Transcript Presentation - American Society for Experimental NeuroTherapeutics

The NIMH Research Domain Criteria Initiative (RDoC):
A Framework for Psychopathology Research
February 20, 2014
• Jill Heemskerk, PhD
• Deputy Director, Division of Adult Translational Research
• National Institute of Mental Health, NIH
American Society for Experimental NeuroTherapeutics | 16th Annual
Meeting
Disclosure
• No Commercial Interest or Financial
Relationships to disclose
American Society for Experimental NeuroTherapeutics | 16th Annual
Meeting
Learning Objectives
• Participants will be able to describe RDoC, a
new framework for understanding mental
disorders.
American Society for Experimental NeuroTherapeutics | 16th Annual
Meeting
Major Points
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Why is NIMH doing RDoC?
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What is RDoC?
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How will RDoC apply to the clinic?
How can NIMH accelerate the discovery of new
treatments for mental illness?
-Insel and Scolnick, 2006
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Problems with our diagnoses
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Current diagnostic schemes (DSM and ICD) are
based on clinical symptoms.
Clinical symptoms alone (e.g., fever, headache)
cannot identify underlying mechanisms to guide
treatment development and selection.
BUT: DSM/ICD is the default standard for research
grants, journal publications, clinical trials, and
regulatory approval.
Developing better treatments
“On average, a marketed psychiatric drug is efficacious in approximately
half of the patients who take it. One reason for this low response rate is
the artificial grouping of heterogeneous syndromes with different
pathophysiological mechanisms into one disorder.”
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NIMH Strategic Plan: Goal 1.4
• “Develop, for research purposes, new ways of classifying
mental disorders based on dimensions of observable
behavior and neurobiological measures.”
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Identify fundamental components that may span multiple disorders
(e.g., executive function, affect regulation)
Determine the full range of variation, from normal to abnormal
Integrate genetic, neurobiological, behavioral, environmental, and
experiential components
Develop reliable and valid measures of these fundamental
components for use in basic and clinical studies
BSNIP: Schizophrenia-bipolar spectrum
Sweeney et al., SOBP Symposium, 2012
BSNIP: Schizophrenia-bipolar spectrum
Sweeney et al., SOBP Symposium, 2012
Research Domain Criteria (RDoC)
Goal: To understand psychiatric dysfunction in terms of biological and
behavioral underpinnings
NIMH RDoC Workshops focused on Five Domains:
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Negative Valence
Positive Valence
Cognitive Systems
Systems for Social Processes
Arousal/Modulatory Systems
Research Domain Criteria Matrix
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Search: RDoC Matrix
What does RDoC mean for clinical trials now?
Heterogeneous DSM categories confound studies of mechanism:
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No 1:1 relationship between a DSM diagnosis and a particular mechanism
(e.g., not all schizophrenia patients have cognitive deficits)
1 feature can appear in multiple DSM disorders (e.g., cognitive deficits are
seen in some schizophrenia, bipolar and depressed patients)
RDoC considerations for early phase clinical trials:
1. Focus on a novel mechanism relevant to a clinical problem regardless of
DSM diagnosis (e.g., anhedonia, working memory)
2. Enroll patients based on deficits in the mechanism, not DSM diagnosis
3. Trial outcomes should reflect the changes in the target mechanism
4. The matrix is evolving: new mechanisms can be proposed for study
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FAST-MAS: An RDoC-inspired Clinical Trial
Kappa opioid receptor antagonist for Anhedonia, a PoC trial
PI: Andrew Krystal, MD
RDoC Study Design Features:
• Inclusion: enroll patients based on anhedonia measure
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DSM diagnoses across the mood and anxiety spectrum
Outcomes:
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Capture multiple aspects of anhedonia
(anticipation, experience, motivation)
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Use objective measures of brain function (fMRI, behavioral task performance)
Regulatory path: include traditional clinical depression and anxiety
measures to explore correlations
RDoC: Summary/Conclusions
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A “translational” approach: view disorders in terms of dysregulation in
basic mechanisms
A framework to study mechanisms that cut across traditional disorder
boundaries
Will inform, not compete with, future versions of DSM and ICD
Toward personalized medicine in psychiatry, consistent with other areas
of medicine
http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml
(search term: RDoC)