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Thomas R. Insel, M.D. Director, NIMH 9/29/10 Neuroscience Research: Challenges and Opportunities

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Mental Disorders are Chronic and Disabling WHO 2008

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Mental Disorders are Chronic and Disabling WHO 2008

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Over 34,000 suicides per year in the U.S. (CDC, 2007) - 90% related to mental illness Mental Disorders: Mortality For context: 18,000 homicides 33,000 traffic fatalities Life expectancy: 56 years (Colton & Mandersheid, 2006)

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The Five Most Costly Conditions $57.5 billion, ranking mental health expenditures the third most costly and equal to that of cancer Not Counted: $193B - lost earnings $24B SSI/SSDI Costs of: Incarceration Homelessness School/Home care Total > $317B/yr (Insel 2008)

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Disruptive Innovations In Mental Health Mental disorders are brain disorders. Mental disorders are developmental disorders.

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Human Neuroimaging: Seeing the Connections Functional Connectivity Molecular Imaging Structural Connectivity Multimodal Integration EEGfMRI New Molecular Imaging New knowledge of human brain function in health, disorders & across lifespan Temporal Connectivity

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Depression is a Brain Disorder Insel, Sci Am, 2010 Hopelessness, helplessness, suicidal thoughts, anorexia, loss of libido, sleep disturbance

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OCD is a Brain Disorder Insel, Sci Am, 2010 Recurrent unwanted thoughts (obsesssions) and/or repetitive behaviors (compulsions)

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PTSD is a Brain Disorder Insel, Sci Am, 2010 Flashbacks, bad dreams, insomnia, frightening thoughts, avoidance, guilt, depression, hyperarousal

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oF11 pACC24 mF9/10 PCC MCC PF9/46 Par40 PM6 sACC25 hth bstem a-ins amg mb- vta hc na- vst thal Salience Motivatio n Mood state Self-awareness insight Cognition (attention-appraisal-action) Interoception (drive-autonomic-circadian) Defining Depression Circuits Response Pathways Br Med Bul 65:193-207, 2003 Arch Gen Psych 61:34-41-2004 CBT PF MF MCC Med s PF P Cg25 PCC BS MEDS

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Moving the Bar for Antidepressants 18 pts with TRD Ketamine 0.5mg/kg vs Placebo given IV single dose 1 week apart

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Effect sizes: Predictors of antidepressant response to ketamine at 230 min Neurobiological parameters may be valuable predictors of treatment response, possibly explaining more variation than common subdiagnostic classifications Small Large

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Jorge Renner Cardoso de Almeida, Amelia Versace, Andrea Mechelli, Stefanie Hassel, Karina Quevedo, David Jerome Kupfer, and Mary Louise Phillips Abnormal Amygdala-Prefrontal Effective Connectivity to Happy Faces Differentiates Bipolar from Major Depression

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Biosignatures Initiative: EMBARC Establishing Moderators/Mediators for a Biosignature of Antidepressant Response in Clinical Care (EMBARC) P.I.s: Madhukar Trivedi and Myrna Weissman Sites: Columbia, MGH, U Mich, UTSW Enrolled N=400 Treat with Citalopram n=200 Treat with Placebo n=200 Responder n=90 Non-Responders n=70 Responders n=60 Non-Responders n=100 Continue Citalopram n=90 Switch to Buspirone SR n=70 Continue Placebo n=60 Switched to Citalopram n=50 STAGE 2 STAGE 1 Randomized Clinical assess. Genetics/Epigen. Cognition Imaging qEEG Predictors of response Early surrogates Predictors of adverse events

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From Description to Mechanism: 2010 Molecule Cell System Individual Social GWAS Sequencing Transgenics Epigenetics Databases Stem Cells Transcript profiles Proteomics Optical imaging Databases Electrode arrays Zebrafish Imaging ChR-2 Databases Sensors Eye gaze Cognitive Tools Epidemiology Web 2.0 Knowledge management

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Biodiagnostics Treatment of core pathology Strategic prevention Cure Therapeutics Diagnosis by symptoms Treatment of episode Pathophysiology Personalized care Discovery Technologies Clinical genomics Neuroimaging Proteomics Molecular diagnostics Preventive interventions Translating Neuroscience to Health Translating Research to Practice Dissemination Access Coordination Genes Cells Systems Individual Social Next-Gen Clin Trials Early Interventions POC Dx

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www.nimh.nih.gov Paving the Way for Prevention, Recovery, and Cure