Several trends intersecting over the past two decades have generated increasing debate as to how the concepts of schizophrenia, the schizophrenia spectrum, and the psychotic disorders spectrum should be regarded. These trends are reflected in various areas of research such as genomics, neuroimaging, and data-driven computational studies of multiple response systems. Growing evidence suggests that schizophrenia represents a broad and heterogenous syndrome, rather than a specific disease entity, that is part of a multi-faceted psychosis spectrum. Progress in explicating these various developments has been hampered by the dependence upon sets of symptoms and signs for determining a diagnosis, and by the reliance on traditional diagnostic categories in reviewing clinical research grants. To address these concerns, the U.S. National Institute of Mental Health initiated the Research Domain Criteria (RDoC) project, a translational research program that calls for studies designed in terms of empirically-based functions (such as cognitive control or reward learning) rather than diagnostic groups. RDoC is a research framework rather than an alternative diagnostic system, intended to provide data that can inform future nosological manuals. This commentary includes a brief summary of RDoC as it pertains to schizophrenia and psychotic spectra, examples of recent data that highlight the utility of the approach, and conclusions regarding the implications for evolving conceptualizations of serious mental illness.
Keywords: psychiatric diagnosis, psychiatric nosology, research domain criteria, psychopathology, schizophrenia spectrum, psychosis spectrum
The concept of schizophrenia (SZ) has elicited continual debate since the first descriptions of psychosis appeared in the middle of the nineteenth century. The nature of the concept has fluctuated across the years according to the views of the scientific zeitgeist and various schools of psychopathology, but has always persevered in one form or another (1). Within the last decade, however, advances in multiple areas of science—genomics, neuroimaging, cognitive science, and epidemiology—have begun to challenge classic conceptions of schizophrenia (2, 3).
Progress in expanding these various developments has been hampered by two major obstacles. First, disorders continue to be defined almost exclusively by sets of symptoms and signs; however, the relationships between diagnostic categories and biological or behavioral measures have proven to be modest and inconsistent, frustrating both a more comprehensive understanding of disorders and the development of more effective treatments (4). Second, research on mental disorders has been constrained by the persistence in grant review committees of a de facto requirement that hypotheses will embody DSM/ICD categories as their scientific focus, thus foiling applications proposing alternative approaches.
To address these problems, the US National Institute of Health (NIMH) initiated the Research Domain Criteria (RDoC) project in 2009 “to develop, for research purposes, new ways of [studying] mental disorders based on dimensions of observable behavior and neurobiological measures” (5). RDoC was conceived as an experimental framework to support research in psychopathology organized around basic functional domains such as cognition, motivation, and motor activity, most of which are pertinent to multiple disorders as currently defined (and may partially account for the extensive co-morbidity in current disorders).
The various elements of the RDoC framework have been described in detail elsewhere (5–7) and are briefly summarized here. RDoC is intended as an explicitly translational program: The focus is on fundamental operations of adaptive behavioral/cognitive and brain functioning (e.g., working memory, fear behavior), and psychopathology is viewed in terms of dysregulation in these systems rather than starting with clinical syndromes and trying to determine their source. A core desideratum of RDoC is to study entire dimensions of functioning from the normal range to increasingly abnormal extents, and no specific cutpoints for disorders are specified in order to encourage studies of transitions from normality to degrees of pathology. To foster such analyses, RDoC calls for study designs that include a broader range of “healthy controls,” patients with mild/subsyndromal psychopathology, and unaffected relatives of probands.
The basic dimensions of RDoC are organized in six superordinate domains of functioning (negative valence, positive valence, cognition, social processes, arousal/regulatory systems, and sensorimotor systems). Each domain contains multiple constructs, which—central to the entire framework—are defined jointly by data for a behavioral or cognitive/affective function, evidence for a neural circuit or system that plays a primary role in implementing the function, and relevance to psychopathology (8).
The domains and constructs were defined in a series of workshops attended by experts in both basic and clinical research. This process was essential for two reasons. First, it is important to communicate to the field well-validated constructs from the basic behavioral neuroscience literature that have demonstrated promise for understanding psychopathology. Second (and less evident), it is critical to provide clear guidelines for grant review. Just as established criteria for defining patient groups contributed significantly to the DSM's hegemony in study sections, examples of domains and constructs are essential to serve as standards for both applicants and reviewers in submitting and evaluating RDoC applications. Since RDoC is an experimental framework, applicants are not required to use one of the current constructs, and no claim is made that the current list of constructs is complete; in fact, a major goal of the program is to encourage research that establishes new constructs or domains, based on the premise that promoting diversity of ideas in research is the best way forward (Note that NIMH accepts DSM-oriented grant applications as always, although applicants are encouraged to address pertinent heterogeneity).
In keeping with the basic-to-clinical translational approach, RDoC focuses on relatively specific aspects of disordered functioning rather than syndromal categories. Study designs might include patients from one or more DSM/ICD categories, analyzing dimensions or subgroups in the full sample or examining selected subjects with particular characteristics (e.g., cognitive control or reward-related deficits). Participants in transdiagnostic studies are typically drawn from related areas of psychopathology, such as mood/anxiety disorders or psychotic disorders (plus comparison participants appropriate for exploring dimensions of functioning). An important emphasis concerns individual differences in psychopathology, given the heterogeneity that is now recognized for all syndromal disorders. Studies that include multiple domains/constructs are encouraged, such as the relationship of threat to attention or reward-related activity to social processes. RDoC-related research further advocates the use of multiple classes of measurement, ranging from genomics and circuit measures to behavioral and self-report, in order to seek an integrative understanding of brain-behavior relationships as they relate to particular functions.
The RDoC program has consistently emphasized its agnostic position with respect to disorders as defined in the DSM/ICD system: The goal is to stimulate research that can inform revisions to future diagnostic manuals, however similar or divergent to current disorders and their definitions. Recent developments in the field demonstrate novel conceptions across the entire range of psychopathology, employing various types of dimensions, clusters, and hierarchical approaches that align with the RDoC approach (9).
Research focused on psychotic disorders amply reflects this trend (10). As one expert recently explained in a publication for psychiatric professionals, “Over the last decade or so, our field has experienced a radical shift in our understanding of schizophrenia and other serious psychotic disorders, such as schizoaffective disorder and bipolar disorder with psychosis. …. Accumulating evidence indicates that psychotic disorders constitute syndromes rather than diseases per se. … Patients with different clinical diagnostic phenotypes … can show similar underlying patterns of cognitive dysfunction and neurobiological abnormalities” (11). Space allows only a small number of papers to be cited here as examples of RDoC approaches in the psychotic spectrum [which are treated more comprehensively in a recent chapter; (7)].