HOUSTON – A multidimensional framework being developed by the National Institute of Mental Health is poised to bring the understanding of neuropsychiatric disorders up to par conceptually with the insight being achieved in most other medical disciplines, according to Dr. Thomas Insel.

In contrast to current diagnostic constructs that rely on categorical labels based on signs and symptoms alone, the Research Domain Criteria (RDoC) integrate dimensions of observable behavior with neurobiologic measures and genetics, said Dr. Insel, director of the National Institute of Mental Health. The experimental system will "cut across traditional definitions of mental disorders" by assessing basic dimensions of functioning, such as fear circuitry and working memory, across these multiple units of analysis, he said. While the concept itself is not new – most medical disciplines integrate multiple sources of information, such as biomarkers and imaging, into their diagnostic tool kits – its application to psychiatry is revolutionary, he said.

"Think about it. We don’t use the word ‘cure’ in psychiatry," yet the term is part of the lexicon of nearly every other medical specialty, Dr. Insel said in a plenary presentation at the annual meeting of the American College of Psychiatrists. "The reality is, for most mental illnesses, the etiology is unknown, prediction is poor, detection is late, diagnosis is by observation, prevention is not well developed, and treatment is trial and error."

And while most psychiatrists have seen spectacular individual successes and have experienced the satisfaction of helping people in fundamental ways, "on population-based measures, the dial has not moved much, and when it has moved, the movement has been in the wrong direction, as evidenced by the increased prevalence and increases in associated morbidity and mortality," Dr. Insel said. This is incongruous with the extraordinary advances in biomedical research that have transformed our understanding of so many diseases over the past 50 years, he said. "No such advances have been made in the diseases that we treat, such as major depression, schizophrenia, bipolar disorder, eating disorders, or [attention-deficit/hyperactivity disorder] in children."

The public health implications linked to this lack of advancement are staggering, Dr. Insel said. "The World Health Organization's most recent estimate is that mental health disorders are the largest source of disability from all medical causes, a major cause of death, and one of the major drivers of health care costs from within and outside the system," he said, noting that the estimated direct and indirect costs of mental disorders are more than $317 billion annually.

"What we’ve come to realize is that part of the reason we have not made significant progress is because we haven’t thought about these disorders in the right way," Dr. Insel stressed. "Our focus in thinking about serious mental illness has historically come from the standpoint of these being mental or behavioral problems requiring mental or behavioral interventions."

Such a mind-set suggests that focusing on observable signs and symptoms exclusively will lead to a precise diagnosis, although experience suggests otherwise, Dr. Insel said. "The lesson from other areas of medicine is that a diagnosis that relies solely on manifest symptoms is not the best guide to choosing the most effective treatment." This is because symptom-focused diagnostic labels, such as depression or schizophrenia, frequently belie heterogeneous disorders that defy such narrow classification, he said.

Neuroscientific research during the past decade has determined that mental disorders are brain and developmental disorders that result from complex genetic risk plus experiential factors, Dr. Insel explained. As such, the consideration of all of the various factors will enable precise diagnoses and prediction of treatment response. "We are talking about a completely different way of approaching these illnesses that offers real hope for transforming the statistics and moving the dial."

The much-heralded and occasionally controversial move to the DSM-5 is among the pioneering efforts to reflect this new understanding. The goal of the DSM-5 is to move beyond the signs and symptoms classification of mental illness to incorporate biologic measures, according to Dr. David J. Kupfer, the Thomas Detre Professor of Psychiatry at the University of Pittsburgh and chair of the DSM-5 Task Force. "The DSM-5 is intended to be a living document with recommendations that are guided by research evidence as it evolves," he said in a plenary presentation at the meeting. It will incorporate dimensional concepts, including measurement of distress, disability, and severity; the development of the various illnesses across the life span; and new knowledge on genetic and environmental risk factors and prevention, he said.

"The reality is, for most mental illnesses, the etiology is unknown, prediction is poor, detection is late, diagnosis is by observation, prevention is not well developed, and treatment is trial and error."

For example, the DSM-5 will consider schizophrenia as a multidimensional syndrome rather then a discrete entity to capture the continuum of its phenomenology and pathophysiology and to help track the course of illness evolution, including prodromal states, said Dr. Kupfer, also professor of neuroscience and clinical and translational science at the university. The diagnostic criteria will include measures of cognition (attention, processing speed, delusions, and other thought disturbances) and mood (affective and negative symptoms). As a result of such changes, he explained, the DSM-5 will begin to bridge the gap between presumptive and evidence-based pathophysiologic etiologies.

The NIMH’s RDoC initiative is a complementary approach to the DSM-5. It is based on three assumptions: Mental illness results from dysfunctional brain circuitry rather than identifiable brain lesions; the dysfunction is identifiable using various clinical neuroscience tools, including electrophysiology, neuroimaging, and new methods for in vivo quantification of connections; and data from genetic and clinical neuroscience research will lead to diagnostic biosignatures, according to Dr. Insel.

The RDoC framework is a matrix consisting of rows of functional constructs – the biologic mechanisms that drive behavioral abnormalities – which are grouped under five major domains: negative affect (fear/extinction, stress/distress, aggression); positive affect (reward seeking, reward/habit learning); cognition (attention, perception, working memory, declarative memory, language behavior, cognitive control); social processes (imitation, theory of mind, social dominance, facial expression identification, attachment/separation fear, self-representation areas); and arousal/regulatory processes (arousal and regulation, resting state activity), Dr. Insel explained. Six units of analysis – genes, molecules, cells, circuits, behavior, and self-reports – make up the columns of the matrix and are used to evaluate the domains and constructs.

Because the RDoC domains traverse diagnostic categories, "it most likely will not parallel current diagnostic categories," Dr. Insel said. "Unlike existing systems in which a disorder is either present or absent, RDoC is dimensional; it incorporates measures of magnitude, analogous to cholesterol or blood pressure tests." Ultimately, the project will foster the development of reliable and valid tests for acquiring such dimensional information, he said.

"The idea is that abnormalities in any of the domains or constructs are not necessarily exclusive to one disorder but may be features of multiple disorders," Dr. Insel said. Through data classification done in this way, "the goal is to uncover common biological mechanisms associated with the various domains, which may lead to new molecular and neuroimaging targets for drug discovery." Such insights are critical to real progress he said. "Right now, we don’t know enough about the pathophysiology of depression to know that the serotonin transporter is the target that we should have. We know that it is the place that we have been focused, yet we haven’t reduced the suicide rate among people with affective illness."

The development of the RDoC is ongoing, with no definitive timeline. "It is a long-term project designed to help the research community by designing fundamental, biologically based organizational principles underlying various psychopathologies," Dr. Insel said in an interview. Considering mental disorders in this way will enable new research paradigms, particularly target validation, he said. "Target validation is the coin of the realm in virtually every area of medicine, yet it is almost entirely ignored in our field. Until now, our whole field has revolved around giving compounds to patients and assuming that we understood what we were doing, so if something doesn’t work, we either keep trying or up the dose, without ever knowing if we’ve hit the target. It’s not informative, and there’s no way to make sense of the failure."

In contrast, understanding mental disorders as circuit illnesses and using neuroimaging technology, such as functional MRI and PET imaging, "we now have the technological ability to know whether we’re influencing the target of interest," Dr. Insel said. The next step, he said, is to design trials embedded with experimental medicine, specifically short, deep trials with a small number of patients, "to determine whether a given compound actually engages the target or not, and to determine the success or failure of the compound quickly."

In fact, success is predicated on failing "fast and often," Dr. Insel said. "Experimental medicine is set up for a fast-scale approach: running compounds through so you know what is not working as quickly as possible. Once you determine that a compound has engaged the target, if the patient doesn’t get better, you forget that target and move on."

To identify potential targets and develop experimental treatments to engage them, "we need studies of pathophysiology that go all the way from understanding the molecular basis of these disorders to understanding the social basis, which will get us to the point where we have biomarkers or diagnostics," Dr. Insel said. "For the first time, we will be able to develop treatments that are focused on targets that we truly understand, paving the way for prevention, recovery, and cure."

Dr. Insel and Dr. Kupfer said they had no relevant financial disclosures.

NIMH Framework Will Usher in New Era of Research