Thursday, October 02, 2014

The Implications of the National Institute of Mental Health Research Domain Criteria for Researchers and Clinicians

The Research Domain Criteria (RDoC) signaled a major and controversial shift in the National Institutes of Mental Health (NIMH) research model and funding policy. It was designed to carry out "Strategy 1.4" of the NIMH Strategic Plan: "Develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behaviour and neurobiological measures." The singular aim of RDoC was to implement precision/personalized medicine (where the individual patient receives the right treatment, at the right time, at the right intensity, for as long as needed) in psychiatric clinical practice, equivalent to other branches of medicine. To accomplish this goal, all future research would have to both identify a molecular, genetic, or biological target and suggest possible (psychopharmacological) interventions.
This is probably one of the worst moves in the ongoing effort of psychiatry to become a science that I have ever seen. At the very best, this model can identify biological markers indicating the presence of potential for disease. BUT it tells us nothing about etiology and is completely divorced from the entirely human and relational sources of most psychological distress.

The implications of the National Institute of Mental Health Research Domain Criteria for researchers and clinicians

S. D. Østergaard, M. Fava, A. J. Rothschild, K. M. Deligiannidis. (2014, Sep 9). The Implications of the National Institute of Mental Health Research Domain Criteria for Researchers and Clinicians. Acta Psychiatrica Scandinavica; DOI: 10.1111/acps.12331

The Research Domain Criteria (RDoC) project launched by the US National Institute of Mental Health (NIMH) in early 2009 [1] is a source of ongoing international discussion. For instance, the entire debate section of the February edition of World Psychiatry (the official journal of the World Psychiatric Association) was dedicated to a discussion of RDoC [2-7], emphasizing that the project is not only of interest to the research community in the USA, but to many other countries as well. But what is RDoC—and why is it causing such an intense debate among academic psychiatrists across the globe? The aim of this editorial was to answer these questions and to provide an overview of the background and likely consequences of RDoC, particularly for researchers and clinicians based outside the USA.

What is RDoC and why was it developed?

RDoC represents a major shift in the NIMH research strategy and funding policy. It was designed to carry out ‘Strategy 1.4’ of the NIMH Strategic Plan: ‘Develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behaviour and neurobiological measures’ [8]. The overarching aim of RDoC was to implement precision/personalized medicine (where the individual patient receives the right treatment, at the right time, at the right intensity, for as long as needed) in psychiatric clinical practice [9], equivalent to other branches of medicine [10-14].
The main driving force behind Strategy 1.4 of the NIMH Strategic Plan, and thus behind the conception of RDoC, was the lack of biological validity of mental disorders as currently defined by the two major diagnostic classifications [15], namely the Diagnostic and Statistical Manual of Mental Disorders (DSM) [16] and the International Classification of Disease (ICD) [17]. Despite decades of research, the pathophysiological mechanisms underlying the DSM/ICD mental disorders remain largely unknown [15]. This is probably, at least partly, a consequence of the significant heterogeneity contained within a diagnostic category [18-21]. Accordingly, no biological markers for illness or treatment stratification have been implemented in clinical practice due to insufficient sensitivity, specificity, and predictive validity [15]. Thus, with the ICD/DSM diagnoses being likely obstacles in the process toward precision medicine, the NIMH found it necessary to create a new platform for psychiatric research, which diverts from the traditional categorical DSM/ICD classifications of mental disorders (schizophrenia, bipolar disorder, major depressive disorder, anxiety, autism spectrum disorder, attention deficit hyperactivity disorder, substance use disorder, etc.).
RDoC urges scientists to study ‘fundamental biobehavioural dimensions that cut across current heterogeneous disorder categories’ [22], that is, to move away from the predominant use of DSM/ICD diagnoses as the sole basis for inclusion criteria in research studies. RDoC is initially intended to guide classification of patients for research studies and not as a clinical tool. It focuses on understanding dimensions of function (and dysfunction) from genes to circuits to clinical behaviour, rather than trying to understand the neurobiological underpinnings of a specific disorder. The belief is that this approach will more rapidly facilitate the elucidation of pathophysiology across psychiatric disorders and ultimately provide urgently needed insight to a more valid classification system and novel therapeutics, which can be utilized in the clinic.

How was RDoC defined?

An internal NIMH steering group advised by external experts met in 2009 to create the initial RDoC framework for conducting research on psychopathology. Based on the initial meetings, the group chose five major domains of functioning to represent central aspects of motivation, cognition, and social behaviour. Subsequent consensus workshops (which are ongoing), including both NIMH scientists and outside experts, developed the constituent elements for each of the five domains. The workshop participants deliberated over which constructs to include within each domain and how they were to be defined. The proceedings of these RDoC workshops are publically available at
Thus, at the micro level, RDoC is best viewed as a matrix defined by five overarching ‘domains’: Negative valence systems, Positive valence systems, Cognitive systems, Systems for social processes, and Arousal/modulatory systems. Under each domain, a number of specifying dimensional ‘constructs’ and ‘subconstructs’ are listed. These constructs/subconstructs can be studied at different levels as indicated by the eight ‘units of analysis’: genes, molecules, cells, circuits, physiology, behaviour, self-reports, and paradigms. The domains, constructs/subconstructs, and units of analysis form the quite extensive matrix shown in Fig. 1, and the initial aim of the RDoC project was essentially to populate this matrix with results from research studies. The hope is that these results will eventually inform the diagnostic processes and choice of treatment in psychiatric clinical practice, thereby introducing precision medicine to psychiatry.

Figure 1. The National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) matrix. This version is slightly modified (the name of some constructs/subconstructs has been abbreviated) from the original version at: The matrix consists of the five domains: Negative valence systems, Positive valence systems, Cognitive systems, Systems for social processes, and Arousal/modulatory systems. Under each domain, a number of specifying dimensional ‘constructs’ and ‘subconstructs’ are listed. These constructs/subconstructs can be studied at different levels as indicated by the eight ‘units of analysis’: genes, molecules, cells, circuits, physiology, behaviour, self-reports, and paradigms. *The working memory construct has a different format. See: for full information.

What does a ‘prototypical’ RDoC study look like?

Research studies based on the RDoC framework will investigate one or more dimensional constructs which cut across multiple disorders as traditionally defined. Thus, studies may include study participants from varying diagnostic groups as appropriate to the research question. For example, historically a study aimed at examining activation of a neural circuit in a particular anxiety disorder would conduct a neuroimaging study in subjects who met criteria for that particular anxiety disorder and compare findings to healthy control subjects. The findings may be specific to that particular anxiety disorder, or as we increasingly understand, more commonly are found across disorders. A study using RDoC principles may instead examine the neurocircuitry underpinning acute threat, or fear, in both healthy controls and subjects presenting with anxiety, regardless of specific anxiety diagnosis, comorbid psychiatric diagnoses or symptom severity. Physiological measures and psychometrics, for example, could then be employed to test hypotheses about activation of specific brain areas in the fear circuit.
An important aim of emerging treatment studies funded by NIMH under the RDoC project will be to demonstrate ‘target engagement’, that is, to determine whether a novel treatment engages a hypothesized target and if by engagement of that target, the behaviour/psychopathology under study is modulated. Thus, treatment studies will contribute to our understanding of the pathophysiology of the disorder as well as identify optimal dosing and duration for the intervention. Targets for pharmacological agents can include molecular and circuit-level mechanisms or cognitive systems for psychological interventions, among others [23].

How has RDoC been received by the research community?

RDoC now constitutes one of the main criteria by which applications for NIMH funding are evaluated [24] and applies to all levels of psychiatric research from preclinical/biological studies, clinical trials (pharmacotherapy, neuromodulation, and psychotherapy), to mental health service intervention/implementation projects [8]. This major change in funding policy has caused quite a stir in the scientific community. In a recent commentary, NIMH Director, Dr. Thomas Insel stated that ‘RDoC is already freeing investigators from the rigid boundaries of symptom-based categories’ [9]. Not all researchers agree that RDoC is a liberation, quite the contrary, as they argue that RDoC is overtly reductionistic [3] and detached from clinical reality [4]. Paradigm shifts will inevitably be subjected to criticism and the NIMH is aware of the fact that the current RDoC matrix may not necessarily reflect the natural neurobiological dissections. Therefore, they welcome criticism and suggestions for changes/additions/deletions [8]. Quite a few suggestions for such modifications have already been proposed by the research community [25, 26].

What are the likely consequences of RDoC for researchers outside the USA?

As in virtually all other branches of medicine, the USA assumes a leading position in psychiatric research. Therefore, in a recent commentary on RDoC, a highly relevant question was posed by a non-US based researcher: ‘Will major mental health funders in other countries follow NIMH down the RDoC road?’ [7]. It seems that this has already happened to some extent. For instance, the 2014–2015 ‘Personalising Health and Care’ call under the Horizon 2020 European Commission Framework Programme for Research and Innovation [27], which has a budget of 306 000 000 Euro, shares important features with the RDoC project. The following quote from the Horizon 2020 ‘Understanding common mechanisms of diseases and their relevance in co-morbidities’ subcall could easily have been a quote from the description of RDoC: ‘The development of new treatments is greatly facilitated by an improved understanding of the pathophysiology of diseases. There is therefore a need to address the current knowledge gaps in disease aetiology in order to support innovation in the development of evidence-based treatments. … Proposals should focus on the integration of pre-clinical and clinical studies for the identification of mechanisms common to several diseases’ [27].

Will RDoC change future clinical practice and diagnostic classifications?

Early findings from RDoC-informed research may initially be challenging to apply clinically as research conducted under RDoC is agnostic to the current disorder classification systems. The NIMH RDoC project seeks to spur advances in genomics, pathophysiology, and behavioural science so that eventually those advances will inform clinical diagnosis and treatment. Ultimately, if the findings from a range of RDoC studies consistently demonstrate that the variance in psychopathology and biology across current diagnoses, for instance major depressive disorder and anxiety disorders, is better accounted for by constructs under the ‘negative valence systems’ domain (acute threat, potential threat, sustained threat, loss, frustrative non-reward), the organizations behind the DSM and ICD may decide to incorporate these constructs/dimensions in their future classifications. This will have substantial consequences for clinical practice, but such development will take time.

Will RDoC affect the type of publications in Acta Psychiatrica Scandinavica?

In 2013, more than 10% of the manuscripts submitted to Acta Psychiatrica Scandinavica came from researchers affiliated with institutions in the USA (numbers provided by the editorial office). The studies conducted by these researchers, and thus, the resulting manuscripts are likely to change significantly in the near future as funded RDoC studies are published. Therefore, even if the RDoC-like funding strategy may not be adopted by countries outside the USA (although it appears that it will) the readers of Acta Psychiatrica Scandinavica, and other non-US based journals, will still benefit from having a basic knowledge of the rationale behind RDoC and the general framework of the matrix. Hopefully this report has provided such knowledge and will be a source of inspiration for further reading.


The NIMH RDoC project represents a major shift in research strategy and funding policy with the overall aim to implement precision medicine in clinical psychiatric practice. Despite being a US-based initiative, RDoC will have implications for the entire field. We therefore encourage all psychiatric researchers and clinicians to follow the progress of RDoC.

Declaration of interests

Søren D. Østergaard (last 3 years): No conflicts of interest.
Maurizio Fava (Lifetime): Research Support: Abbot Laboratories; Alkermes, Inc.; American Cyanamid; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Clintara, LLC; Covance; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; MedAvante; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates., Inc.; Pharmavite® LLC;PharmoRx Therapeutics; Photothera; Reckitt-Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Synthelabo; Wyeth-Ayerst Laboratories. Advisory/Consulting: Abbott Laboratories; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Bayer AG; Best Practice Project Management, Inc.; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells Inc; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon, Inc.; Cerecor; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dinippon Sumitomo Pharma Co. Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai Inc.; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; ePharmaSolutions; EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; i3 Innovus/Ingenis; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Neuralstem, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG;Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Otsuka Pharmaceuticals; Pamlab, LLC.; Pfizer Inc.; PharmaStar; Pharmavite® LLC.; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; Puretech Ventures; PsychoGenics; Psylin Neurosciences, Inc.;RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; Sanofi-Aventis US LLC.; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex Pharmaceuticals, Inc.; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Vanda Pharmaceuticals, Inc. Speaking/Publishing: Adamed, Co; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc.; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar; United BioSource,Corp.; Wyeth-Ayerst Laboratories. Equity Holdings: Compellis; PsyBrain, Inc. Royalty/patent, other income: Patent for Sequential Parallel Comparison Design (SPCD), which are licensed by MGH to RCT Logic, LLC; and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD). Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte.Ltd.
Anthony J. Rothschild (last 3 years): Dr. Rothschild receives grant or research support from Alkermes, AssureRx, Cyberonics, the National Institute of Mental Health, and St Jude Medical, and is a consultant to Allergan, Eli Lilly and Company, GlaxoSmithKline, Noven Pharmaceuticals, and Pfizer Inc. Dr. Rothschild has received royalties for the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT)®; Clinical Manual for the Diagnosis and Treatment of Psychotic Depression, American Psychiatric Press, 2009; The Evidence-Based Guide to Antipsychotic Medications, American Psychiatric Press, 2010; and The Evidence-Based Guide to Antidepressant Medications, American Psychiatric Press, 2012.
Kristina M. Deligiannidis (last 3 years): Research/grant support: National Institutes of Health (NIH); Worcester Foundation for Biomedical Research; Forest Research Institute; University of Massachusetts Medical School; Assumption College; Michigan Institute for Clinical and Health Research. Royalty/patent: National Institute of Health (NIH) Employee Invention (with royalties). Travel/award funding: American College of Neuropsychopharmacology (ACNP); Society of Biological Psychiatry; Research Career Development Institute (CDI); National Network of Depression Centers (NNDC), Elsevier; American Society of Clinical Psychopharmacology (ASCP). Honoraria: Elsevier; Wiley; Oxford University Press;


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