Thomas R. Insel, M.D.

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NIMH Setting Priorities
Thomas R. Insel, M.D. Director National Institute
of Mental Health 2/15/05
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NIMH Mission

• Reduce the burden of mental illness and
  behavioral disorders through research on mind,
  brain and behavior

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Causes of Disability by Illness CategoryUnited
States and Canada15-44 years old
WHO World Health Report 2002
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Causes of Disability by Specific IllnessUnited
States and Canada15-44 years old
WHO World Health Report 2002
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What is greater source of mortality suicide or
homicide?

• Each year in the U.S., there are approx. 30,000
  suicides and 18,000 homicides.

• Approx. 90 of suicides involve mental disorder.

• Suicide is the third leading cause of death
  among adolescents.

• Suicide is 4X as common in men, and especially
  high in men 65 years old (10 of pop 20
  suicides).

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What is the economic cost of mental illness?
PCMH estimates cost at 150B (1997 data)
Indirect costs direct costs (Mental disorder
largest single group on SSI)
Both direct and indirect costs are public
sector (50 of all Rxs for atypical
antipsychotics paid for by Medicaid)
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NIMH Budget(dollars in millions)
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How do we set priorities?

• Relevance what do we need?

• Traction what can we do?

• Innovation what is new?

Relevance Traction Innovation IMPACT
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Discovery to Recovery Translation is the Key
Bench
Bedside
Pathophysiology Diagnostic tests Biomarkers New
treatments
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Cognition, emotion, behavior
Schizophrenia Autism Mood Disorders Anxiety
Disorders ADHD
temperament
Cells subtle molecular abnormalities
Genes multiple susceptibility alleles each of
small effect
Systems abnormal information processing
Behavior complex functional interactions and
emergent phenomena
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Schizophrenia susceptibility genes Current
candidates
Whole genome linkage 1q,2p,5q,6p,6q,8p,10p,11q,13
q,15q,22q Finer mapping SNP
association dysbindin (6p) (seven) neuregulin
(8p) (six) G72 (13q) (three) MRDS1 (6p)
(four)
Expression profiling RGS4 (1q) (four)
Chromosomal translocation DISC1 (1q)
(three) PRODH (22q) (two)
Functional candidates COMT (22q) (eight) GRM3
(7q) (four) GAD 1 (2q) (four) CNRNA7 (15q)
(two) PPP3CC (8p) (two) Akt1 (two)
Weinberger et al, 2004
Number of positive samples worldwide
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Mental disorders are brain disorders Loss of
gray matter in childhood schizophrenia
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Genes x Environment
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Science, 302 386-388, 2003
1057 consecutive births in Dunedin, New Zealand
followed for 26 years with extensive evaluation
every 2-3 years beginning in first year.
At age 26, 17 met criteria for major depressive
disorder. Neither life stress not serotonin
transporter genotype predicted depression.
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Genotype Interacts with Stress to Increase Risk
of Depression
Among those who had 4 episodes of life stress
33 of s genotype developed MDD vs. 17 of
those with l type genotype
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Maternal Behavior Where Nurture Meets Nature
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Individual Variation in Maternal Licking and
Grooming
Meaney, Ann Rev Neurosci. 2001
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Offspring of high licking-grooming mothers -
response to stress is reduced




Plasma Corticosterone (µg/dl)

High LG/NA
Low LG/NA
Meaney, Ann Rev Neurosci. 2001
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Offspring of high licking-grooming mothers -
increased glucocorticoid receptors in the
hippocampus
High
(r 0.76, p
Low


Grains per 100 µM
GR mRNA (grains/area)
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Licking and Grooming
Hippocampal Cell Field
Meaney, Ann Rev Neurosci. 2001
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How Does Maternal Care Alter Stress
Responsiveness?
Increased licking and grooming in first 6 days
decreases methylation of GR promoter, increasing
GR expression.
Increased GR expression in hippocampus reduces
stress responsiveness throughout lifespan.
Epigenetics
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Discovery to Recovery Translation is the Key
Bench
Bedside
Pathophysiology Diagnostic tests Biomarkers New
treatments
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Clinical Trials in PsychopharmacologyFrom
Efficacy to Effectiveness
Efficacy trials short duration, carefully
selected subjects often in academic setting,
outcome measured by rating scale Example drug
vs placebo licensing trial
Effectiveness trials long duration, broad
inclusion criteria often in community setting,
outcome measured by function Example NIMH
Practical trial contracts
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NIMH Effectiveness Trialswhat treatment for
which person
TADS Treatment of adolescents with
depression 432 enrolled, published 2004
STEP-BD Treatment of adults with bipolar
disorder 3065 enrolled, multiple treatment trials
CATIE Effectiveness of antipsychotic drugs 1450
enrolled, value of atypicals vs conventional
STARD Adults with treatment resistant
depression 4041 enrolled, 40 sites (20 primary
care)
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Mental Health Care in the Pre-Genomic Era???
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Mental Health Care in the Genomic
Era (Revolutionary Technologies and Evolutionary
Practices)
Automated data - integrated systems
Personalized Health Care Pre-sx
prevention Lifetime care Unique Rx
Prevention tools
Molecular dx
Risk Assessment Clinical Genomics Biomarkers
Translational Model Biodiagnosis Rx of core
illness
Revolutionary Technologies
Dx Imaging
Current Model Dx by observ Rx symptoms
Mental health record
Episodic Organized
Personalized
Evolutionary Practices
Adapted from Kovac, IBM 4/04
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NIMH and NIDA

• Dual diagnosis comorbidity is the rule (NCS
  Study 2005)
• Shared opportunities scientific, Blueprint,
  training
• Shared challenges stigma, translating
  findings to practice
• Public outreach Partners program

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