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Neuropsychopharmacology: The Fifth Generation of Progress

Back to Psychopharmacology - The Fourth Generation of Progress

Introduction to Clinical Neuropsychopharmacology

David J. Kupfer


One of the major goals of this volume is both to demonstrate and to emphasize the growing linkages between basic preclinical science research, clinical neuroscience, and clinical therapeutics. We believe that a major aspect of recent advances in neuropsychopharmacology and, thus, the basis for the Fourth Generation has been to establish such linkages and to exemplify various strategies that are being used to achieve a new level of integration. As may be obvious to most readers, the role of drugs and drug development essentially is to provide clinicians with the ability to treat psychopathology and aberrant behavior and their concomitant levels of dysfunctioning
- primarily central nervous system (CNS) dysfunctioning. To treat the psychopathology in the most rational and empirical manner, one would like not only to understand the mechanisms of action of drugs used for treatment, but also to utilize drug treatment findings to learn more about the pathogenesis and pathophysiology of the underlying disorders. In this manner, the integration of brain and behavior becomes a key objective and motivates our scientific pursuits toward a basic science thrust and cellular and molecular research that can inform and guide important strands of clinical research activity. In these pursuits, we need to appreciate the broad dimensions of normal development and behavior and how the emerging and developing CNS interacts with changes in behavior over the early periods of the life cycle, as well as across the entire life span. Advances in the past 5 years on neuronal development and plasticity have rekindled a focus on the interaction between neuronal activity and behavior. As a consequence of this increasing interest in developmental neurobiology, considerable opportunity now exists to understand more about pathological or abnormal development in the central nervous system, as well as about parallel developments in behavior "going astray." As we proceed to integrate what we know about normal and pathological development, it thus is our mission also to utilize the tools of neuropsychopharmacology to consolidate these linkages and to provide improved clinical treatments for individuals who suffer from either syndromes or symptoms we generally characterize as neuropsychiatric disorders.


This chapter serves to introduce the clinical sections of the Fourth Generation of Progress. It will provide an overview, especially for those individuals with limited experience in clinical science of the chapters contained in this section. Initial attention is paid to the principal methods that are used in clinical psychopharmacology and how data are obtained and analyzed (chapters on the critical analysis of methods).

The next group of chapters spans those serious neuropsychiatric disorders that represent the target disorders of clinical psychopharmacology. Considerable effort has been devoted to documenting the range of mental disorders that affect over 22% of the population in any given year with 9% demonstrating significant dysfunction. Of these disorders, the most severe illnesses (e.g., schizophrenia and unipolar and bipolar recurrent disorders) affect some 5 million American adults (2.8% of the adult population) causing considerable suffering to patients and their families. In addition to considerable pain experienced by those afflicted with these disorders and their families, they also result in profound economic cost, reflecting lost productivity, disability and social service payments, and increased morbidity and mortality.

For each of these disorders covered in the chapters on psychobiology and treatment, the extent of coverage is related to advances made since the last volume. Differential coverage highlights differential advances made in certain disorders. The more extensive coverage devoted to mood disorders and schizophrenia reflects their continuing prominence in our field as the most serious, chronic disorders. It is interesting to note, however, that anxiety disorders are also well represented. Considerable advances have occurred in the geriatric disorders, which is reflected in the broadening range of coverage devoted to them. It is noteworthy that a greater level of attention is also devoted to so-called neurological disorders. Brief updates are included on personality, eating and sleep disorders. Although we continue to remain optimistic concerning psychopharmacological intervention in childhood disorders, progress has not been dramatic since the last edition. The final group of disorders is concerned with substance abuse. This interesting area is covered in ten chapters devoted to use of abuse of different substances. Finally, although methods have been discussed throughout the clinical section, we wish to redirect our attention to genetics, strategies for multimodality research, and specific methodological and statistical approaches. One of the major objectives of these sections will be the translation of new knowledge derived from preclinical science into the design of psychobiological and therapeutic investigations. It is expected that this overall format can provide greater ease for the reader in reviewing the clinical sections of the volume and, perhaps more importantly, facilitate the utilization of specific chapters from the preclinical section. As we discuss different changes and advances that have occurred and how they are integrated through our increasing knowledge of preclinical science, we hope the reader will be able to make use of the entire volume.


As discussed earlier, four strategies are used to analyze the neuroscientific substrates of neuropsychological phenomena: molecular, cellular, multicellular (or systems), and behavioral (see Introduction to Preclinical Neuropsychopharmacology). These four terms constitute the minimal approach to a complex hierarchical ensemble that have been used to characterize the principle methods of neuroscience research (1). A major concept is that "drugs which influence behavior and improve the functional status of patients with neurologic or psychiatric diseases, act by enhancing or blunting the effectiveness of chemical transmission at the sites of principal interneuronal communication, the specialized chemical junctions termed synapses" (see Introduction to Preclinical Neuropsychopharmacology).

The emphasis of the clinical section is placed on the interaction of psychopharmacology and behavior (the fourth hierarchical level). In this area, the relationship of normative behavior and its threshold or transition into psychopathology is a central, perplexing, conceptual, as well as pragmatic problem, which clinicians continue to address. At this time, we have not yet achieved a level of hierarchical thresholds at the clinical surface comparable to what has been described for the preclinical realm.

For the preclinical scientist the nosology of psychiatric disorders may appear to be somewhat bewildering, both in terms of complexity and language. There has been considerable debate concerning the definition and classification of mental disorders and the determination of various thresholds that have been utilized to reflect impairment. It is important, however, to realize that specific behaviors in isolation of their related impact on functioning does not necessarily connote a mental disorder. In our clinical approaches we have sought to design operational clinical criteria for disorders that can be discriminated from each other in a number of ways. Indeed, to accomplish validity of a diagnosis numerous authors have proposed strategies involving an iterative process with five phases: clinical description, laboratory studies, delineation from other disorders, follow-up study, and family study (2). More recently, the possibility of more direct genetic approaches rather than the more traditional descriptive approaches have been proposed as methods to discriminate groups of patients with neuropsychiatric disorders and to differentiate subtypes (see Genetics). Basic to all these approaches, however, is whether an individual suffers from a disorder or symptom cluster in such a way that the behavior leads to dysfunction in work, school, family and other aspects of the individual's life, since it is the degree of this dysfunction that often prompts an individual and family to seek treatment and that usually leads our society to diagnose deviant behavior that is not of "psychotic" dimension. The interaction between behavioral symptoms and functioning represents the clinician's dilemma in diagnosis and treatment. Part of this difficulty is that the diagnosis of these disorders is quite complex unless there are drastic behavior manifestations, such as obvious delusional thoughts and hallucinations, or profound mood disturbances where individuals display severe manic or depressive behavior. Nevertheless, advances in clinical diagnosis and treatment have encouraged scientists to search for neurobiological correlates and to develop animal models that might mimic human psychopathology and allow us to examine the brain bases of certain syndromes. Chapters in this volume, in both the preclinical and clinical sections, devote considerable attention to potential linkages between neurotransmitters and brain circuitry, which, in turn, can link molecules to brain systems and behavior. Recent changes in our treatment strategies are now allowing us to follow the longitudinal course of schizophrenia, major depression, and manicBdepressive disorders providing methods for discrimination of these disorders from each other and the testing of specific long-term treatments. The delineation of specific treatments, their efficacy, as well as the definition of criteria for remission and recovery, have, in turn, provided stimulus to both preclinical and clinical scientists to examine with increased vigor how the clinical pathophysiology and treatment of specific disorders affect the functioning of the CNS and vice-versa.

Several alternative strategies were available for organizing the clinical sections. One approach would have been to discuss normal development and behavior and place them in the context of gender and development across the life span. Using such a mode of organization, one would have proceeded from normal development to symptom formation and the concomitant dysfunctioning in behavior, interpersonal relationships, and interactions with the environment. This represents a dimensional approach to psychopathology which has inherent advantages over a categorical one in that it allows us to build conceptual models on the emergence and longitudinal course of mental disorders and to establish tentative relationships to CNS functioning and even potentially CNS neuroanatomy. However, as is discussed in one of the methodological chapters (see The DSM-IV Classification and Psychopharmacology), the use of syndromes and what is considered a more descriptive psychiatric approach remains the hallmark of our level of organization of psychopathology and represents the most successful approach to date. The use of a categorical approach has inherent advantages as well, most importantly in that it represents a more pragmatic attempt to cope with various "consumers" and providers of medical care. However, although the use of syndromes facilitates communication, it often fails to capture fully the rich relationships between brain and behavior and also does not lend itself to conveying the pathways in and out of illness that can be observed in many patients. Thus, other strategies are needed to provide a more dynamic longitudinal, even developmental perspective on psychiatric symptoms and syndromes and to provide the framework for understanding relationships between neuropsychopharmacology and behavior over time. In such an approach, notions relating to state (episodic) versus trait (persistent) characteristics of disorders gain a prominent position, since they are most important in examining the psychobiological aspects of a disorder. This emphasis provides an opportunity to compare individuals across time as they may go in and out of episodes of illness, as well as to compare individuals with a particular disorder to healthy controls.

Regardless of the overall approach that one takes to the classification of psychopathology, the major task for the authors of this volume is to provide a road map in which CNS functioning and CNS neurochemistry can be related and correlated with behavior. The exciting advances of the last 10 years provide a new set of tools, such as functional neuroimaging to examine brainBbehavior relationships in a more dynamic functional manner than previously available. For example, both position emission tomography (PET) with its possibilities of neuroreceptor strategies and nuclear magnetic resonance (NMR) with its capability for both structural and functional analysis are most important in providing new leads for the next 10 years. We have elected to provide in most "disease areas" chapters that specialize on psychobiology and others that focus primarily on treatment. In some areas where fewer advances have occurred, a single chapter provides both the psychobiological and therapeutic update.

Finally, an area that has received some attention in past editions but requires increasing concentration of efforts over the next decade is that of genetics and the integration of genetic neurodevelopmental science with the existing knowledge base on onset of psychopathology (see Basic Concepts and Techniques of Molecular Genetics and Genetics). Not only do we have new tools for genetic research, but combining such tools with a neurodevelopmental approach will provide important opportunities to understand how schizophrenia, for example, develops (see Neurodevelopmental Perspectives on Schizophrenia). These strategies may also be useful in developing treatment interventions for schizophrenia, as well as for autism and other disorders.

In short, the work currently ongoing in both preclinical and clinical neuroscience provides the theater in which clinical therapeutics and the application of new and more traditional neuropsychopharmacological agents can occur. The play itself is becoming more interesting, where previously it represented a one-act play with a small cast, it is now possible to conceptualize both one-act and three-act plays within the context of intervention (short-term and long-term) but also ones that include not only the traditional actors and actresses, but an extended cast, with new roles designed specifically for the particular play. The advances in preclinical science are providing the basis for the design of new psychopharmacological agents (see New Drug Design in Psychopharmacology: The Impact of Molecular Biology), but they also help us to use our current armamentarium in more imaginative ways. The aim of the chapters on critical analysis of methods is designed with the above concept in mind. In a similar fashion, the chapters on integrative concepts represent attempts to provide a greater degree of vertical integration with the remaining sections of the clinical set of chapters which are syndrome driven.


As in the preclinical science arena, our choice of chapters covering critical methods represent those viewed as the most promising and essential tools used in clinical science and neuropsychopharmacology. These chapters are not meant to provide exhaustive coverage of the entire array of methods used in clinical psychopharmacology. Rather, they reflect advances that have occurred since the last Generation and strategies and methods which are likely to be used increasingly over the next 5 to 10 years. The first such tool has already been alluded to and essentially represents the need to classify psychopathology in order to conduct both clinical trials and to understand the efficacy and effectiveness of neuropsychopharmacological agents. (The DSM-IV Classification and Psychopharmacology by Frances et al.) is concerned with the development of the current classification system for psychiatric disorders, DSM-IV, and points to several key areas and their limitations important to our current psychopharmacological research efforts. Key issues in psychiatric nosology, such as reliability, generalizability, and validity are highlighted, as are several of the newer approaches taken in the preparation of DSM-IV. These include reanalyses of data sets collected on psychopathology but, more interestingly, also a number of field trials conducted to outline both the promises and descriptive limitations of the DSM-IV nosology. The descriptive limitations of the criteria sets raise issues of reliability and validity discussed extensively by Kraemer in the subsequent integrative chapter (Methodological and Statistical Progress in Psychiatric Clinical Research: A Statistician’s Perspective). Although the DSM-IV will continue to provide a necessary common language for study and practice, issues of thresholds and categorical versus dimensional approaches remain very much of central interest, and an improved categorical classification system certainly does not represent the only manner in which advances in this area will continue to occur.

The next set of methods described represent a range of issues related to clinical study design (see Clinical Study Design - Critical Issues). The critical issues discussed include issues pertaining to the traditional randomized controlled trials (RCTs) as well as involved specialized trial designs (cross-over, longitudinal, doseBresponse, and concentration control studies). The emphasis in this chapter is also on documentation and a greater attention to biostatistical approaches throughout the design data collection and data analysis phases of RCTs. In the section of this chapter highlighting future directions, the authors point to changes that have occurred since the last Generation was produced, including increased emphasis on documentation of research data, adequate informed consent, and audit procedures. Other issues highlighted are greater emphasis on longer term studies and the resulting push to improve our study designs for long-term trials. This change, in turn, also raises the need for continuing efforts to define those methods that should be used for evaluation and outcome comparison of appropriate therapeutic alternatives. Increased emphasis on longer term trials also reflects the importance of issues concerning research on cost effectiveness and of health economic methodologies, which will need to be applied more extensively (see Economic Evaluation of Drug Treatment for Psychiatric Disorders: The New Clinical Trial Protocol).

The need for improved clinical design methodologies is also reflected in the discussion concerning short-term and long-term psychopharmacological treatment strategies (see Short-and Long-Term Psychopharmacological Treatment Strategies). In this methods chapter, the authors have set out to establish a rationale for longer term medication strategies and how "treatment strategies" need to play an increasing role in our psychopharmacological research and practice. Using three disorders as examples (schizophrenia, depression, and anxiety disorders), they demonstrate how short-term and long-term strategies have common principles for these serious disorders and how the effective psychopharmacological management of these disorders requires adequate dosages and duration of treatments, including phases of long-term maintenance treatment. The authors argue that this approach represents a paradigm shift in our treatment strategies for psychiatric disorders (see also Strategies for Multimodality Research).

The need to understand more about our psychopharmacological approaches is reflected also in the next chapter on pharmacokinetics and pharmacodynamics (see Pharmacokinetics and Pharmacodynamics). In this discussion we receive an essential update on the methods now available in both pharmacokinetics and pharmacodynamics to examine sensitivity and specificity of treatments. Pharmacokinetics utilizes mathematical models to describe and predict the time course of drug concentrations in body fluids. With improved measurement methods and by applying pharmacokinetic models, the level of sophistication in therapeutic drug monitoring has increased significantly. For example, these techniques are extremely useful in quantitating drug toxicity. Pharmacodynamics, which is the study of time course and intensity of drug effects on the organism, has also experienced major advances, especially increasing our capacity to measure long-term drug effects. The thrust of this methods chapter is to help us understand individual variability in drug response, a theme developed further in later sections of the volume (see Ethnicity, Culture, and Psychopharmacology).

The need for the next methods chapter (Cytochrome P450 Enzymes and Psychopharmacology) on cytochrome P450 enzymes and psychopharmacology has become apparent within the last 10 years. This work complements the previous chapter (Pharmacokinetics and Pharmacodynamics) and provides a primer to better understand pharmacokinetically mediated drug-drug interactions. Furthermore, it highlights the opportunity to examine genetic and environmental factors in drug response and the use of these techniques for the drug developmental process.

The next methods chapter heightens our appreciation of new tools that were not previously available. In a brief chapter on neuropathology we are treated to an introductory set of principles on methods of neuropathology likely to play a role in our understanding of CNS alterations and serious psychiatric disorders (see Methodological Issues in the Neuropathology of Mental Illness). Our research strategies for investigating CNS (structural and neurochemical) abnormalities in psychiatric disorders will be aided tremendously by a greater concentrated effort in neuropathology spanning both animal models and human work. Much has already been gained in studies on Huntington's disease and Parkinson's disease, in which the study of postmortem human brain tissue has improved our overall understanding of behavioral manifestations. The application of these techniques to specific forms of psychopathology is likely to drive progress in our understanding of their brain bases.

The chapter just reviewed should be put in the context of the subsequent three chapters, which demonstrate collectively the major advances made concerning tools for understanding the living CNS and brain functioning. The first of these chapters represents a primer on both positive emission tomography (PET) and single photon emission computerized tomography (SPECT) (see Positron and Single Photon Emission Tomography: Principles and Applications in Psychopharmacology). As the authors indicate, these contemporary brain imaging methods allow and offer exciting opportunities to study CNS function in vivo. The major principles of PET and SPECT are described, as well as their current limitations. All consumers now know that these imaging techniques are methods of high sensitivity in which the injection of radioactively labeled drugs can provide measures of local neuronal activity, in vivo neurochemistry, or in vivo pharmacology. Thus, they provide an interesting window to examine in vivo brain functioning and drawing upon advances in preclinical science, and opportunity to integrate them with clinical research (see Brain Imaging in Mood Disorders, Functional Brain-Imaging Studies in Schizophrenia, Neuroimaging Studies of Human Anxiety Disorders: Cutting Paths of Knowledge through the Field of Neurotic Phenomena, and Anatomic and Functional Brain Imaging in Alzheimer’s Disease). Given the high cost and technical complexity of these research methods, however, they will certainly require multidisciplinary collaboration and considerable further research to provide more opportunity for clinical research and to be applied in clinical trials of neuropsychopharmacological agents.

The next updated chapter, also part of the functional imaging array of contemporary developments, deals more directly with in vivo structural brain assessment (see In Vivo Structural Brain Assessment). Here the technical improvements have allowed us within a very few years to make major improvements in the acquisition and processing of structural imaging data, utilizing primarily magnetic resonance imaging (MRI) with its superior tissue contrasts and resolution. Improved differentiation of white from gray matter and a much improved flexibility to view and measure specific structures represent major advances. Because it is likely that most of the structural changes in psychiatric disorders will be subtle, opportunities to have systematic and reliable quantification techniques are vital to further progress. The use of MRI allows us to give greater attention to normal developmental and aging effects, variations in normative distribution of size and tissue loss, as well as provide the opportunity to do longitudinal studies despite their greater complexity. Finally, MRI also promises to open avenues of functional brain imaging, which may eventually replace some of the current PET and SPECT work.

The last chapter in this section on new tools to assess CNS functioning is an update on electrophysiological techniques currently available to the clinical researcher (see Methodological Issues in Event-Related Brain Potential and Magnetic Field Studies). This discussion deals with the methodological issues that are involved in both event-related brain potential and magnetic field studies. The discussion of newer electrophysiological techniques, particularly those involved in a spacial localization of brain processes, highlights several advances over and above what we have examined with respect to event-related potentials (ERPs) in the past. It is now possible to elicit event-related magnetic fields (ERFs) in a fashion time-locked to specific events and analogous to ERPs. Magnetoencephalogram (MEG) and ERFs definitely convey different information than EEG and ERPs and in this manner offer new strategies for testing information processing, complex behavior, and cognitive processing not as easily available with other systems of functional imaging. As the methodologies for evoked brain potential and magnetic field studies continue to develop technologically, the coordination of EEG and MEG data with data from MRI, PET, and SPECT scans will be necessary. The integration of findings across different forms of functional brain imaging and processing may very well represent the uses and promising strategy to obtain comprehensive sets of data on both normals and individuals with neuropsychiatric disorders.

The final chapter in this section provides an update on psychiatric molecular genetics (Psychiatric Genetics). It provides a vocabulary for the rapid gene mapping progress, potential applications in research in psychiatric genetics as well as an overview of recent findings in the major psychoses and substance dependence.


In the three chapters dealing with integrative themes, perspectives on genetics, strategies for multimodality research, and methodological and statistical advances in psychiatric clinical research are discussed. These three areas represent important integrative arenas in which much of the clinical neuropsychopharmacological research occurs. Genetics seeks to provide an integrative discussion to demonstrate that the advances in human genetics and recombinant DNA technology, as well as those relating the explosion of knowledge on the human genome are very important for psychiatry. Progress in understanding the human genome is also paralleled by developments in genetic research in rodents and other species of relevances as potential animal models. The implications for psychiatry are obvious. Currently, many of the major disorders covered in our volume are examined in collaborative efforts to determine and explore the potential genetic linkages that contribute to schizophrenia, the mood, disorders, Alzheimer's disease, and alcoholism. The data derived from molecular genetic strategies and genetic epidemiology will ultimately have a major influence on psychopharmacological approaches to treating these disorders (see Psychiatric Genetics and Genetic Influences in Drug Abuse). Current research activities in mood disorders, schizophrenia, Tourette's syndrome, panic disorder, and alcoholism are briefly reviewed as representative examples of the ongoing work in psychiatry (see The Interface of Genetics, Neuroimaging and Neurochemistry in Attention-Deficit Hyperactivity Disorder). These research activities are contrasted with those on several other neuropsychiatric disorders, notably fragile X syndrome and Huntington's disease. The chapter represents not only a primer for genetics but an integrated review of approaches that can be placed in the context of other sections throughout the clinical portion of the volume which relate to genetics.

This leads us directly into the next chapter offering an extensive discussion of strategies for multimodality research (see Strategies for Multimodality Research). Given the likelihood that treatment outcome research will increasingly involve both pharmacotherapeutic and psychotherapeutic treatment modalities, we must realize that combination treatment will need to play an important role in our treatment strategies for various disorders and both for short and long-term treatment (see Long-Term Treatment of Mood Disorders and Maintenance Drug Treatment for Schizophrenia). This chapter is reminiscent of a chapter in the earlier methods sections which focused on strategies for acute and long-term treatment (see Short-and Long-Term Psychopharmacological Treatment Strategies), but goes one step further to include psychotherapeutic approaches to specify a more complex set design, such as that need to deal with combination treatments issues relating to the types of trials, duration, dosages, and comparability across treatments; and the utility of assessing psychosocial variables.

The last integrative chapter (Methodological and Statistical Progress in Psychiatric Clinical Research: A Statistician’s Perspective) is one that revisits many of the topics that have been discussed throughout the clinical chapters and relate to fundamental questions underlying psychopharmacological research. The sections on diagnosis, longitudinal research, and specific applications of mathematical models seek to integrate discussions on clinical treatment issues. The author raises a series of cautionary and provocative questions, which have become increasingly important as we conduct more research applying DSM-IV criteria for short and long-term clinical trials (see The DSM-IV Classification and Psychopharmacology, Clinical Study Design-Critical Issues, and Short-and Long-Term Psychopharmacological Treatment Strategies).


We have discussed several of the key issues relating to critical analysis of methods and integrative concepts for the clinical sections; however, it may be useful to also highlight changes both in coverage or emphasis that reflect advances made in major disorders since the last edition. In the area of mood disorders a total of ten chapters deal with issues relating to the psychobiology of mood disorders. These chapters encompass a series of detailed reviews concerning specific neurotransmitters and their behavioral and therapeutic implications (see Recent Studies on Norepinephrine Systems in Mood Disorders, Dopaminergic Mechanisms in Depression and Mania, The Serotonin Hypothesis of Major Depression, and The Role of Acetylcholine Mechanisms in Affective Disorders) presented in the basic section; specific aspects of neuroendocrinology and neuropeptide alterations in mood disorders (see Neuroendocrinology of Mood Disorders and Neuropeptide Alterations in Mood Disorders); advances in psychoimmunology (see Psychoneuroimmunology of Depression) and mood disorders; as well as an extensive chapter on biological rhythms in mood disorders. This latter chapter (Biological Rhythms in Mood Disorders), as is true of some of the earlier chapters in the psychobiology of mood disorders, presents interesting links to the preclinical sections reviewing neurotransmitter systems, neuroendocrine interactions (see Neuroendocrine Interactions), and neuroimmune interactions (see Interactions Between the Nervous System and the Immune System: Implications for Psychopharmacology). The remaining two chapters in the portion on the psychobiology of mood disorders deal with areas important to the diagnosis, pathophysiology, and treatment of mood disorders. The chapter on brain imaging in mood disorders (see Brain Imaging in Mood Disorders) represents an application of earlier approaches discussed in the section on critical methods. The chapter on gender issues and cycle effects (see Mood Disorders Linked to the Reproductive Cycle in Women) is important, since it ties together with the earlier clinical chapter on biological rhythms (see Biological Rhythms in Mood Disorders) and linkages with basic neuroendocrine interactions (see Neuroendocrine Interactions).

Treatment approaches in mood disorders are covered by nine chapters reflecting the current state-of-the-art in the entire range of clinical therapeutics. One of the major changes since the last edition is a greater emphasis on a longitudinal approach to the treatment of mood disorders, as well as the introduction of newer compounds (SSRIs). Thus, the chapter on SSRIs for acute treatment (see Selective Serotonin Reuptake Inhibitors in the Acute Treatment of Depression) is juxtaposed with a chapter on standard treatment approaches (see Standard Antidepressant Pharmacotherapy for the Acute Treatment of Mood Disorders) and followed by a chapter on the long-term treatment of mood disorders (see Long-Term Treatment of Mood Disorders). Recognition that mood disorders, despite overall gains in treatment efficacy, are still faced with a great degree of treatment resistance has led to the inclusion of a separate chapter on treatment-resistant depression (see Treatment-Resistant Depression). Several subsequent chapters highlight treatment approaches for particular subgroups of mood disorder patients. Recent advances in the use of lithium and anticonvulsants, primarily but not exclusively applied in bipolar disorder are discussed in Lithium and the Anticonvulsants in Bipolar Disorder The increasing understanding that psychosocial factors may play an important role in treatment outcome is then reflected in a further chapter (see Psychosocial Predictors of Outcome in Depression) which followed by two chapters dealing with new (old) approaches to the treatment of affective disorders, including a review of the role of electroconvulsive therapy (see Electroconvulsive Therapy) and of novel pharmacological approaches (see Novel Pharmacological Approaches to the Treatment of Depression). A chapter in the treatment section reviews our current understanding of treatment resistance in bridging neurobiology and preclinical science (see The Neurobiology of Treatment-Resistant Mood Disorders). The final chapter in the treatment section provides a new review for post-traumatic stress disorder (PTSD) (see Post-Traumatic Stress Disorder).

The section on schizophrenia is also divided into psychobiology and treatment chapters. In the eight chapters devoted to the psychobiology of schizophrenia, attention is now being paid to the neurodevelopmental perspectives on schizophrenia (see Neurodevelopmental Perspectives on Schizophrenia), which are also reflected in a subsequent chapter providing an introduction to developmental neurobiology and a review of other direct applications from the preclinical area (see The Development of Brain and Behavior). We hope that the clinical scientist will again utilize the sections on critical analysis of integrative concepts in the preclinical section to appreciate the full impact of the advances made over the past 10 years in understanding the psychobiology of schizophrenia. The second chapter (Physiological Indicators of the Schizophrenia Phenotype) in this section reviews the key physiological indicators of the schizophrenia phenotype, including eye movement dysfunction, acoustic startle and cognitive evoked potentials. The third chapter on schizophrenia deals with functional brain imaging (Functional Brain-Imaging Studies in Schizophrenia), which recaptures the emphasis placed in the new functional neuroimaging methods discussed earlier. Although attention is paid to particular neurotransmitters, notably the effect of dopamine on schizophrenia (see New Developments in Dopamine and Schizophrenia and The Effects of Neuroleptics on Plasma Homovanillic Acid), the roles of other neurotransmitters potentially involved in schizophrenia are discussed. This is reflected in Schizophrenia and Glutamate on glutamate in schizophrenia as well as in a review of the potential role of serotonin in schizophrenia (The Role of Serotonin in Schizophrenia). Importantly, our improved understanding of the symptomatology of schizophrenia is leading us to a broader appreciation of the neurocognitive and neurophysiological aspects of the disorder, as reflected in two subsequent chapters on neurocognitive functioning in patients with schizophrenia (see Neurocognitive Functioning in Patients with Schizophrenia: An Overview). A final chapter reviews the current state of neurophysiological and psychophysiological approaches to schizophrenia (see Neurophysiological and Psychophysiological Approaches to Schizophrenia).

Treatment approaches for schizophrenia have also improved over the last 10 years, based on numerous studies that address both acute and long-term treatment. These areas are reviewed in the respective chapters on the acute treatment of schizophrenia (see Acute Treatment of Schizophrenia) and on maintenance drug treatments (see Maintenance Drug Treatment for Schizophrenia). These chapters reflect the rapid advances in treatment strategies developed over the last five years. The final chapter on the treatment of schizophrenia is concerned with atypical antipsychotics and emphasizes recent opportunities and gains made in using atypical antipsychotics for selected patients with schizophrenia (see Atypical Antipsychotic Drugs).

The next section is devoted to anxiety disorders, with four chapters covering the psychobiology of anxiety disorders and three reviewing treatment approaches. Not surprisingly, in the sections dealing with psychobiology the important role of functional neuroimaging in improving our basic understanding of the pathophysiology of anxiety disorders is highlighted (see Neuroimaging Studies of Human Anxiety Disorders: Cutting Paths of Knowledge through the Field of Neurotic Phenomena).  Anxiety and Serotonin1A Receptor on the 5-HT1A receptor compliments the chapters that deal with this topic in the preclinical sections, particularly those chapters on indoleamines (see Serotonin Receptor Subtypes and Ligands and Indoleamines: The Role of Serotonin in Clinical Disorders). Although discussed in chapters on mood disorders and schizophrenia, the use of psychopharmacological challenges and "probes" for anxiety disorders is highlighted in the next chapter (Pharmacological Challenges in Anxiety Disorders). The final chapter in the psychobiology section deals with environmental factors in the etiology of anxiety disorders, issues that have become increasingly important in understanding the long-term pathway of the development, onset, and maintenance of anxiety states (Environmental Factors in the Etiology of Anxiety). The two treatment chapters highlight the need to appreciate that anxiety disorder is a disorder with an often chronic persistent course (see Short-and Long-Term Psychopharmacological Treatment Strategies). A specific chapter on issues of long-term treatment (see Issues in the Long-Term Treatment of Anxiety Disorders) is complimented by a chapter on acute treatment strategies (see The Pharmacotherapy of Acute Anxiety: A Mini-Update). Finally, this section on anxiety disorders contains a chapter on the pharmacotherapy of panic disorder (Pharmacotherapy of Panic Disorder).

The section on geriatric disorders has changed rather dramatically from the previous edition, as is reflected in the seven chapters devoted to Alzheimer's disease alone. The first two chapters deal with aspects of genetics (see Towards an Understanding of the Genetics of Alzheimer’s Disease) and a subsequent one with amyloid development in Alzheimer's disease and the use of animal models (see Amyloidogenesis in Alzheimer’s Disease and Animal Models). A review follows of cognitive and memory changes that occur in Alzheimer's disease, including a discussion of appropriate assessment (see Neuropsychological Assessment of Patients with Alzheimer’s Disease). Although our understanding of Alzheimer's disease is moving rapidly in the direction of developing pharmacological approaches for treatment intervention, we need to address the probability of using biological correlates in assessing treatment outcome in this disorder. The chapter on biological markers (see Biological Markers in Alzheimer’s Disease) is followed by one on anatomic and functional brain imaging in Alzheimer's disease (Anatomic and Functional Brain Imaging in Alzheimer’s Disease), a chapter demonstrating once more the pervasive impact of newer functional neuroimaging techniques. Even though therapeutic interventions for Alzheimer's disease are sparse, reflecting a long unsuccessful history with such endeavors, two chapters review experimental treatments for Alzheimer's disease (see Experimental Therapeutics) and the treatment of noncognitive behavioral abnormalities (see Alzheimer’s Disease: Treatment of Noncognitive Behavioral Abnormalities).

One set of chapters in the geriatric section relate to specific characteristics of psychotic disorders occurring in the elderly. The first chapter in this section focuses on paraphrenia and other related late-life psychoses and reviews both diagnostic and treatment issues (see Late-Onset Schizophrenia and Other Related Psychoses). The next chapters deals very specifically with advances made over the past 10 years on the characterization of the cognitive impairment in geriatric schizophrenia patients including postmortem data (see Methodological Issues in the Neuropathology of Mental Illness and Cognitive Impairment in Geriatric Schizophrenic Patients:  Clinical and Postmortem Characterization). A final set of issues relates to specialized psychopharmacological interventions in this age group. Chapters outline specific issues relating to psychotropic drug distribution in the elderly (see Psychotropic Drug Metabolism in Old Age: Principles and Problems of Assessment) and the principles of treatment for depression in late life, including the newer pharmacological interventions (see Pharmacological Treatment of Depression in Late Life).

The next chapters in the clinical section are concerned with "neurologic disorders" and highlight a set of approaches and descriptions which again represent major advances since the last edition. After a chapter on Parkinson's disease (see Parkinson’s Disease), several interrelated chapters discuss key issues relating to tardive dyskinesia. Since the tardive dyskinesias represents a public health problem, we have devoted a chapter to their epidemiological and clinical presentation (Tardive Dyskinesia: Epidemiological and Clinical Presentation), followed by an update on the pathophysiology of tardive dyskinesia (Tardive Dyskinesia: Pathphysiology) and completed by a chapter on treatment approach (The Treatment of Tardive Dyskinesias). Several other CNS disorders are included in this section to gain a fuller appreciation of both the major changes that have occurred since the last edition, but also to highlight new opportunities to explore the psychopathology and psychopharmacology of these disorders. A chapter on multiinfarct dementia (see Multi-Infarct Dimentia) is followed by one on Prion diseases (see Prion Diseases). Current advances in Huntington's disease and amyotrophic lateral sclerosis are reviewed (see Amyotrophic Lateral Sclerosis, Glutamate, and Oxidative Stress and Huntington's Disease) with a special emphasis on the advances in genetics and possible pathophysiology of Huntington’s disease (Huntington's Disease).

Although not a section of the previous Generation of Progress, it is clear that the AIDS epidemic as part of its clinical picture and pathological manifestations, has important aspects relating to clinical psychopathology and dysfunctioning. We have now devoted two chapters to this area; one reviewing neuropsychiatric manifestations of HIV infection (Neuropsychiatric Manifestations of HIV-1 Infection and AIDS) and the second potential mechanism of neurological dysfunction in HIV infection (Potential Mechanisms of Neurologic Disease in HIV Infection).

The following section on personality disorders includes a comprehensive chapter on the neuropsychopharmacology of personality disorder (see The Neuropsychopharmacology of Personality Disorders). Advances in eating disorders are captured in the subsequent sections. Three chapters cover the psychopharmacology of anorexia nervosa, bulimia, and binge eating (Psychopharmacology of Anorexia Nervosa, Bulimia Nervosa, and Binge Eating); a recent update on obesity, fat intake and chronic disease with therapeutic implications (Obesity, Fat Intake and Chronic Disease); a basic biological overview of this set of disorders (Basic Biological Overview of Eating Disorders), and finally a chapter (Pharmacological Treatment of Obesity) focusing on the pharmacological treatment of obesity. A comprehensive updated review on selected sleep disorders follows (Disordered Sleep: Developmental and Biopsychosocial Perspectives on the Diagnosis and Treatment of Persistent Insomnia).

Childhood disorders are the exclusive focus of the following section of five chapters. They review our current state of knowledge on selected childhood disorders with a neuropsychopharmacological component. The first chapter focuses on early-onset mood illness (Early-Onset Mood Disorder), followed by a chapter on attention deficit-hyperactive disorder dealing with the interface of neurochemistry, genetics and neuroimaging (The Interface of Genetics, Neuroimaging and Neurochemistry in Attention-Deficit Hyperactivity Disorder). The remaining portion of this section includes a revised chapter on autism (Autism and Pervasive Developmental Disorders), a revised review of current work on tic disorders (Tic Disorders), and a specific chapter on eating disorders in childhood (Eating Disturbances and Eating Disorders in Childhood), and a final chapter on childhood anxiety disorders (Childhood Anxiety Disorders).

Research advances in substance abuse and psychopharmacology are reviewed in an expanded major section. The reader is first referred to several chapters on integrative concepts in the preclinical section (see Animal Models of Drug Addiction and Genetic Stategies in Preclinical Subtsance Abuse Research). In ten chapters, an attempt is made to provide comprehensive coverage of specific areas of substance use and abuse with each chapter providing both an overview and a specific set of treatment approaches. The first few chapters deal with cocaine, caffeine, amphetamines, tobacco, and opioids (Cocaine, Caffeine–A Drug of Abuse?, Chronic Amphetamine Use and Abuse, Pathophysiology of Tobacco Dependence, and Opioids). These are followed by chapters on alcoholism, marijuana, phencyclidine, benzodiazepines abuse and barbiturates (Pharmacotherapy of Alcoholism, Marijuana, Phencyclidine, Abuse and Therapeutic Use of  Benzodiazepines and Benzodiazepine-Like Drugs, and Barbiturates). Considerable advances in our understanding of preclinical research and their application for possible pharmacothearpeutic approaches in alcoholism are reflect in Pharmacotherapy of Alcoholism.  Genetic Influences in Drug Abuse in this section deals with genetic influences in drug abuse and the final chapter in this section emphasizes the use of behavioral treatments in this set of disorders (Behavioral Treatment of Drug and Alcohol Abuse).


Since the Third Generation of Progress was published, there has been a wealth of advances in various areas affecting neuropsychopharmacology. It has been the major aim of this volume to demonstrate how these advances link together and can provide the foundation for further advances in clinical therapeutics and basic neuropsychopharmacology.

In the final section on future directions, we review under "Special Topics" several areas of interest we have chosen, since we believe they will play an increasingly important role in neuropsychopharmacology. These topics include new drug design, bioethics, the economics of drug development, the economic evaluation of drug treatment, ethnic and cultural aspects of psychopharmacology and, finally, violence and aggression.

A first chapter deals with the impact of molecular biology, new drug design based on the cloning of receptor molecules, and other advances in molecular biology in which new drug candidates will be developed by rational design from three-dimensional structures of target molecules (see New Drug Design in Psychopharmacology: The Impact of Molecular Biology). As the authors review this particular approach, they indicate how the improved precision of drug design will force a certain perspective and impact on molecular design and discovery within the pharmaceutical industry. The next two chapters highlight a set of current bioethical issues confronting clinical and basic researchers associated with genetic screening and testing, gene therapy and scientific conduct (see Ethical Issues in Genetic Screening and Testing, Gene Therapy, and Scientific Conduct and Psychiatric Genetic Counseling). The authors review the impact of the human genome project and current developments in genetic counseling. They propose a proactive approach and preventive ethics, which will necessitate new specific codes of conduct. In the first chapter, they point to the example of the presymptomatic Huntington's disease testing program as one model of dealing with genetic counseling, bioethics, and the impact of a partnership with "patients" on the likelihood as prospective disease.

In the next chapter, the development of psychotropic drugs is placed in the context of other drug development strategies (The Economics of Psychotropic Drug Development). The authors demonstrate that psychotropic drug development in the United States has been lengthier and economically riskier than average and that these factors have led to above-average costs for psychotropics. However, this needs to be placed in the context of strongly growing markets and the extreme lucrativeness of new psychotropic drugs with demonstrable effectiveness. The authors point to several dilemmas impeding the search and timing for new psychotropic drugs, akin to some of the same problems discussed in an earlier chapter on drug design (see New Drug Design in Psychopharmacology: The Impact of Molecular Biology). This discussion of the economics of drug development leads directly into a subsequent chapter on economic evaluation of drug treatment for selected psychiatric disorders (Economic Evaluation of Drug Treatment for Psychiatric Disorders: The New Clinical Trial Protocol). The authors provide specific examples of what has been collected traditionally to assess outcome and discuss how such measures are inappropriate for economic evaluations of drug treatments in the psychiatric disorders. They describe several techniques and types of data that should be utilized in clinical trials for economic evaluation and also provide recommendations for the integration of data from clinical trials, clinical practice, and post-market studies.

The next chapter in this section deals with ethnicity and psychopharmacology (see Ethnicity, Culture, and Psychopharmacology), a topic related directly to the methodological chapter on pharmacokinetics and pharmacodynamics (see Pharmacokinetics and Pharmacodynamics). The authors review the influence of ethnicity on psychotropic responses and point to the new field of pharmacogenetics in which it was found that ethnic differences in drug responses may be genetically determined. The case is reviewed in different classes of psychotropics, as is the role of these parameters in relationship to ethnic concerns. The authors suggest that cross-ethnic research designs will represent a powerful tool for psychopharmacological research in the future.

The final chapter in the critical analysis section is concerned with issues relating to violence and aggression (Neurobiology of Suicide & Aggression). Although these issues do not concern every one of the disorders discussed throughout the clinical section, it is noteworthy that there are a number of disorders in which both outwardly directed aggression as well as internally directed aggression (suicidal behavior) have played a role in long-term prognosis. The author reviews a number of key issues, models of aggression, as well as self-injurious behavior in animals. The linkage between the neurobiology of aggression and suicidal behavior is important as one thinks of the potential serotonergic influences on much of the psychopharmacological discussion with respect to mood disorders and schizophrenia. Furthermore, this chapter ties in with the preclinical discussion on the neurobiology of neurotransmitters.

As we indicated earlier, the volume is not meant to be encyclopedic, but comprehensive in highlighting advances in neuropsychopharmacology over the last 10 years. While one could anticipate a number of advances that will no doubt be covered in the next edition, we believe that the present volume includes most seminal developments and can represent a specialized set of reviews useful for both the clinical investigator and the basic neuroscientist. In this manner, we hope it will facilitate and accelerate the further integration of basic and clinical research in neuropsychopharmacology.

published 2000