thomas r. insel, m.d. director, nimh rethinking mental illness: how research will change practice...
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Thomas R. Insel, M.D.Thomas R. Insel, M.D.
Director, NIMHDirector, NIMH
Rethinking Mental Illness: Rethinking Mental Illness: How Research Will Change How Research Will Change
PracticePractice
October 22, 2008
500
400
300
200
100
50 55 60 65 70 75 80 85 90 95 00
Death
s p
er
10
0,0
00
Year
~ 514,000 ActualDeaths in 2000
~ 1,329,000 ProjectedDeaths in 2000
63% decrease in mortality
~ 1 million early deaths averted per year
$2.6 trillion in economic return
New, effective treatments and prevention strategies
Impact of Research on Heart Disease
For the first time in recorded history, annual cancer deaths in the United States have fallen
10 million survivors
Mill
ions
of
People
1971 1986 1990 2003
9
6
3
Number of Survivors
Impact of Research on Cancer
Impact of Research on Mental Illness
Diagnosis is by observation, detection is late, prediction is poor.
Etiology is unknown; prevention is empirical and not well-developed for most disorders.
Treatment is trial and error – no cures, no vaccines.
Bottom line: Prevalence has not decreased for any illness. Mortality has not decreased for any illness.
Source: WHO World Health Report 2002
0 5 10 15 20 25 30 35
Mental Illness*
Injuries, including self-inflicted
Alcohol and drug use
Malignant neoplasms (cancer)
Cardiovascular disease
Respiratory disease
Musculoskeletal disease
Sense organ disease
Digestive disease
Burden of Disease (DALYs) U.S., Canada, and Western Europe 15-44 years old
Source: WHO World Health Report 2002
Burden of Disease by Specific Illness – DALYsUnited States, Canada, and Western Europe
15-44 years old
0 2 4 6 8 10 12 14 16 18 20 22
Unipolar depression
Alcohol use
Road traffic accidents
Drug use
Self-inflicted injuries
Bipolar disorder
Migraine
Schizophrenia
Hearing loss
COPD
Mental Illnesses:Why the high morbidity?
Prevalent (6% U.S. - serious)
Disabling (largest population on SSI, SSDI)
Chronic disorders of young people
• Over 30,000 suicides per year (in the U.S.)
- 90% related to mental illness
Mental Disorders: Mortality
• For context:
• 18,000 homicides
• 20,000 AIDS deaths
• only 3 forms of cancer > 30,000
Public Health Impact:Early Mortality in Individuals with
Major Mental Illness (MMI)
0
5
10
15
20
25
30
35
Average Arizona Missouri Oklahoma RhodeIsland
Texas Utah
Ye
ars
of
Po
ten
tia
l Lif
e L
os
t
Adapted from Colton and Manderscheid, 2006, Prev Chronic Dis
• Data from outpatient and inpatient clientsdiagnosed with MMI
• Average age at time of death : 56 years
• Increased likelihood of dying from suicide
• Decreased likelihoodof dying from cancer
Disruptive InnovationsDisruptive InnovationsIn Mental HealthIn Mental Health
Mental disorders are brain disorders.
Mental disorders are developmental disorders.
Current treatments may be necessary but not sufficient for recovery.
Mental disorders result from complex genetic risk plus experiential factors.
Affect in Subgenual Cingulate (BA25)
Mayberg et al. Am J Psych 156:675-82 1999
increasedCBF/Met’b
decreasedCBF/Met’b
Depressed Affect
R
Cg25
Prefrontal 9
Cg25
Cg25
Depression Recovery
Cg25
Prefrontal 9
Non-Responders
FluoxetineResponders
Is Cg25 change necessary for antidepressant efficacy?
F9
Cg25
F9
hc
Cg25
hc
hchc
Cg25
pCg31F9
p
pCg31
Mayberg, 2006
oF11pACC24
mF9/10
PCCMCC
PF9/46 Par40PM6
sACC25
hth bstema-ins
amg mb-vta
hc
na-vst thal
SalienceMotivation
MoodstateSelf-awareness
insight
Cognition(attention-appraisal-action)
Interoception(drive-autonomic-circadian)
Defining Depression CircuitsResponse Pathways
Br Med Bul 65:193-207, 2003Arch Gen Psych 61:34-41-2004
CBT
PF
MF
MCC
MedsPF
P
Cg25
PCC
BS
MEDS
Disruptive InnovationsDisruptive InnovationsIn Mental HealthIn Mental Health
Mental disorders are brain disorders.
Mental disorders are developmental disorders.
Current treatments may be necessary but not sufficient for recovery.
Mental disorders result from complex genetic risk plus experiential factors.
Source: J Giedd, NIMH
Developmental Regression in the Brain
Schizophrenia as a Developmental Disorder
10 15 20 25
Age
# ofCortical
Synapses
Normal Development
Based on McGlashan and Hoffman (2000)
A Developmental Brain Model for Schizophrenia
Psychosis Threshold
Possible Paths to
Schizophrenia
Intervention
Genetic riskUnusual thought contentSuspicion/paranoiaSocial impairmentHistory of substance abuse
68-80% prediction
Arch Gen Psych, 2008
Schizophrenia: A Developmental Brain Disorder
Progressive Brain Structural Changes Mapped as Psychosis Develops in “At Risk” Individuals
Sun et al, Schiz Res., 2008
Schizophrenia TrajectoryStage 1: Presymptomatic, Risk factors,
Cognitive deficit with challenge [< Age 15]
Stage 2: Prodrome, cognitive deficits emerging, minor disability
Stage 3: Psychosis, acute disability,
family costs [Age 18 – 24]
Stage 4: Chronic illness, medical
complications, social costs [> Age 24]
1988
20082020
[Age 15 – 18]
Disruptive InnovationsDisruptive InnovationsIn Mental HealthIn Mental Health
Mental disorders are brain disorders.
Mental disorders are developmental disorders.
Current treatments may be necessary but not sufficient for recovery.
Mental disorders result from complex genetic risk plus experiential factors.
The Genomics Revolution
Human Genome Project (2003)Mapped 3 billion bases of DNA in human genome
…CTAGGCTTAAGCGGACCTGCTCTAGGTCAGTC….
Human HapMap Project (2005)Mapped all the common variations in the human genome
…CTAGGCTTAAGCGTACCTGCTCTAGCTCAGTC….3 million common Single Nucleotide Polymorphism (SNP)
Structural Variations in the Genome (2007)
…CTAGGCTTAGGCTTAGGCTTAGGCTTAAGCG
GACCTGCTCTAGGTCAGTC….
200520062007 first quarter2007 second quarter2007 third quarter2007 fourth quarterFirst quarter 2008 Second quarter 2008
Manolio, Brooks, Collins, J Clin Invest 2008; 118:1590-625.
Autism Genes: What do we know from association studies?
• CNTNAP2
• Neuroligins/Neurexins
• Shank3
• Wnt2
• GABA-B3• SLC25A12 (mit asp/glut carrier)
• MET (7q31)
Phenotype?
Autism as a Synaptic Disorder
AJHG 2008
Genomes Vary in Structure as well as Sequence
From Scherer et al, Nature 2007
Pathways to Pathophysiology
Meyer-Lindenberg & Weinberger, Nature Rev Neurosci, 2007
Disruptive InnovationsDisruptive InnovationsIn Mental HealthIn Mental Health
Mental disorders are brain disorders.
Mental disorders are developmental disorders.
Current treatments may be necessary but not sufficient for recovery.
Mental disorders result from complex genetic risk plus experiential factors.
Current Treatments: How Good?
CATIE (chronic schiz)
STEP-BD (Bipolar)
STAR*D (MDD)
Real world setting
Recovery of function
Practical questions
10,000 patients, 200 sites, 3 diseases, practical trials
• Schizophrenia: 74% discontinuation of anti-psychotics, limited access to psychosocial Rxs
• Depression: 31% remitted at 14 weeks, 67% at 1 year, limited access to CBT
• Bipolar: 21% stable for 8 weeks in first 6 months, high rates of medical co-morbidity
• Childhood disorders: dx prevalence increase 10-fold for autism, 40-fold for bipolar, no selective meds and few proven behavioral approaches
Current Treatments: How Good?
Practical Trials – What Did We Learn?
• We can optimize care in real world settings
• With optimized care, outcomes are not optimal
• Current treatments help too few people get better and very few get well
NIMH MissionTo transform the understanding and treatment of mental illnesses
through basic and clinical research, paving the way for
prevention, recovery, and cure.
NIMH Strategic Plan•Strategic Objective #1: Promote Discovery in the Brain and Behavioral Sciences to Fuel Research on the Causes of Mental Disorders
•Strategic Objective #2: Chart Mental Illness Trajectories to Determine When, Where and How to Intervene
•Strategic Objective #3: Develop New and Better Interventions for Mental Disorders that Incorporate the Diverse Needs and Circumstances of People with Mental Illness
•Strategic Objective #4: Strengthen the Public Health Impact of NIMH-Supported Research
NIMH Strategic Plan
•Strategic Objective #1: Promote Discovery in the Brain and Behavioral Sciences to Fuel Research on the Causes of Mental Disorders
Genes to circuits to behavior cycleGenomics and epigenomicsDevelopmental neuroscience
Strategic Objective #2: Chart Mental Illness Trajectories to Determine When, Where and How to Intervene
NIMH Strategic Plan
Predictive biosignatures
Longitudinal designs
Individual risk
NIMH Strategic PlanStrategic Objective #3: Develop New and Better Interventions for Mental Disorders that Incorporate the Diverse Needs and Circumstances of People with Mental Illness
Rational therapeutics
Preemptive and personalized interventions
Moderator trials
NIMH Strategic PlanStrategic Objective #4: Strengthen the Public Health Impact of NIMH-Supported Research
Participatory research
Impact on practice
Health disparities
NIMH Strategic Plan•Strategic Objective #1: Promote Discovery in the Brain and Behavioral Sciences to Fuel Research on the Causes of Mental Disorders
•Strategic Objective #2: Chart Mental Illness Trajectories to Determine When, Where and How to Intervene
•Strategic Objective #3: Develop New and Better Interventions for Mental Disorders that Incorporate the Diverse Needs and Circumstances of People with Mental Illness
•Strategic Objective #4: Strengthen the Public Health Impact of NIMH-Supported Research
Yes, but this year the answers are completely different.
But Professor Einstein, these are the same questions you used on last year’s exam?
www.nimh.nih.govwww.nimh.nih.gov
Paving the Way for Prevention, Recovery, and Cure
Then (1998)
Mechanism: Chemical imbalance
Treatment: First generation
Diagnosis: Unitary
Now (2008)
Diagnosis: Categorical but co-morbid
Mechanism: Brain circuit dysfunction
Treatment: Second generation
Imagine (2018)
Diagnosis: Dimensional
Mechanism: Genes to behavior
Treatment: Personal & pre-emptive
RE
SEA
RC
H
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