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Beyond DSM: Seeking a Brain-Based Classification of Mental Illness

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Science  19 Mar 2010:
Vol. 327, Issue 5972, pp. 1437
DOI: 10.1126/science.327.5972.1437

If a fright or despondency lasts for a long time, it is a melancholic affection.
—Hippocrates
, Aphorisms, 400 B.C.E.

Since the time of the ancient Greeks, mental disorders have been classified according to their outward signs. But even in Hippocrates' day, attention was paid to the underlying causes. The word “melancholy” derives from the Greek word for black bile, an excess of which was thought to cause prolonged sadness.

Modern research in neuroscience and genetics has provided a more sophisticated understanding of mental illness, and harnessing this knowledge to improve the diagnosis of psychiatric disorders was a major impetus for undertaking a revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM) (Science, 12 February, p. 770). But even some of those leading the revision say there's still too little known about the biological basis of mental illness, and as a result DSM continues to be based on symptoms rather than causes. “We just don't know enough to do a lot better,” says psychiatrist Steven Hyman, the provost of Harvard University and a member of the committee in charge of the new edition, DSM-V.

A new initiative by the U.S. National Institute of Mental Health (NIMH) aims to foster the research needed to close this knowledge gap. “What we are doing is trying to develop new ways to classify disorders that are based on identifiable neural circuits,” says Bruce Cuthbert, an NIMH psychophysiologist leading the effort, called Research Domain Criteria (RDoC). NIMH expects to start rolling out the project in earnest next month, beginning with a draft document that sketches out five “domains” of mental function that correspond—with varying degrees of confidence—to specific brain regions or neurochemical signaling pathways or both. This new classification isn't intended to compete with DSM anytime soon, Cuthbert says, but it is intended to change the way researchers study mental disorders.

The impetus for RDoC dates back to Hyman's tenure as NIMH director in the late 1990s. Hyman says he became concerned that the DSM classification of mental disorders was hampering research. Investigators used DSM criteria to frame their research questions, study sections used them to evaluate grant applications, journal editors used them to judge papers, and pharmaceutical companies used them to design clinical trials. At the same time, Hyman says, “it was clear that DSM was a poor mirror of nature.”

By way of illustration, he notes in a recent review article that the DSM-IV diagnosis of major depression requires that a patient have at least five of nine possible symptoms. In this scenario, it's possible for two patients to receive the same diagnosis with only one symptom in common. Their inner turmoil and its biological roots might differ substantially, but they could easily be lumped together in a study on “major depression.” “We needed some way to break out of the cognitive box and encourage scientists to do research that disregards the current disease boundaries,” Hyman says.

Hyman's successor at NIMH, Thomas Insel, made this a priority for the institute, and RDoC is the product. The draft document, to be posted on the RDoC Web site* next month, describes five broad mental domains that are present in everyone but whose extremes correspond to mental illness: negative emotionality, positive emotionality, cognitive processes, social processes, and arousal/regulatory systems. It further divides each of these domains into individual entries linked to particular neural circuits. Under negative emotionality, for example, are entries for three specific subtypes: fear (hypothesized to result from dysfunction in the amygdala and connected brain regions), stress and anxiety (linked to abnormalities in the hypothalamic-pituitary-adrenal system and stress hormones), and aggression (involving the amygdala and hypothalamus, as well as hormones such as testosterone and vasopressin).

Faulty circuit.

The amydgala (red), the hub of the brain's fear circuitry, could feature prominently in a brain-based system to classify mental disorders.

CREDIT: DATABASE CENTER FOR LIFE SCIENCE (DBCLS)

The current DSM diagnoses don't necessarily map neatly onto the RDoC entries, Cuthbert says, and that's partly the point. “Exactly the problem with the DSM disorders is that they're very heterogeneous and may involve multiple brain systems,” he says.

Beginning this summer, workshops will bring together groups of experts to refine the RDoC entries and to identify gaps in the current understanding of the genetic risks, neural dysfunction, and behavioral problems associated with each one. Over the next 2 to 3 years, NIMH will encourage researchers to shift from using DSM criteria in their grant proposals to using the RDoC categories.

One goal of RDoC is to change the current practice of selecting research subjects based on their DSM diagnosis and to encourage studies that use biological indicators instead. A study on anxiety disorders, for example, might examine people who show a heightened amygdala response to frightening pictures, regardless of whether their DSM diagnosis is panic disorder or social phobia. Another study might enroll people with a particular variation of the DISC1 gene, regardless of whether they have a diagnosis of bipolar disorder or schizophrenia (both of which have been linked to DISC1). Such studies are essential for connecting the dots between biological abnormalities and the symptoms of mental illness, Cuthbert says.

Ultimately, NIMH hopes RDoC will inform clinical practice. In the future, a psychiatrist might examine Hyman's two hypothetical depression patients and diagnose one with anhedonia resulting from a glitch in the mesolimbic dopamine system, and diagnose the other with a disruption in serotonin signaling, coupled with anxiety caused by dysregulation of corticotropin-releasing factor in the hypothalamus. And then, with luck, the psychiatrist would know just what treatment each one requires.

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