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."