1. 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 | 16 th Annual Meeting

2. Disclosure No Commercial Interest or Financial Relationships to disclose American Society for Experimental NeuroTherapeutics | 16 th Annual Meeting

3. Learning Objectives Participants will be able to describe RDoC, a new framework for understanding mental disorders. American Society for Experimental NeuroTherapeutics | 16 th Annual Meeting

4. Major Points Why is NIMH doing RDoC? What is RDoC? How will RDoC apply to the clinic? 4

5. 5 How can NIMH accelerate the discovery of new treatments for mental illness? -Insel and Scolnick, 2006

6. Problems with our diagnoses 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. Current diagnostic schemes (DSM and ICD) are based on clinical symptoms. 6

7. Developing better treatments 7 “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.”

8. 8 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.” 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

9. BSNIP: Schizophrenia-bipolar spectrum Sweeney et al., SOBP Symposium, 2012

10. BSNIP: Schizophrenia-bipolar spectrum Sweeney et al., SOBP Symposium, 2012

11. Research Domain Criteria (RDoC) 11 Goal:To understand psychiatric dysfunction in terms of biological and behavioral underpinnings NIMH RDoC Workshops focused on Five Domains: Negative Valence Positive Valence Cognitive Systems Systems for Social Processes Arousal/Modulatory Systems

12. 12 Research Domain Criteria Matrix Search: RDoC Matrix

13. What does RDoC mean for clinical trials now? 13 Heterogeneous DSM categories confound studies of mechanism: 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

14. FAST-MAS: An RDoC-inspired Clinical Trial 14 Kappa opioid receptor antagonist for Anhedonia, a PoC trial PI: Andrew Krystal, MD RDoC Study Design Features: Inclusion: enroll patients based on anhedonia measure DSM diagnoses across the mood and anxiety spectrum Outcomes: Capture multiple aspects of anhedonia (anticipation, experience, motivation) Use objective measures of brain function (fMRI, behavioral task performance) Regulatory path: include traditional clinical depression and anxiety measures to explore correlations

15. 15 RDoC: Summary/Conclusions 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)