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

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

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

3. Causes of Disability by Illness CategoryUnited States and Canada15-44 years old WHO World Health Report 2002

4. Causes of Disability by Specific IllnessUnited States and Canada15-44 years old WHO World Health Report 2002

5. 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).

6. 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)

7. NIMH Budget(dollars in millions)

8. How do we set priorities? • Relevance – what do we need? • Traction – what can we do? • Innovation – what is new? Relevance + Traction + Innovation = IMPACT

9. Practice Clinical Trials Networks Practical trials Services research Handoff for dissemination Discovery to Recovery: Translation is the Key Bench Bedside Pathophysiology Diagnostic tests Biomarkers New treatments

10. 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

11. Schizophreniasusceptibility genes: Current candidates Whole genome linkage 1q,2p,5q,6p,6q,8p,10p,11q,13q,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

12. Mental disorders are brain disorders: Loss of gray matter in childhood schizophrenia

13. Development Behavior Emotion Cognition Perception Genes x Environment

14. 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.

15. 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

16. Maternal Behavior: Where Nurture Meets Nature

17. Individual Variation in Maternal Licking and Grooming Meaney, Ann Rev Neurosci. 2001

18. 80 70 60 50 40 30 20 10 0 Pre S10 S20 P20 P40 P60 P120 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

19. 30 30 25 20 20 15 10 10 5 0 0 40 40 60 80 100 120 140 160 180 200 DG CA1 CA3 Offspring of high licking-grooming mothers - increased glucocorticoid receptors in the hippocampus High *** (r= +0.76, p<.002) Low ** * Grains per 100 µM GR mRNA (grains/area) 2 Hippocampal Cell Field Licking and Grooming Meaney, Ann Rev Neurosci. 2001

20. 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

21. Practice Clinical Trials Networks Practical trials Services research Handoff for dissemination Discovery to Recovery: Translation is the Key Bench Bedside Pathophysiology Diagnostic tests Biomarkers New treatments

22. Clinical Trials in Psychopharmacology:From 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

23. NIMH Effectiveness Trials:“what 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 STAR*D: Adults with treatment resistant depression 4041 enrolled, 40 sites (20 primary care)

24. Mental Health Care in the Pre-Genomic Era???

25. 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

26. 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

27. www.nimh.nih.gov