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Pharmacogenetics of Psychotropic Drugs
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  • Cited by 9
  • Edited by Bernard Lerer, Hadassah-Hebrew Medical Center, Jerusalem
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Book description

Pharmacogenetics and pharmacogenomics are areas of significant importance at the interface of molecular genetics and psychopharmacology, with implications for drug development and clinical practice. This 2002 book provides a conceptual framework for understanding and studying the pharmacogenetics of psychotropic drugs, reviews advances in the field, and describes the established findings. Coverage extends to antipsychotics, antidepressants, mood stabilising, cognitive-enhancing and anxiolytic drugs. Chapters also examine the interface of pharmacogenetics with substance dependence and brain imaging, and consider its impact on the biotechnology and pharmaceutical industries. This book defines the young field of pharmacogenetics as it applies to psychotropic drugs, and is therefore of interest to all clinicians and researchers working in this field.

Reviews

Review of the hardback:‘… this is a well-written book on a subject which is often found complicated and difficult … the book will be informative for the reader who wants a general review of the field of psychopharmacogenetics, but will also be useful for the reader who wants updated information on a specific topic …’European Journal of Clinical Pharmacology

Review of the hardback:'This book gives a comprehensive review of the current state of the art covering almost all aspects of psychiatric pharmacogenetics. It provides an excellent introduction to the newcomer in this field and at the same time it is a most valuable source of information also for the experts.'Acta Psychiatrica Scandinavica

Review of the hardback:'Bernard Lerer is to be congratulated in bringing together a group of authors who have presented an excellent, yet concise, overview of the importance of pharmacogenetics in contemporary psychopharmacology. … this monograph is recommended to all those wishing to keep abreast of this important area of neuroscience.'Human Psychopharmacology

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Contents


Page 1 of 2


  • 1 - Genes and psychopharmacology: exploring the interface
    pp 3-18
    • By Bernard Lerer, Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah–Hebrew University Medical Center, Jerusalem, Israel
  • View abstract

    Summary

    This chapter serves as a general introduction to psychopharmacogenetics and to the topics covered in this book, which provides the researcher and clinician with an overview of the pivotal topics in psychopharmacogenetics. For much of its history, the focus of pharmacogenetics has been on drug-metabolizing enzymes. This was because of the availability of techniques to detect phenotypic differences between individuals in the plasma level of drugs and to study their genetic basis. The chapter focuses on the methodological issues in pharmacogenetic research design. The interface between psychopharmacology and molecular genetics is already a focus of considerable research activity and this is likely to intensify as anticipated technological advances provide the tools for even more sophisticated studies. It may take longer than originally thought, but ultimately pharmacogenetics and pharmacogenomics will revolutionize the field of clinical psychopharmacology and the development of psychotropic drugs.
  • 2 - From pharmacogenetics to pharmacogenomics of psychotropic drug response
    pp 21-35
  • View abstract

    Summary

    This chapter discusses the evidence for a heritable component to psychotropic drug response. It reviews basic methodological issues in pharmacogenetic studies of psychotropic drug response, and highlights future directions for pharmacogenetics research in psychiatry. The majority of heritability data on psychotropic drugs is from studies of antidepressant drug response. Antipsychotic drugs are potent dopamine receptor antagonists. Many of the single nucleotide polymorphisms (SNPs) that are being identified may be useful in pharmacogenetic studies. The considerable advantages of the case-control approach for pharmacogenetic studies, coupled with the genomic control methods, suggest that it should be feasible to conduct large-scale pharmacogenetic studies with increased power and with decreased potential for undetected ethnic stratification. The first generation of pharmacogenetic studies that utilized SNPs in relatively limited numbers of candidate genes will be replaced by pharmacogenomic studies in which the complete genome is assessed.
  • 3 - Neuropsychopharmacology: the interface between genes and psychiatric nosology
    pp 36-56
  • View abstract

    Summary

    Neuropsychopharmacology has the unique capability of linking the effect of a psychotropic drug on mental illness with the effect of the substance on brain structures involved in the action mechanism of the drug. To provide orientation points about what nosology could offer genetic research, the history of psychiatric nosology is reviewed and the varying constructs that can be used are illustrated. The use of nosologic homotypes derived by the employment of a specially devised nosologic matrix is recommended for obtaining interpretable findings. The data collected by using the nosologic matrix also serves as the starting point for the development of an empirically derived, pharmacologically meaningful classification of mental illness. Genetic heterogeneity, coupled with heterogeneity in pharmacological responsiveness, has also precluded meaningful research with the employment of 'forward genetics' in schizophrenia and manic-depressive illness.
  • 4 - Methodological issues in psychopharmacogenetics
    pp 57-71
    • By Sheldon H. Preskorn, Psychiatric Research Institute, University of Kansas School of Medicine, Wichita, Kansas, USA
  • View abstract

    Summary

    This chapter discusses methodological issues relevant to conducting pharmacogenetic studies in clinical psychopharmacology. First, basic pharmacologic principles are reviewed, followed by a discussion of the drug development process. In addition to aiding in the drug discovery process, pharmacogenetic finding would also help with the signal:noise problem, at the human testing phase of drug development (that is, phase I through III). Scientists can select the specific subset of the population (that is, those with the genetic variant) likely to respond to the drug. The chapter reviews the significant potential for advancing psychiatric drug development as a result of improved understanding of the pharmacogenetics and pharmacogenomics relevant to the effects of drugs on the human brain. Last, the research linking cytochrome P-450 CPY2D6 poor metabolizers with increased risk of toxicity on routine doses of tricyclic antidepressants (TCAs) are reviewed as an example of the methodological issues encountered when conducting such studies.
  • 5 - Statistical approaches in psychopharmacogenetics
    pp 72-92
    • By Fabio Macciardi, Center for Addiction and Mental Health, University of Toronto. Toronto, Canada
  • View abstract

    Summary

    The statistical analysis of data in psychopharmacogenetics is a key factor in the evaluation of importance of gene or a set of genes in controlling the response to a given drug or to explain the emergence of side effect as a consequence of the administered drug. The association strategy conceptually entails the candidate gene paradigm based on a 'forward genetics' design. This chapter explains how to analyze the genetic architecture of a pharmacogenetic trait. First, a definition of a pharmacogenetic trait is presented, with the consequential methods of analysis, followed by some considerations for defining a phenotype suitable for investigation. Then, the chapter deals with genetic polymorphisms, with a particular focus on single nucleotide polymorphisms (SNPs). The chapter concludes with a discussion on ethnic and interindividual differences in the distribution of genetic variants, and explains how they can affect any investigation.
  • 6 - The psychopharmacogenetic–neurodevelopmental interface in serotonergic gene pathways
    pp 95-126
    • By K. Peter Lesch, Department of Psychiatry and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany, Jens Benninghoff, Department of Psychiatry and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany, Angelika Schmitt, Department of Psychiatry and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany
  • View abstract

    Summary

    This chapter appraises prototypical genomic variation with impact on gene expression, and complementary studies of gene and environmental effects on brain development and synaptic plasticity in the mouse model. Special emphasis is given to molecular mechanisms of neurodevelopmental genetics. Relevant conceptual and methodological issues pertinent to the dissection of the psychopharmacogenetic-neurodevelopmental interface are also considered. Many genes that influence complex traits and psychopharmacological drug responses are likely to be distributed continuously. Such genes are referred to as quantitative trait loci. Connecting drug response with relevant functional DNA variants in the brain and with differences in gene expression in brain regions represents the ultimate goal for pharmacogenetic research. The serotonergic gene pathways is a rewarding area of investigation because of numerous and essential functions of the central serotonin (5-HT) system, the wealth of drug targets within this system, and the range of serotonergic compounds available in the clinical setting.
  • 7 - RNA processing regulation and interindividual variation
    pp 127-154
  • View abstract

    Summary

    In the search for causes of human disease and variability of drug response, the study of interindividual differences in RNA processing has lagged substantially behind analyses at the DNA level. This chapter focuses on the post-transcriptional processes of RNA editing and alternative splicing. It considers the contribution of aberrations within these events to the efficacy of pharmacotherapy for psychiatric diseases. Specific examples of RNA processing defects within receptors for various neurotransmitters such as dopamine, glutamate, and serotonin are presented. In addition, mechanisms involved in the regulation of RNA editing and splicing are addressed as contributors to disease etiology and treatment. The chapter focuses on A-to-I editing and its role in the processing of several RNA transcripts in the central nervous system, including glutamate receptor subunits, the serotonin (5-HT) 2C receptor (5-HT2CR), and one of the enzymes catalyzing A-to-I modifications, adenosine deaminase (ADA), which acts on RNA 2 (or ADAR2).
  • 8 - Pharmacogenetics of psychotropic drug metabolism
    pp 157-180
    • By Vural Ozdemir, Centre for Addiction and Mental Health, University of Toronto, Canada; Department of Pharmacology, University of Toronto, Canada, Angela D.M. Kashuba, School of Pharmacy, University of North Carolina, Chapel Hill, USA, Vincenzo S. Basile, Centre for Addiction and Mental Health, University of Toronto, Canada, James L. Kennedy, Centre for Addiction and Mental Health, University of Toronto, Canada
  • View abstract

    Summary

    Drug metabolism is a critical determinant of therapeutic and adverse effects of many psychotropic drugs. This chapter reviews the basic concepts and definitions pertinent to pharmacogenetics of psychotropic drug metabolism from a clinical psychiatry perspective. It discusses the CYP2D6 genetic polymorphism as a classic example of a monogenic variation in drug metabolism and as a high-affinity and low-capacity elimination route. In addition to genetic contribution to interindividual differences in drug metabolism, the chapter reviews various sources of intraindividual variations and gene-environment interactions of relevance for psychopharmacology. It highlights some of the future research directions in psychotropic drug metabolism and emphasizes the need to evaluate genetic variability in drug metabolism in conjunction with other genes encoding drug transporters, receptors and ion channels, which can all influence individual's risk for adverse drug reactions or therapeutic failure.
  • 9 - Pharmacogenetics of chiral psychotropic drugs
    pp 181-214
    • By Pierre Baumann, University Department of Adult Psychiatry, Prilly-Lausanne, Switzerland, Chin B. Eap, University Department of Adult Psychiatry, Prilly-Lausanne, Switzerland
  • View abstract

    Summary

    Knowledge about the pharmacogenetics of metabolism of psychotropic drugs is based mainly on the study of the polymorphic enzymes CYP2D6 and CYP2C19. This chapter summarizes the knowledge on the pharmacology, metabolism, pharmacokinetics, and pharmacogenetics of antidepressants, antipsychotics, and methadone. Numerous psychotropic drugs are chiral and are introduced as racemates. Chiral drugs have one or several asymmetric centers: at least one carbon (or sulfur) atom of their molecule has four different atoms or groups attached to it. Most psychotropic drugs have active metabolites, and many achiral drugs give rise to chiral metabolites, the formation of which may be stereoselective and depend on the genotype of the patients. Chiral psychotropic drugs represent a useful tool for the study of neuropharmacological mechanisms and of the function of metabolizing enzymes. Many widely used drugs are introduced as racemic compounds, the enantiomers of which clearly differ in their pharmacology, metabolism, and pharmacogenetics.
  • 10 - Clozapine response and genetic variation in neurotransmitter receptor targets
    pp 217-244
    • By David A. Collier, Section of Genetics Institute of Psychiatry, London, UK, Maria J. Arranz, Section of Clinical Neuropharmacology Institute of Psychiatry, London, UK, Sarah Osborne, Section of Clinical Neuropharmacology Institute of Psychiatry, London, UK, Katherine J. Aitchison, Section of Clinical Neuropharmacology Institute of Psychiatry, London, UK, Janet Munro, Section of Clinical Neuropharmacology Institute of Psychiatry, London, UK, Dalu Mancama, Section of Clinical Neuropharmacology Institute of Psychiatry, London, UK, Robert W. Kerwin, Section of Clinical Neuropharmacology Institute of Psychiatry, London, UK
  • View abstract

    Summary

    Clozapine is an atypical antipsychotic drug with unique clinical features, particularly in treatment resistant schizophrenia. This chapter concentrates on the genetics of response to the antipsychotic drug clozapine, focusing mainly on pharmacodynamic factors related to clozapine's receptor binding. It is important to note, however, that a pharmacogenetic effect is dependent on functional genetic variation; for some genes, there may be no genetic variation that affects clozapine's action. The use of neuropsychology to assess treatment response in schizophrenia is a new area of investigation. Genetic variation in clozapine's receptor targets is a potential source of pharmacodynamic influence on drug response, by altering drug action. Clozapine therapy has been used as a model system for pharmacogenetic research into antipsychotic drugs. This is largely for the historical reasons that it has high affinity for the dopamine D4 receptor, which shows extensive genetic variability, but also because its pharmacology is well understood.
  • 11 - Genetic factors underlying drug-induced tardive dyskinesia
    pp 245-266
    • By Ronnen H. Segman, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, Bernard Lerer, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  • View abstract

    Summary

    Tardive dyskinesia (TD) affects about one fifth of schizophrenia patients following chronic exposure to dopamine receptor antagonist drugs. Drug- and patient-related risk factors for the development of TD have received much research attention but appear to predict only a minor part of the variance in the incidence of TD. This chapter reviews this rapidly developing field, incorporating recently available molecular genetic tools for a renewed exploration of the biological basis of TD. Genes coding for known drug targets can be directly explored for involvement in TD susceptibility. Genetic variability in dopamine receptors may predict functional differences in response patterns to neuroleptic agents and may be relevant to the expression of idiosyncratic reactions. Other promising findings, including the reported associations with 5-HT2A receptor (5-HTR2A) and 5-HTR2C and manganese superoxide dismutase (MnSOD) genetic polymorphic sites, require independent replications.
  • 12 - Functional gene-linked polymorphic regions in pharmacogenetics
    pp 267-282
    • By Marco Catalano, IRCCS H. San Raffaele, Department of Neuropsychiatric Sciences, Milan, Italy
  • View abstract

    Summary

    Starting from the complexity of neural pathways and their close integration, this chapter focuses on the possible advantages of investigating polymorphisms involved in the regulation of gene expression or in variation of enzymatic activity, using examples related to neurotransmitter pathway modulation. These examples (that is, serotonin transporter-linked polymorphic region, monoamine oxidase A (MAO-A) promoter region, and catechol-O-methyltransferase (COMT)) are also used to support the hypothesis that quantitative variations of expression and functional levels would be better than structural changes at single receptor sites to identify differences in both treatment response and, likely, psychopathology. Variations in MAO-A activity in female patients are discussed in relation to the pharmacogenetics of panic disorder, together with some hypotheses regarding the chromosomal location of the gene. Finally, the expected impact of new approaches (that is, orphan receptor research, nucleic acid chips, and single nucleotide polymorphisms) is discussed in terms of the advantages and pitfalls.
  • 13 - Alternative phenotypes and the pharmacogenetics of mood and anxiety disorders
    pp 283-299
    • By Emanuela Mundo, Centre for Addiction and Mental Health, University of Toronto, Canada, James L. Kennedy, Centre for Addiction and Mental Health, University of Toronto, Canada
  • View abstract

    Summary

    Biological mechanisms of action of the main classes of antidepressant compound involve the serotonin (5-HT) system. This chapter presents recent findings on genetic predictors of the response to antidepressants in mood and anxiety disorders. It proposes and discusses the role of alternative phenotypes in pharmacogenetic studies focused on the prediction of the clinical effect of antidepressants. As an example, the phenomenon of antidepressant-induced mania, as an abnormal response to antidepressants, is described. Recent data on the role of candidate genes in contributing to the risk of developing this phenotype are presented and discussed. The chapter concludes with a discussion on the importance of having stable predictors of normal and abnormal responses to antidepressants. It also talks about the role of molecular genetic strategies in the clinical management of psychiatric disorders requiring treatment with antidepressant compounds.
  • 14 - Pharmacogenetics of anxiolytic drugs and the GABA–benzodiazepine receptor complex
    pp 300-319
    • By Smita A. Pandit, Psychopharmacology Unit, School of Medical Sciences, Bristol, UK, Spilios V. Argyropoulos, Psychopharmacology Unit, School of Medical Sciences, Bristol, UK, Patrick G. Kehoe, Psychopharmacology Unit, School of Medical Sciences, Bristol, UK, David J. Nutt, Psychopharmacology Unit, School of Medical Sciences, Bristol, UK
  • View abstract

    Summary

    The benzodiazepines (BDZ) have proven to be both effective and controversial in the treatment of anxiety. New insights into the genetics of the BD2 receptor system may lead to the development of new drugs that act on the γ-aminobutyric acid (GABA) receptor complex and are devoid of the problems associated with the classical BDZs. This pharmacotherapeutic approach has gathered impetus following the discovery of the various subunits of the GABA receptor, which play an important role in the regulation of anxiety and the actions of anxiolytics, and which demonstrate differential brain expression. This chapter discusses the above with reference to recent evidence from animal and human studies, as well as the implications for future anxiolytic treatment strategies. It focuses on the development of the GABA-BDZ receptor field of research. Unlike the BDZ site, the modulation of the GABA receptor by neurosteroids requires the presence of a β-subunit.
  • 15 - Genetic factors and long-term prophylaxis in bipolar disorder
    pp 320-332
    • By Martin Alda, Department of Psychiatry, Dalhousie University, Halifax, Canada
  • View abstract

    Summary

    Response to long-term lithium treatment in bipolar disorder appears to be related to the family history of a patient. Conversely, some studies have indicated that treatment response could identify a subtype of bipolar disorder characterized by a stronger role of genetic factors and possibly by major-gene effects. Several groups have now conducted molecular genetic studies in order to identify genes contributing to the etiology of bipolar disorder as well as genes that may influence long-term treatment response. There is limited evidence that the response to mood stabilizers could be individually specific. This chapter focuses on individual treatments, in particular on lithium for which the most data are available. Subsequently, several other studies found an association between prophylactic lithium response and a family history of bipolar disorder. The chapter presents a study of patients with bipolar disorder responsive to lithium in collaboration with the International Group for Study of Lithium (IGSLI).
  • 16 - Genetic influences on responsiveness to anticonvulsant drugs
    pp 333-359
    • By Thomas N. Ferraro, Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, USA
  • View abstract

    Summary

    This chapter addresses pharmacogenetic issues associated with the clinical use of anticonvulsant drugs (ACDs). There are a number of different kinds of natural genetic variation that result in functional protein differences and affect drug responsiveness. The type of variation that is most prevalent in the genome and, arguably, the most relevant to common diseases and complex traits is represented by single nucleotide polymorphisms (SNPs). The chapter presents general comments relevant to the mechanisms of action of conventional classes of ACD. It then addresses how these mechanisms are potentially influenced by genetic variation. Subsequently, commonly used drugs are discussed individually in some depth relative to genes that may affect various aspects of their pharmacology, including metabolism. Among the nonsedating standard ACDs, those most frequently prescribed are phenytoin, carbamazepine, and valproic acid with the depressant drugs phenobarbital and clonazepam also being in common use.
  • 17 - Apolipoprotein E as a marker in the treatment of Alzheimer's disease
    pp 360-371
  • View abstract

    Summary

    This chapter focuses specifically on the pharmacogenetic role of the risk factor gene apolipoprotein E (ApoE) in Alzheimer's disease (AD) and in the response of patients with AD to treatment. ApoE has been extensively studied in non-nervous tissues as one of several proteins that regulate lipid transport and metabolism. ApoE facilitates cholesterol (and phospholipid) transport between different cell types and different organs. It binds to large lipid-protein particles (called lipoproteins). The chapter divides AD drug therapy into two broad categories, the cholinergic and noncholinergic drugs. One of the goals of pharmacogenetics is to deliver the right medicine to the right patient. The retrospective studies presented here show that the pharmacogenetic impact of the apoE alleles are a step in this direction as there are definitely drugs that work better in non-apoE4 carriers (for example, tacrine) and those that work better in the apoE4 carriers (for example, S12024).
  • 18 - Genetic variation and drug dependence risk factors
    pp 372-388
    • By Joel Gelernter, Yale University School of Medicine and VA CT Healthcare Center, West Haven, USA, Henry Kranzler, University of Connecticut School of Medicine, Farmington, USA
  • View abstract

    Summary

    This chapter discusses pharmacogenetics in the context of substance abuse and dependence. Genetic factors are important contributors to risk for substance dependence. Some are specific to the substance (e.g., resulting in different euphoric effects by individual), and some are more general (e.g., personality features, like novelty seeking, antisocial personality, and so on, which may influence exposure to substances or the transition from substance use to dependence). If the set of all genetically influenced disorders is considered, some forms of substance dependence are uniquely influenced by pharmacogenetic factors. The chapter explores some of the mechanisms involved, and their implications for diagnosis, treatment, and research. Specific pharmacogenetic interactions relevant to the understanding of dependence on cocaine, opioids, and nicotine have either been demonstrated or proposed. The chapter presents examples relevant to each phenotype. Pharmacokinetic phenomena relevant to cocaine and nicotine dependence are also discussed.
  • 19 - Brain imaging and pharmacogenetics in Alzheimer's disease and schizophrenia
    pp 391-400
    • By Steven G. Potkin, Department of Psychiatry and Human Behavior, University of California, Irvine, USA, James L. Kennedy, Clarke Institute of Psychiatry, University of Toronto, Canada, Vincenzo S. Basile, Clarke Institute of Psychiatry, University of Toronto, Canada
  • View abstract

    Summary

    Brain imaging techniques combined with genetics contribute to developing an understanding of the pathophysiological mechanism of disease and treatment response. Psychiatric genetics identifies associations between allelic variation in genes and the risk for the development of psychiatric illness. Although the genetic association of apoE4 with the development of Alzheimer's disease is well established, there is a need to devise strategies that can fill in the missing links between apoE gene variation and the pathophysiological mechanism of Alzheimer's disease. Brain imaging addresses and bridges this gap. The combination of imaging, allelic characterization, and clinical response synergistically contributes to understanding the role apoE4 plays in the development of Alzheimer's disease and its response to treatment. An analogous argument is made for combining brain imaging with allelic subtyping to understand clinical antipsychotic response in schizophrenia. This chapter establishes the efficacy of new pharmacological treatments for groups of patients with schizophrenia and Alzheimer's disease.
  • 20 - Pharmacogenetics in psychotropic drug discovery and development
    pp 403-421
  • View abstract

    Summary

    Drug development for the central nervous system (CNS) emphasizes whole-genome single nucleotide polymorphism (SNP) disequilibrium mapping of patients in phase II trials followed by a more focused abbreviated SNP linkage disequilibrium mapping in phase III trials, as proposed by Roses. This chapter discusses why this is not the general case and emphasizes the need for success stories to allow those involved in leading CNS drug development to obtain the necessary support for a sustainable effort in pharmacogenetics. Determination of the association between genotype and phenotype requires an a priori hypothesis that a particular candidate allele is responsible for expression of the phenotype. Genetic studies can help to identify molecular targets and thereby accelerate drug discovery. Despite the concerns about the value of genetic research in the pharmaceutical industry, pharmacogenetics and pharmacogenomics will be a foundation for modern drug development.

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