New Understandings of Mental Health

and Brain/Behavioral Disorders

National Press
Foundation
Bruce N. Cuthbert, Ph. D.
Director, RDoC Unit
National Institute of Mental Health
19 September 2016

Traditional Approaches to Mental Illness

Alienists: mental disorders as distinct from normality

Kraepelin, Bleuler: first systematic descriptions of disorder
Disease models in psychiatry:
(1) Symptoms/signs, course of illness

(2) Assume existence of complex, yet specific diseases on

the basis of symptoms/signs

Cf. Kraepelin, mental disorders as natural disease units

(natuerliche Krankheitseinheit) [Heckers, Schiz. Bull.,2008]

The current disease model is

no longer valid for research

Current systems: DSM (Diagnostic and Statistical

Manual) and ICD (International Classification of
Diseases)
Data from genetics, pathophysiology, & psychological
mechanisms do not align well with the categories
Syndrome: A condition characterized by a set of
associated symptoms (Oxford Engl. Dict.)
Excessive heterogeneity, co-morbidity
Problem: Diagnostic categories drive the entire
research system (research grants,
pathophysiology, journals, trials, regulatory)

Two major needs for reducing

the burden of mental disorders
(1) More access to the treatments that we have
(2) Better understanding of disorder mechanisms, leading to
improved treatment and prevention interventions
.

Changing perspectives on mental disorders

Marked advances in understanding:

Instead of continuing with symptom-based definitions

(1) Understanding of major brain circuits .

(2) And the behaviors that they implement (fear, reward,

memory)
Can we understand mental disorders as deviations from
normal functioning of brain systems?

The Overarching Goals of RDoC

Develop a framework for studying psychopathology based on
dimensions of observable behavior and neurobiological
measures. research.
Posit 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

Exactly what does RDoC involve?

Focused research initiative moving toward a new
classification system: study and validate trans-diagnostic,
dimensional constructs
Concept:
1) Deeper understanding of psychological & biological systems
related to mental illness
2) New biomarkers & biosignatures
3) More homogeneous groupings for
psychopathology/pathophysiology
4) new intervention development

Not a new idea but the first implementation by a funding

agency
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(1) The RDoC Concept: Five components

Environment

Domains

Units of Analysis

Neurodevelopment
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RDoC Matrix: Integrative Framework

(Workshops July 2010 June 2012)

[Symptoms]
Altered Stress Reactivity
Emotion regulation problems
Lack of pleasure in usual activities
Lack of energy for productive tasks
Language delays
Executive function problems
Social withdrawal
Poor relationships
Problems with arousal-modulating systems
Sleep problems
9

Dimensional Psychiatry: Shift from

(categorical) infectious disease model to

Healthy

Disease

Level of Functioning

Complex Trait Model (full distribution)

//

Level of Functioning

Mild, Moderate, Severe levels of disorder

//

Empirically-based cutpoints for (e.g.) mild,

moderate, severe levels of dysfunction

Dimensions: Continuity in autism risk genes

Robinson, & Daly, Nat. Gen., 2016

Dimensions, Heterogeneity
in Psychotic Spectrum

Only 30% of people with psychotic illness have schizophrenia (others: brief psychotic disorder, delusional
disorder, etc.)
people with this psychosis spectrum syndrome ... Display extreme heterogeneity, both within and between
people, in psychopathology, treatment response, and outcome.
van Os, BMJ, 2016

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Framework: Always Under Construction

[Symptoms]
Altered Stress Reactivity
Emotion regulation problems
Lack of pleasure in usual activities
Lack of energy for productive tasks
Language delays
Executive function problems
Social withdrawal
Poor relationships
Problems with arousal-modulating systems
Sleep problems
15

(2) RDoC as a practical rubric

DSM/ICD = de facto requirement for research grants and

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so, journal publications, clinical trials, regulatory approvals

DSM goal: a standard & set of criteria for research (as well
as clinical practice)
However, DSM is inadequate for current research
But: have to have *some* standards and guidelines for
evaluating research grants in psychopathology, if DSM/ICD
system is not used.

New Ways of Grouping Patients

Experimental designs require groups and/or dimensions

How are new groups/dimensions to be discovered?
Examples from:
(1) Anxiety Disorders
(2) Psychotic disorders
(None incorporate normal-to-abnormal dimension)

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Anxiety Disorders: Transdiagnostic

dimensions of response

Lang, McTeague, & Bradley, Psychophysiology, 2016

Contemporaneous Dimensional Approaches to Diagnosis

Psychiatry will need to move from using traditional descriptive diagnoses to clinical
entities (categories and/or dimensions) that relate more closely to the underlying
workings of the brain. Craddock & Owen, Br J Psych (2010)

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Example: BSNIP*, parsing the

schizophrenia-bipolar spectrum

* Bipolar-Schizophrenia Network on Intermediate Phenotypes

BSNIP Biotypes: (1) Cognitive

Control, (2) Sensorimotor Reactivity

Clementz, . & Tamminga, Am J Psychiatry, in press

BSNIP: Gray Matter Loss by Biotype:

Probands and Relatives

Clementz, . & Tamminga, Am J Psychiatry, in press

Toward Individualized Prevention: Early

(pre-clinical) signs of psychosis risk

Pennsylvania
Neurodevelopmental
Cohort (N = 4,642):
Gur et al., JAMA
Psychiatry, 2014

Potential consequences of the RDoC approach

(1) Clinical trials: target engagement, experimental medicine

RDoC: Enroll patients based on measurable impairment in a
specific mechanism (e.g., excessive fear, working memory
deficit, effort valuation)

Outcome measures based on change in these functions

(2) More emphasis on (quantifiable) functioning than (selfreported) symptoms

E.g., EMA and FDA approval for cognition as an indication in

depression (following the same for schizophrenia)

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Drug hunters challenges in developing better treatments

Int J Neuropsychopharmacol. 2010 Oct;13(9):1269-84. Epub 2010 Aug 18.

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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What might future diagnostic manuals look like?

RDoC goal: Inform future versions of ICD and DSM

Likely: incremental, not radical, change
(1) More specific dimensions/subgroups within DSM/ICD
categories

(2) Over time: broader syndromes?

E.g., internalizing (or, distress disorder?); externalizing (or,
behavioral regulation disorder?); psychotic spectrum

More specific and focused treatment plans based upon

detailed assessments

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Summary: Contemporary
Directions for Mental Disorders

Transition: broad syndromes to dimensional brain-behavior

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models that include neurodevelopment, environment

Transition: symptom management toward cure, pre-emption,
and prevention
Big data, common data elements, different sampling frames
The future: toward precision treatment and prevention for
CNS disorders, consistent with other areas of medicine