A Research Agenda for DSM-V: Summary of the DSM-V Preplanning White Papers Published in May 2002

Michael B. First, M.D.

The publication of "A Research Agenda for DSM-V" in May 2002 signals completion of the initial phase in the DSM-V pre-planning process that began in 1999. (Click here to download the book from the APPI web site). The monograph, containing six "white papers," is an attempt to stimulate research and discussion in the field in preparation for the eventual DSM-V revision process that is currently slated to begin in 2006. The white papers were produced under a partnership between the American Psychiatric Association, the National Institute of Mental Health, National Institute for Alcoholism and Alcohol Abuse, and the National Institute for Drug Abuse with the goal of providing direction and potential incentives for research that will provide an improved scientific basis for future classifications.

Research planning workgroups responsible for the development of these white papers were constituted for two primary reasons: 1) to stimulate research that will enrich the empirical data base prior to the start of the DSM-V revision process; and 2) to devise a research and analytic agenda that would facilitate the integration of findings from animal studies, genetics, neuroscience, epidemiology, clinical research, cross-cultural research, clinical services research and experience, which will lead to the eventual development of an etiologically-based, scientifically-sound classification system.

Workgroup members were selected primarily for their expertise in diverse areas such as family and twin studies, molecular genetics, basic and clinical neuroscience, cognitive and behavioral science, development, life span issues, disability, psychopathology, and treatment. In order to encourage thinking beyond the current DSM-IV framework, most of the workgroup members had not been closely involved in the DSM-IV development process. They were encouraged to consider new and emerging data, to identify knowledge gaps, and to suggest how data might be generated to fill those gaps. They were cautioned against thinking too narrowly with regard to how new information from emerging fields such as neuroscience and genetics may be used in a classification system.

In the remainder of this piece, we summarize the contents of the six white papers. For more information we suggest you review the actual monograph, which is available for purchase from American Psychiatric Publishing, Inc. The monographs can also be viewed online free-of-charge at this site.

Basic Nomenclature Issues

The Nomenclature Workgroup, chaired by Bruce Rounsaville, M.D., focused on a variety of issues that had to do with the way disorders are classified in the DSM. The group noted a lack of clarity regarding the definition of "mental disorder" in the DSM and suggested that it would be desirable in DSM-V to provide a definition of mental disorder that can be used as a criterion for assessing potential candidates for inclusion in the classification and deletions from it.

A second issue examined by the workgroup concerns problems in how psychiatric diagnoses are validated in the DSM. Disorders are generally evaluated using validators such as family history, treatment response and course. One problem is that different diagnostic validators of a given nosologic problem do not all produce the same answer. For example, if the goal is to define schizophrenia as a disorder with high diagnostic stability, then the diagnostic criteria should require prior chronicity (e.g. 6 months of illness). By contrast, if the validating criterion to be applied is familial aggregation, then the “most valid” criteria set would be much broader and include a range of other psychotic disorders as well as schizophrenia-spectrum personality disorders. One way to address this problem is to develop a hierarchy of validators that ideally would cut across the disorders and to test alternative criteria sets against different orderings in the hierarchy.

A third nomenclature issue concerns the markedly different knowledge bases from which the criteria sets were developed and validated across diagnoses. The workgroup considered whether it might be advisable and feasible to rate the quality and quantity of information available to support the different disorders in order to indicate the disparity of empirical support across the diagnostic system.

A fourth issue examined by the workgroup was what the criteria should be for making changes in the diagnostic criteria sets. Given the many burdens imposed on the user community as a result of changes in the diagnostic system, changes should only be made when the advantages outweigh the disadvantages. The group suggested developing criteria by which to determine whether the advantages (e.g., simplification, validity) justify the disadvantages of change.

A fifth issue covered by the workgroup concerned the fundamental structure of the DSM. Is the classification best served by continuing to use a categorical approach in which the patient is considered to have one or more disorders (i.e., a disorder is either present or absent)? In contrast, a dimensional approach would describe the patient’s psychopathology in terms of where the symptomatology falls along a number of dimensions, for example, low on depression, high on psychosis, etc. Although the categorical approach more closely conforms to the way clinicians think, a dimensional approach without discreet boundaries more closely conforms to clinical reality.

A sixth issue concerns the need to close the gaps between DSM and ICD classifications. Although efforts were made to make DSM-IV and ICD-10 as compatible as possible, many small and large incompatibilities persist. The group suggested a research agenda to identify and reconcile differences so as to allow for a single, unified DSM-V/ICD-11 classification system.

A final issue considered by the group concerned the use of the DSM in non-psychiatric settings. As greater emphasis is placed on detection and early intervention for mental disorders in settings other than traditional psychiatric clinics and practices, there is a need to define or operationalize diagnostic criteria using methods other than the traditional psychiatric interviews which require considerable training and clinical judgment. Strategies to reduce reliance on clinical judgment include increased use of laboratory tests, psychological testing, and standardized self-report rating scales.

Basic and Clinical Neuroscience and Genetics Research Agenda

The central focus of the Neuroscience and Genetics Workgroup, chaired by Dennis S. Charney, M.D., was to develop a basic and clinical neuroscience and genetics research agenda to guide the development of a future pathophysiologically-based diagnostic classification. The current DSM-IV classification adopts a descriptive approach to diagnosis in which disorders are defined by clusters of symptoms and characteristics of clinical course. This approach has allowed for the development of a classification system that successfully met the field’s need for a common language without being mired in ideological hypotheses about the causes of psychiatric illness. Many critics, however, charge that the DSM’s descriptive approach has outlived its usefulness and may in fact be potentially misleading.

Current DSM definitions are virtually devoid of biology, despite a large body of research that indicates a neurobiological basis for most mental disorders. A primary purpose of this group then, was to determine why progress has been so limited and to offer strategic insights that may lead to a more etiologically-based diagnostic system. The group ultimately concluded that given the current state of technological limitations, the field is years, and possibly decades, away from having a fully explicated etiology- and pathophysiology-based classification system for psychiatry. Although the past two decades have produced a great deal of progress in neurobiological investigations, the field has thus far failed to identify a single neurobiological phenotypic marker or gene that is useful in making a diagnosis of a major psychiatric disorder or for predicting response to psychopharmacological treatment.

Essential elements of a research agenda that would elucidate an etiology-based system include genetic studies, brain imaging, post-mortem studies, and animal studies. Genetic studies, despite several decades of effort, have not yet identified with certainty any bona fide psychiatric disease gene, although the field is getting closer and new advances in genetics (including the availability of the human genome sequence) portend rapid progress. Brain imaging studies in humans promise, for the first time, to provide detailed information about molecular and cellular substrates of the brain involved in psychiatric disorders. While currently available imaging techniques have thus far failed to provide diagnostic tests for psychotic, affective, or anxiety disorders, it is only a matter of time before these techniques have the spatial and temporal resolution, and chemical specificity to study relevant pathophysiological mechanisms. Finally, studies of brain samples obtained at autopsy should permit more detailed molecular analyses of the pathophysiology of psychiatric disorders. Over the last decade, the field has greatly increased the sophistication with which it utilizes postmortem tissue.

There is no question that animal research has vastly expanded our knowledge of normal brain function. It also has been invaluable in identifying the initial protein targets through which most currently used pharmacotherapeutic agents produce beneficial clinical effects as well as identifying the protein targets through which most drugs of abuse cause addiction. It also has been possible to develop several animal models that have outstanding predictive value in developing new medications with fewer side effects than older agents. The second generation antipsychotic agents, the serotonin-selective and norepinephrine-selective reuptake inhibitor antidepressants, and the benzodiazepine-like agents that act on selected subunits of the GABA-A receptor, have all derived directly from rational drug-design efforts based on animal models.

The group outlined a “blueprint for the future” that included a review of emerging technologies and approaches, and suggested future directions for research. For preclinical animal work, the group focused on four domains: 1) better animal models for the major psychiatric disorders; 2) genes that help determine abnormal behavior in animal models; 3) imaging studies in animals to better understand the nature of imaged signals in humans; and 4) functional genomics and proteomics involved in psychiatric disorders, that is the identification of genes or proteins that are regulated in particular brain regions by a given drug or behavioral state.

Other domains included in the blueprint include: 1) work to identify disease-related genes from among the 26,000 identified in the human genome project; 2) post-mortem studies to examine circuitry and gene expression; 3) the newer brain imaging techniques; 4) approaches that integrate the use of multiple modalities; and 5) neuroinfomatics, the integration and management of large amounts of data produced at various levels of investigation.

Advances in Developmental Sciences

The Developmental Issues and Diagnosis Workgroup, chaired by Daniel S. Pine, M.D., focused on outlining a research agenda to inform developmental aspects of the diagnostic classification. This workgroup presented an approach to development encapsulated by the concept of bioecology which considers the progressive, mutual accommodation, throughout the life span, between a growing human organism and the changing immediate environment. Under this approach, development involves interactions between the individual and nested systems in the individual’s environment through a transactional process; the individual affects the environment, which, in turn, affects the individual.

The initial focus of the workgroup was on the manner in which contextual, ethnic, and cultural issues affect and are affected by nosology. Contextual factors have been shown to affect either the expression of particular behaviors or the risk for psychopathology during development. The current ICD and DSM systems, however, provide definitions of mental disorders that, as far as possible, are applicable across age groups, genders, ethnicity, and context. The workgroup thus expressed concern about studying the effects of context on diagnoses that rely on a psychiatric nosology designed for use across multiple contexts.

The second part of the group’s report summarizes key advances in four areas of developmental science as they relate to nosology. Domains covered include: 1) progress in developmental psychology and psychopathology -- the roots of many chronic mental disorders, such as antisocial personality disorder, schizophrenia, mood, and anxiety disorders, are found in childhood; 2) developmental neuroscience --evidence of developmental plasticity in the nervous system; 3) developmental genetics -- studies identifying genetic causes of neurodevelopmental and neuropsychiatric syndromes demonstrate both clinical heterogeneity across individuals with common genetic abnormalities and genetic heterogeneity across individuals with comparable behavioral phenotypes; and 4) epidemiology and services research -- understanding the relationship between risk and pathophysiology requires epidemiological samples because apparent associations seen in treatment-seeking samples can be the result of “referral biases.” Seeking the answers to questions raised by studies in these domains may provide novel opportunities for scientific breakthrough in the coming decades.

The third section of the Developmental Workgroup white paper reviews the current DSM classification, noting innovations that have set the stage for future advances and deficiencies that need to be addressed in the future. Identified strengths of DSM include the explicit definitions of disorders; many of the identified symptom groupings (e.g., basic distinctions between emotional syndromes like childhood anxiety disorders, and behavioral syndromes, like conduct disorder and attention deficit hyperactivity disorder); emphasis on an empirically-driven revision process; and adoption of a developmental perspective (e.g., having a section on disorders first diagnosed in infancy, childhood, and adolescence). Identified weaknesses include problematic distinctions between some disorders (e.g., between oppositional defiant disorder and conduct disorder) as well as problems and deficiencies in the multiaxial system.

Finally, the group proposes a research agenda for the next decade focusing on six areas of research that have the potential to refine the classification of developmental psychopathology, as follows. 1) Developmental neuroscience and genetics: studies in animals to determine associations between maternal behavior and hypothalamic-pituitary-adrenal axis regulation; 2) Prevention and early intervention: studies of early intervention for children and adolescents; (3) Improved diagnostic classification of disorders of infancy and early childhood; (4) Improvements in the multi-axial system; (5) Approaches to psychiatric assessment: integration of information from different assessment approaches; and (6) Developmental epidemiology: large scale population-based samples of children studied from birth, or even earlier, through adulthood.

Personality and Relational Disorders

This workgroup, chaired by Michael B. First, M.D., focused on two major gaps in the DSM-IV, namely inadequacies in the classification of personality disorders and of relational disorders. Although some have criticized the validity of the personality disorder construct, the group noted that personality disorders are an important component of the DSM classification and should continue to be included in future iterations of the DSM. The presence of a personality disorder has been shown to have a significant negative impact on the management and outcome of a comorbid mental disorder or physical condition. Furthermore, personality disorders by themselves can cause clinically significant impairment. For example, antisocial personality disorder increases one’s risk for unemployment, impoverishment, injury, violent death, incarceration, recidivism, and relationship instability.

The current categorical method for diagnosing personality disorders, however, has some serious shortcomings. The personality disorder construct in DSM-IV is ill-defined, leading to confusion regarding the difference between personality disorders and chronic, early-onset Axis I disorders such as dysthymic disorder or social anxiety disorder. The lack of clear boundaries between the disorders results in considerable comorbidity, so much so that a diagnosis of several personality disorders is the rule rather than the exception. Distinctions between disorder, trait, and normal personality are arbitrary, based on symptom thresholds that are without significant empirical basis. Furthermore, there is no documented clinical utility for the DSM-IV categories in terms of guiding treatment decisions. Finally, the current 11 categories have problematic coverage; Personality Disorder NOS, for example, is the most commonly diagnosed personality disorder in many settings.

The group focused on two different aspect of the personality disorders problem. It was proposed that a dimensional approach to diagnosing personality disorder be considered in place of the current categorical system. Under the dimensional approach, a personality trait is considered to be a maladaptive variant of general personality functioning. A number of different dimensional personality systems have been devised by research psychologists over the past 20 years. In fact, the possibility of including a dimensional personality approach in DSM-IV was considered but ultimately rejected on the grounds that there was no consensus in the field as to which of the many proposed dimensional systems should be adopted and because of concerns about clinical utility and practicality. In general, the dimensional systems differ in terms of how they were developed and whether the dimensional items are confined to personality disorder symptoms or reflect the full range of normal and abnormal functioning.

Among the research questions that need to be considered: 1) Do the dimensional models cover the symptoms defined by the existing disorders? 2) Which model best conforms to fundamental biobehavioral dimensions of personality and temperament? 3) Which model has the best clinical utility and predictive validity? 4) Can there be a more explicit rationale for what constitutes a personality disorder.

A second area of group focus was the relationship between personality disorders and certain Axis I disorders. Very high rates of comorbidity have been reported between Axis I and Axis II disorders (up to 79 percent in some settings), raising questions about whether there is some common etiological or pathophysiological process underlying some Axis I/Axis II disorders (the so-called spectrum model). This model proposes that schizotypal personality disorder is in the schizophrenia spectrum, that avoidant personality disorder is in the anxiety disorders spectrum and that borderline personality disorder is in the mood disorders spectrum. The group advocated a research agenda that would focus on elucidating the etiological and pathophysiological processes for established spectrum conditions, for example, schizotypal personality disorder.

The group also proposed a research agenda that would address the question of relational disorders: whether to expand the relational disorders in DSM-V and to add specific diagnostic criteria for each disorder. The locus of a relational disorder, in contrast to other DSM-IV disorders, is on the relationship rather than on any one individual in the relationship (e.g., a parent is withdrawn with one child but not with other siblings). Despite this major conceptual difference, relational disorders share many elements in common with other disorders: there are distinctive features for classification; they can cause clinically significant impairment; there are recognizable clinical courses and patterns of comorbidity; they respond to specific treatments; and they can be prevented with early interventions. Specific tasks in a proposed research agenda: develop assessment modules; determine the clinical utility of relational disorders; determine the role of relational disorders in the etiology and maintenance of individual disorders; and consider aspects of relational disorders that might be modulated by individual disorders.

Mental Disorders and Disability

The workgroup chaired by Anthony F. Lehman, M.D. focused on disentangling the concepts of symptom severity and disability. In the absence of objective criteria based on understanding underlying pathophysiology, DSM-IV disorders are defined by clusters of symptoms that, in milder forms, often occur in mentally healthy individuals. To help differentiate between normals and those with a disorder, DSM-IV criteria sets often include a requirement that the disorder causes clinically significant impairment. This requirement combines the constructs of symptoms and impairment, obscuring attempts to study factors which explain the varying degrees of disability observed across patients given the same level of symptom severity. In addition, requiring that the disorder cause disability complicates efforts to recognize mental disorders earlier in their course (i.e., before they are severe enough to cause impairment), to intervene, and potentially to prevent worsening of the illness.

The group proposed a research agenda that would provide substantial new knowledge enabling transition to a diagnostic system that allows for separate, but coordinated consideration of disease and disability. The agenda would include research on: 1) methods to define and assess disability for both clinical and research applications; 2) multifaceted approaches to the intra-individual factors at the biological and psychological levels that contribute to disability; 3) multifaceted examination of the extra-individual factors that contribute to disability, including influences from family, social networks, the community, and the cultural context in which patients live; 4) pathways to and from disability, including natural course and the impacts of interventions on course of illness; and 5) the role of the health care system and government policies in promoting recovery and in addressing barriers to overcoming disabilities.

Cross-Cultural Issues

Renato D. Alarcon, M.D. chaired the workgroup that considered cross-cultural issues in diagnosis and classification. Mental disorders are multi-factorial in nature. For any psychiatric diagnosis to be truly comprehensive and culturally valid, it has to take account of a multitude of variables, from race and ethnicity to the more encompassing notions of language, education, religion, habits, values, and gender and sexual orientation. Cultural processes can influence psychiatric diagnosis by: 1) defining and creating specific sources of stress and distress; 2) shaping the form and quality of illness experience; 3) producing the symptomatology of generalized distress and of specific syndromes; 4) determining the interpretation of symptoms and hence, their subsequent cognitive and social impact; 5) providing specific modes of coping with distress; 6) guiding help-seeking and the response to treatment; and 7) governing social responses to distress and disability. As a result of these pervasive and ubiquitous effects, there is no “natural history” of disease but rather a social course that must be described relative to specific contexts. The diagnostic and assessment process should address cultural differences, language barriers, and the implications of nosological labeling in clinical reasoning and as determinants of the patient’s behaviors