Pharmacogenomics- a step to personalized medicinesApusi Chowdhury
Pharmacogenomics aims to optimize drug therapy based on a patient's genotype to maximize efficacy and minimize adverse effects. It involves studying how genetic factors influence individual responses to drugs in terms of absorption, distribution, metabolism, and excretion. Genetic polymorphisms like SNPs that occur in over 1% of the population can impact a drug's effects. Pharmacogenomic testing identifies biomarkers related to drug metabolism and targets to determine effective treatments and dosages for patients. While it holds promise for improving drug development and personalized medicine, limitations include insufficient validation and high costs.
Pharmacogenomics aims to optimize drug therapy based on a patient's genotype. Genetic factors can account for 20-95% of variability in drug response. Polymorphisms like SNPs that occur in over 1% of a population can impact drug metabolism and effects. Pharmacogenomic testing targets biomarkers for specific drug classes to determine efficacy and avoid toxicity. While it has potential to improve prescribing, limitations include many genes influencing drugs and ethical issues. Personalized medicine based on pharmacogenomics is still developing.
Pharmacogenomics is the study of how genes affect individual responses to drugs. It combines pharmacology and genomics to develop safe and effective personalized medications and dosages based on a person's genetic makeup. The goal is to improve treatment outcomes by predicting drug effectiveness and reducing adverse reactions. Challenges include implementing genetic tests in clinical practice and addressing cost, ethical and legal issues. Future applications include developing tailored drugs for many diseases and faster, more targeted clinical trials through biomarkers.
INTRODUCTION
What is pharmacogenomics
History
Principle
So what’s new about pharmacogenomics?
single nucleotide polymorphism (SNP)?
Genes commonly involved in pharmacogenomic drug metabolism and response
The anticipated benefits of pharmacogenomics
Pharmacogenetics Research/Database Program
Some of the barriers to using pharmacogenomics
Conclusion
References
The document discusses the role of genomics in pharmacogenomics and drug development. It defines key terms like pharmacogenomics and pharmacogenetics. It explains how genomics technologies can help optimize drug efficacy and minimize toxicity by identifying genetic variations that influence individual drug responses. Genomic information from the human genome project can aid drug target identification and reduce bottlenecks in development. Single nucleotide polymorphisms are discussed as the most common genetic variations affecting drug metabolism. The applications of pharmacogenomics in precision medicine to improve drug safety and efficacy are summarized.
Pharmacogenomics leads to more personalized drug therapy by understanding how an individual's genetics affects their response to medications. Variations in genes can impact drug receptors, metabolism, and other factors. Understanding these genetic differences could allow doctors to prescribe safer and more effective medications at the right dose for each patient.
This document discusses the potential for genetic biomarkers to improve psychiatric treatment by predicting treatment response. It notes that while causes of psychiatric disorders are unclear, identifying genetic factors can help select the best treatments. Several studies are exploring candidate genes for conditions like depression. Ultimately, genetic testing may guide antidepressant selection in clinical practice, though social and ethical issues require consideration. Biomarkers could enhance psychiatry similarly to other fields by enabling personalized treatment.
This document discusses the potential for using genetic biomarkers to improve treatment for psychiatric disorders. It notes that while the causes of psychiatric disorders are still unclear, identifying genetic markers that predict treatment response could help tailor medication selection. The document outlines several studies that have identified candidate genes associated with response to antidepressants and other psychotropic drugs. It acknowledges limitations but argues that further research in pharmacogenetics, using larger, more standardized studies, could help incorporate genetic testing into clinical practice to select safer, more effective treatments for individual patients.
Pharmacogenomics- a step to personalized medicinesApusi Chowdhury
Pharmacogenomics aims to optimize drug therapy based on a patient's genotype to maximize efficacy and minimize adverse effects. It involves studying how genetic factors influence individual responses to drugs in terms of absorption, distribution, metabolism, and excretion. Genetic polymorphisms like SNPs that occur in over 1% of the population can impact a drug's effects. Pharmacogenomic testing identifies biomarkers related to drug metabolism and targets to determine effective treatments and dosages for patients. While it holds promise for improving drug development and personalized medicine, limitations include insufficient validation and high costs.
Pharmacogenomics aims to optimize drug therapy based on a patient's genotype. Genetic factors can account for 20-95% of variability in drug response. Polymorphisms like SNPs that occur in over 1% of a population can impact drug metabolism and effects. Pharmacogenomic testing targets biomarkers for specific drug classes to determine efficacy and avoid toxicity. While it has potential to improve prescribing, limitations include many genes influencing drugs and ethical issues. Personalized medicine based on pharmacogenomics is still developing.
Pharmacogenomics is the study of how genes affect individual responses to drugs. It combines pharmacology and genomics to develop safe and effective personalized medications and dosages based on a person's genetic makeup. The goal is to improve treatment outcomes by predicting drug effectiveness and reducing adverse reactions. Challenges include implementing genetic tests in clinical practice and addressing cost, ethical and legal issues. Future applications include developing tailored drugs for many diseases and faster, more targeted clinical trials through biomarkers.
INTRODUCTION
What is pharmacogenomics
History
Principle
So what’s new about pharmacogenomics?
single nucleotide polymorphism (SNP)?
Genes commonly involved in pharmacogenomic drug metabolism and response
The anticipated benefits of pharmacogenomics
Pharmacogenetics Research/Database Program
Some of the barriers to using pharmacogenomics
Conclusion
References
The document discusses the role of genomics in pharmacogenomics and drug development. It defines key terms like pharmacogenomics and pharmacogenetics. It explains how genomics technologies can help optimize drug efficacy and minimize toxicity by identifying genetic variations that influence individual drug responses. Genomic information from the human genome project can aid drug target identification and reduce bottlenecks in development. Single nucleotide polymorphisms are discussed as the most common genetic variations affecting drug metabolism. The applications of pharmacogenomics in precision medicine to improve drug safety and efficacy are summarized.
Pharmacogenomics leads to more personalized drug therapy by understanding how an individual's genetics affects their response to medications. Variations in genes can impact drug receptors, metabolism, and other factors. Understanding these genetic differences could allow doctors to prescribe safer and more effective medications at the right dose for each patient.
This document discusses the potential for genetic biomarkers to improve psychiatric treatment by predicting treatment response. It notes that while causes of psychiatric disorders are unclear, identifying genetic factors can help select the best treatments. Several studies are exploring candidate genes for conditions like depression. Ultimately, genetic testing may guide antidepressant selection in clinical practice, though social and ethical issues require consideration. Biomarkers could enhance psychiatry similarly to other fields by enabling personalized treatment.
This document discusses the potential for using genetic biomarkers to improve treatment for psychiatric disorders. It notes that while the causes of psychiatric disorders are still unclear, identifying genetic markers that predict treatment response could help tailor medication selection. The document outlines several studies that have identified candidate genes associated with response to antidepressants and other psychotropic drugs. It acknowledges limitations but argues that further research in pharmacogenetics, using larger, more standardized studies, could help incorporate genetic testing into clinical practice to select safer, more effective treatments for individual patients.
DDS personalised medicines M.Pharma 1st Sem Pharmaceutics.pptxkushaltegginamani18
The document discusses personalized medicines and customized drug delivery systems. It defines personalized medicine as using genetic profiling and other individual patient characteristics to guide medical treatment. Customized drug delivery systems aim to optimize drug therapy for each patient by controlling dosage and delivery through technologies like bioelectronic medicines, 3D printing of pharmaceuticals, and telepharmacy.
Pharmacogenetics- Introduction, History with case StudyPushpak Bhati
Pharmacogenetics is the study of how an individual's genetic makeup influences their response to drugs. It allows for a personalized medication approach to optimize drug selection and dosing based on genetic factors. Integrating pharmacogenomics into clinical decision making can streamline treatment by minimizing adverse events and improving outcomes through more effective strategies. Proactive pharmacogenetic testing holds promise in preventing medication issues by offering a personalized, preventative approach to care. While challenges remain, advancements in technology and research are advancing pharmacogenetics' role in precision medicine.
Pharmacogenomics is the study of how an individual's genetic inheritance affects their body's response to drugs. It combines knowledge of genetics with pharmacology to develop tailored treatments for individuals based on their genetic makeup. The goal is to understand how genetic variations influence drug metabolism and response in order to optimize drug efficacy and safety for each patient. Pharmacogenomics holds promise for more powerful and safer medications, better screening for disease, and improvements in the drug development process through a more personalized approach to medicine. However, challenges remain in fully realizing this potential due to the complexity of genetic variations and interactions.
- Classical/receptor pharmacology, also known as forward pharmacology, uses phenotypic screening of natural or synthetic molecules to identify potential therapeutic agents based on observable changes in disease models. This approach has historically led to many drug discoveries but fell out of favor as reverse pharmacology focusing on specific targets became popular.
- However, reverse pharmacology relying solely on target identification has faced many late-stage clinical failures due to lack of efficacy. Phenotypic screening still plays an important role in drug development by discovering drugs with novel mechanisms of action and multi-target effects without requiring an identified target.
- Both classical and reverse pharmacology approaches have advantages and disadvantages, and a balanced approach integrating both may be optimal for future drug discovery and
PERSONALIZED MEDICINE AND PHARMACOGENETICSAravindgowda6
This document discusses personalized medicine and pharmacogenetics. It defines personalized medicine as tailoring medical treatment to an individual's characteristics. Pharmacogenetics is the study of how genetic differences influence variability in drug responses. The document outlines how genetic polymorphisms can impact drug metabolism and efficacy through variations in phase I and phase II drug metabolizing enzymes. It also categorizes different types of patients who may benefit from personalized medicine approaches based on factors like age, gender, medical conditions, and genetics.
This document provides an introduction to pharmacogenomics. It defines pharmacogenomics as the study of how genetic variations affect drug response and metabolism. It discusses key concepts like interracial and individual variability in drug metabolism due to single nucleotide polymorphisms and variable number tandem repeats. Case studies on tamoxifen metabolism and alcohol metabolism are presented. Challenges to implementing pharmacogenomics in clinical practice are noted. Applications to drug development and personalized medicine are mentioned.
This document discusses the importance and benefits of pharmacogenomics in clinical practice. Pharmacogenomics is the study of how genes affect a person's response to medications. It combines pharmacology and genomics to develop safe and effective medication doses tailored to a person's genetic makeup. Integrating pharmacogenomic testing into practice can help reduce adverse drug reactions, enhance patient outcomes, and lower healthcare costs by avoiding trial-and-error prescribing. Certain populations, such as older adults taking multiple chronic medications, are most likely to benefit from this personalized approach to medication treatment and management. Successful integration requires a partnership approach to help navigate workflow requirements and provide expertise, education and support to providers.
Soal dan Pembahasan Farmakogenomik dan Personalized MedicineNesha Mutiara
Materi farmakologi molekular farmakogenomik dan personalized medicine :
- penjelasan farmakogenomik, farmakogenetik, dan personalized medicine
- mekanisme kerja molekular warfarin dan clopidogrel terkait farmakogenomik
This document discusses personalized medicine (PM), which aims to provide customized treatment and care based on a patient's genetic profile. PM considers how genetic variations affect an individual's response to medications and susceptibility to diseases. The document outlines key benefits of PM, such as improved medication selection and safer dosing to minimize adverse reactions. It also discusses some current genetic tests used in PM, such as tests for enzymes involved in drug metabolism. Overall, the document presents PM as a promising approach that may enable more effective, targeted treatment tailored to individual patients.
Pharmacogenomics shows promise for improving patient outcomes and safety by enabling more personalized treatment approaches based on a patient's genetics. However, fully realizing its benefits faces several challenges, including the need for healthcare stakeholders to coordinate effectively, securing adequate resources, and educating physicians on pharmacogenomics. Additionally, drug interactions and environmental factors can complicate the relationship between genetics and drug response, requiring more research before pharmacogenomic testing can be widely implemented in clinical practice.
Pharmacogenomics is the study of how genetic factors affect individual responses to drugs. It aims to develop effective and safe medications tailored to a person's genetic profile. Variations in genes involved in drug metabolism and transport can impact drug efficacy and toxicity between individuals. Understanding these genetic differences may help optimize drug selection and dosing on a personalized level. While pharmacogenomics offers advantages like improved drug response and safety, challenges remain in fully validating results and identifying all relevant genetic variations due to drug pathways' complexity.
This document discusses genomics, proteomics, bioinformatics, pharmacogenomics, and the human genome project. It provides information on how genetic polymorphisms can influence drug disposition by affecting metabolizing enzymes and transporters. The human genome project mapped the entire human genome sequence to further the goals of personalized medicine based on an individual's genetic profile. Single nucleotide polymorphisms are particularly important for understanding how individuals respond differently to drugs.
This document discusses the importance and benefits of pharmacogenetic testing for physicians and their patients. It notes that pharmacogenetic testing can help physicians determine the right drug, dose, and timing for each individual patient to reduce adverse drug reactions and improve outcomes. Not utilizing this testing could open physicians up to legal liability issues. The document provides several case studies demonstrating how pharmacogenetic testing could have helped identify the right treatment for patients and avoided negative health consequences or legal risks for physicians. It also addresses the ease of testing, billing, and reimbursement to make the case for integrating pharmacogenetics into medical practice.
The basic aspects of drug discovery starts from target discovery and validation further going to lead identification and optimization. In this particular slide discussion is regarding the target discovery and the tools that have been utilized in this process.
This document discusses the integration of pharmacogenomics into clinical trials. It defines pharmacogenomics as investigating drug responses based on genes, with the goal of predicting side effects and making personalized drug therapy. The causes of using pharmacogenomics in clinical trials include increasing drug failures, costs, and complex diseases. Pharmacogenomics can contribute to innovation in drug discovery and development by allowing targeted drugs tailored to individuals. However, challenges include a lack of standard methods and high costs. Overall, pharmacogenomics holds promise for the future by enabling precision medicine through rigorous research.
Genetics of antipsychotic drug outcome and implications for the clinician in...BARRY STANLEY 2 fasd
Summary: Several promising findings were obtained implicating gene variants of the dopamine receptor genes
in addition to gene variants of serotonin receptors for response and common side effects. Notably, effect
sizes appear to be particularly high in the genetics of side effects compared to response.
This document provides an overview of a presentation on medicinal chemistry rules of thumb, myths, and realities in central nervous system (CNS) drug discovery. It discusses key aspects of the drug discovery and development process including target identification and validation, lead discovery and optimization, preclinical development, and clinical trials. It also covers themes in drug discovery like risk reduction, contemporary drug discovery approaches, pharmacokinetics and pharmacodynamics, molecular properties and tissue permeability, natural products as starting points, safety considerations for alternative drug uses, and how structure-activity relationships can impact project management.
The document discusses pharmacoepidemiology, which is the study of drug use and effects in large populations. It describes the importance of pharmacoepidemiological studies in evaluating drug safety and effectiveness after approval. The document outlines different types of pharmacoepidemiology studies including experimental and non-experimental designs. It also discusses reasons for conducting pharmacoepidemiology studies such as for regulatory purposes, marketing, clinical research, and legal reasons. The future of pharmacoepidemiology is seen as growing with advances in areas like molecular pharmacoepidemiology and risk management.
Main PostPharmacokinetics and PharmacodynamicsAs advance.docxwkyra78
Main Post
Pharmacokinetics and Pharmacodynamics
As advanced practice nurses it is important that we understand pharmacokinetics and pharmacodynamics when caring for our patients. There are many factors to consider when prescribing medications because not one person is the same. Pharmacokinetics is the study of drug movement throughout the body, and has four basic processes: absorption, distribution, metabolism, and excretion (Rosenthal, 2021, p 13). Pharmacodynamics is the study of the biochemical and physiologic effects of drugs on the body and the molecular mechanisms by which those effects are produced (Rosenthal, 2021, p 22). In my experience I can not pinpoint one specific scenario in which pharmacokinetic and pharmacodynamic factors altered an anticipated response to a drug but multiple scenarios.
I can think of things to consider when prescribing medications like their medical history, medications they take, whether prescribed or over the counter, compliance, genetics, age, race, and family history. Other things to consider is the patients liver function and renal function, which affect the drugs absorption and excretion rate. One class of drugs that comes to mind are chemotherapy medications. Not everyone has the same outcome with chemotherapeutic agents when treating cancers. Another class of medications are psychotropic medications, some psych medications work better for others and do not work at all for some. And one of the most common ailments hypertension, antihypertensive drugs that work for some and not others. Immunosuppressed, CHF, renal failure, liver failure patients and patients with multiple ailments on multiple medications, all have to be prescribed medications carefully because of possible polypharmacy and drug interactions. A-fib patients prescribed coumadin needing their PT/INR checked to make sure their coumadin is therapeutic, educating them not to eat green leafy vegetables or drink grapefruit juice.
A patient’s genetics may play a role in whether the medication prescribed is going to work or not. It became evident in the 60’s that therapeutic doses of psychotropic medications vary markedly from person to person, with some patients failing to respond despite treatment with high dosages (Lerer, 2004, p158). Among many factors that may influence the drug response, hepatic function, and drug metabolism ae of great importance for nearly all medications used in psychiatry and even more importantly patient compliance with medication use (Lerer, 2004, p158). The CYP2D6 genetic polymorphism was discovered in late 1970’s and represents one of the most intensively studied monogenic variations in drug metabolism, approx. 7% of Caucasians are poor metabolizers of CYP2D6 substrates while the rest are considered as extensive metabolizers (Lerer, 2004, p160). CYP2D6 enzyme has particular significance for clinical psychiatry as it is involved in clearance of many psychotropic drugs such as tricyclic, antidepressants, selective.
Pharmacogenomics, Pharmacogenetics and Pharmacokinetics Zohaib HUSSAIN
Introduction
With the information available about human genome and human proteome, it is now well understood that there are a lot of variations between individuals. These minor variations account for many differences like adverse drug reactions, which are responsible for many hospitalizations and casualties. The observed variable effect of drug is due to difference in sensitivity as some people need higher dose and some need lower dose to get similar therapeutic effect, but in some people drug has no therapeutic effects and in some it shows strong adverse reactions.
1. Discuss the organization and the family role in every one of the.docxcroysierkathey
1. Discuss the organization and the family role in every one of the heritages mentioned about and how they affect (positively or negatively) the delivery of health care.
2. Identify sociocultural variables within the Irish, Italian and Puerto Rican heritage and mention some examples.
References must be no older than 5 years. A minimum of 700 words is required.
.
1. Compare and contrast DEmilios Capitalism and Gay Identity .docxcroysierkathey
1. Compare and contrast D'Emilio's
Capitalism and Gay Identity
with the
From Mary to Modern Woman
reading. What patterns do you see that are similar to the modern American society? What can be said about global notions of gender in the modern age? Feel free to invoke Foucault.
2. How is the writer's experience important in the story being told in
Middlesex
? Describe your reaction to the reading and invoke some of the concepts discussed in the
Queer Theory
reading to try to make sense of sexuality when it does not match your own conventions. Compare both readings, but go deeper to explore your own stereotypes and socialization.
**PLEASE READ THE READINGS IN ODER TO DO THIS ASSIGNMENT.
.
More Related Content
Similar to linical pharmacogenomics consists of the appli-cation of res.docx
DDS personalised medicines M.Pharma 1st Sem Pharmaceutics.pptxkushaltegginamani18
The document discusses personalized medicines and customized drug delivery systems. It defines personalized medicine as using genetic profiling and other individual patient characteristics to guide medical treatment. Customized drug delivery systems aim to optimize drug therapy for each patient by controlling dosage and delivery through technologies like bioelectronic medicines, 3D printing of pharmaceuticals, and telepharmacy.
Pharmacogenetics- Introduction, History with case StudyPushpak Bhati
Pharmacogenetics is the study of how an individual's genetic makeup influences their response to drugs. It allows for a personalized medication approach to optimize drug selection and dosing based on genetic factors. Integrating pharmacogenomics into clinical decision making can streamline treatment by minimizing adverse events and improving outcomes through more effective strategies. Proactive pharmacogenetic testing holds promise in preventing medication issues by offering a personalized, preventative approach to care. While challenges remain, advancements in technology and research are advancing pharmacogenetics' role in precision medicine.
Pharmacogenomics is the study of how an individual's genetic inheritance affects their body's response to drugs. It combines knowledge of genetics with pharmacology to develop tailored treatments for individuals based on their genetic makeup. The goal is to understand how genetic variations influence drug metabolism and response in order to optimize drug efficacy and safety for each patient. Pharmacogenomics holds promise for more powerful and safer medications, better screening for disease, and improvements in the drug development process through a more personalized approach to medicine. However, challenges remain in fully realizing this potential due to the complexity of genetic variations and interactions.
- Classical/receptor pharmacology, also known as forward pharmacology, uses phenotypic screening of natural or synthetic molecules to identify potential therapeutic agents based on observable changes in disease models. This approach has historically led to many drug discoveries but fell out of favor as reverse pharmacology focusing on specific targets became popular.
- However, reverse pharmacology relying solely on target identification has faced many late-stage clinical failures due to lack of efficacy. Phenotypic screening still plays an important role in drug development by discovering drugs with novel mechanisms of action and multi-target effects without requiring an identified target.
- Both classical and reverse pharmacology approaches have advantages and disadvantages, and a balanced approach integrating both may be optimal for future drug discovery and
PERSONALIZED MEDICINE AND PHARMACOGENETICSAravindgowda6
This document discusses personalized medicine and pharmacogenetics. It defines personalized medicine as tailoring medical treatment to an individual's characteristics. Pharmacogenetics is the study of how genetic differences influence variability in drug responses. The document outlines how genetic polymorphisms can impact drug metabolism and efficacy through variations in phase I and phase II drug metabolizing enzymes. It also categorizes different types of patients who may benefit from personalized medicine approaches based on factors like age, gender, medical conditions, and genetics.
This document provides an introduction to pharmacogenomics. It defines pharmacogenomics as the study of how genetic variations affect drug response and metabolism. It discusses key concepts like interracial and individual variability in drug metabolism due to single nucleotide polymorphisms and variable number tandem repeats. Case studies on tamoxifen metabolism and alcohol metabolism are presented. Challenges to implementing pharmacogenomics in clinical practice are noted. Applications to drug development and personalized medicine are mentioned.
This document discusses the importance and benefits of pharmacogenomics in clinical practice. Pharmacogenomics is the study of how genes affect a person's response to medications. It combines pharmacology and genomics to develop safe and effective medication doses tailored to a person's genetic makeup. Integrating pharmacogenomic testing into practice can help reduce adverse drug reactions, enhance patient outcomes, and lower healthcare costs by avoiding trial-and-error prescribing. Certain populations, such as older adults taking multiple chronic medications, are most likely to benefit from this personalized approach to medication treatment and management. Successful integration requires a partnership approach to help navigate workflow requirements and provide expertise, education and support to providers.
Soal dan Pembahasan Farmakogenomik dan Personalized MedicineNesha Mutiara
Materi farmakologi molekular farmakogenomik dan personalized medicine :
- penjelasan farmakogenomik, farmakogenetik, dan personalized medicine
- mekanisme kerja molekular warfarin dan clopidogrel terkait farmakogenomik
This document discusses personalized medicine (PM), which aims to provide customized treatment and care based on a patient's genetic profile. PM considers how genetic variations affect an individual's response to medications and susceptibility to diseases. The document outlines key benefits of PM, such as improved medication selection and safer dosing to minimize adverse reactions. It also discusses some current genetic tests used in PM, such as tests for enzymes involved in drug metabolism. Overall, the document presents PM as a promising approach that may enable more effective, targeted treatment tailored to individual patients.
Pharmacogenomics shows promise for improving patient outcomes and safety by enabling more personalized treatment approaches based on a patient's genetics. However, fully realizing its benefits faces several challenges, including the need for healthcare stakeholders to coordinate effectively, securing adequate resources, and educating physicians on pharmacogenomics. Additionally, drug interactions and environmental factors can complicate the relationship between genetics and drug response, requiring more research before pharmacogenomic testing can be widely implemented in clinical practice.
Pharmacogenomics is the study of how genetic factors affect individual responses to drugs. It aims to develop effective and safe medications tailored to a person's genetic profile. Variations in genes involved in drug metabolism and transport can impact drug efficacy and toxicity between individuals. Understanding these genetic differences may help optimize drug selection and dosing on a personalized level. While pharmacogenomics offers advantages like improved drug response and safety, challenges remain in fully validating results and identifying all relevant genetic variations due to drug pathways' complexity.
This document discusses genomics, proteomics, bioinformatics, pharmacogenomics, and the human genome project. It provides information on how genetic polymorphisms can influence drug disposition by affecting metabolizing enzymes and transporters. The human genome project mapped the entire human genome sequence to further the goals of personalized medicine based on an individual's genetic profile. Single nucleotide polymorphisms are particularly important for understanding how individuals respond differently to drugs.
This document discusses the importance and benefits of pharmacogenetic testing for physicians and their patients. It notes that pharmacogenetic testing can help physicians determine the right drug, dose, and timing for each individual patient to reduce adverse drug reactions and improve outcomes. Not utilizing this testing could open physicians up to legal liability issues. The document provides several case studies demonstrating how pharmacogenetic testing could have helped identify the right treatment for patients and avoided negative health consequences or legal risks for physicians. It also addresses the ease of testing, billing, and reimbursement to make the case for integrating pharmacogenetics into medical practice.
The basic aspects of drug discovery starts from target discovery and validation further going to lead identification and optimization. In this particular slide discussion is regarding the target discovery and the tools that have been utilized in this process.
This document discusses the integration of pharmacogenomics into clinical trials. It defines pharmacogenomics as investigating drug responses based on genes, with the goal of predicting side effects and making personalized drug therapy. The causes of using pharmacogenomics in clinical trials include increasing drug failures, costs, and complex diseases. Pharmacogenomics can contribute to innovation in drug discovery and development by allowing targeted drugs tailored to individuals. However, challenges include a lack of standard methods and high costs. Overall, pharmacogenomics holds promise for the future by enabling precision medicine through rigorous research.
Genetics of antipsychotic drug outcome and implications for the clinician in...BARRY STANLEY 2 fasd
Summary: Several promising findings were obtained implicating gene variants of the dopamine receptor genes
in addition to gene variants of serotonin receptors for response and common side effects. Notably, effect
sizes appear to be particularly high in the genetics of side effects compared to response.
This document provides an overview of a presentation on medicinal chemistry rules of thumb, myths, and realities in central nervous system (CNS) drug discovery. It discusses key aspects of the drug discovery and development process including target identification and validation, lead discovery and optimization, preclinical development, and clinical trials. It also covers themes in drug discovery like risk reduction, contemporary drug discovery approaches, pharmacokinetics and pharmacodynamics, molecular properties and tissue permeability, natural products as starting points, safety considerations for alternative drug uses, and how structure-activity relationships can impact project management.
The document discusses pharmacoepidemiology, which is the study of drug use and effects in large populations. It describes the importance of pharmacoepidemiological studies in evaluating drug safety and effectiveness after approval. The document outlines different types of pharmacoepidemiology studies including experimental and non-experimental designs. It also discusses reasons for conducting pharmacoepidemiology studies such as for regulatory purposes, marketing, clinical research, and legal reasons. The future of pharmacoepidemiology is seen as growing with advances in areas like molecular pharmacoepidemiology and risk management.
Main PostPharmacokinetics and PharmacodynamicsAs advance.docxwkyra78
Main Post
Pharmacokinetics and Pharmacodynamics
As advanced practice nurses it is important that we understand pharmacokinetics and pharmacodynamics when caring for our patients. There are many factors to consider when prescribing medications because not one person is the same. Pharmacokinetics is the study of drug movement throughout the body, and has four basic processes: absorption, distribution, metabolism, and excretion (Rosenthal, 2021, p 13). Pharmacodynamics is the study of the biochemical and physiologic effects of drugs on the body and the molecular mechanisms by which those effects are produced (Rosenthal, 2021, p 22). In my experience I can not pinpoint one specific scenario in which pharmacokinetic and pharmacodynamic factors altered an anticipated response to a drug but multiple scenarios.
I can think of things to consider when prescribing medications like their medical history, medications they take, whether prescribed or over the counter, compliance, genetics, age, race, and family history. Other things to consider is the patients liver function and renal function, which affect the drugs absorption and excretion rate. One class of drugs that comes to mind are chemotherapy medications. Not everyone has the same outcome with chemotherapeutic agents when treating cancers. Another class of medications are psychotropic medications, some psych medications work better for others and do not work at all for some. And one of the most common ailments hypertension, antihypertensive drugs that work for some and not others. Immunosuppressed, CHF, renal failure, liver failure patients and patients with multiple ailments on multiple medications, all have to be prescribed medications carefully because of possible polypharmacy and drug interactions. A-fib patients prescribed coumadin needing their PT/INR checked to make sure their coumadin is therapeutic, educating them not to eat green leafy vegetables or drink grapefruit juice.
A patient’s genetics may play a role in whether the medication prescribed is going to work or not. It became evident in the 60’s that therapeutic doses of psychotropic medications vary markedly from person to person, with some patients failing to respond despite treatment with high dosages (Lerer, 2004, p158). Among many factors that may influence the drug response, hepatic function, and drug metabolism ae of great importance for nearly all medications used in psychiatry and even more importantly patient compliance with medication use (Lerer, 2004, p158). The CYP2D6 genetic polymorphism was discovered in late 1970’s and represents one of the most intensively studied monogenic variations in drug metabolism, approx. 7% of Caucasians are poor metabolizers of CYP2D6 substrates while the rest are considered as extensive metabolizers (Lerer, 2004, p160). CYP2D6 enzyme has particular significance for clinical psychiatry as it is involved in clearance of many psychotropic drugs such as tricyclic, antidepressants, selective.
Pharmacogenomics, Pharmacogenetics and Pharmacokinetics Zohaib HUSSAIN
Introduction
With the information available about human genome and human proteome, it is now well understood that there are a lot of variations between individuals. These minor variations account for many differences like adverse drug reactions, which are responsible for many hospitalizations and casualties. The observed variable effect of drug is due to difference in sensitivity as some people need higher dose and some need lower dose to get similar therapeutic effect, but in some people drug has no therapeutic effects and in some it shows strong adverse reactions.
Similar to linical pharmacogenomics consists of the appli-cation of res.docx (20)
1. Discuss the organization and the family role in every one of the.docxcroysierkathey
1. Discuss the organization and the family role in every one of the heritages mentioned about and how they affect (positively or negatively) the delivery of health care.
2. Identify sociocultural variables within the Irish, Italian and Puerto Rican heritage and mention some examples.
References must be no older than 5 years. A minimum of 700 words is required.
.
1. Compare and contrast DEmilios Capitalism and Gay Identity .docxcroysierkathey
1. Compare and contrast D'Emilio's
Capitalism and Gay Identity
with the
From Mary to Modern Woman
reading. What patterns do you see that are similar to the modern American society? What can be said about global notions of gender in the modern age? Feel free to invoke Foucault.
2. How is the writer's experience important in the story being told in
Middlesex
? Describe your reaction to the reading and invoke some of the concepts discussed in the
Queer Theory
reading to try to make sense of sexuality when it does not match your own conventions. Compare both readings, but go deeper to explore your own stereotypes and socialization.
**PLEASE READ THE READINGS IN ODER TO DO THIS ASSIGNMENT.
.
1.Purpose the purpose of this essay is to spread awareness .docxcroysierkathey
1.
Purpose: the purpose of this essay is to spread awareness around stereotyping and how it can be very hurtful to some people.
2.
Audience: Anyone that uses stereotypical jokes or saying around people that are different than them even without realizing that they are making a stereotypical joke or statement.
3.
Genre: the genre that I will be trying to reach out to in this essay will be informational, reason being is that I mainly look at informational online documentaries and stories.
4.
Stance and tone: I’m just a young man who grew up around a lot of people from different places and have different cultures and never paid attention in my younger years to what was happening from stereotyping others that they are different till recently.
5.
Graphic design
: My essay will be a strict academic essay
.
1. Tell us why it is your favorite film.2. Talk about the .docxcroysierkathey
1. Tell us why it is your favorite film.
2. Talk about the interconnection between the aesthetic and the technical aspects of the film. This should include at least seven of the following: Editing, Film Structure, Cinematography, Lighting, Colors, Screenwriting, Special effects, Sound and Music.
3. After this course, will you see you favorite film in a different light? Why or why not?
.
1.What are the main issues facing Fargo and Town Manager Susan.docxcroysierkathey
1.What are the main issues facing Fargo and Town Manager Susan Harlow?
Fargo and Town Manager Harlow are on a slippery slope to corruption. I think that Harlow is handling her position the correct way by trying to remain neutral and sticking to a code of ethics so the problem really comes down to the political actors in the town. It is good that Harlow declined the invite to the dinner party, and cracked down on employees playing politics at work, that is a step in the right direction to removing the possibility of political corruption.
2.What is the basis for your answer to question #1?
At the end of the article Harlow remembers another city manager saying “you never have more authority than the day you walk into your office” What I get from that, and what I think Harlow got from that is that when you come into a position as a public manager everyone is going to want something from you. Political actors are going to want political favors, quid pro quos, you have something that everyone else wants and they are going to try and get that from you.
3.What are your recommended solutions to the problems you identified?
I think the best thing to do would be to continue to try to remain neutral. It will always be impossible to please absolutely everybody so the best thing to do is try to avoid doing everything everyone asks and stick to some sort of code of ethics.
4.What points do you agree, disagree or want further discussion from your fellow classmates and why? (tell them not me)
I think the overarching theme of this article is that people are going to want things from the government. I agree with Harlow's steps to avoid political corruption in her administration by cracking down on political favors with the snow plows and referring to the ICMA code of ethics.
.
1.Writing Practice in Reading a PhotographAttached Files.docxcroysierkathey
This document provides instructions for analyzing a photograph by Jonathan Bachman titled "Bachman, Ieshia Evans, Baton Rouge (2016)". Students are asked to select three rhetorical elements from a provided list and write three paragraphs analyzing how each element contributes to the overall meaning or message of the photograph. Additional context is provided about when and where the photo was taken, and that it was a finalist for a Pulitzer Prize. Students are then given similar instructions to analyze a political advertisement, and to watch and take notes on the documentary film "Advertising and the End of the World" by Sut Jhally. A folder of additional images is also provided for future analysis.
1.Some say that analytics in general dehumanize managerial activitie.docxcroysierkathey
1.Some say that analytics in general dehumanize managerial activities, and others say they do not. Discuss arguments for both points of view.
2.What are some of the major privacy concerns in employing intelligent systems on mobile data?
3. Identify some cases of violations of user privacy from current literature and their impact on data science as a profession.
4.Search the Internet to find examples of how intelligent systems can facilitate activities such as empowerment, mass customization, and teamwork.
Note: Each question must be answered in 5 lines and refrences must be APA cited.
.
1.What is the psychological term for the symptoms James experiences .docxcroysierkathey
1.What is the psychological term for the symptoms James experiences after abstaining from consuming
alcohol? How do changes in the functioning of neurotransmitter systems produce these symptoms?
2.With reference to associative learning principles/models/theories, why does James consume alcohol
to alleviate these symptoms? What motivates his drinking behaviour given that he no longer enjoys this
activity (most of the time)?
3.How do these factors prevent James from quitting his drinking, and lead to a cycle of relapse when he
attempts to do so? Why are these processes important for our understanding of addiction and
substance use disorders.
1 Page
at least 3 sources
APA
.
1.Write at least 500 words discussing the benefits of using R with H.docxcroysierkathey
1.Write at least 500 words discussing the benefits of using R with Hadoop. Use APA format and Include at least 3 quotes from your sources enclosed in quotation marks.
2.Write at least 500 words discussing how insurance companies use text mining to reduce fraud. Use APA format and Include at least 3 quotes from your sources enclosed in quotation marks.
.
1.What is Starbucks’ ROA for 2012, 2011, and 2010 Why might focusin.docxcroysierkathey
1.What is Starbucks’ ROA for 2012, 2011, and 2010? Why might focusing specifically on ROA be misleading when assessing asset management (aka management efficiency)?
2.Why is ROE considered the most useful metric in measuring the overall ability of a business strategy to generate returns for shareholders?
3. How do the financial statements reveal company strategy (i.e., what story do the numbers tell and does that story align with the strategy of Starbucks?)?
.
1. Discuss the cultural development of the Japanese and the Jewis.docxcroysierkathey
This assignment requires discussing the cultural development of the Japanese and Jewish heritage in regards to their health care beliefs and how those beliefs influence evidence-based health care delivery. At least two references no older than five years must be used, and the paper must be a minimum of 600 words excluding the cover page and references.
1. Discuss at least 2 contextual factors(family, peers, school,.docxcroysierkathey
1.
Discuss at least 2 contextual factors(family, peers, school, community, work, etc.) that might make young people more or less likely to experience adolescence as a period of storm and stress.
2. How might the dramatic physical changes that adolescents undergo—and the accompanying reactions from others—influence other aspects of development, such as social or emotional development?
3. Describe some ways in which adolescent decision making is a product of interactions among puberty, brain development, cognitive growth, and contextual influences such as parents, peers, and community.
.
1.Write at least 500 words in APA format discussing how to use senti.docxcroysierkathey
1.Write at least 500 words in APA format discussing how to use sentiment analysis how political speech affects voters. Use at least 3 references in APA format.
2.Read the below article(link below) on statistics for categorical variables. Write at least 500 words in APA format discussing how to use these statistics to help understand big data.
Link: https://uc-r.github.io/descriptives_categorical
.
1.The following clause was added to the Food and Drug Actthe S.docxcroysierkathey
1.The following clause was added to the Food and Drug Act:
“the Secretary [of the Food and Drug Administration] shall not approve for use in food any chemical additive found to induce cancer in man, or, after tests, found to induce cancer in animals.”
After this clause was adopted, no new additives could be approved for use in food if they caused cancer in people or animals.
The public loved this and industry hated it.
What do you think of this clause? Do you support it or do you oppose it?
At the top of your post, please indicate SUPPORT or OPPOSE and then give your rationale. Then after you can view your classmates' posts, make your case to your fellow students.
2.There was a law that individuals who were indigent and who wished to litigate could apply to the courts for a total waiver of the normal filing fee. In the legislative session, however, a statute was enacted which limits the courts' authority to waive filing fees in lawsuits brought by prisoners against the state government.
Under this new law, a court has to require the prisoner to pay a filing fee "equal to 20 percent ... of the average monthly deposits made to the prisoner's [prison] account ... or the average balance in that account", whichever is greater (unless this calculation yields a figure larger than the normal filing fee).
A prisoner (who was indigent) wanted to appeal his case and was to be charged this fee. He filed suit claiming it was unconstitutional to charge this fee to prisoners.
Choose the side of the prisoner or the side of the state and tell why you would rule for the side you chose.
At the top of your post, please indicate SUPPORT PRISONER or OPPOSE PRISONER and then give your rationale. After you can view your classmates' posts, make your case to your fellow students.
3.A defendant pleaded guilty to receiving and possessing child pornography and was sentenced to 108 months in prison. The sentencing judge raised the defendant’s base offense level….by two levels because "a computer was used for the transmission" of the illegal material.
The appeal filed challenged the punishment enhancement (not his guilt of the base punishment.)
The defendant argued the law did not apply to him because he did not use a computer to transmit the material. (ie He was the receiver, not the sender, of the child pornography.)
Do you believe that the sentence enhancement should be upheld? Give an economic analysis and rational for your choice.
At the top of your post, please indicate SENTENCE UPHELD or SENTENCE REVERSED and then give your economic analysis/rationale. After you can view your classmates' posts, make your case to your fellow students.
4.The ordinance was enacted that gives tenants more legal rights including:
the payment of interest on security deposits;
requires that those deposits be held in Illinois banks;
allows (with some limitations) a tenant to withhold rent in an amount reflecting the cost to him of the landlord's v.
1.What are social determinants of health Explain how social determ.docxcroysierkathey
1.What are social determinants of health? Explain how social determinants of health contribute to the development of disease. Describe the fundamental idea that the communicable disease chain model is designed to represent. Give an example of the steps a nurse can take to break the link within the communicable disease chain.
Resources within your text covering international/global health, and the websites in the topic materials, will assist you in answering this discussion question.
2. Select a global health issue affecting the international health community. Briefly describe the global health issue and its impact on the larger public health care systems (i.e., continents, regions, countries, states, and health departments). Discuss how health care delivery systems work collaboratively to address global health concerns and some of the stakeholders that work on these issues.
Resources within your text covering international/global health, and the websites in the topic materials, will assist you in answering this discussion question.
.
1.This week, we’ve been introduced to the humanities and have ta.docxcroysierkathey
1.
This week, we’ve been introduced to the humanities and have taken some time to consider the role of the humanities in establishing socio-cultural values, including how the humanities differ from the sciences in terms of offering unique lenses on the world and our reality. Since one of the greatest rewards of being a human is engaging with different forms of art, we’ve taken some time this week to learn about what it means to identify and respond to a work of art. We’ve learned about the difference between abstract ideas and concrete images and concepts like structure and artistic form. To help you deepen your understanding of these foundational ideas, your Unit 1 assignment will consist of writing an essay addressing using the following criteria:
Essay Requirements:
• 1,000 words or roughly four double-spaced pages.
• Make use of at least three scholarly sources to support and develop your ideas. Our course text may serve as one of these three sources.
• Your essay should demonstrate a thorough understanding of the READ and ATTEND sections.
• Be sure to cite your sources using proper APA format (7th edition).
Essay Prompt:
• In this essay, you will consider the meaning of art and artistic form by responding to these questions:
o To what extent does Kevin Carter’s Pulitzer Prize-winning photograph (figure 2-5) have artistic form?
o Using what you’ve learned in Chapters 1, 2 and 14 explain if you consider Carter’s photograph a work of art? Be sure to point to specific qualities of the photograph to support/develop your response.
o How do you measure the intensity of your experience in response to Carter’s photograph? What does it make you see/feel/imagine and how does your response/reaction support Carter’s image as a work of art?
.
1.What are barriers to listening2.Communicators identif.docxcroysierkathey
1.
What are barriers to listening?
2.
Communicators identified the following as major listening poor habits. Search what each poor habit means and try to set an example using your own experience.
Poor listening habit:
Pseudo-listening, Stage hogging, Filling in gaps, Selective listening, Ambushing (
Definition & Example)
.
1.Timeline description and details There are multiple way.docxcroysierkathey
1.
Timeline description and details
: There are multiple ways to construct a timeline. Find one that fits you and your information.
Include 10-15 events, each including the following descriptors:
- titles of books or writings or some sort of identifier
- your age or some time reference
- and whether it was a positive or negative experience
.
1.The PresidentArticle II of the Constitution establishe.docxcroysierkathey
1.
The President
Article II of the Constitution established the institution of the presidency. Select any TWO Presidents prior to 1933 and any TWO Presidents since 1933 and for EACH one:
a.
Discuss
any
expressed
power used by each president and the
impact
that decision had on American society at the time of its use
b.
Explain
whether you
agree/disagree
with the presidential action taken and
WHY
c.
Describe
one
legislative initiative
promoted by each president and the
impact
on America at the
time of its passage
as well as what the impact of that legislation is
TODAY
d.
Discuss
one
executive order
issued by each president and whether you
agree/disagree
with the order and
WHY
1.
Select any FOUR United States Supreme court decisions related to Civil Rights/Civil Liberties and for
each one
:
a.
Describe
the facts of the case
b.
Discuss
the arguments of each side as it pertains to the
Constitutional issue
being addressed
c.
Explain
the decision citing
Constitutional rationale
of the court including any dissenting opinion if not a unanimous verdict
d.
Explain
whether you
agree/disagree
with the court’s decision and
WHY
.
1.What other potential root causes might influence patient fal.docxcroysierkathey
1.
What other potential root causes might influence patient falls?
2.
Equipped with the data, what would you do about the hypotheses that proved to be unsupported?
3.
Based on the correctly identified hypothesis in the case scenario, what would be your course of action if you were the CEO/president of St. Xavier Memorial Hospital?
4.
What do you think of the CNO’s (Sara Mullins) position of “waiting and seeing what the data tells us” instead of immediately jumping to conclusions?
.
Strategies for Effective Upskilling is a presentation by Chinwendu Peace in a Your Skill Boost Masterclass organisation by the Excellence Foundation for South Sudan on 08th and 09th June 2024 from 1 PM to 3 PM on each day.
How to Add Chatter in the odoo 17 ERP ModuleCeline George
In Odoo, the chatter is like a chat tool that helps you work together on records. You can leave notes and track things, making it easier to talk with your team and partners. Inside chatter, all communication history, activity, and changes will be displayed.
LAND USE LAND COVER AND NDVI OF MIRZAPUR DISTRICT, UPRAHUL
This Dissertation explores the particular circumstances of Mirzapur, a region located in the
core of India. Mirzapur, with its varied terrains and abundant biodiversity, offers an optimal
environment for investigating the changes in vegetation cover dynamics. Our study utilizes
advanced technologies such as GIS (Geographic Information Systems) and Remote sensing to
analyze the transformations that have taken place over the course of a decade.
The complex relationship between human activities and the environment has been the focus
of extensive research and worry. As the global community grapples with swift urbanization,
population expansion, and economic progress, the effects on natural ecosystems are becoming
more evident. A crucial element of this impact is the alteration of vegetation cover, which plays a
significant role in maintaining the ecological equilibrium of our planet.Land serves as the foundation for all human activities and provides the necessary materials for
these activities. As the most crucial natural resource, its utilization by humans results in different
'Land uses,' which are determined by both human activities and the physical characteristics of the
land.
The utilization of land is impacted by human needs and environmental factors. In countries
like India, rapid population growth and the emphasis on extensive resource exploitation can lead
to significant land degradation, adversely affecting the region's land cover.
Therefore, human intervention has significantly influenced land use patterns over many
centuries, evolving its structure over time and space. In the present era, these changes have
accelerated due to factors such as agriculture and urbanization. Information regarding land use and
cover is essential for various planning and management tasks related to the Earth's surface,
providing crucial environmental data for scientific, resource management, policy purposes, and
diverse human activities.
Accurate understanding of land use and cover is imperative for the development planning
of any area. Consequently, a wide range of professionals, including earth system scientists, land
and water managers, and urban planners, are interested in obtaining data on land use and cover
changes, conversion trends, and other related patterns. The spatial dimensions of land use and
cover support policymakers and scientists in making well-informed decisions, as alterations in
these patterns indicate shifts in economic and social conditions. Monitoring such changes with the
help of Advanced technologies like Remote Sensing and Geographic Information Systems is
crucial for coordinated efforts across different administrative levels. Advanced technologies like
Remote Sensing and Geographic Information Systems
9
Changes in vegetation cover refer to variations in the distribution, composition, and overall
structure of plant communities across different temporal and spatial scales. These changes can
occur natural.
This presentation was provided by Steph Pollock of The American Psychological Association’s Journals Program, and Damita Snow, of The American Society of Civil Engineers (ASCE), for the initial session of NISO's 2024 Training Series "DEIA in the Scholarly Landscape." Session One: 'Setting Expectations: a DEIA Primer,' was held June 6, 2024.
This document provides an overview of wound healing, its functions, stages, mechanisms, factors affecting it, and complications.
A wound is a break in the integrity of the skin or tissues, which may be associated with disruption of the structure and function.
Healing is the body’s response to injury in an attempt to restore normal structure and functions.
Healing can occur in two ways: Regeneration and Repair
There are 4 phases of wound healing: hemostasis, inflammation, proliferation, and remodeling. This document also describes the mechanism of wound healing. Factors that affect healing include infection, uncontrolled diabetes, poor nutrition, age, anemia, the presence of foreign bodies, etc.
Complications of wound healing like infection, hyperpigmentation of scar, contractures, and keloid formation.
A review of the growth of the Israel Genealogy Research Association Database Collection for the last 12 months. Our collection is now passed the 3 million mark and still growing. See which archives have contributed the most. See the different types of records we have, and which years have had records added. You can also see what we have for the future.
How to Make a Field Mandatory in Odoo 17Celine George
In Odoo, making a field required can be done through both Python code and XML views. When you set the required attribute to True in Python code, it makes the field required across all views where it's used. Conversely, when you set the required attribute in XML views, it makes the field required only in the context of that particular view.
Leveraging Generative AI to Drive Nonprofit InnovationTechSoup
In this webinar, participants learned how to utilize Generative AI to streamline operations and elevate member engagement. Amazon Web Service experts provided a customer specific use cases and dived into low/no-code tools that are quick and easy to deploy through Amazon Web Service (AWS.)
it describes the bony anatomy including the femoral head , acetabulum, labrum . also discusses the capsule , ligaments . muscle that act on the hip joint and the range of motion are outlined. factors affecting hip joint stability and weight transmission through the joint are summarized.
বাংলাদেশের অর্থনৈতিক সমীক্ষা ২০২৪ [Bangladesh Economic Review 2024 Bangla.pdf] কম্পিউটার , ট্যাব ও স্মার্ট ফোন ভার্সন সহ সম্পূর্ণ বাংলা ই-বুক বা pdf বই " সুচিপত্র ...বুকমার্ক মেনু 🔖 ও হাইপার লিংক মেনু 📝👆 যুক্ত ..
আমাদের সবার জন্য খুব খুব গুরুত্বপূর্ণ একটি বই ..বিসিএস, ব্যাংক, ইউনিভার্সিটি ভর্তি ও যে কোন প্রতিযোগিতা মূলক পরীক্ষার জন্য এর খুব ইম্পরট্যান্ট একটি বিষয় ...তাছাড়া বাংলাদেশের সাম্প্রতিক যে কোন ডাটা বা তথ্য এই বইতে পাবেন ...
তাই একজন নাগরিক হিসাবে এই তথ্য গুলো আপনার জানা প্রয়োজন ...।
বিসিএস ও ব্যাংক এর লিখিত পরীক্ষা ...+এছাড়া মাধ্যমিক ও উচ্চমাধ্যমিকের স্টুডেন্টদের জন্য অনেক কাজে আসবে ...
How to Fix the Import Error in the Odoo 17Celine George
An import error occurs when a program fails to import a module or library, disrupting its execution. In languages like Python, this issue arises when the specified module cannot be found or accessed, hindering the program's functionality. Resolving import errors is crucial for maintaining smooth software operation and uninterrupted development processes.
ISO/IEC 27001, ISO/IEC 42001, and GDPR: Best Practices for Implementation and...PECB
Denis is a dynamic and results-driven Chief Information Officer (CIO) with a distinguished career spanning information systems analysis and technical project management. With a proven track record of spearheading the design and delivery of cutting-edge Information Management solutions, he has consistently elevated business operations, streamlined reporting functions, and maximized process efficiency.
Certified as an ISO/IEC 27001: Information Security Management Systems (ISMS) Lead Implementer, Data Protection Officer, and Cyber Risks Analyst, Denis brings a heightened focus on data security, privacy, and cyber resilience to every endeavor.
His expertise extends across a diverse spectrum of reporting, database, and web development applications, underpinned by an exceptional grasp of data storage and virtualization technologies. His proficiency in application testing, database administration, and data cleansing ensures seamless execution of complex projects.
What sets Denis apart is his comprehensive understanding of Business and Systems Analysis technologies, honed through involvement in all phases of the Software Development Lifecycle (SDLC). From meticulous requirements gathering to precise analysis, innovative design, rigorous development, thorough testing, and successful implementation, he has consistently delivered exceptional results.
Throughout his career, he has taken on multifaceted roles, from leading technical project management teams to owning solutions that drive operational excellence. His conscientious and proactive approach is unwavering, whether he is working independently or collaboratively within a team. His ability to connect with colleagues on a personal level underscores his commitment to fostering a harmonious and productive workplace environment.
Date: May 29, 2024
Tags: Information Security, ISO/IEC 27001, ISO/IEC 42001, Artificial Intelligence, GDPR
-------------------------------------------------------------------------------
Find out more about ISO training and certification services
Training: ISO/IEC 27001 Information Security Management System - EN | PECB
ISO/IEC 42001 Artificial Intelligence Management System - EN | PECB
General Data Protection Regulation (GDPR) - Training Courses - EN | PECB
Webinars: https://pecb.com/webinars
Article: https://pecb.com/article
-------------------------------------------------------------------------------
For more information about PECB:
Website: https://pecb.com/
LinkedIn: https://www.linkedin.com/company/pecb/
Facebook: https://www.facebook.com/PECBInternational/
Slideshare: http://www.slideshare.net/PECBCERTIFICATION
ISO/IEC 27001, ISO/IEC 42001, and GDPR: Best Practices for Implementation and...
linical pharmacogenomics consists of the appli-cation of res.docx
1. linical pharmacogenomics consists of the appli-
cation of research that links measurable genetic variants
with the prediction of drug response.1 Every medical
specialty can utilize the results of pharmacogenomic
probe studies to inform the adoption of individualized
pharmacotherapy. However, psychiatric pharmacother-
apy is particularly likely to benefit from the introduction
of pharmacogenomic testing, because there are many
psychotropic agents available for selection that target
specific symptoms.
The terms pharmacogenetics and pharmacogenomics
are currently used interchangeably. However, with the
growing understanding that multiple intragenic varia-
tions should be considered in making predictions related
to medication response, the use of the term pharma-
cogenomics has become more frequently chosen to des-
ignate the process of using documented genetic variation
to guide medication selection and dosing.
Historically, psychiatrists have used empirical strategies
to select medications. In the best practices, the choice of
medications has evolved based on a rational trial-and-
error process that has used clinical indicators to select
medications and then relied on documenting treatment
responses to titrate the optimal dose for a particular
patient. Psychiatrists learn to “start low and go slow” in
order to minimize side effects. They also know that it is
6 9
P h a r m a c o l o g i c a l a s p e c t s
C
4. common practice of augmenting an initial medication
with a second psychotropic drug.2 However, there is no
scientifically available evidence to support the practice
of using four or five psychotropic medications simulta-
neously. Nevertheless, patients routinely receive multi-
ple psychotropic medications in an attempt to identify
the “right combination.” While some patients do achieve
a good therapeutic response using this trial-and-error
approach to individualized medicine, it is also true that
others become overmedicated or suffer from iatrogenic
side effects.
Pharmacogenomic testing provides an innovative strat-
egy to improve the likelihood of selecting an effective
psychotropic medication. The earliest medical texts rec-
ognize that individual patients experience quite dra-
matically different responses to the same drug. There is
also a longstanding observation that unusual drug
responses can occur in members of the same family. The
identification of specific gene variants associated with
idiosyncratic responses is about 50 years old,3 and the
recognition that some psychiatric patients metabolize
antidepressants at dramatically different rates has been
documented for several decades.4 However, with the use
of newer antidepressant medications that rarely have
life-threatening complications, the relatively expensive
practice of monitoring the serum levels of newer anti-
depressant medications has become uncommon in the
United States. This change has occurred despite the fact
that serum levels of these newer agents also have dra-
matic variations based on the metabolic capacity of each
patient.
A decade ago, the cost of genotyping began to become
more affordable, and individual laboratories initiated
pharmacogenomic testing that would provide genotyping
of individual cytochrome P450 genes. However, there was
5. no standard or well-validated methodology for the geno-
typing of these informative genes. There was also consid-
erable variability in the interpretation of the results. In
2004, the US Food and Drug Administration (FDA)
approved the use of a new product, the AmpliChip.5 The
introduction of the AmpliChip provided reference labo-
ratories with a standard method for identifying variations
in two of the cytochrome P450 genes: cytochrome P450
2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19).
The approval of the AmpliChip was an important land-
mark in the history of psychiatric pharmacogenomic test-
ing, and within 3 years, CYP2D6 and CYP2C19 were
being genotyped by every reference laboratory in the
country. However, this advance also highlighted some of
the challenges associated with the introduction of clinical
testing. One of the most obvious challenges that must be
addressed is how to begin to assess new variants of these
two genes in updated versions of the assay. Ideally, the
methodology for establishing drug-metabolizing pheno-
types should be updated regularly based on new molecu-
lar genetic findings showing how new genotypic variants
influence gene function. Also, the clarification of the pre-
dictive capacity of previously identified gene variants
influencing gene function is similarly evolving, and newly
identified associations between gene structure and func-
tion should ideally be incorporated into algorithms that
define the metabolic capacity of psychiatric patients.
The evolution of pharmacogenomic research should
inform modifications in pharmacogenomic testing.
However, an implication of the rapid increase in our
knowledge base is that these new studies demonstrate
limitations in the accuracy of older genotyping method-
ologies that were designed prior to the discovery of
more recent variants. What is often not well appreciated
is that even older pharmacogenomic methods provided
important information for many patients, as these early
6. innovations were a major advance over psychopharma-
cological practice without pharmacogenomic insights.
However, as newer methodologies have further
improved the accuracy of the prediction of medication
response, the clinical utility of pharmacogenomic testing
continues to increase.
Pharmacogenomic testing in psychiatric practice initially
focused on identifying pharmacokinetic variability that
P h a r m a c o l o g i c a l a s p e c t s
7 0
DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 70
would influence the responses of patients who had atyp-
ical genotypes. Pharmacokinetic variation influences
the concentration of a drug at its sites of action.
Pharmacogenomic testing of drug-metabolizing enzyme
genes provides a prediction of how an individual patient
will metabolize a specific psychotropic medication. More
recently, the focus of pharmacogenomic testing has
expanded to include determining variability in the phar-
macodynamic response of a patient to a specific med-
ication. This variability reflects the capacity of the indi-
vidual patient to respond to adequate exposure to the
drug. Prediction of response is estimated based on the
documentation of variations in “target genes” that code
for receptors and transporters that influence the
response of the patient to a particular medication.
This review will first identify the most widely genotyped
drug-metabolizing enzyme genes that influence the
pharmacokinetic metabolic capacity of a patient. Then,
it will focus on genes that influence the pharmacody-
7. namic responses of individual patients, before conclud-
ing with a brief discussion of the clinical utility of phar-
macogenomic testing and some of the ethical
considerations related to its routine use.
Pharmacogenomic testing to establish the
metabolic capacity of psychiatric patients
Many genes code for enzymes that influence drug
response. However, only the clinical implications of geno-
typing four of the most commonly tested cytochrome
P450 genes will be reviewed. The focus of this discussion
will be the clinical benefit for the patient of identifying
individualized molecular variations, and the implications
for those patients who have a quite significant decrement
in their capacity to metabolize specific psychotropic med-
ications. Identifying these individual patients provides
clinicians with a clear method of minimizing side effects.
This determination of decreased metabolic capacity is the
most obvious benefit of pharmacogenomic testing, but
implications of the pharmacogenomic testing for patients
with increased metabolic capacity will also be discussed,
as these patients are less likely to respond to specific psy-
chotropic medications.
The cytochrome P450 2D6 gene (CYP2D6)
CYP2D6 was the first drug-metabolizing enzyme gene
that was genotyped to identify psychiatric patients with
increased or decreased metabolic capacity. It is located
on chromosome 22 and consists of 4382 nucleotides.
CYP2D6 codes for an enzyme that is composed of 497
amino acids.
The CYP2D6 enzyme plays a primary role in the metab-
olism of more than 70 substrate medications, including
8. twelve psychotropic medications. CYP2D6 is one of the
most highly variable drug-metabolizing enzyme genes.
However, many of the other 29 P450 drug-metabolizing
enzyme genes are also highly variable. The specific
genetic variations that define variable phenotypes can
be located on a Web site maintained by the Karolinska
Institute (http://www.cypalleles.ki.se/). Each newly iden-
tified variant is included on the Web site after confir-
mation that it is unique.
There are currently 75 distinct CYP2D6 alleles posted
on this site, as well as an additional 55 CYP2D6 variants
that closely resemble one of the primary variants.
Traditionally, these variants have been classified as being
normal, deficient, or inactive drug-metabolizing alleles.
Additionally, some alleles have more recently been
demonstrated to code for an increased amount of
enzyme which enhances the metabolic activity of the
patient. Furthermore, patients can have a variable num-
ber of copies of CYP2D6. The most common number of
copies of CYP2D6 that patients carry is two. However,
some patients have only one copy and, rarely, none at all.
It is also possible to have more than two copies, and one
patient has been reported to have 13 copies.4 The devel-
opment of several different classification systems to cat-
egorize 2D6 substrate metabolic capacity of patients into
four phenotypic categories has been problematic. The
use of alternative methodologies by different research
teams has made it more difficult to study the implica-
tions of this variability.
The most important CYP2D6 phenotype to identify is
the poor 2D6 substrate metabolizer phenotype. Patients
who are poor metabolizers are at increased risk for
adverse events when they are prescribed 2D6 substrate
medications, because of their low metabolic capacity.
Patients are now classified as poor metabolizers if they
have two inactive alleles, or one inactive allele and one
9. deficient allele.
The second most clinically important CYP2D6 pheno-
type is the ultrarapid metabolizer phenotype. Patients
are ultrarapid metabolizers if they have either three or
more active copies of CYP2D6 or two or more enhanced
copies of CYP2D6. They are unlikely to respond to 2D6
Psychiatric pharmacogenomic testing - Mrazek Dialogues in
Clinical Neuroscience - Vol 12 . No. 1 . 2010
7 1
DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 71
substrate medications at standard doses because their
ability to rapidly metabolize these medications makes it
difficult to sustain therapeutic serum levels.
The third clinically important CYP2D6 phenotype is the
intermediate metabolizer phenotype. These patients
have one normal copy of CYP2D6, and one copy that is
either deficient or inactive. While these patients can nor-
mally benefit from 2D6 substrate medications at low-to-
moderate doses, they are at increased risk for the devel-
opment of side effects at higher doses because of their
decreased metabolic capacity, and they are more at risk
for enzyme inhibition as a consequence of drug-drug
interactions. When intermediate metabolizers are
exposed to powerful 2D6 inhibitors such as paroxetine
or fluoxetine, their metabolic capacity can be further
decreased to the level of a poor metabolizer.6
There are many psychotropic medications metabolized
by the 2D6 enzyme. Specifically, this enzyme:
• primarily metabolizes five antidepressants: fluoxetine,
10. paroxetine, venlafaxine, desipramine, and nortriptyline
• substantially metabolizes amitriptyline, imipramine,
doxepin, duloxetine, trazodone, and mirtazapine
• primarily metabolizes risperidone and four of the typ-
ical antipsychotic medications: chlorpromazine, thior-
idazine, perphenazine, and haloperidol
• has substantial involvement in the metabolism of arip-
iprazole and olanzapine
• primarily metabolizes atomoxetine and dextroam-
phetamine.
Beyond the prescription of psychotropic medications,
psychiatric patients are given many other 2D6 substrate
medications. Specifically, dextromethorphan is a cough
suppressant that is metabolized by the 2D6 enzyme.
Patients who are poor metabolizers of 2D6 substrate
medications are at increased risk for cognitive side effects
if taking standard doses of preparations that contain dex-
tromethorphan. Another example is codeine, which is a
prodrug. A prodrug must be converted to an active
metabolite in order to have a therapeutic effect. Patients
who are poor 2D6 metabolizers do not receive analgesic
benefit from codeine because they do not metabolize
codeine to morphine. Tamoxifen is also a prodrug that is
the most frequently prescribed treatment for breast can-
cer. Poor metabolizers have little or no benefit from
tamoxifen because they are not able to metabolize
tamoxifen to endoxifen.7,8 Additionally, paroxetine, flu-
oxetine, or bupropion should not be given to patients
who are receiving tamoxifen because they inhibit the
11. 2D6 enzyme. Giving these inhibitors to intermediate
metabolizers can convert them to functional poor metab-
olizers. Consequently, they become unable to produce
endoxifen.9
The cytochrome P450 2C19 gene (CYP2C19)
CYP2C19 was the second drug-metabolizing enzyme
gene that was widely genotyped to identify patients with
increased or decreased metabolic capacity. It is a large
gene located on chromosome 10. It consists of 90 209
nucleotides, but codes for an enzyme that contains only
490 amino acids.
The identification of patients with low 2C19 metabolic
capacity is clinically important because it allows clini-
cians to decrease the risk of iatrogenic side effects.
The 2C19 enzyme:
• primarily metabolizes citalopram, escitalopram,
clomipramine, and amitriptyline
• has substantial involvement in the metabolism of ser-
traline, imipramine, nortriptyline, and doxepin
• plays an important role in the metabolism of clozapine
and a minimal role in the metabolism of thioridazine
• is the primary enzyme involved in the metabolism of
diazepam.
Recently, a new variant of CYP2C19 has been identified
which has enhanced function.10 Patients who are
homozygous for this new allele are less likely to respond
to 2C19 substrate medications at standard doses. The
identification of ultrarapid 2C19 metabolizers can be
helpful in evaluating patients who do not respond to
standard doses of any of these psychotropic medications.
12. The cytochrome P450 2C9 gene (CYP2C9)
CYP2C9 is located on chromosome 10 in relative close
proximity to CYP2C19. However, it is only about half
the size of CYP2C9 as it consists of 50 708 nucleotides.
Like CYP2C19, CYP2C9 codes for an enzyme that con-
tains 490 amino acids.
CYP2C9 is a drug-metabolizing enzyme gene that is less
routinely genotyped to identify the increased or
decreased metabolic capacity of psychiatric patients for
2C9 substrate medications. It does not play a primary
role in the metabolism of any currently prescribed psy-
chotropic medications. However, the 2C9 enzyme pro-
vides the only secondary pathway for the metabolism of
fluoxetine, so patients who are poor metabolizers of
P h a r m a c o l o g i c a l a s p e c t s
7 2
DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 72
Psychiatric pharmacogenomic testing - Mrazek Dialogues in
Clinical Neuroscience - Vol 12 . No. 1 . 2010
7 3
both 2D6 substrates and 2C9 substrates are at very high
risk for adverse effects if treated with standard dose of
fluoxetine.
The cytochrome P450 1A2 gene (CYP1A2)
13. CYP1A2 is a less well-studied drug-metabolizing
enzyme gene, but it codes for an enzyme that plays an
important role in the metabolism of fluvoxamine. It is
also involved in the metabolism of duloxetine and olan-
zapine. CYP1A2 is located on chromosome 15 and con-
sists of 7758 nucleotides. CYP1A2 codes for an enzyme
that is composed of 516 amino acids.
A somewhat atypical aspect of the CYP1A2 gene is that
there are alleles of this gene that are inducible by smok-
ing tobacco or consuming cruciferous vegetables, such
as cabbage or Brussels sprouts. Consequently, patients
who smoke tobacco and have two alleles of CYP1A2
that are inducible by their smoking can be difficult to
maintain on 1A2 substrate medications. A relatively
common problem occurs when these patients are treated
with olanzapine or clozapine on an inpatient psychiatric
unit that does not allow them to smoke. When they
begin to smoke after they are discharged, their serum
level drops and their psychotic symptoms often reoccur.
In some populations of European ancestry, as many as
25% of the population can have an inducible ultrarapid
CYP1A2 phenotype.
Pharmacogenomic testing to identify
variability in pharmacodynamic responses
A goal of individualized molecular psychopharmacology
is to identify medications for an individual patient that
will not only be safe, but will be effective. Progress in
making predictions of medication response has occurred,
and while the goal of being able to predict this response
with certainty has not been achieved, we can make
increasingly accurate probabilistic predictions of the
likelihood of response. Psychiatrists are familiar with this
limitation. While hundreds of randomized clinical trials
of psychotropic medications have been conducted to
14. identify effective psychotropic drugs, the results of these
trials only provide assurance that for a sample of
patients there is reasonable likelihood that the medica-
tion will be of more benefit than a placebo. While selec-
tive serotonin reuptake blockers are among the most
widely prescribed medications in the world, many
patients do not respond. Specifically, the largest clinical
effectiveness study of citalopram reported that less than
30% of the entire sample of patients experienced a com-
plete remission of their symptoms.11 While the ultimate
goal of pharmacodynamically designed pharmacoge-
nomic testing is to identify a drug for a specific patient
that will definitely be effective, at the current stage of
our understanding, it is only possible to identify a med-
ication that is more likely to be effective.
The serotonin transporter gene (SLC6A4)
SLC6A4 is located on chromosome 17 and consists of 37
800 nucleotides. It codes for an enzyme that is composed
of 630 amino acids.
SLC6A4 is the most widely genotyped pharmacoge-
nomic “target” gene. A meta-analysis of studies of the
relationship between the more active long form of the
indel promoter variant of this gene and responses to
selective serotonin reuptake inhibitors12 confirmed the
early finding that the long form is associated with a more
rapid and better response.13 However, this has not con-
sistently been demonstrated in patients of Asian ances-
try.14,15 The importance of ancestral heritage has been fur-
ther demonstrated by multiple analyses of the large
STAR*D effective treatment study.
Analyses that did not consider ancestral background did
not demonstrate a significant association,16 while those
that focused on patients who identified themselves as
15. “white” but not “Hispanic” did confirm the relationship
that patients who were homozygous for the more active
long form of the indel promoter polymorphism were
more likely to respond to citalopram. Other variants,
such as rs2553117 and the second intronic VNTR18 are
likely to influence the activity level of the gene and, con-
sequently, its response to medications that block its abil-
ity to reuptake serotonin in the synapses of the central
nervous system.
The serotonin receptor 2A gene (HTR2A)
HTR2A is located on chromosome 13 and consists of 62
663 nucleotides. Despite its large size, it codes for an
enzyme that is composed of only 471 amino acids.
There have been a series of studies examining the asso-
ciation between variants of HTR2A and antidepressant
response. A large study examining the response of
depressed patients of European ancestry to citalopram
DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 73
found that a positive response to citalopram was associ-
ated with having a copy of the adenine allele of
rs7997012.19
Another study examining a different HTR2A variant,
rs6313, reported that patients who were homozygous for
the cytosine allele were less likely to tolerate taking
paroxetine than those who had one or more copies of
the thymine allele.20
A series of studies have reported a better response to
clozapine in patients who had the thymine allele of
16. rs6313. The thymine allele of rs6313 has also been asso-
ciated with a lower risk for the development of
extrapyramidal side effects when taking antipsychotic
medications.21-23
The serotonin receptor 2C gene (HTR2C)
HTR2C is a very large gene that is located on the X
chromosome and consists of 326 074 nucleotides.
However, it codes for a protein product that is composed
of only 458 amino acids.
Variations in the HTR2C gene have been associated
with a better clinical response to clozapine. Specifically,
patients with schizophrenia who have a copy of the cyto-
sine allele of rs6318 have achieved better control of their
psychotic symptoms than patients with the guanine
allele.24,25 However, this same variant has been associated
with a higher risk for the development of extrapyrami-
dal side effects in patients who are taking typical antipsy-
chotic medications.26
An increased risk for the development of weight gain
has been linked to a different HTR2C variant.
Specifically, the cytosine allele of rs518147 is associated
with increased weight gain, while the thymine allele is
conceptualized as providing protection against weight
gain.27-29
The clinical utility of pharmacogenomic
testing in psychiatric practice
Assessing the clinical utility of pharmacogenomic test-
ing is an ongoing process, given that the accuracy of
genotyping is continually improving, and new research
is identifying additional genetic variants that influence
medication responses. Reports of adverse responses to
17. 2D6 substrate medications in patients with decreased
2D6 metabolic capacity support the use of testing at this
most basic level. Specifically, poor 2D6 metabolizers
have had quite dramatic side effects to 2D6 substrate
medications3 and some toxic reactions have been
lethal.30,31 However, there have been no large random-
ized clinical trials to demonstrate the clinical utility of
pharmacogenomic testing. Such trials would reinforce
the use of testing. However, it is unlikely that these tri-
als will ever be conducted because, by definition, they
are not designed to concentrate on those patients who
are the most likely to benefit from pharmacogenomic
testing. Trials that screen vulnerable populations and
identify patients at risk for suboptimal responses to med-
ications are a more efficient method to address the clin-
ical usefulness of testing patients with decreased meta-
bolic capacity. These screened patients could then be
enrolled in protocols designed to provide optimal
response for their specific genotypes and predicted phar-
macogenomic phenotypes.
Ethical considerations for pharmacogenomic
testing in psychiatric practice
The provision of pharmacogenomic testing involves rel-
atively few risks, but ethical safeguards are still impor-
tant to consider. These are essentially the same consid-
erations that are important to think through when
ordering any laboratory test that has the potential to
direct a treatment decision.
First, clinical pharmacogenomic testing requires obtain-
ing appropriate consent. This has become a guiding prin-
ciple for all diagnostic and therapeutic procedures.
Clinicians should provide the basic rationale for pro-
ceeding with pharmacogenomic testing so that their
18. patients have the opportunity to provide explicit
informed consent.
Secondly, as a component of obtaining clinical consent,
it must be clear that clinical testing is a voluntary proce-
dure. This is true for virtually all clinical laboratory test-
ing with the relatively rare exceptions of mandatory test-
ing that can identify a condition with a potential
negative influence on the public health of the commu-
nity. A common example of compulsory testing is the
monitoring of infections in order to prevent contagion.
A third principle is that clinicians must insure the confi-
dentiality of sensitive medical information that becomes
a part of the medical record of the patient. This is true
whether the information is derived from a pathological
specimen that reveals a malignant carcinoma or from
magnetic resonance imaging that demonstrates atrophy
P h a r m a c o l o g i c a l a s p e c t s
7 4
DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 74
of the hippocampus. The security of the medical record
is the responsibility of the clinician.
Finally, any diagnostic medical procedure must have an
acceptable level of reliability. The degree of accuracy of
any clinical laboratory testing is dependent on a number
of key variables. Two of these variables are the serious-
ness of the prognosis for the patient if the test is positive
and the efficacy of available treatments. In designing the
treatment plan for a potentially lethal condition that is
likely to respond well to a relatively benign intervention
if it is administered early in the course of the illness, a
19. laboratory test with high sensitivity is desirable. The
most important objective in this situation is to identify
as quickly as possible those patients who will benefit
from treatment.
Future developments that will influence
pharmacogenomic testing in
psychiatric practice
In the 2009 presidential lecture of the American
Psychiatric Association, it was predicted that pharma-
cogenomic testing would become a part of everyday psy-
chiatric practice.32 Ironically, in many academic health
centers, pharmacogenomic testing has been utilized since
2004—the time of the introduction of the AmpliChip.
Over the intervening years, early adopters have inte-
grated pharmacogenomic testing into their inpatient
protocols and ultimately into their outpatient practices.
However, this testing has not yet been included in many
clinical guidelines.
Pharmacogenomic testing is an innovation, and it takes
time for innovations to become integrated into standard
practice. While it is difficult to predict with accuracy just
how quickly pharmacogenomic testing will become an
essential component of clinical psychopharmacological
practice, there is no question that this will happen.
Ironically, given advances in our ability to sequence genes
both rapidly and inexpensively, there will come a time in
the near future when most patients will know their 2D6
phenotype in the same way as today they know their
blood type. However, well before we reach a state of uni-
versal awareness of our informative genotypes, our
patients will no longer accept avoidable side effects, and
will demand basic pharmacogenomic testing prior to tak-
20. ing antidepressant or antipsychotic medications. ❏
Psychiatric pharmacogenomic testing - Mrazek Dialogues in
Clinical Neuroscience - Vol 12 . No. 1 . 2010
7 5
REFERENCES
1. Mrazek DA. Psychiatric Pharmacogenomics. New York, NY:
Oxford
University Press; 2010.
2. Thase ME, Friedman ES, Biggs MM, et al. Cognitive therapy
versus med-
ication in augmentation and switch strategies as second-step
treatments: a
STAR*D report. Am J Psychiatry. 2007;164:739-752.
3. Weinshilboum R. Inheritance and drug response. N Engl J
Med.
2003;348:529-537.
4. Dalen P, Dahl ML, Ruiz ML, Nordin J, Bertilsson L. 10-
Hydroxylation of
nortriptyline in white persons with 0, 1, 2, 3, and 13 functional
CYP2D6
genes. Clin Pharmacol Ther. 1998;63:444-452.
5. Mrazek D. Out of the pipeline: pharmacogenomic DNA chip.
Curr
Psychiatr. 2005;4:67-73.
6. Preskorn S. Reproducibility of the in vivo effect of the
selective sero-
tonin reuptake inhibitors on the in vivo function of cytochrome
P450 2D6:
an update (part II). J Psychiatr Pract. 2003;9:150-158.
7. Goetz MP, Knox SK, Suman VJ, et al. The impact of
cytochrome P450
2D6 metabolism in women receiving adjuvant tamoxifen. Breast
21. Cancer Res
Treat. 2007;101:113-21.
8. Schroth W, Goetz MP, Hamann U, et al. Associaiton between
CYP2D6
polymorphisms and outcomes among women with early stage
breast can-
cer treated with tamoxifen. JAMA. 2009;302:1429-1436.
9. Henry NL, Stearns V, Flockhart DA, Hayes DF, Riba M.
Drug interactions
and pharmacogenomics in the treatment of breast cancer and
depression.
Am J Psychiatry. 2008;165:1251-1255.
10. Sim SC, Risinger C, Dahl ML, et al. A common novel
CYP2C19 gene vari-
ant causes ultrarapid drug metabolism relevant for the drug
response to
proton pump inhibitors and antidepressants. Clin Pharmacol
Ther.
2006;79:103-113.
11. Trivedi M, Rush A, Wisniewski S, et al. Evaluation of
outcomes with
citalopram for depression using measurement-based care in
STAR*D: impli-
cations for clinical practice. Am J Psychiatry. 2006;163:28.
12. Serretti A, Kato M, De Ronchi D, Kinoshita T. Meta-
analysis of serotonin
transporter gene promoter polymorphism (5-HTTLPR)
association with selec-
tive serotonin reuptake inhibitor efficacy in depressed patients.
Mol
Psychiatry. 2007;12:247-257.
13. Serretti A, Zanardi R, Rossini D, Cusin C, Lilli R, Smeraldi
E. Influence of
tryptophan hydroxylase and serotonin transporter genes on
fluvoxamine
22. antidepressant activity. Mol Psychiatry. 2001;6:586-592.
14. Yoshida K, Itoa K, Satoa K, et al. Influence of the serotonin
transporter
gene-linked polymorphic region on the antidepressant response
to fluvox-
amine in Japanese depressed patients. Prog
Neuropsychopharmacol Biol
Psychiatry. 2002;26:383-386.
15. Kim DK, Lim SW, Lee S, et al. Serotonin transporter gene
polymorphism
and antidepressant response. Neuroreport. 2000;11:215-219.
16. Peters E, Slager S, McGrath P, Knowles J, Hamilton S.
Investigation of
serotonin-related genes in antidepressant response. Mol
Psychiatry.
2004;9:879-889.
17. Hu XZ, Rush AJ, Charney D, et al. Association between a
functional
serotonin transporter promoter polymorphism and citalopram
treatment
in adult outpatients with major depression. Arch Gen
Psychiatry. 2007;64:783-
792.
18. Mrazek DA, Rush AJ, Biernacka JM, et al. SLC6A4
variation and citalo-
pram response. Am J Med Genet Part B. 2009;150:341-351.
19. McMahon FJ, Buervenich S, Charney D, et al. Variation in
the gene
encoding the serotonin 2A receptor is associated with outcome
of antide-
pressant treatment. Am J Hum Genet. 2006;78:804-814.
20. Murphy GM, Kremer C, Rodrigues HE, Schatzberg AF.
Pharmacogenetics
of antidepressant medication intolerance. Am J Psychiatry.
2003;160:1830-
1835.
23. DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 75
P h a r m a c o l o g i c a l a s p e c t s
7 6
Pruebas farmacogenómicas en la práctica
clínica psiquiátrica
La incorporación en psiquiatría clínica de las prue-
bas farmacogenómicas ha ocurrido rápidamente en
los últimos siete años. Inicialmente se identificaron
genes de enzimas metabolizadoras de fármacos,
como el gen del citocromo P450 2D6. La tipificación
del gen del citocromo P450 2D6 que es altamente
variable da la oportunidad actualmente a los clíni-
cos de identificar a los metabolizadores pobres y los
ultrarrápidos para las sustancias que son sustrato
del 2D6. Con posterioridad se ha podido disponer
en la práctica clínica de genes que influyen en la
respuesta farmacodinámica de los medicamentos.
Entre los primeros “genes blanco” estuvo el gen del
transportador de serotonina (SLC6A4), el cual tiene
variantes que han demostrado que influyen en la
respuesta clínica de los pacientes con ancestros
europeos cuando son tratados con inhibidores
selectivos de la recaptura de serotonina. La tipifi-
cación de algunos de los genes del receptor de sero-
tonina también está disponible para guiar la prác-
tica clínica. La cuantificación de la utilidad clínica de
las pruebas farmacogenómicas está en desarrollo y
se han establecido las consideraciones éticas para
su realización. Considerando la cada vez más clara
24. costo-eficacia de la tipificación génica, reciente-
mente se ha pronosticado que las pruebas farma-
cogenómicas se solicitarán de rutina para orientar
la selección y dosificación de los fármacos psicotró-
picos.
Évaluation pharmacogénomique
psychiatrique en pratique clinique
L’évaluation pharmacogénomique psychiatrique
s’est rapidement imposée en pratique clinique au
cours de ces 7 dernières années. Les gènes d’en-
zymes métabolisant les médicaments, comme le
cytochrome P450 2D6 (CYP2D6), ont d’abord été
identifiés. Le génotypage de ce gène très variable
permet maintenant aux cliniciens d’identifier des
métaboliseurs lents et des métaboliseurs ultrara-
pides des substrats du 2D6. Des gènes influant sur
la réponse pharmacodynamique des médicaments
sont ensuite devenus disponibles en pratique cli-
nique. Parmi les premiers « gènes cibles », le gène
du transporteur de la sérotonine (SLC6A4) possède
des variants qui influent sur la réponse clinique des
patients d’ascendance européenne lorsqu’ils sont
traités avec des inhibiteurs sélectifs de la recapture
de la sérotonine. Le génotypage de certains gènes
du récepteur de la sérotonine est également dis-
ponible pour guider la réponse clinique. La quan-
tification de l’utilité clinique de l’évaluation phar-
macogénomique évolue et fait l’objet de
considérations éthiques. Il a été récemment prédit
qu’en raison de l’évidente rentabilité croissante du
génotypage, l’évaluation pharmacogénomique
devrait faire partie des examens de routine pour
sélectionner et ajuster la posologie des médica-
ments psychotropes.
25. 21. Segman RH, Heresco-Levy U, Finkel B, et al. Association
between the
serotonin 2A receptor gene and tardive dyskinesia in chronic
schizophre-
nia. Mol Psychiatry. 2001;6:225-229.
22. Tan EC, Chong SA, Mahendran R, Dong F, Tan CH.
Susceptibility to neu-
roleptic-induced tardive dyskinesia and the T102C
polymorphism in the sero-
tonin type 2A receptor. Biol Psychiatry. 2001;50:144-147.
23. Lattuada E, Cavallaro R, Serretti A, Lorenzi C, Smeraldi E.
Tardive dyski-
nesia and DRD2, DRD3, DRD4, 5-HT2A variants in
schizophrenia: an associa-
tion study with repeated assessment. Int J Neuropsychopharmcol
2004;7:489-493.
24. Sodhi MS, Arranz MJ, Curtis D, et al. Association between
clozapine
response and allelic variation in the 5-HT2C receptor gene.
Neuroreport.
1995;7:169-172.
25. Arranz MJ, Munro J, Birkett J, et al. Pharmacogenetic
prediction of
clozapine response. Lancet. 2000;355:1615-1616.
26. Gunes A, Scordo MG, Jaanson P, Dahl ML. Serotonin and
dopamine
receptor gene polymorphisms and the risk of extrapyramidal
side effects in
perphenazine-treated schizophrenic patients.
Psychopharmacology
2007;190:479-484.
27. Reynolds GP, Zhang ZJ, Zhang XB. Association of
antipsychotic drug-
induced weight gain with a 5-HT2C receptor gene
26. polymorphism. Lancet.
2002;359:2086-2087.
28. Templeman LA, Reynolds GP, Arranz B, San L.
Polymorphisms of the 5-
HT2C receptor and leptin genes are associated with
antipsychotic drug-
induced weight gain in Caucasian subjects with a first-episode
psychosis.
Pharmacogenet Genomics. 2005;15:195-200.
29. De Luca V, Muller DJ, Hwang R, et al. HTR2C haplotypes
and antipsy-
chotics-induced weight gain: X-linked multimarker analysis.
Hum
Psychopharmacol. 2007;22:463-467.
30. Sallee FR, DeVane CL, Ferrell RE. Fluoxetine-related death
in a child with
cytochrome P-450 2D6 genetic deficiency. J Child Adolesc
Psychopharmacol.
2000;10:27-34.
31. Koski A, Ojanpera I, Vuori E, Sajantila A. A fatal doxepin
poisoning
associated with a defective CYP2D6 genotype. Am J Forensic
Med Pathol.
2007;28:259-261.
32. Stotland NL. Presidential address. Am J Psychiatry.
2009;166:1100-1104.
DCNS_44_5.qxd:DCNS#44 10/03/10 1:44 Page 76
E-Mail [email protected]
Editorial
27. Psychother Psychosom 2016;85:129–135
DOI: 10.1159/000443512
The Limitations of Genetic Testing in
Psychiatry
Steven L. Dubovsky
Department of Psychiatry, State University of New York at
Buffalo, Buffalo, N.Y. , and Departments of Psychiatry and
Medicine, University of Colorado, Denver, Colo. , USA
tocols for them [4] . In moderately differentiated breast
cancers, which comprise 50% of breast tumors, gene ex-
pression signatures for mitotic index, angiogenic poten-
tial, p53 mutational status, and estrogen and progester-
one dependence provide better stratification of prognosis
than histology [6] . However, despite such advances, there
is still not much clear integration between genomics and
clinical practice in oncology [7] .
Psychiatric Diagnosis
Numerous markers have been associated with psychi-
atric disorders, including genes for BDNF (brain-derived
neurotrophic factor), FOS (FBJ murine osteosarcoma vi-
ral oncogene homolog), COMT, DRD1, DRD2, DISC1,
GABABR1 (γ-aminobutyric acid B receptor 1), NR4A2
(nuclear receptor subfamily 4, group A, member 2),
ADORA2A (adenosine A2a receptor), CACNA1C (cal-
cium channel gene), sirtuin 1, LHPP, 5HTR1A, RNA-
binding proteins, and genes for myelination, glutaminer-
gic and GABAergic neurotransmission, oxidative stress,
signal transduction, response to the environment, cell
survival and proliferation, and cell shrinkage and apop-
28. tosis, among others [8–13] . Yet no genetic marker has yet
been shown to be useful in prospectively identifying any
specific psychiatric disorder [14] . Because genetic predis-
Despite the burgeoning number of psychiatric treat-
ments, we still do not know how to predict which one will
work best for which patient. The hope that genetic (single
gene effects) and genomic (multiple gene effects) testing
might be useful for diagnosis and treatment has been en-
couraged by decreased costs of genome sequencing and
studies demonstrating an association between mutations
in more than 3,000 genes and specific disease phenotypes
[1–3] . Are the data as promising in psychiatry as they are
in other fields?
Cancer Genomics
Genetic testing has been most promising in oncology.
For example, about 10% of cases of breast cancer have an
autosomal dominant pattern of transmission, most com-
monly mutations in the tumor suppressor genes BRCA1
and BRCA2 [4] . When BRCA1/2 mutations are found,
healthy women are offered a very close follow-up, as well
as prophylactic antiestrogen therapy or surgery, yet in
one study only 9.5% of high-risk women even underwent
genetic counseling, let alone testing [5] . Breast cancer risk
alleles have also been found for p53, PTEN (phosphate
and tensin homolog deleted from chromosome 10),
STK11, CDH1 and PALB2; however, these genetic factors
are rare, and there is not much research on screening pro-
Received: December 15, 2015
Accepted after revision: December 20, 2015
Published online: April 5, 2016
Steven L. Dubovsky, MD
30. Descriptive diagnoses in psychiatry have multiple do-
mains such as age of onset, constellations of specific
symptoms, functioning, comorbidity, and evolution over
time that assort differently in different patients in the
same category to produce functionally different condi-
tions [19] . Genetic profiles associated with any one of
these features are not likely to predict more global diag-
noses. If the direct path from genotype to phenotype ends
at discrete endophenotypes such as arousal, anhedonia,
information processing, stress responses, inflammation
and mood, rather than global diagnosis, attempts to link
the latter to specific genes are likely to prove frustrating
[20–23] , just as descriptive diagnoses in psychiatry do not
adequately consider important subtypes that exhibit dif-
ferent assortments of features such as age of onset, sever-
ity, progression or functioning.
Genetic Pharmacokinetic Studies
Since cytochrome P450 (CYP450) 1A2, 2D6, 2C9,
2C19, and 3A4 account for 60% of psychiatric drug me-
tabolism [24] , considerable interest has centered on using
the CYP450 genotype to predict response to psychotropic
medications [3] . However, genotype does not inevitably
predict phenotype because multiple copies of a more or
less active gene can result in more or less metabolic activ-
ity than would be expected from the allele that is identi-
fied. In addition, the metabolizer phenotype associated
with a particular genotype can be inhibited or enhanced
by a number of medications, substances, and foods [25–
30] . In an open study of 900 patients treated with venla-
faxine who were both genotyped and phenotyped for
CYP2D6, 4% were genotypically poor metabolizers, while
27% were phenotypically poor metabolizers, suggesting
that 23% of patients with other genotypes had converted
31. to a poor metabolizer phenotype as a result of concomi-
tant medications [31] .
Even if genotype inevitably predicted phenotype, the
correlation is stronger between CYP450 phenotype and
drug level than clinical response [32] , which is modified
by metabolism of most medications by more than one
enzyme, lack of linear kinetics and saturable elimination
for many drugs, unclear correlations between blood level
and response for many medications, and therapeutic win-
dows requiring therapeutic monitoring anyway for some
of them [24, 26, 33, 34] . Expression of CYP450 enzymes
in the brain, which influences drug effect, may be differ-
ent from their expression in the blood, or even in the in-
testine and liver [24] .
Drug Transporter Studies
Drug transporters, including P-glycoprotein (P-gp), or-
ganic ion transporters, and multidrug and toxin extrusion
proteins, modify the effect of CYP450 phenotype on drug
levels and drug action because they influence gastrointesti-
nal absorption, tissue uptake, and renal elimination as well
as transport in and out of the brain [35, 36] . In the iSPOT-
D (International Study to Predict Optimized Treatment in
Depression), two different MDR1 single nucleotide poly-
morphisms (SNPs) of the gene for P-gp (MDR1 or ABCB1)
were associated with better responses either to escitalo-
pram and sertraline or to venlafaxine, but there was no a
priori hypothesis, other relevant factors such as drug me-
tabolism, ethnicity, age, specific symptoms, or concomitant
illness were not addressed [36] , and DNA was collected af-
ter results were known rather than prospectively [37] .
Pharmacodynamic Studies
32. Both a deletion (short polymorphism or s-allele) and
an insertion (long polymorphism or l-allele) have been
found in the gene (SCL6A4) for the promoter region
(5-HTTLPR) of the gene for the serotonin transporter
(SERT) [32] . The short polymorphism (s) decreases and
the long polymorphism (l) increases SLC6A4 transcrip-
tion rates, resulting in less or more SERT expression, re-
spectively [32] . Research on the association of the s/s ge-
notype with a lower response rate to serotonin reuptake
inhibitors in some ethnic groups has been contradictory
[38–40] , and even without correction for multiple statisti-
cal tests, the SCL6A4 genotype explains at most 5% of the
variance in antidepressant response [30] . Attempts have
http://dx.doi.org/10.1159%2F000443512
Genetics in Psychiatry Psychother Psychosom 2016;85:129–
135
DOI: 10.1159/000443512
131
been made to correlate SNPs of the brain-specific voltage-
gated rectifier potassium channel (Kv11.1–3.1) and the
cardiac specific version (Kv11.1–1A) with risperidone
treatment response and changes in cardiac conduction,
respectively, in schizophrenia [41] , but the results have
not been robust.
Gene Network Studies
Because treatment outcome seems to be influenced by
multiple genetic polymorphisms, each with a small effect
[3, 21] , research has moved toward analysis of networks
of genes in the hope of developing more clinically useful
33. information [42–44] . However, such studies have not
produced clinically meaningful results [43, 44] . The Ge-
nome-Based Therapeutic Drugs for Depression (GEN-
DEP; n = 811) study, a substudy of the Sequenced Treat-
ment Alternatives to Relive Depression (STAR * D; n =
1,491) study, and the Munich Antidepressant Response
Study (n = 339), did not find any combination of genetic
markers that influenced treatment response in depres-
sion [1, 44] . Genome-wide association studies did not re-
veal any SNPs associated with response or remission of
nonbipolar, nonpsychotic, major depressive disorder
treated openly with serotonin reuptake inhibitors [45] ,
and the STAR * D study did not reveal any positive ge-
nome-wide association or top 25 SNP associations with
treatment response [45] . A genome-wide association
study from the Clinical Antipsychotic Trials of Interven-
tion Effectiveness (CATIE, n = 738) did not find any com-
binations of genetic markers that influenced treatment
response in schizophrenia [1, 44] .
Prospective Treatment Studies
Only a small number of reports have involved the pro-
spective use of genotyping to make treatment decisions.
An open study of 58 depressed inpatients reported that
genotyping for ABCB1 was associated with a shorter hos-
pital stay because patients with the TT/GG genotype were
more likely to have an increase in the dose of an antide-
pressant that was a P-gp substrate, although changing to
a non-P-gp substrate did not affect outcome [46] . The
study was not randomized, and numerous intervening
variables, including pharmacokinetics, comorbidity, and
history, were not considered.
Four studies have been supported by the manufactur-
er of a proprietary survey (GeneSight) of CYP2D6, 2C19,
34. 2C9, and 1A2, SLC6A4, and 5HTR2A genotypes that gen-
erates a ‘composite report’ classifying antidepressants
and antipsychotic drugs used in the treatment of depres-
sion into three categories: ‘use as directed’, ‘use with cau-
tion’, and ‘use with caution and with more frequent mon-
itoring’. An 8-week open study of 44 patients assigned in
a nonrandom manner to treatment guided by the com-
posite report (guided treatment) or nonguided treatment
by the same clinicians, who were involved with the prod-
uct, reported that patients in the guided group were less
likely to receive medications in the ‘use with caution and
with more frequent monitoring’ category, presumably
because of reluctance by the guided clinicians to prescribe
medications that required more monitoring [47] . Al-
though improvement of depression was similar for the
first 4 weeks in both groups, a single measure at 8 weeks
indicated increased depression scores for the nonguided
but not the guided group. No explanation was offered for
the final increase in depression scores in the nonguided
group, when multiple earlier ratings demonstrated a
steady decrease in scores. Improvement in the guided
group was not impressive, and it is impossible to know
whether comorbid factors, concomitant medications,
treatment adherence, patient enthusiasm, substance use,
adjunctive psychotherapy, clinician knowledge of treat-
ment condition, and open ratings affected the conduct of
treatment or the outcome assessment.
A second open, nonrandomized study conducted by
the same group in 227 mildly-moderately depressed pa-
tients, 165 of whom completed 8 weeks of treatment, re-
ported that patients in the guided group were twice as
likely to respond [48] . Since clinicians reported substan-
tial levels of confidence in the genetic reports, it is possi-
ble that they worked more vigorously with patients in the
35. guided group, that patients in the guided group were
more adherent with a treatment approach they thought
would be more effective, or that they reported better re-
sults to please the investigators.
In a double-blind, randomized, controlled trial of
GeneSight, 25 depressed patients were assigned to treat-
ment as usual and 26 to guided treatment [49] . Improve-
ment was numerically greater in patients in the guided
than in the treatment-as-usual group, but none of the
group differences were statistically significant. In a fourth
report from the same company [50] , 97 patients with a
depressive or anxiety disorder treated openly by a single
psychiatrist with one of the medications in the genetic sur-
vey were followed openly for 1 year. The 9 patients taking
at least one medication in the ‘use with caution’ category
had significantly more total health care visits and nonpsy-
http://dx.doi.org/10.1159%2F000443512
Dubovsky
Psychother Psychosom 2016;85:129–135
DOI: 10.1159/000443512
132
chiatric medical visits than the other subjects and had a
higher average cost of care. However, these patients also
took more medications than the other subjects, and there
was a significant correlation between the number of med-
ications taken and the two outcome variables. When dif-
ferent statistical analyses were performed on the same
data (e.g. analysis of variance and t tests), some were sig-
36. nificant and some were not, and no correction was made
for multiple statistical tests. Although the authors con-
tended that their genetic analysis could save health care
costs, this hypothesis was not actually tested. Since no data
were available on medical comorbidity and severity of
psychiatric illness, the possibility was not considered that
the small number of patients in the ‘use with caution’ cat-
egory had more health care visits and took more medi-
cations because they were sicker psychiatrically or medi-
cally.
Gene Expression
Current genotyping approaches in psychiatry consider
the presence or absence of a particular allele or group of
alleles, but expression of those genes may be suppressed,
modified, or enhanced by a number of factors, including
circadian transcription patterns, epistasis (gene interac-
tions), regulatory regions, epigenetic factors, and noncod-
ing RNA [14] . Histone modification and DNA methyla-
tion in response to experience, inflammation, the illness,
and the medications used to treat it can induce or suppress
multiple genes, and genotype itself can affect methylation
of regulatory sites that leads to epigenetic changes in brain
development [51] . Micro-RNAs and short interfering
RNAs are short, noncoding posttranslational regulators of
gene expression that target hundreds of mRNA transcripts
to influence gene networks [27, 52, 53] . The expression of
genes for CYP450 enzymes is altered by promoter meth-
ylation, micro-RNAs associated with inflammation and
other illnesses [27] , and some medications [54] , resulting
in an altered CYP450 phenotype.
Limitations of Pharmacogenetic Testing in
Psychiatry
37. No matter how much we may want to translate direct-
ly to clinical diagnosis reports of an association between
a diagnosis and a genetic marker, the nature of the current
level of knowledge does not permit this application. Sam-
ple sizes in most existing studies have been too small to
produce meaningful, replicable results because of the
clinical and genetic heterogeneity of psychiatric disorders
[55] , and the combined influence of multiple genes, each
with a small effect size [1, 15, 16] . Most studies have uti-
lized retrospective or post hoc analyses rather than pro-
spective a priori hypotheses [56] , and statistical signifi-
cance is often inflated by lack of correction for multiple
statistical tests [16] . The majority of studies lack replica-
tion in independent samples, especially by different in-
vestigators [16] . Even robust findings would not be clini-
cally applicable until a prospective study demonstrated
their ability to preferentially predict one diagnosis or even
clinically relevant feature over another.
Using genotype to predict response to medications is
even more problematic. Pharmacogenetic studies have
been conducted in normal subjects or patients who are
not taking other medications and who do not have other
illnesses, limiting extrapolation to most clinical settings
[33, 34] . Most studies do not control for the effect on the
expression of CYP450 and other genes of age [27] , ethnic-
ity [30] , smoking [30, 34] , and use of substances such as
alcohol, hormones, St. John’s wort, caffeine, cabbage, and
grapefruit juice [30] . Genetic studies of treatment out-
come have not measured nonadherence [57] , but as the
rate of nonadherence increases in any population, statis-
tical power to detect a genotype effect decreases substan-
tially [1] . For medications that are chiral mixtures of en-
antiomers with different actions, the metabolism of each
38. enantiomer may be by different enzymes [58] . Active me-
tabolites with their own metabolic pathways may en-
hance or interfere with therapeutic or toxic effects pre-
dicted by the presumed metabolism of the parent drug
[59, 60] . In most instances, more than one genetic factor
affects drug levels and disposition [3] , and interactions
between these factors can be difficult to predict.
A clear demonstration of a genotype/blood level rela-
tionship in a single dose or 8-week study may not corre-
late with chronic treatment, in which compensatory
changes in secondary metabolic pathways and drug trans-
porters, gene up- or downregulation, saturation pharma-
cokinetics and other factors may modify the impact of
oxidative enzyme polymorphisms on final drug level [24,
59] . With chronic treatment, some psychotropic drug
metabolites form complexes with P450 enzymes that alter
or even reverse the acute effect on metabolism [25] . Long-
term changes in P450 enzymes also occur in the brain,
with further unpredictable effects, not only on the sub-
strate drug, but on neurotransmitters and neurosteroids
metabolized by the same enzymes on which the medica-
tion may act [25] . Another complicating factor is that the
http://dx.doi.org/10.1159%2F000443512
Genetics in Psychiatry Psychother Psychosom 2016;85:129–
135
DOI: 10.1159/000443512
133
illness, as well as medications used to treat it, can alter the
relationship between pharmacologic genotype and phe-
notype. For example, many proinflammatory cytokines
39. and acute-phase proteins that are associated with mood
and anxiety disorders [61] act on transcription or post-
translational protein modification to downregulate some
CYP450 genes and upregulate others [62] . At the same
time, suppression of cytokines by antidepressants can al-
ter gene expression in directions that antagonize im-
provement of depression [25] . The impact of evolution of
the illness and its response to different treatments in
modifying therapeutic strategies during the course of
treatment of cancer is relatively straightforward to study
by virtue of methodologies for examining genotype and
phenotype of cellular clones, but it is still difficult to de-
velop the correct approach to well-characterized tumors
[63] . The absence of such measures in psychiatric diagno-
ses makes this prospect considerably more difficult.
Where Do We Go from Here?
Psychiatrists, whose work frequently involves ambigu-
ous clinical problems, and who must often consider con-
tradictory elements of patient presentations and avoid
premature closure, can have a remarkably low tolerance
for ambiguity, conflict, and delayed gratification when it
comes to the latest laboratory study. The hope that phar-
macogenetic testing will result in unambiguous ‘person-
alized psychiatry’ should not lead to quick adoption of
technologies that have not yet been demonstrated to reli-
ably predict a specific course or a need for a specific med-
ication, the choice of which remains largely empirical. Af-
ter all, genetic associations are statistical, but medical
practice is personal [14] . Yet there is tremendous pressure
to translate each new report of such associations to our
patients, not only from our own need to appear ‘scien-
tific’ and from industry marketing of proprietary tests,
but from the marketing of ideas by thought leaders with
40. an intellectual attachment to the latest conceptualization
of genetic causality [64] .
It is a continuing challenge to examine new genetic
findings critically without applying them immediately in
the clinic. When adequately powered studies that address
gene number and expression and that control for real-life
factors that affect outcome such as comorbidity, poly-
pharmacy, environmental exposure, age, gender, ethnic-
ity, substance use, and treatment adherence emerge [44] ,
clinicians who have not put new information into action
before integrating it with emerging knowledge about di-
agnosis, neurobiology, and the evolution of complex dis-
orders will be ready to apply them effectively.
Disclosure Statement
Dr. Dubovsky has received research support from Janssen, Ot-
suka, Sumitomo, Neurocrine, Tower Foundation, Wendt
Founda-
tion, Oshei Foundation and Patrick Lee Foundation. The author
has no other conflicts of interest to disclose.
References
1 Malhotra AK, Zhang J-P, Lencz T: Pharmaco-
genetics in psychiatry: translating research
into clinical practice. Mol Psychiatry 2012; 17:
760–769.
2 Cox DBT, Platt RJ, Zhang F: Therapeutic ge-
nome editing: prospects and challenges. Nat
Med 2015; 21: 121–131.
3 Trembplay J, Hamet P: Role of genomics on
41. the path to personalized medicine. Metabo-
lism 2013; 62:S2–S5.
4 Stuckey AR, Onstad MA: Hereditary breast
cancer: an update on risk assessment and ge-
netic testing in 2015. Am J Obstet Gynecol
2015; 213: 161–165.
5 Bellcross CA, Peipins LA, McCarty FA, Ro-
driguez JL, Hawkins NA, Hensley Alford S,
Leadbetter S: Characteristics associated with
genetic counseling referral and BRCA1/2 test-
ing among women in a large integrated health
system. Genet Med 2015; 17: 43–50.
6 Ivshina AV, George J, Senko O, Mow B, Putti
TC, Smeds J, Lindahl T, Pawitan Y, Hall P,
Nordgren H, Wong JEL, Liu ET, Bergh J,
Kuznetsove VA, Miller LD: Genetic reclassi-
fication of histologic grade delineates new
clinical subtypes of breast cancer. Cancer Res
2006; 66: 10292–10301.
7 Anonymous: The future of cancer genomics.
Nat Med 2015; 21: 99.
8 Le-Niculescu H, Balaraman Y, Patel SD,
Ayalew M, Gupta J, Kuczenski R, Shekhar A,
Shekhar A, Schork N, Geyer MA, Niculescu
AB: Convergent functional genomics of anxi-
ety disorders: translational identification of
genes, biomarkers, pathways and mecha-
nisms. Transl Psychiatry 2011; 1:e9.
9 Carrard A, Salzmann A, Malafosse A, Karege
F: Increased DNA methylation status of the
42. serotonin receptor 5HTR1A gene promoter
in schizophrenia and bipolar disorder. J Af-
fect Disord 2011; 132: 450–453.
10 Mill J, Tang T, Kaminsky Z, Khare T, Yaz-
danpanah S, Bouchard L, Jia P, Assadzadeh A,
Flanagan J, Schumacher A, Wang SC, Petro-
nis A: Epigenomic profiling reveals DNA-
methylation changes associated with major
psychosis. Am J Hum Genet 2008; 82: 696–
711.
11 Fullerton JM, Tiwari Y, Agahi G, Heath A,
Berk M, Mitchell PB, Schofield PR: Assessing
oxidative pathway genes as risk factors for bi-
polar disorder. Bipolar Disord 2010; 12: 550–
556.
12 Hoenicka J, Garrido E, Ponce G, Rodriguez-
Jimenez R, Martinez I, Rubio G, Jimenez-Ar-
riero MA, Palomo T: Sexually dimorphic in-
teraction between the DRD1 and COMT
genes in schizophrenia. Am J Med Genet
2010; 153B:984–954.
http://dx.doi.org/10.1159%2F000443512
Dubovsky
Psychother Psychosom 2016;85:129–135
DOI: 10.1159/000443512
134
43. 13 Hong CJ, Liou YJ, Bai Y, Chen TT, Wang Y,
Tsai SJ: Dopamine receptor D2 gene is associ-
ated with weight gain in schizophrenia pa-
tients under long-term atypical antipsychotic
treatment. Pharmacogenet Genomics 2010;
20: 359–366.
14 Li JZ: Circadian rhythms and mood: opportu-
nities for multi-level analyses in genomics
and neuroscience. Bioessays 2013; 36: 305–
315.
15 Genetics of Personality Consortium: Meta-
analysis of genome-wide association studies
for neuroticism, and the polygenic associa-
tion with major depression. JAMA Psychiatry
2015; 72: 642–650.
16 Gillis NK, Innocenti F: Evidence required to
demonstrate clinical utility of pharmacoge-
netic testing: the debate continues. Clin Phar-
macol Ther 2014; 96: 655–657.
17 Fanous AH, Kendler KS: Genetic heterogene-
ity, modifier genes, and quantitative pheno-
types in psychiatric illness: searching for a
framework. Mol Psychiatry 2005; 10: 6–13.
18 Patel SD, Le-Niculescu H, Koller DL, Green
SD, Lahiri DK, McMahon FJ, Nurnberger JIJ,
Niculescu AB: Coming to grips with complex
disorders: genetic risk prediction in bipolar
disorder using panels of genes identified
through convergent functional genomics. Am
J Med Genet 2010; 153B:850–877.
44. 19 Fava GA, Guidi J, Grandi S, Hasler G: The
missing link between clinical states and bio-
markers in mental disorders. Psychother Psy-
chosom 2014; 83: 136–141.
20 Van Borkulo C, Boschioo L, Borsboom D,
Pennix BWJH, Waldorp LJ, Schoevers RA:
Association of symptom network structure
with the course of longitudinal depression.
JAMA Psychiatry 2015; 72: 1219–1226.
21 Keers R, Aitchison KJ: Pharmacokinetics of
antidepressant response. Expert Rev Neu-
rother 2011; 11: 101–125.
22 Domschke K: Clinical and molecular genetics
of psychotic depression. Schizophr Bull 2013;
39: 766–775.
23 Fabbri C, Porcelli S, Serretti A: From pharma-
cogenetics to pharmacogenomics: the way to-
ward the personalization of antidepressant
treatment. Can J Psychiatry 2014; 59: 62–75.
24 Preissner SC, Hoffmann MF, Preissner R,
Dunkel M, Gewiess A, Preissner S: Polymor-
phic cytochrome P450 enzymes (CYPs) and
their role in personalized therapy. PLoS One
2013; 8:e82562.
25 Wladyslawa AD: The influence of long-term
treatment with psychotropic drugs on cyto-
chrome P450: the involvement of different
mechanisms. Expert Opin Drug Metab Toxi-
col 2005; 1: 203–217.
45. 26 Crews KR, Gaedigk A, Dunnenberger HM,
Leeder JS, Klein TE, Caudle KE, Haidar CE,
Shen DD, Callaghan JT, Sadhasivam S, Prows
CA, Kharasch ED, Skaar TC: Clinical Phar-
macogenetics Implementation Consortium
guidelines for cytochrome P450 2D6 geno-
type and codeine therapy: 2014 update. Clin
Pharmacol Ther 2014; 95: 376–382.
27 Zanger UM, Klein K, Thomas M, Rieger JK,
Tremmel R, Kandel BA, Klein BA, Klein M,
Magdy T: Genetics, epigenetics, and regulation
of drug-metabolizing cytochrome p450 en-
zymes. Clin Pharmacol Ther 2014; 95: 258–261.
28 Misaka S, Kawabe K, Onoue S, Werba JP, Gi-
roli M, Tamaki S, Kan T, Kimura J, Watanabe
H, Yamada S: Effects of green tea catechins on
cytochrome P450 2B6, 2C8, 2C19, 2D6 and
3A activities in human liver and intestinal mi-
crosomes. Drug Metab Pharmacokinet 2013;
28: 244–249.
29 Yamasaki I, Yamada M, Uotsu N, Teramoto
S, Takayanagi R, Yamada Y: Inhibitory effects
of kale ingestion on metabolism by cyto-
chrome P450 enzymes. Biomed Res 2012; 33:
235–242.
30 Jones DS, Perlis RH: Pharmacogenetics, race,
and psychiatry: prospects and challenges.
Harvard Rev Psychiatry 2006; 14: 92–108.
31 Preskorn SH, Kane CP, Lobello K, Nichols AI,
Fayyad R, Buckley G, Focht K, Guico-Pabia
CJ: Cytochrome P450 2D6 phenoconversion
46. is common in patients being treated for de-
pression: implications for personalized medi-
cine. J Clin Psychiatry 2013; 74: 614–621.
32 Alter CN, Hornberger J, Shewade A, Cruz V,
Garrison J, Mrazek D: Clinical validity of cy-
tochrome P450 metabolism and serotonin
gene variants in psychiatric pharmacothera-
py. Int Rev Psychiatry 2013; 25: 509–533.
33 De Leon J, Arranz GR: Pharmacogenetic test-
ing in psychiatry: a review of features and clin-
ical realities. Clin Lab Med 2008; 28: 599–617.
34 Kirchheiner J, Brosen K, Dahl ML, Gram LF,
Kasper S, Roots I, Sjoqvist F, Spina E, Brock-
moller J: CYP2D6 and CYP2C19 genotype-
based dose recommendations for antidepres-
sants: a first step towards subpopulation-spe-
cific dosages. Acta Psychiatr Scand 2001; 104:
173–192.
35 Rosenhagen MC, Uhr M: The clinical impact
of ABCB1 polymorphisms in the treatment of
psychiatric diseases. Curr Pharm Des 2011;
17: 2843–2851.
36 Goswami S, Yee SW, Stocker S, Mosley JD,
Kubo M, Castro R, Mefford JA, Wen C, Liang
X, Witte J, Brett C, Maeda S, Simpson MD,
Hedderson MM, Davis RL, Roden DM, Gia-
comini KM, Savic RM: Genetic variants in
transcription factors are associated with the
pharmacokinetics and pharmacodynamics of
metformin. Clin Pharmacol Ther 2014; 96:
370–370.
47. 37 Schatzberg AF, DeBattista C, Lazzeroni LC,
Etkin A, Murphy GM, Williams LM: ABCB1
genetic effects on antidepressant outcomes: a
report from the iSPOT-D trial. Am J Psychia-
try 2015; 172: 751–759.
38 Porcelli S, Fabbri C, Serretti A: Meta-analysis
of serotonin transporter gene promoter poly-
morphism (5-HTTLPR) association with an-
tidepressant efficacy. Eur Neuropsychophar-
macol 2012; 22: 239–258.
39 Taylor MJ, Sen S, Bhagwagar Z: Antidepres-
sant response and the serotonin transporter-
linked polymorphic region. Biol Psychiatry
2010; 68: 536–543.
40 Kang HJ, Kim JM, Stewart R, Kim SY, Bae KY,
Kim SW, Shin MG, Yoon JS: Association of
SLC6A4 methylation with early adversity,
characteristics and outcomes in depression.
Prog Neuropsychopharmacol Biol Psychiatry
2013; 44: 23–28.
41 Heide J, Zhang F, Bigos KL, Mann SA, Carr
VJ, Weickert CS, Green MJ, Weinberger
DR, Vandenberg JI: Differential response to
risperidone in schizophrenia patients by
KCNH2 genotype and drug metabolizer sta-
tus. Am J Psychiatry 2016; 173: 53–59.
42 Costa e Silva JA: Personalized medicine in
psychiatry: new technologies and approaches.
Metabolism 2013; 62:S40–S44.
48. 43 Singh AB, Bousman CA, Ng C, Berk M: Anti-
depressant pharmacogenetics. Curr Opin
Psychiatry 2014; 27: 43–51.
44 Hamilton SP: The promise of psychiatric
pharmacogenomics. Biol Psychiatry 2015; 77:
29–35.
45 Ji Y, Biernacka JM, Hebbring S, Jenkins GD,
Batzler A, Snyder KA, Drews MS, Desta Z,
Flockart D, Mushiroda T, Kubo M, Naka-
mura Y, Kamatani N, Schaid D, Weinshil-
boum RM, Mrazek D: Pharmacogenomics
of selective serotonin reuptake inhibitor
treatment for major depressive disorder: ge-
nome-wide associations and functional ge-
nomics. Pharmacogenomics J 2013; 13: 456–
463.
46 Breitenstein B, Scheuer S, Pfister H, Uhr M,
Lucae S, Holsboer F, Ising M, Bruckl T: The
clinical application of ABCB1 genotyping in
antidepressant treatment: a pilot study. CNS
Spectr 2014; 19: 165–175.
47 Hall-Flavin DK, Winner JG, Allen J, Jordan JJ,
Nesheim RS, Snyder KA, Drews MS, Eister-
hold LL, Biernacka JM, Mrazek D: Using a
pharmacogenomic algorithm to guide the
treatment of depression. Transl Psychiatry
2012; 2:e172.
48 Hall-Flavin DK, Winner JG, Allen J, Carhart
JM, Proctor B, Snyder KA, Drews MS, Eister-
hold LL, Geske J, Mrazek D: Utility of inte-
grated pharmacogenomic testing to support
49. the treatment of major depressive disorder in
a psychiatric outpatient setting. Pharmaco-
genet Genomics 2013; 23: 535–548.
49 Winner JG, Carhart JM, Alter CN, Allen J,
Dechairo BM: A prospective, randomized,
double-blind study assessing the clinical im-
pact of integrated pharmacogenomic testing
for major depressive disorder. Discov Med
2013; 16: 219–227.
50 Winner JG, Allen J, Altar CA, Spahic-Miha-
jlovic A: Psychiatric pharmacogenomics pre-
dicts health resource utilization of outpatients
with anxiety and depression. Transl Psychia-
try 2013; 3:e242.
http://dx.doi.org/10.1159%2F000443512
Genetics in Psychiatry Psychother Psychosom 2016;85:129–
135
DOI: 10.1159/000443512
135
51 Hannon E, Spiers H, Viana J, Pidsley R, Bur-
rage J, Murphy TM, Troakes C, Turecki G,
O’Donovan MC, Schalkwyk LC, Bray NJ, Mill
J: Methylation QTLS in the developing brain
and their enrichment in schizophrenia risk
loci. Nat Neurosci 2016; 19: 48–54.
52 Geaghan M, Cairns MJ: MicroRNA and post-
transcriptional dysregulation in psychiatry.
Biol Psychiatry 2015; 78: 231–239.
50. 53 Xu Q, Wu X, Xiong Y, Xing Q, He L, Qin S:
Pharmacogenomics can improve antipsy-
chotic treatment in schizophrenia. Front Med
2013; 7: 180–190.
54 Gardiner E, Carroll A, Tooney PA, Cairns MJ:
Antipsychotic drug-associated gene-miRNA
interaction in T-lymphocytes. Int J Neuro-
psychopharmacol 2014; 17: 929–943.
55 Le-Niculescu H, Kurian SM, Yehyawi N, Dike
C, Patel SD, Edenberg HJ, Tsuang MT, Salo-
mon DR, Nurnberger JIJ, Niculescu AB: Iden-
tifying blood biomarkers for mood disorders
using convergent functional genomics. Mol
Psychiatry 2009; 14: 156–174.
56 Janssens ACJW, Deverka PA: Useless until
proven effective: the clinical utility of pre-
emptive pharmacogenetic testing. Clin Phar-
macol Ther 2014; 96: 652–654.
57 Melfi CA, Chawla AJ, Croghan TW, Hanna
MP, Kennedy S, Sredl K: The effects of adher-
ence to antidepressant treatment guidelines
on relapse and recurrence of depression. Arch
Gen Psychiatry 1998; 55: 1128–1132.
58 Crettol S, de Leon J, Hiemke C, Eap CB: Phar-
macogenomics in psychiatry: from therapeu-
tic drug monitoring to genomic medicine.
Clin Pharmacol Ther 2014; 95: 254–257.
59 Kirchheiner J, Nickchen K, Bauer M, Wong
M-L, Roots I, Brockmoller J: Pharmacogenet-
51. ics of antidepressants and antipsychotics: the
contribution of allelic variations to the phe-
notype of drug response. Mol Psychiatry
2004; 9: 442–473.
60 Seeringer A, Kirchheiner J: Pharmacogenet-
ics-guided dose modifications of antidepres-
sants. Clin Lab Med 2008; 28: 619–626.
61 Young JJ, Bruno D, Pomara N: A review of the
relationship between proinflammatory cyto-
kines and major depressive disorder. J Affect
Disord 2014; 169: 15–20.
62 Harvey RD, Morgan ET: Cancer, inflamma-
tion, and therapy: effects on cytochrome
p450-mediated drug metabolism and impli-
cations for novel immunotherapeutic agents.
Clin Pharmacol Ther 2014; 96: 449–457.
63 Michor F, Beal K: Improving cancer treat-
ment via mathematical modeling: surmount-
ing the challenges is worth the effort. Cell
2015; 163: 1059–1063.
64 Dubovsky SL, Dubovsky AN: Psychotropic
Drug Prescriber’s Survival Guide: Ethical Pre-
scribing in the Age of Big Pharma. New York,
Norton, 2007.
http://dx.doi.org/10.1159%2F000443512
CitRef_1: CitRef_2: CitRef_3: CitRef_4: CitRef_5: CitRef_6:
CitRef_7: CitRef_8: CitRef_9: CitRef_10: CitRef_11:
CitRef_12: CitRef_13: CitRef_14: CitRef_15: CitRef_16: