Neuroscience Research:
Challenges and
Opportunities
Thomas R. Insel, M.D.
Director, NIMH
9/29/10
Mental Disorders are Chronic and Disabling
WHO 2008
Mental Disorders are Chronic and Disabling
WHO 2008
Mental Disorders: Mortality
• Over 34,000 suicides per
year in the U.S. (CDC, 2007)
- 90% related to mental illness
• For context:
• 18,000 homicides
• 33,000 traffic fatalities
Life expectancy: 56 years
(Colton & Mandersheid, 2006)
The Five Most Costly Conditions
Not Counted:
$193B - lost earnings
$57.5 billion,
$24B – SSI/SSDI
ranking
mental
health
expenditures
the third
most costly
and equal to
that of
cancer
Costs of:
Incarceration
Homelessness
School/Home care
Total > $317B/yr
(Insel 2008)
Disruptive Innovations
In Mental Health
Mental disorders are brain disorders.
Mental disorders are developmental
disorders.
Human Neuroimaging:
Seeing the Connections
Structural
Connectivity
Functional
Connectivity
Temporal
Connectivity
EEG
fMRI
Multimodal
Integration
Molecular Imaging
New Molecular
Imaging
New
knowledge of
human brain
function in
health,
disorders &
across
lifespan
Depression is a Brain Disorder
Hopelessness, helplessness, suicidal
thoughts, anorexia, loss of libido, sleep
disturbance
Insel, Sci Am, 2010
OCD is a Brain Disorder
Recurrent unwanted thoughts
(obsesssions) and/or repetitive behaviors
(compulsions)
Insel, Sci Am, 2010
PTSD is a Brain Disorder
Flashbacks, bad dreams, insomnia,
frightening thoughts, avoidance, guilt,
depression, hyperarousal
Insel, Sci Am, 2010
Defining Depression Circuits
Response Pathways
PF
MCC
MF
CBT
Cognition
(attention-appraisal-action)
PF9/46 PM6 Par40 hc
MCC
mF9/10
pACC24
Self-awareness
oF11
insight
PCC
navst
amg
thal
mbvta
sACC25
Salience
Motivatio
n
a-ins hth bstem
PF
Interoception
Br Med Bul 65:193-207, 2003(drive-autonomic-circadian)
Arch Gen Psych 61:34-41-2004
P
Mood
state
MEDS
Med PCC
Cg25
s
BS
Moving the Bar for Antidepressants
18 pts with TRD
Ketamine 0.5mg/kg
vs Placebo
given IV single dose
1 week apart
Effect sizes: Predictors of antidepressant response
to ketamine at 230 min
Small
Large
• Neurobiological parameters may be valuable
predictors of treatment response, possibly
explaining more variation than common
subdiagnostic classifications
Abnormal Amygdala-Prefrontal Effective Connectivity to
Happy Faces Differentiates Bipolar from Major Depression
Jorge Renner Cardoso de Almeida, Amelia
Versace, Andrea Mechelli, Stefanie Hassel,
Karina Quevedo, David Jerome Kupfer, and
Mary Louise Phillips
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
STAGE 1
Enrolled N=400
Randomized
Treat with
Citalopram n=200
Responder
n=90
Treat with
Placebo n=200
Non-Responders
n=70
Responders
n=60
Non-Responders
n=100
Continue
Placebo n=60
Switched to
Citalopram n=50
STAGE 2
Continue
Citalopram n=90
Switch to
Buspirone SR n=70
Clinical assess.
Genetics/Epigen.
Cognition
Imaging
qEEG
Predictors of
response
Early
surrogates
Predictors of
adverse events
From Description to Mechanism: 2010
Molecule
GWAS
Sequencing
Transgenics
Epigenetics
Databases
Cell
System
Stem Cells
Transcript
profiles
Proteomics
Optical
imaging
Databases
Electrode
arrays
Zebrafish
Imaging
ChR-2
Databases
Individual
Social
Sensors
Web 2.0
Eye gaze
Knowledge
Cognitive
management
Tools
Epidemiology
Translating Neuroscience to Health
Strategic prevention
Cure Therapeutics
Discovery Technologies
Preventive
interventions
Molecular
diagnostics
Proteomics
Next-Gen Clin Trials
Early Interventions
POC Dx
Biodiagnostics
Treatment of core pathology
Neuroimaging
Clinical
genomics
Genes
Cells
Systems
Individual
Social
Diagnosis by symptoms
Treatment of episode
Dissemination
Access
Coordination
Translating Research to Practice
Paving the Way for Prevention, Recovery, and Cure
www.nimh.nih.gov