What RDoC Research Might Look Like

The month of May is a violent thing
In the city their hearts start to sing
Well, some people sing, it sounds like they're screaming
I used to doubt it, but now I believe it

Month Of May
   ------The Arcade Fire

Today is Mental Health Month Blog Day, sponsored by the American Psychological Association (APA). It's designed to:

...educate the public about mental health, decrease stigma about mental illness, and discuss strategies for making lasting lifestyle and behavior changes that promote overall health and wellness.

If the public has been following the recent hullabaloo about how to diagnose mental illnesses, they might be confused about the current and future direction of the field. How did we get here?

As most of you know, the American Psychiatric Association (the other APA) is about to release its updated Diagnostic and Statistical Manual of Mental Disorders, the much maligned DSM-5. Weeks before the big launch, however, the National Institute of Mental Health (NIMH) stole the show by announcing that it will be re-orienting its research away from DSM categories:

...While DSM has been described as a “Bible” for the field, it is, at best, a dictionary, creating a set of labels and defining each. The strength of each of the editions of DSM has been “reliability” – each edition has ensured that clinicians use the same terms in the same ways. The weakness is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure.

Instead, the Research Domain Criteria (RDoC) framework would become the preferred method for organizing biologically-based research on mental illnesses, with the ultimate goal of constructing a new classification scheme.

This caused quite a commotion, leading many to comment on NIMH's shocking repudiation of DSM-5. However, to long-time observers of RDoC's development, this was not a surprise. And the initial lack of clarity on the distinction between the RDoC Dimensional Approach for Research vs. DSM-5 for Diagnosis didn't help matters, nor did the uncertainty about whether NIMH would fund DSM-based research at all.¹

NIMH issued a press release on May 13 to clarify its position:

DSM-5 and RDoC: Shared Interests

Thomas R. Insel, M.D., director, NIMH
Jeffrey A. Lieberman, M.D., president-elect, APA

NIMH and APA have a shared interest in ensuring that patients and health providers have the best available tools and information today to identify and treat mental health issues, while we continue to invest in improving and advancing mental disorder diagnostics for the future.

Today, the APA's Diagnostic and Statistical Manual of Mental Disorders (DSM), along with the International Classification of Diseases (ICD) represents the best information currently available for clinical diagnosis of mental disorders  Patients, families, and insurers can be confident that effective treatments are available and that the DSM is the key resource for delivering the best available care. The NIMH has not changed its position on DSM-5. As NIMH’s Research Domain Criteria (RDoC) project website states, “The diagnostic categories represented in the DSM-IV and the International Classification of Diseases-10 (ICD-10, containing virtually identical disorder codes) remain the contemporary consensus standard for how mental disorders are diagnosed and treated.”

Yet, what may be realistically feasible today for practitioners is no longer sufficient for researchers. Looking forward, laying the groundwork for a future diagnostic system that more directly reflects modern brain science will require openness to rethinking traditional categories. It is increasingly evident that mental illness will be best understood as disorders of brain structure and function that implicate specific domains of cognition, emotion, and behavior. This is the focus of the NIMH’s Research Domain Criteria (RDoC) project. RDoC is an attempt to create a new kind of taxonomy for mental disorders by bringing the power of modern research approaches in genetics, neuroscience, and behavioral science to the problem of mental illness.

So what is RDoC, and how might it be applied to new research projects? From the DSM perspective of categorical disorders (e.g, schizophrenia, major depression, and obsessive compulsive disorder), RDoC embraces diagnostic messiness. Patients previously excluded from a study due to comorbidities, or because they don't meet full criteria? Misfits from the "Not Otherwise Specified" (NOS) category? Now they're in. Specifically, the instructions for RFA-MH-14-050 state:

Priority will be given to applications that have a well-justified plan to include patients from multiple diagnostic groups (including Not Otherwise Specified and forme fruste diagnoses) as appropriate for explicating the dimensions and constructs of interest in the study design. Studies that include patients from a single diagnostic group may also be considered if there is a particularly strong justification for examining constructs of interest within one diagnostic category.  A defensible approach might be to study all patients presenting themselves at a specialty clinic, e.g., mood disorders clinic, anxiety clinic, or psychotic disorders clinic, regardless of whether they meet criteria for a particular DSM diagnosis.

One potential pitfall of this approach is the money required to enroll huge numbers of patients. If commonalities in cognitive function or brain circuitry or especially genetic risk factors are to emerge from studying all patients with mood disorder-like symptoms, then sample sizes must be very large to overcome potential noise in the system(s).

The applicant would propose to study one or more of the five different domains, or constructs, that have been fleshed out at NIMH Workshops:

Negative Valence Systems
Positive Valence Systems
Cognitive Systems
Systems for Social Processes
Arousal/Regulatory Systems

The possible units of analysis run the gamut from genes to circuits to behavior, and the studies should use specific tasks (paradigms) and self-report measures, as shown in the Negative Valence Systems matrix below.

Draft Research Domain Criteria Matrix

Animal models of active threat ("fear") like the startle response are pretty well established and would allow a much more detailed analysis of mechanisms, from genes to behavior. In the realm of human research, one example of a proposed project for RFA-MH-14-050 is:

• Evaluation of the relationship between measures of exaggerated fear response, reports of overall distress and anxiety, and chronicity of internalizing disorders

This project could study common and unique aspects of the startle response in patients with phobias, panic disorder, OCD, generalized anxiety, and major depression ("internalizing disorders"), as described in this review article (Vaidyanathan et al.  2011).

Another recent review tackles the neurobiology of reward, which falls under the rubric of Positive Valence Systems. It's a 43 page tour de force with 756 references (Dichter et al., 2012):

This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.

The idea is to find common neurobiological substrates of altered reward circuitry that cut across DSM-esque categories (e.g., drug and alcohol use disorders, serious gambling problems, mania), where individuals seek out reward without regard to the consequences. At the other end of the spectrum is anhedonia, or the inability to feel pleasure from previously rewarding activities. Anhedonia is often (but not always) seen in major depression and schizophrenia, two disorders usually considered to have little overlap.

Will RDoC succeed in carving out a new nosology and generating a new guidebook? Will it lead to diagnostic tests that can identify specific cognitive, emotional, motivational, or social weaknesses that can be treated with targeted pharmaceuticals, deep brain stimulation, and/or improved psychotherapies?

This quote from Chapter 1 of a 2002 white paper collection indicates the DSM-5 revision committee (a joint APA / NIMH production) didn't exactly expect that all of its goals would be reached (PDF):

"Given the relatively short time frame for generating breakthrough research findings between now [1999] and the probable publication of DSM-V in 2010 [2013], it is anticipated that some of the research agendas suggested in these chapters might not bear fruit until the DSM-VI or even DSM-VII revision processes!"

So don't hold your breath, unless you want to experience severe anoxia.


Footnotes

¹ See the Appendix for a compendium of quotes.


References

Dichter, G., Damiano, C., & Allen, J. (2012). Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings Journal of Neurodevelopmental Disorders, 4 (1) DOI: 10.1186/1866-1955-4-19

Vaidyanathan, U., Nelson, L., & Patrick, C. (2011). Clarifying domains of internalizing psychopathology using neurophysiology Psychological Medicine, 42 (03), 447-459 DOI: 10.1017/S0033291711001528


Appendix

May 6
Matthew Herper (Forbes reporter covering science and medicine): “I spoke to NIMH. This is a broadening, not an exclusion.” ...

DSM-5 Task Force member Dr.  David J. Kupfer strikes back in the NYT, blaming NIMH and the sluggish rate of scientific progress: “The problem that we’ve had in dealing with the data that we’ve had over the five to 10 years since we began the revision process of D.S.M.-5 is a failure of our neuroscience and biology to give us the level of diagnostic criteria, a level of sensitivity and specificity that we would be able to introduce into the diagnostic manual.”


May 7
“Some people have the idea that we’re trying to ditch or diss the DSM and that’s not a fair assessment,” says Insel.

Dr. Bruce Cuthbert: “The sensationalist headlines out there are entirely misleading, and we will continue to support DSM-based research as we increase our portfolio of RDoC grants. RDoC is intended to inform future versions of the ICD and DSM; we have no intention of coming out with a competing system. The implication of this is that the fruits of RDoC are likely to be taken up into the ICD/DSM piecemeal rather than in one entire set, at such times as the evidence for various aspects becomes strong enough to warrant changes to the nosologies.”

Dr. Thomas Insel: “We cannot ‘ditch’ or ‘reject’ terms like schizophrenia or bipolar. We just need to view them as constructs, perhaps including many different disorders that require different treatments or obscuring disorders than cut across the current categories. A symptom-only system will not be sufficient for identifying brain disorders—whether the initial label is dementia or schizophrenia.”

Dr. Cuthbert: “As with most shifts in science, changes in research priorities require a transition. Because almost all clinical researchers today grew up with the DSM system both clinically and in research, it will take some time to get a “feel” for the relationships between DSM disorders and various kinds of RDoC phenomena (both in terms of the types of symptoms, and in overall severity), learn how to write grant applications with the new criteria, and evolve new review criteria. So, there will be a period of some time while these crosswalks are worked out.”


May 8
Dr. Cuthbert: “Using DSM diagnoses for research has become a de facto standard ever since the DSM-III came out in 1980. What we are trying to do is to study neural systems directly because they cut across lots of the dsm disorders. ... We are moving in a new direction. That doesn’t mean that next month we’ll stop accepting DSM diagnoses. It rather is a shift in emphasis.”