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

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

3. Causes of Disability by Illness Category United States and Canada 15-44 years old WHO World Health Report 2002

4. Causes of Disability by Specific Illness United States and Canada 15-44 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. Discovery to Recovery: Translation is the Key BenchBedside Pathophysiology Diagnostic tests Biomarkers New treatments Practice Clinical Trials Networks Practical trials Services research Handoff for dissemination

10. Genes: multiple susceptibility alleles each of small effect Cells: subtle molecular abnormalities Systems: abnormal information processing Behavior: complex functional interactions and emergent phenomena Schizophrenia Autism Mood Disorders Anxiety Disorders ADHD temperament Cognition, emotion, behavior

11. Schizophrenia susceptibility 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)* Functional candidates COMT (22q) (eight)* GRM3 (7q) (four)* GAD 1 ( 2q ) (four)* CNRNA7 (15q) (two)* PPP3CC (8p) (two)* Akt1 (two) Chromosomal translocation DISC1 (1q) (three)* PRODH (22q) (two) Expression profiling RGS4 (1q) (four)* * Number of positive samples worldwide Weinberger et al, 2004

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

13. Genes x Environment Development Behavior Emotion Cognition Perception

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. Among those who had 4+ episodes of life stress; 33% of “s” genotype developed MDD vs. 17% of those with “l” type genotype Genotype Interacts with Stress to Increase Risk of Depression

16. Maternal Behavior: Where Nurture Meets Nature

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

18. PreS10S20P20P40P60P120 0 10 20 30 40 50 60 70 80 High LG/NA Low LG/NA     Plasma Corticosterone (µg/dl) Meaney, Ann Rev Neurosci. 2001 Offspring of high licking-grooming mothers - response to stress is reduced

19. GR mRNA (grains/area) 200180160140120100806040 0 5 10 15 20 25 30 Licking and Grooming (r= +0.76, p<.002) DGCA1CA3 0 10 20 30 High Low Hippocampal Cell Field    Grains per 100 µM 2 Meaney, Ann Rev Neurosci. 2001 Offspring of high licking-grooming mothers - increased glucocorticoid receptors in the hippocampus

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

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” STEP-BD: Treatment of adults with bipolar disorder 3065 enrolled, multiple treatment trials TADS: Treatment of adolescents with depression 432 enrolled, published 2004 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. Evolutionary Practices Revolutionary Technologies Automated data - integrated systems Episodic Organized Personalized Current Model Dx by observ Rx symptoms Translational Model Biodiagnosis Rx of core illness Personalized Health Care Pre-sx prevention Lifetime care Unique Rx Dx Imaging Risk Assessment Clinical Genomics Biomarkers Molecular dx Prevention tools Mental Health Care in the Genomic Era (Revolutionary Technologies and Evolutionary Practices) Adapted from Kovac, IBM 4/04 Mental health record

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