current pharmacogenomics guidelines formulated by different countries, such as the Clinical Pharmacogenetics Implementation Consortium, the Dutch Pharmacogenetics Working Group, the Canadian Pharmacogenomics Network for Drug Safety, and the French National Network (Réseau) of Pharmacogenetics, play important roles in clinical practices. However, the standards for these guidelines vary significantly, resulting in differences in recommendations. The present article discusses these differences by head-to-head comparison of the existing pharmacogenomics guidelines and proposes new strategies for their future development.
Topics: Guidelines as Topic; Humans; Pharmacogenetics
PubMed: 31009088
DOI: 10.1111/1440-1681.13097 -
Pharmacogenomics Aug 2022Pharmacogenetics is the relationship between an individual's genetic variations and their response to pharmacological treatment. We conducted an overview of reviews on... (Review)
Review
Pharmacogenetics is the relationship between an individual's genetic variations and their response to pharmacological treatment. We conducted an overview of reviews on the use of post-treatment pharmacogenetic testing for oncology, based on clinically relevant gene-drug pairs. We conducted a search on Medline, Embase and Cochrane Library, from their inception to 18 June 2020. We selected six eligible systematic reviews. The most studied drug categories were estrogen agonists/antagonists and fluoropyrimidines associated with cytochrome P450 and dihydropyrimidine dehydrogenase genes ( and ), but many studies were classified as being of critically low or low quality. There is a need for more high-quality primary studies and systematic reviews that assess the risk of bias, with consistent definitions of clinical outcomes to consider the benefits of pharmacogenetic testing for oncology.
Topics: Humans; Medical Oncology; Pharmacogenetics; Pharmacogenomic Testing; Systematic Reviews as Topic
PubMed: 36001087
DOI: 10.2217/pgs-2022-0064 -
CNS Drugs Dec 2016Genetic variation underlies both the response to antidepressant treatment and the occurrence of side effects. Over the past two decades, a number of pharmacogenetic... (Review)
Review
Genetic variation underlies both the response to antidepressant treatment and the occurrence of side effects. Over the past two decades, a number of pharmacogenetic variants, among these the SCL6A4, BDNF, FKBP5, GNB3, GRIK4, and ABCB1 genes, have come to the forefront in this regard. However, small effects sizes, mixed results in independent samples, and conflicting meta-analyses results led to inherent difficulties in the field of pharmacogenetics translating these findings into clinical practice. Nearly all antidepressant pharmacogenetic variants have potentially pleiotropic effects in which they are associated with major depressive disorder, intermediate phenotypes involved in emotional processes, and brain areas affected by antidepressant treatment. The purpose of this article is to provide a comprehensive review of the advances made in the field of pharmacogenetics of antidepressant efficacy and side effects, imaging findings of antidepressant response, and the latest results in the expanding field of imaging-pharmacogenetics studies. We suggest there is mounting evidence that genetic factors exert their impact on treatment response by influencing brain structural and functional changes during antidepressant treatment, and combining neuroimaging and genetic methods may be a more powerful way to detect biological mechanisms of response than either method alone. The most promising imaging-pharmacogenetics findings exist for the SCL6A4 gene, with converging associations with antidepressant response, frontolimbic predictors of affective symptoms, and normalization of frontolimbic activity following antidepressant treatment. More research is required before imaging-pharmacogenetics informed personalized medicine can be applied to antidepressant treatment; nevertheless, inroads have been made towards assessing genetic and neuroanatomical liability and potential clinical application.
Topics: Animals; Antidepressive Agents; Depressive Disorder, Major; Genetic Variation; Humans; Pharmacogenetics; Precision Medicine
PubMed: 27752945
DOI: 10.1007/s40263-016-0385-9 -
Pharmacological Research Aug 2019Natural products have represented attractive alternatives for disease prevention and treatment over the course of human history and have contributed to the development... (Review)
Review
Natural products have represented attractive alternatives for disease prevention and treatment over the course of human history and have contributed to the development of modern drugs. These natural products possess beneficial efficacies as well as adverse efffects, which vary largely among individuals because of genetic variations in their pharmacokinetics and pharmacodynamics. As with other synthetic chemical drugs, the dosing of natural products can be optimized to improve efficacy and reduce toxicity according to the pharmacogenetic properties. With the emergence and development of pharmacogenomics, it is possible to discover and identify the targets/mechanisms of pharmacological effects and therapeutic responses of natural products effectively and efficiently on the whole genome level. This review covers the effects of genetic variations in drug metabolizing enzymes, drug transporters, and direct and indirect interactions with the pharmacological targets/pathways on the individual response to natural products, and provides suggestions on dosing regimen adjustments of natural products based on their pharmacokinetic and pharmacogenetic paratmeters. Finally, we provide our viewpoints on the importance and necessity of pharmacogenetic and pharmacogenomic research of natural products in natural medicine's rational development and clinical application of precision medicine.
Topics: Biological Products; Biological Transport; Humans; Pharmacogenetics
PubMed: 31129178
DOI: 10.1016/j.phrs.2019.104283