NIMH Builds New Framework for Understanding Mental Illness

The National Institute of Mental Health (NIMH) is drawing a brand-new blueprint for studying and understanding mental disorders that will fully integrate behavior, the brain, and genetics.

The initiative, known as Research Domain Criteria (RDoC), has been established to carry out one of the goals in NIMH's strategic plan: “to develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures.”

The dimensions refer to basic brain functions such as fear and its extinction, response to stress, impulsive behavior, executive function, and working memory. Increasing evidence suggests that abnormality in one dimension frequently occurs in multiple diagnoses of mental disorders, Bruce Cuthbert, Ph.D., director of the NIMH Division of Adult Translational Research and leader of the RDoC project, told Psychiatric News.

For example, cognitive impairment is observed in schizophrenia as well as in unipolar and bipolar depression, hypersensitivity to stress stimuli is present in various types of anxiety disorders, and impulsivity is seen in both attention-deficit/hyperactivity disorder and conduct disorder.

“Our initial definitions call for five major domains of brain functioning: negative emotionality such as fear and its extinction, stress and anxiety, and aggression; positive emotionality involving reward motivation and reinforcement; cognitive processes; social processes; and arousal/regulatory systems,” said Cuthbert. Although scientists have defined some functional dimensions, identifying all the dimensions and their related brain circuits will be a priority for RDoC efforts.

Reshape Research Framework

The RDoC will build a framework to help researchers structure their psychiatric research in a way different from the traditional diagnosis-based approach, Cuthbert explained. By relying on clinical diagnostic criteria, researchers often exclude patients with overlapping functional impairments, and thus potentially overlapping pathology, while combining patients with heterogeneous syndromes that currently belong to one disorder category.

The RDoC can guide neuropsychiatric research toward finer grains of functional dimensions, brain circuits, and genetic risks, NIMH's Web site notes. Although the investigational tools still involve brain imaging, cellular and molecular analysis, genomic and genetic tests, and behavioral measurements, the RDoC will change the way study subjects are selected, said Cuthbert. Researchers may enroll people with a particular dimensional dysfunction, such as working-memory impairment, even if they have different diagnoses. Alternatively, researchers may study individuals who share a certain genetic risk factor and investigate its impact on specific brain circuits and functions.

If successful, the RDoC is expected to quicken the discovery of brain-circuit pathology responsible for dimensional dysfunction. “It will shift the way we do research and think about mental disorders,” said Cuthbert. In addition, research guided by the project may reveal targets in the brain for new drugs and interventions. Safer and more effective treatments could be designed with a more rational approach than relying on accidental discovery, he noted.

Won't Replace Diagnostic Criteria

Since spring 2009, an RDoC work group has been laying the groundwork for the initiative, said Cuthbert. Last July, that work group met with APA and World Health Organization representatives to clarify RDoC's difference from and potential synergy with DSM-5 and ICD-11, the two diagnostic systems that are currently being drafted.

“RDoC is not intended as a competitor or replacement for DSM or ICD, which currently remain the best understanding for the diagnosis of mental disorders,” Cuthbert emphasized. The RDoC project, in contrast, is intended to accelerate clinical research that will profoundly improve the understanding of the mechanisms of mental disorders, which subsequently can inform and influence diagnostic criteria.

NIMH is planning to hold a series of conferences to present the RDoC initiative to researchers and obtain their feedback. The first conference, to be held this summer, will focus on executive function. As the efforts continue, more information will be posted on the NIMH Web site for public access and commentary that will help refine the framework.

As the RDoC takes shape, “we anticipate substantial research funding to be committed for a long time,” said Cuthbert. This is not a time-limited project with a predefined amount of grants. Rather, the project is expected to be wide reaching and an important component of NIMH's commitment to translational research.

“The development of an improved research base for understanding how neurocircuitry, neuronal cell physiology, and genetic vulnerability relate to symptomatic and syndromal expressions of mental disorders is a welcome NIMH initiative,” Darrel Regier, M.D., M.P.H., vice chair of the DSM-5 Task Force and head of APA's Division of Research, told Psychiatric News.

Meanwhile, DSM-5 is also placing more emphasis on dimensions, such as mood, anxiety, anger, impulsivity, and cognitive impairment, across diagnostic boundaries, which “should provide a useful source of clinical information for testing the RDoC dimensional hypotheses as they are developed in the coming years,” Regier said. Insights gained from the RDoC, he believes, may eventually “support better diagnostic definitions that can be incorporated into DSM-5 and its future revisions as a living document as evidence accumulates.”

“This is intended to be a long-term effort,” Cuthbert emphasized. In other words, the revolution will involve a long march.