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

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

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.

The Burden of Mental Illness is Enormous

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.

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 Percent of Total Source: World Health Organization – World Health Report, 2001

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 Percent of Total Source: World Health Organization – World Health Report, 2001

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 Percent of Total Source: WHO – Burden of Disease Statistics, 2001

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

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

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

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 Antisocial Personality Disorder 84 29.6 Personality Disorders

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

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

Neurogenesis in the Adult Human II 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. Source: Eriksson et al., 1999

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

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. 1999 Mar;2(3):266-70. Source: van Praag et al., 1999

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

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

Anxiety PTSD

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. 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 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 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.

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

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

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’ 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

Depression: a disease of the mind, brain and body Source: Gold et al. 2002 Am J Psychiatry Nov 159(11):1826

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

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

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 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

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