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Pharmacogenomics Oct 2010Bipolar disorder (BD) is a serious mental illness with well-established, but poorly characterized genetic risk. Lithium is among the best proven mood stabilizer... (Review)
Review
Bipolar disorder (BD) is a serious mental illness with well-established, but poorly characterized genetic risk. Lithium is among the best proven mood stabilizer therapies for BD, but treatment responses vary considerably. Based upon these and other findings, it has been suggested that lithium-responsive BD may be a genetically distinct phenotype within the mood disorder spectrum. This assertion has practical implications both for the treatment of BD and for understanding the neurobiological basis of the illness: genetic variation within lithium-sensitive signaling pathways may confer preferential treatment response, and the involved genes may underlie BD in some individuals. Presently, the mechanism of lithium is reviewed with an emphasis on gene-expression changes in response to lithium. Within this context, findings from genetic-association studies designed to identify lithium response genes in BD patients are evaluated. Finally, a framework is proposed by which future pharmacogenetic studies can incorporate advances in genetics, molecular biology and bioinformatics in a pathway-based approach to predicting lithium treatment response.
Topics: Animals; Bipolar Disorder; Genetic Association Studies; Humans; Lithium; Pharmacogenetics; Phenotype; Treatment Outcome
PubMed: 21047205
DOI: 10.2217/pgs.10.127 -
Molecular Psychiatry Jul 2012Pharmacogenetic/pharmacogenomic (PGx) approaches to psychopharmacology aim to identify clinically meaningful predictors of drug efficacy and/or side-effect burden. To... (Review)
Review
Pharmacogenetic/pharmacogenomic (PGx) approaches to psychopharmacology aim to identify clinically meaningful predictors of drug efficacy and/or side-effect burden. To date, however, PGx studies in psychiatry have not yielded compelling results, and clinical utilization of PGx testing in psychiatry is extremely limited. In this review, the authors provide a brief overview on the status of PGx studies in psychiatry, review the commercialization process for PGx tests and then discuss methodological considerations that may enhance the potential for clinically applicable PGx tests in psychiatry. The authors focus on design considerations that include increased ascertainment of subjects in the earliest phases of illness, discuss the advantages of drug-induced adverse events as phenotypes for examination and emphasize the importance of maximizing adherence to treatment in pharmacogenetic studies. Finally, the authors discuss unique aspects of pharmacogenetic studies that may distinguish them from studies of other complex traits. Taken together, these data provide insights into the design and methodological considerations that may enhance the potential for clinical utility of PGx studies.
Topics: Biomarkers, Pharmacological; Genetic Testing; Humans; Pharmacogenetics; Psychotropic Drugs; Research Design; Translational Research, Biomedical
PubMed: 22083729
DOI: 10.1038/mp.2011.146 -
American Journal of Health-system... Dec 2016The operational elements essential for establishing an inpatient pharmacogenetic service are reviewed, and the role of the pharmacist in the provision of genotype-guided... (Review)
Review
PURPOSE
The operational elements essential for establishing an inpatient pharmacogenetic service are reviewed, and the role of the pharmacist in the provision of genotype-guided drug therapy in pharmacogenetics programs at three institutions is highlighted.
SUMMARY
Pharmacists are well positioned to assume important roles in facilitating the clinical use of genetic information to optimize drug therapy given their expertise in clinical pharmacology and therapeutics. Pharmacists have assumed important roles in implementing inpatient pharmacogenetics programs. This includes programs designed to incorporate genetic test results to optimize antiplatelet drug selection after percutaneous coronary intervention and personalize warfarin dosing. Pharmacist involvement occurs on many levels, including championing and leading pharmacogenetics implementation efforts, establishing clinical processes to support genotype-guided therapy, assisting the clinical staff with interpreting genetic test results and applying them to prescribing decisions, and educating other healthcare providers and patients on genomic medicine. The three inpatient pharmacogenetics programs described use reactive versus preemptive genotyping, the most feasible approach under the current third-party payment structure. All three sites also follow Clinical Pharmacogenetics Implementation Consortium guidelines for drug therapy recommendations based on genetic test results.
CONCLUSION
With the clinical emergence of pharmacogenetics into the inpatient setting, it is important that pharmacists caring for hospitalized patients are well prepared to serve as experts in interpreting and applying genetic test results to guide drug therapy decisions. Since genetic test results may not be available until after patient discharge, pharmacists practicing in the ambulatory care setting should also be prepared to assist with genotype-guided drug therapy as part of transitions in care.
Topics: Genotype; Hospitalization; Humans; Patient Care Team; Pharmacogenetics; Pharmacy Service, Hospital; Professional Role; Program Development
PubMed: 27864202
DOI: 10.2146/ajhp150946 -
Pharmacological Research Apr 2004The study of the influence of genotype on drug activity and efficacy (pharmacogenetics) and the genome-wide approach to drug discovery and interpretation of complex... (Review)
Review
The study of the influence of genotype on drug activity and efficacy (pharmacogenetics) and the genome-wide approach to drug discovery and interpretation of complex pharmacological responses (pharmacogenomics) are gaining momentum in current molecular medicine. The reasons of the variable activity and tolerability of cancer chemotherapy are being unraveled by the discovery of genotypic alterations affecting pharmacokinetics and pharmacodynamics of drugs. Indeed, genetic variability may alter drug catabolism (i.e. dihydropyrimidine dehydrogenase for 5-fluorouracil, thiopurine-S-methyl transferase for thiopurines, aldehyde dehydrogenase for cyclophosphamide) and anabolism (i.e. thymidine phosphorylase for capecitabine, deoxycitidine kinase for gemcitabine). Moreover, increased expression of transporter systems (i.e. the ATP binding cassette (ABC) superfamily) is associated with reduction of the cytoplasmic levels of drugs which may be unable to exert a cytotoxic effect. Additional systems could protect tumor cells from drug cytotoxicity, including the DNA repair machinery (nucleotide excision repair (NER) and DNA alkyltransferases) and antiapoptotic systems (i.e. bcl-2). Finally, alterations of drug targets may be associated with a decrease in the effectiveness of chemotherapy (i.e. mutations affecting tubulin and topoisomerase I for taxanes and irinotecan, respectively, and increased expression of thymidilate synthase for 5-fluorouracil). Therefore, genetic analysis has the potential to predict treatment efficacy and tolerability. However, major problems encountered in pharmacogenetic and pharmacogenomic studies are the need of extensive validation of available technology, the difficulties in obtaining a suitable amount of tissue from patients during the course of their disease and the extremely complex regulation of gene function. From this perspective, the evaluation of the cellular effect of drugs in relation to protein expression and function (pharmacoproteomics) may be able to overcome these obstacles, and allow the optimisation of cancer chemotherapy in association with a pharmacogenetic approach.
Topics: Animals; Antineoplastic Agents; Humans; Neoplasms; Pharmacogenetics
PubMed: 15202512
DOI: 10.1016/j.phrs.2003.05.002 -
American Family Physician Oct 2007Pharmacogenetics is a growing field of research that focuses on the interaction between genetics and drug therapy. Relationships between genetic variation and drug... (Review)
Review
Pharmacogenetics is a growing field of research that focuses on the interaction between genetics and drug therapy. Relationships between genetic variation and drug effect have been observed for a growing number of commonly used drugs. Validation studies may soon define the use of these relationships in clinical practice, moving the field toward routine application. Currently, there are only a few pharmacogenetic diagnostic tests available, and clinical guidelines for pharmacogenetically tailored therapy are lacking. It is likely that guidelines for pharmacogenetic dosing of certain commonly used drugs such as warfarin, codeine, and inhaled beta agonists will become available within the next few years.
Topics: Biotransformation; Drug Resistance; Humans; Pharmacogenetics; Polymorphism, Genetic
PubMed: 17990842
DOI: No ID Found -
Bioethics Aug 2004
Topics: Ethical Analysis; Humans; Pharmacogenetics; Risk Assessment; Terminology as Topic
PubMed: 15449403
DOI: 10.1111/j.1467-8519.2004.00398.x -
Drug Discovery Today Oct 2011Pharmacogenetics (PGx) is increasingly used as a way to target treatment to patients who are most likely to benefit. To date, PGx has shown clinical significance across... (Review)
Review
Pharmacogenetics (PGx) is increasingly used as a way to target treatment to patients who are most likely to benefit. To date, PGx has shown clinical significance across a few applications but widespread use has been limited by the need for further technical, methodological and practical advances and for educating clinical researchers on the value of PGx. Here, I describe the current scope of PGx research, including recent contributions to prospective study design. A case study is included to demonstrate the limitations of current practice and to describe some practical steps for improving the chances of identifying genetic effects. Additionally, I describe some opportunities for the integration and application of disparate data sources in exploratory PGx research.
Topics: Biomedical Research; Humans; Pharmacogenetics; Research Design; Statistics as Topic
PubMed: 21875683
DOI: 10.1016/j.drudis.2011.08.008 -
Behavioural Brain Research Mar 2021Decades of research have produced extensive evidence of the contribution of genetic factors to the efficacy and toxicity of antipsychotics. Numerous genetic variants in...
Decades of research have produced extensive evidence of the contribution of genetic factors to the efficacy and toxicity of antipsychotics. Numerous genetic variants in genes controlling drug availability or involved in antipsychotic processes have been linked to treatment variability. The complex mechanism of action and multitarget profile of most antipsychotic drugs hinder the identification of pharmacogenetic markers of clinical value. Nevertheless, the validity of associations between variants in CYP1A2, CYP2D6, CYP2C19, ABCB1, DRD2, DRD3, HTR2A, HTR2C, BDNF, COMT, MC4R genes and antipsychotic response has been confirmed in independent candidate gene studies. Genome wide pharmacogenomic studies have proven the role of the glutamatergic pathway in mediating antipsychotic activity and have reported novel associations with antipsychotic response. However, only a limited number of the findings, mainly functional variants of CYP metabolic enzymes, have been shown to be of clinical utility and translated into useful pharmacogenetic markers. Based on the currently available information, actionable pharmacogenetics should be reduced to antipsychotics' dose adjustment according to the genetically predicted metabolic status (CYPs' profile) of the patient. Growing evidence suggests that such interventions will reduce antipsychotics' side-effects and increase treatment safety. Despite this evidence, the use of pharmacogenetics in psychiatric wards is minimal. Hopefully, further evidence on the clinical and economic benefits, the development of clinical protocols based on pharmacogenetic information, and improved and cheaper genetic testing will increase the implementation of pharmacogenetic guided prescription in clinical settings.
Topics: Antipsychotic Agents; Humans; Pharmacogenetics; Precision Medicine
PubMed: 33316324
DOI: 10.1016/j.bbr.2020.113058 -
Current Opinion in Psychiatry Jan 2019The implementation of pharmacogenetic testing in psychiatry is underway but is not yet standard protocol. Barriers to pharmacogenetics becoming standard practice are the... (Review)
Review
PURPOSE OF REVIEW
The implementation of pharmacogenetic testing in psychiatry is underway but is not yet standard protocol. Barriers to pharmacogenetics becoming standard practice are the lack of translation of evidence-based recommendations and standardization of genetic testing panels. As for the latter, there are currently no regulatory standards related to the gene and allele content of testing panels used to derive medication selection and dosing advice. To address these barriers, we summarize the current gene-drug interaction knowledgebase and proposed a minimum gene and allele set for pharmacogenetic testing in psychiatry.
RECENT FINDINGS
The Pharmacogenomics Knowledgebase has cataloged 448 gene-drug interactions relevant to psychiatry based on the current scientific literature, drug labels, and pharmacogenetic-based implementation guidelines. A majority of these interactions involved two cytochrome P450 enzymes (CYP2D6 and CYP2C19) and antidepressant medications, however, CYP2C9, HLA-A, and HLA-B are relevant to mood stabilizers/anticonvulsants.
SUMMARY
On the basis of evidence base, we proposed a minimum gene and allele set for pharmacogenetic testing in psychiatry that includes 16 variant alleles within five genes (CYP2C9, CYP2C19, CYP2D6, HLA-A, HLA-B). The intent is to assist clinicians in judging the gene and allele content of pharmacogenetic tests and to facilitate pharmacogenetic testing as a standard protocol and companion tool for psychotropic medication selection and dosing.
Topics: Alleles; Evidence-Based Medicine; Genetic Testing; Humans; Mental Disorders; Pharmacogenetics; Pharmacogenomic Testing; Psychiatry
PubMed: 30299306
DOI: 10.1097/YCO.0000000000000465 -
BioTechniques Oct 2005Pharmacogenetics and pharmacogenomics are keys to the success of personalized medicine, prescribing drugs based on a patient's individual genetic and biological profile.... (Review)
Review
Pharmacogenetics and pharmacogenomics are keys to the success of personalized medicine, prescribing drugs based on a patient's individual genetic and biological profile. In this review, we will focus on the application of pharmacogenetics and pharmacogenomics in developing monoclonal antibody (MAb) therapeutics in oncology. The significance of pharmacogenomics in MAb therapeutics is highlighted by the association between polymorphisms in Fc receptors and clinical response to anti-CD20 MAb rituximab (Rituxan) or anti-ganglioside GD2 MAb 3F8, as well as the potential link between polymorphisms in HER2 and cardiac toxicity in patients treated with the anti-HER2 MAb trastuzumab (Herceptin). The dependence on gene copy number or expression levels ofHER2 and epidermal growth factor receptor (EGFR) for therapeutic efficacy of trastuzumab and cetuximab (Erbitux), respectively, supports the importance of selecting suitable patient populations based on their pharmacogenetic profile. In addition, a better understanding of target mutation status and biological consequences will benefit MAb development and may guide clinical development and use of these innovative therapeutics. The application of pharmacogenetics and pharmacogenomics in developing MAb therapeutics will be largely dependent on the discovery of novel surrogate biomarkers and identification of disease- and therapeutics-relevant polymorphisms. Challenges and opportunities in biomarker discovery and validation, and in implementing clinical pharmacogenetics and pharmacogenomics in oncology MAb development and clinical practice will also be discussed.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Humans; Medical Oncology; Neoplasms; Pharmacogenetics; Technology, Pharmaceutical
PubMed: 18957038
DOI: 10.2144/000112043