1. Science and Service: Opening Pathways to Better Mental Health
Complexities of Co-occurring Conditions Meeting
Richard K. Nakamura, Ph.D.
Deputy Director
National Institute of Mental Health

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

3. How do we do this? NIMH budget is over $1.3 billion
7th Largest Institute of the NIH
Most goes into 2000 research grants around the country based on expert review that funds less than 1/3 of applications.

4. The Burden of Mental Illness is Enormous

5. the World Health Organization Disability Adjusted Life Year
World Bank and
the World Health Organization
Global Burden of Disease
To measure both premature death and disability, a single measure was developed:
Disability Adjusted Life Year
DALY
One DALY is one lost year of healthy life.

6. Disease Burden by Illness - DALY World, 2000 All Ages
Lower respiratory infections
Perinatal conditions
HIV/AIDS
Unipolar depressive disorders
Diarrhoeal diseases
Ischaemic heart disease
Cerebrovascular disease
Road traffic accidents
Malaria
Tuberculosis
Percent of Total
Source: World Health Organization – World Health Report, 2001

7. Disease Burden by Illness - DALY World, 2000 15-44 year olds
HIV/AIDS
Unipolar depressive disorders
Road traffic accidents
Tuberculosis
Alcohol use disorders
Self inflicted injuries
Iron-deficiency anemia
Schizophrenia
Bipolar affective disorder
Violence
Percent of Total
Source: World Health Organization – World Health Report, 2001

8. Disease Burden by Illness - DALY United States, Canada and Western Europe, 2000 15 - 44 year olds
Unipolar depressive disorders
Alcohol use disorders
Road traffic accidents
Drug use disorders
Self inflicted injuries
Bipolar disorder
Migraine
Schizophrenia
Hearing Loss, adult onset
HIV/AIDS
Percent of Total
Source: WHO – Burden of Disease Statistics, 2001

9. Disease Burden by Illness - DALY
United States, Canada and Western Europe, 2000
All Ages
Source: World Health Organization – Burden of Disease Statistics, 2001
Percent of
total DALYs
Cardiovascular diseases
Mental Illness*
Malignant neoplasms (cancer)
Injuries (disabling)
Alcohol and Drug Use Disorders
All respiratory diseases
Digestive diseases
Musculoskeletal diseases
17.0
14.8
14.4
7.3
7.2
5.4
4.2
*Includes self-inflicted injuries

10. United States, Canada and Western Europe, 2000
Causes of Disability
United States, Canada and Western Europe, 2000
All Ages
Percent of
Source: World Health Organization – Burden of Disease Statistics, 2001
total YLDs
Mental Illness*
Alcohol and Drug Use Disorders
Alzheimer’s Disease and Dementias
Musculoskeletal Diseases
Respiratory Diseases
Cardiovascular Diseases
Sense organ Diseases
Injuries (Disabling)
24.1
12.5
7.7
7.5
6.4
5.4
4.9
4.7
*Includes self-inflicted injuries

11. Suicide in America 11th Leading cause of death (1.3% of all deaths)
30,662 in 2001 (undercounting likely)
8th leading cause of death in men
3rd leading cause of death in year olds
Suicide outnumbered homicide by 3 to 2
There are now twice as many deaths due to suicide than due to HIV/AIDS
90% had a mental illness
Source: National Center for Health Statistics. Data are from 2001, the latest available as of 12/03

12. Comorbidity of Mental Disorders with
Any Substance Abuse
Rank Order of Mental Disorders by Odds Ratio
% with Substance Odds
Axis / Disorders Abuse or Dependence Ratio
Bipolar I
Bipolar II
Schizophrenia
Panic Disorder
Obsessive Compulsive Disorder
Dysthymia
Unipolar Depression
Phobia
Antisocial Personality Disorder
Personality Disorders

13. The Brain Changes
We now understand that our genes specify a general plan with many options. Our brain changes its physical structure through behavior and interactions with the environment

14. A Revolution Our new understanding of the brain integrates:
nature and nurture
mind and brain
genes and the environment

15. Neurogenesis in the Adult HumanII
Fig. I: Newly generated cells can be detected in the adult human brain in patients previously treated with BrdU.
(a) The hippocampal region of the adult human brain immunoperoxidase-stained for the neuronal marker NeuN.
(b) The hippocampal dentate gyrus granule cell layer (GCL) visualized with immunoperoxidase staining for NeuN.
(c) Differential interference contrast photomicrograph showing BrdU-labeled nuclei (arrows) in the dentate granule cell layer (GCL).
(d) Differential interference contrast photomicrograph showing a BrdU-labeled nucleus (arrow) in the human dentate GCL. BrdU-positive nuclei have a rounded appearance and resemble the chromatin structure of mature granule cells and are found within the granule cell layer.
(e) Differential interference contrast photomicrograph showing BrdU-positive cells (arrows) adjacent to the ependymal lining in the subventricular zone of the human caudate nucleus. Cells with elongated nuclei resembling migrating cells are in the rat subventricular zone (SVZ).
(f) Differential interference contrast photomicrograph showing BrdU-positive cells (arrows) with round to elongated nuclei in the subventricular zone of the human caudate nucleus.
All scale bars represent 50 microns.
Fig. II: Quantitation of newly generated cells in the adult human hippocampus.
The density of BrdU immunoperoxidase-stained cells in the subgranular zone (SGC) (a) and the granule cell layer (GCL) (b) and the hilus (c) was determined in 5 to 7 sections per patient (mean number of BrdU-positive cells per mm3 sample volume s.e.m.) The corresponding patient's age at the time of death and interval as BrdU infusion are given for each BrdU-treated patient (n = 5).
Methods:
Postmortem tissue from the hippocampus and the subventricular zone of caudate nucleus was obtained from cancer patients (n = 5) who received one intravenous infusion (250 mg; 2.5 mg/ml, 100 ml) of bromodeoxyuridine (BrdU) for diagnostic purposes. One patient diagnosed with a similar type and location of cancer, but without BrdU treatment, was included as a control.
Source:
Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med Nov;4(11):
Source: Eriksson et al., 1999

16. Stress Impairs Neurogenesis
Dentate Gyrus, Marmoset Monkey
400
300
BrdU Labeled Cells/mm3 *
p<.05
200
100
Gould 1998
Control
Stress
Dentate Gyrus, Adult Rat
4000
3000 *
p<.05
BrdU Labeled Cells
2000
1000
Gould 2000
Dominant
Subordinate

17. Physical Activity & Neurogenesis
Running significantly increased cell proliferation/neurogenesis in the dentate gyrus of mice.
(a) Total number of BrdU-positive cells per dentate gyrus one day after the last BrdU injection, to estimate ongoing proliferation. Significantly more cells were labeled in the runners as compared to the other groups. * p < 0.02.
Enrichment and running significantly increased the survival of newborn cells.
(b) Total number of BrdU-positive cells per dentate gyrus four weeks after the last BrdU injection, to estimate survival of labeled cells. Enrichment and running significantly increased the survival of newborn cells. *p < 0.02.
van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci Mar;2(3):
Source: van Praag et al., 1999

18. Source: Santarelli L et al. 2003 Science Aug 8 301:805-809.

19. Figure 1 Chronic time-lapse imaging of dendritic spines in the barrel cortex in vivo.
a, Diagram of the barrel cortex and its topographic structure (boxed region, right). b, Lowmagnification
dorsal view of the apical dendrites of three layer-5 pyramidal neurons. Scale
bar, 100mm. c, Higher-magnification view of one apical tuft (yellow box in b). Scale bar,
50mm. d, Neuron reconstructed from images of fixed sections obtained after collection of
the last vital image (same neuron as in c). e, Dorsal view of the reconstructed apical tuft,
depicting the positions of each dendritic branch relative to the barrel map. f, Highresolution
time-lapse images of a dendritic region (yellow box in c). Examples of transient,
semi-stable and stable spines are labeled with blue, red and yellow arrowheads,
respectively. Scale bar, 5mm.
Source: Trachtenberg et al Nature, December 2002

20. Anxiety
PTSD

21. Evidence in Humans: PTSD Patients Fail to Show mPFC Activation When Exposed to Traumatic Reminders
Shin et al., Biological Psychiatry, 2001
Source: Shin et al Biological Psychiatry Dec 50(12):
PTSD in Vietnam Veterans. The arrow in the upper scan shows an activated area of anterior cingulate frontal cortex present in those without PTSD.

22. Non-PTSD
Source: The Nature of Traumatic Memories: A 4-T fMRI Functional Connectivity Analysis
Ruth A. Lanius, M.D., Ph.D., Peter C. Williamson, M.D., Maria Densmore, B.Sc., Kristine Boksman, M.A., R. W. Neufeld, Ph.D., Joseph S. Gati, M.Sc., and Ravi S. Menon, Ph.D Am J Psychiatry 161:36-44, January 2004 Comparison of rape victims with and without subsequent PTSD
Figure 1. Brain Regions With Activation Showing Significantly Greater Connectivity/Covariation With Activation in the Right Anterior Cingulate in Traumatized Subjects Without PTSD Than in Traumatized Subjects With PTSD During Recall of a Traumatic Eventa aAreas of connectivity/covariation determined by the statistical parametric map of the t statistic (SPM[t]) showing the psychophysiological interaction between activity in the right anterior cingulate cortex (Talairach coordinates x=2, y=20, z=36) and activity in other brain regions. The grid diagrams show all areas with significantly greater covariation in the subjects without PTSD. The cross-sectional brain images show sites of significant covariation in areas of interest.

23. PTSD
Source: The Nature of Traumatic Memories: A 4-T fMRI Functional Connectivity Analysis
Ruth A. Lanius, M.D., Ph.D., Peter C. Williamson, M.D., Maria Densmore, B.Sc., Kristine Boksman, M.A., R. W. Neufeld, Ph.D., Joseph S. Gati, M.Sc., and Ravi S. Menon, Ph.D Am J Psychiatry 161:36-44, January 2004
Figure 2. Brain Regions With Activation Showing Significantly Greater Connectivity/Covariation With Activation in the Right Anterior Cingulate in Traumatized Subjects With PTSD Than in Traumatized Subjects Without PTSD During Recall of a Traumatic Eventa aAreas of connectivity/covariation determined by the statistical parametric map of the t statistic (SPM[t]) showing the psychophysiological interaction between activity in the right anterior cingulate cortex (Talairach coordinates x=2, y=20, z=36) and activity in other brain regions. The grid diagrams show all areas with significantly greater covariation in the subjects with PTSD. The cross-sectional brain images show sites of significant covariation in areas of interest.

24. Source: Caspi A et al. 2003 Science 302:386-388.

25. Nemeroff et al. 2003. PNAS November 100(24):14293-14296

26. Nemeroff et al. 2003. PNAS November 100(24):14293-14296

27. Modulation of Cortical-Limbic Pathways in Major Depression
Treatment-Specific Effects of Cognitive Behavior Therapy
Kimberly Goldapple, MSc; Zindel Segal, PhD; Carol Garson,MA; Mark Lau, PhD; Peter Bieling, PhD; Sidney Kennedy, MD; Helen Mayberg, MD
Arch Gen Psychiatry. 2004;61:34-41.

28. Summary: Modulation of Common ‘System’ Treatment-Specific Effects
attention-cognition
PF9
P40
pCg -
CBT
hippocampus
mF9/10
Emotion-cognition integration
mood
state
aCg24 bg
thal
oF11
Slide from Helen Mayberg, submitted
SRI only
CBT
SRI
inverse
CBT only
Cg25
a-ins -
drug am
hth bs
vegetative-circadian

29. Depression: a disease of the mind, brain and body
Source: Gold et al Am J Psychiatry Nov 159(11):1826

30. Source: Jorge et al 2003 Am J Psych October 160(10):1823-1829

31. Source: Jorge et al 2003 Am J Psych October 160(10):1823-1829

32. Anxiety
PTSD

33. BEST BUYS IN MENTAL HEALTH
Gavin Andrews, Cathy Issakidis, Kristy Sanderson, Justine Corry, Helen Lapsley
Policy & Epidemiology Group, School of Psychiatry, UNSW
& WHO Collaborating Centre, St Vincent’s Hospital Sydney

34. ‘Best Buys’ study: disorders covered
Affective: depression, dysthymia, bipolar disorder
Anxiety: panic/agoraphobia, social phobia, generalized anxiety disorder, post-traumatic stress disorder
Alcohol: abuse and dependence
Schizophrenia
We have done these calculations for individual disorders as listed, but I’ll be presenting in disorder groups for simplicity.

35. Results: Current Treatment
Coverage Effective Burden Efficiency
coverage averted
% % % $/YLD
Depressive Disorders
Anxiety Disorders
Alcohol Disorders
Schizophrenia 100 ~
Total

36. Results: Optimal Treatment
Coverage Effective Burden Efficiency
coverage averted
% % % $/YLD
Depressive Disorders
Anxiety Disorders
Alcohol Disorders
Schizophrenia
Total