# Presentation: 540016

## Science and Service: 

**Deputy Director**
**National Institute of Mental Health**

**Science and Service: **
**Opening Pathways to **
**Better Mental Health****                          **
**Complexities of Co-occurring Conditions Meeting**

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

**NIMH Mission**

## How do we do this?

**7****th**** 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.**

**How do we do this?**

## The Burden of Mental Illness is Enormous

**The Burden of Mental Illness is Enormous**

## World Bank and 

**To measure both premature death and disability, a single measure was developed: **
_**D**_**isability **_**A**_**djusted **_**L**_**ife **_**Y**_**ear**
**  ****DALY  **
**One DALY is one lost year of healthy life.**

**World Bank and **
**the World Health Organization**

## 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

**0****	****1****	****2****	****3****	****4****	**** 5****	****6****	****7**

***Source: World Health Organization – World Health Report, 2001***

**Percent of Total**

## 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

**0****	****2****	****4****	****6****	**** 8****	****10****	****12**

***Source: World Health Organization – World Health Report, 2001***

**Percent of Total**

## Disease Burden by Illness - DALY United States, Canada and Western Europe, 200015 - 44 year olds

**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

**0     2    4     6     8    10   12   14     16 ****	****	****18**

***Source: WHO – Burden of Disease Statistics, 2001***

**Percent of Total**

## Disease Burden by Illness - DALY

**Disease Burden by Illness - DALY**
**United States, Canada and Western Europe, 2000**
***All Ages***

- Percent of

- total DALYs

****Includes self-inflicted injuries***

*Source****: World Health Organization – Burden of Disease Statistics, 2001***

## Causes of Disability

**Causes of Disability**
**United States, Canada and Western Europe, 2000**
***All Ages***

- Percent of

- total YLDs

****Includes self-inflicted injuries***

*Source****: World Health Organization – Burden of Disease Statistics, 2001***

## Suicide in America

**11****th**** Leading cause of death (1.3% of all deaths)**
**30,662 in 2001 (undercounting likely)**
**8****th**** leading cause of death in men**
**3****rd**** leading cause of death in 15-24 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**
**                                           **

**Notes:**
Source:  National Center for Health Statistics.  Data are from 2001, the latest available as of 12/03

## Comorbidity of Mental Disorders with 

**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****	****	****	****	****61****	****	****	****7.9**
**Bipolar II****	****	****	****	****48****	****	****	****4.7**
**Schizophrenia****	****	****	****47****	****	****	****4.6**
**Panic Disorder****	****	****	****36****	****	****	****2.9**
**Obsessive Compulsive Disorder ****	****33****	****	****	****2.5**
**Dysthymia****	****	****	****	****31****	****	****	****2.4**
**Unipolar Depression****	****	****	****27****	****	****	****1.9**
**Phobia****	****	****	****	****23****	****	****	****1.6**

## 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**

**The Brain Changes**

## A Revolution

**nature and nurture**
**mind and brain**
**genes and the environment**

**A Revolution**

## Neurogenesis in the Adult Human

**I**

**II**

- Source: Eriksson et al., 1999

**Notes:**
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. 1998 Nov;4(11):1313-7.

## Stress Impairs Neurogenesis

**Gould 2000**

**400**

**300**

**200**

**100**

**0**

**BrdU Labeled Cells/mm****3**

**Control**

**Stress**

**Dentate Gyrus, Marmoset Monkey**

**4000**

**3000**

**2000**

**1000**

**0**

**BrdU Labeled Cells**

**Dominant**

**Subordinate**

**p<.05**

- *

- *

**Gould 1998**

**Dentate Gyrus, Adult Rat**

**p<.05**

## Physical Activity & Neurogenesis

- Source: van Praag et al., 1999

**Notes:**
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. 1999 Mar;2(3):266-70.

## Science 301: 805-809, 2003

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

## Source: Trachtenberg et al  Nature, December 2002

**Notes:**
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.

## Anxiety

**Anxiety**
**PTSD**

## Evidence in Humans: PTSD Patients Fail to Show mPFC Activation When Exposed to Traumatic Reminders

**Evidence in Humans: PTSD Patients Fail to Show mPFC Activation When Exposed to Traumatic Reminders**

**Notes:**
Source:  Shin et al.  2001 Biological Psychiatry Dec 50(12):932-942
PTSD in Vietnam Veterans.  The arrow in the upper scan shows an activated area of anterior cingulate frontal cortex present in those without PTSD.

## Non-PTSD

**Notes:**
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.

## PTSD 

**Notes:**
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.

## Science, 302: 386-388, 2003

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

## Slide 25

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

## Slide 26

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

## 	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.** **

## Summary: Modulation of Common ‘System’

- <date/time>

- PF9

- thal

- bg

- Cg25

- P40

- hippocampus

- hth

- bs

- a-ins

- am

**Summary: Modulation of Common ‘System’**
**Treatment-Specific Effects **

***drug***

- -

- -

- pCg

***CBT***

- attention-cognition

- vegetative-circadian

- mood
- state

- mF9/10

- oF11

**aCg24**

- Emotion-cognition integration

**Notes:**
Slide from Helen Mayberg, submitted

## Slide 29

**Notes:**
Depression:  a disease of the mind, brain and body

Source:  Gold et al.  2002 Am J Psychiatry Nov 159(11):1826

## Slide 30

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

## Slide 31

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

## Anxiety

**Anxiety**
**PTSD**

## 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

## ‘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**

**Notes:**
We have done these calculations for individual disorders as listed, but I’ll be presenting in disorder groups for simplicity.

## Results: Current Treatment

- 		Coverage	Effective	Burden	Efficiency
- 			coverage	averted
- 		%	%	%	$/YLD
- Depressive Disorders	60	34	15	20 000
- Anxiety Disorders	35	20	13	15 000
- Alcohol Disorders	11	6	2	98 000
- Schizophrenia	100	~	13	196 000
- Total	40	23	13	30 000

## Results: Optimal Treatment

- 		Coverage	Effective	Burden	Efficiency
- 			coverage	averted
- 		%	%	%	$/YLD
- Depressive Disorders	60	60	23	11 000
- Anxiety Disorders	35	35	20	9 000
- Alcohol Disorders	11	11	5	53 000
- Schizophrenia	100	100	22	107 000
- Total	40	40	20	18 000

## www.nimh.nih.gov

**www.nimh.nih.gov**