anxiety and related disorders: neurobiology and...
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Anxiety and Related Disorders: Neurobiology and Treatment
Kerry Ressler, MD,PhD
James and Patricia Poitras Chair in Psychiatry Chief, Division of Depression & Anxiety Disorders
McLean Hospital Professor of Psychiatry, Harvard Medical School
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Disclosures
Dr. Ressler is a founding member of Extinction Pharmaceuticals/ Therapade Technologies, which exist to develop d-Cycloserine for use to augment the effectiveness of psychotherapy. He has received no equity or income from this relationship within the last 3 years. Patents: D-cycloserine and psychotherapy, targeting PACAP for extinction, targeting tachykinin 2 for prevention of fear, targeting angiotensin to improve extinction of fear. Funding: NIMH, HHMI, NARSAD, Burroughs Wellcome Foundation
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GENES
ENVIRONMENT TRAUMA
Fear-Related
Disorders PTSD
Genes + Environment Increase Risk of Fear Disorders and Posttraumatic Stress
Dev
elop
men
t
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Fear is evolutionarily useful LeDoux, 1996
- Single or repeated exposure to extremely traumatic situations - Characteristic symptoms of PTSD
- Increased anxiety (and hypervigilance) - Declarative memory alterations - Problems in sleep and concentration - Flashbacks - Inability to inhibit fear
but… Dysregulated Fear leads to Phobia, Panic, and PTSD
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Neural Circuits Regulating Fear Processing
Hippocampus Amygdala
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The Human Amygdala and Fear
Etkin & Wager, 2007
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PANIC ATTACK: "All of a sudden I felt dizzy, my legs gave out on me, and I couldn't catch a breath. It felt like someone was choking me. I could feel my heart was beating too fast and
I was terrified I was dying. I knew I had to get away before I lost it."
Increased heart rate Chest discomfort Chills, hotflushes Sweating Nausea / abdominal distress Lightheadedness / faint Shortness of breath Choking sensation Expressions of fear Fear of dying / losing control
PANIC ATTACK
Panic Disorder Simple Phobia Social Phobia (Agoraphobia) Posttraumatic Stress Disorder Acute Stress Disorder
PANIC ATTACK = ‘Fear Attack’ in Fear-related Disorders
Lateral hypothalamus heart rate, blood pressure Dorsal vagal N. bradycardia, ulcers
Central Gray Area freezing, social interaction
Retic. Pontis Caudalis increased startle response Basal forebrain arousal, vigilance, attention Parabrachial N. panting, respiratory distress
Paraventricular N. corticosteroid release
LA
Basolateral
learning expression
CeA
Fear / Panic Symptoms:
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Monoamine Dysfunction: Principal Evidence for Noradrenergic and Serotonergic
Dysfunction in Anxiety / MDD
Norepinephrine (NE) dysregulation • Evidence suggests possibility of
overactivation of NE release or hypersensitivity of receptor systems
Serotonergic (5HT) dysregulation • Overall evidence for decreased
activity of serotonin system
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Aston-Jones G, et al. Prog Brain Res. 1991;88:501
Physiology of NE and 5HT Firing
• Crucial role in organizing the behavioral state – Arousal / Vigilance / Stress response – Modulation of emotional memory systems – Burst firing with switch from calm wakefulness vigilance /
attention
b a NE
5HT
• Most active with quiet, internally directed activity • Inhibited by orientation
Fornal CA et al. Brain Res. 1996;716:123.
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Koob. Biol Psychiatry. 1999;46:1167.
Regulation Of Amygdala By NE Feed-Forward CRF-NE-CRF Stress System
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TH Levels Decrease With Antidepressants or ECT
Nestler EJ, et al. Proc Natl Assoc Sci USA. 1990;87:7522.
- + - + - + - + Treatment
TH
TH
NOR ECS TCP FLU
BUP HAL DZ MS
TH=Tyrosine Hydroxylase
www.mghcme.org Blier P, Bouchard C. Br J Pharmacol. 1994;113:485.
Hypothalamus
Hippocampus
Frontal Cortex
*
*
*
Control Chronic paroxetine
Enhanced 5-HT Release Following Chronic Antidepressant Treatment
*p<.05
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Stress and Antidepressant Effects on Hippocampal Neurogenesis and Atrophy
Control Stress Antidepressant
Duman RS. Mol Psychiatry. 2002;7:S29.
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The Amygdala In Depression & Anxiety
• NE and 5HT modulation of cortical-hippocampal-amygdala pathways likely modulates: – attention and vigilance – response to aversive experience
• perceived stress • perceived fearful stimuli
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* P <.005. ** P <.01. Ferry et al. Biol Psychiatry. 1999;46:1140.
NE Release In Amygdala Stimulated By Aversive Events
NE Level (% Of Baseline)
225
200
175
150
125
100
75 0 30 60 90 120 Time (min)
*
**
No Foot Shock Low Intensity (0.3 mA) High Intensity (1.2 mA)
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Regulation Of Amygdala By NE & 5HT Summary
• NE enhances learning of fearful and other amygdala-dependent events
• NE blockade may ↓ or block fear learning • 5-HT in some paradigms inhibits fear
learning • This inhibition appears to be due to 5-HT
activation of inhibitory interneurons
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Amygdala
Locus Coeruleus
NE CRF
Dorsal PFC
Ventral PFC
Raphe Nucleus
5-HT
Euthymia
Hippocamp
External sensory Internal memory
Stress fear
Aversion tolerance
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Amygdala
Locus Coeruleus
NE CRF
Dorsal PFC
Ventral PFC
Raphe Nucleus
5-HT
Hippocamp
Anxiety/MDD
External sensory Internal memory
Stress fear
Aversion tolerance
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Amygdala
Locus Coeruleus
NE CRF
Dorsal PFC
Ventral PFC
Raphe Nucleus
5-HT
Treatment of Anxiety / MDD
SSRIs
SNRIs / NRIs
ECT Psychotherapy?
Hippocamp
Benzodiazepines
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Grady Trauma Project: Civilian inner-city trauma Understanding the Genomic Structure of PTSD
Our Ongoing GWAS: 1M SNPS (Illumina Omni-1M)
+ CNVs
N=8000 all-traumatized ~30% PTSD, ~60% no PTSD
~40% male, ~60% female
Psychiatric Genomic Consortium-PTSD subgroup (in progress):
>10,000 cases >50,000 trauma controls
(lead by Koenen, Nievergelt, Liberzon, Ressler)
To Date: >5500 Salivary DNA samples >750 whole blood, serum, plasma, buffy coats >500 Startle / human physiology ~500 whole genome methylation ~500 Gene expression array
Schizophrenia PGC2 10/2012
25K cases 62 loci
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Modeling Fear Disorders Pre-existing Sensitivity (gene + environment)
Learning of Fear (Traumatic event)
Consolidation of Fear Hours – days following event
Expression of Fear Memories, Nightmares, Flashbacks
Avoidance, Sympathetic Response, Startle
Extinction Diminished response to cues Over time
Generalization Recruitment of Non-associated cues
Sensitization Increased Fear With repeated exposure
Discrimination Fear is limited to specific trauma cue
PTSD
+ -
recovery
gene gene
gene gene
gene gene
gene gene
gene
gene gene
gene gene
gene gene
gene
gene gene
gene
gene
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1) Identify Genes Associated with Developmental Risk: e.g., FKBP5
Modeling Fear Disorders Pre-existing Sensitivity (gene + environment)
Learning of Fear (Traumatic event)
Consolidation of Fear Hours – days following event
Expression of Fear Memories, Nightmares, Flashbacks
Avoidance, Sympathetic Response, Startle
Extinction Diminished response to cues Over time
Generalization Recruitment of Non-associated cues
Sensitization Increased Fear With repeated exposure
Discrimination Fear is limited to specific trauma cue
PTSD
+ -
recovery
2) Identify New Risk Pathways: Convergent Genomics e.g., PACAP 3) Enhance Extinction
e.g., target plasticity
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Am J Psychiatry 1983
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FK506 binding protein = FKBP5
AAAAA
FKBP5
Ultrashort negative feedback on GR sensitivity
GR GR
FKBP5
HSP90 cortisol
GR GR HSP90
FKBP4
P23
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Both Adult Trauma and Child Abuse strongly predict Adult PTSD symptoms
0
5
10
15
20
25
no trauma 1 trauma 2-3 trauma 4 or more number of adult trauma types
PTSD
Sym
ptom
Sco
re (P
SS)
0
5
10
15
20
25
no childhood abuse 1 type of childhood abuse
2 types of childhood abuse
PSS
scor
e
17.02 – 24.84 20.93 + 1.95 + 54
2 Types of Child Abuse
12.94 – 16.36 14.65 + 0.87 $ 189
1 Type of Child Abuse
7.17 – 8.90 8.03 + 0.44 * 566 No Child Abuse
95% confidence intervals
PTSD Symptom Scale (PSS) Mean + sem
N Level of Child Abuse Trauma
15.00 – 18.47 16.74 + 0.88+ 215 > 4 Types
10.16 – 12.98 11.57 + 0.72+ 265 2-3 Types
5.83 - 8.76 7.30 + 0.74$,+ 183 1 Type
2.60 – 4.56 3.58 + 0.50*,+ 159 None
95% confidence intervals
PTSD Symptom Scale (PSS) Mean + sem
N Level of Non-Child Abuse
Trauma#
30% have experienced some form of child abuse
p<.000001
p<.00001
Binder et al., JAMA, March, 2008
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Variants of a stress response gene (FKBP5) + Child Trauma: Effects on PTSD and Amygdala Activation
0
5
10
15
20
25
30
35
40
Incidence of child abuse
PTSD
Sym
ptom
s
White…Hariri, 2012 Genes, Brain and Behavior
Binder et al., 2008 JAMA
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Hippocampal Volume Reduction in PTSD
• NORMAL PTSD
J Douglas Bremner, MD, Emory University
Bremner et al., Am. J. Psychiatry 1995; 152:973-981. Bremner et al., Biol. Psychiatry 1997; 41:23-32.
Gurvits et al., Biol Psychiatry 1996;40:192-199. Stein et al., Psychol Med 1997;27:951-959. DeBellis 1999-no
change in children with PTSD
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Statistical parametric map of brain activation during the processing of threat incongruent versus
threat congruent faces in TC/TT > CC
Hippocampal activation and structural differences in FKBP5 risk allele carriers
Fani et al., 2013, JAMA Psychiatry
FKBP5 Genotype and Structural Integrity of the Posterior Cingulum
Fani et al., in press, Neuropsychopharmacology
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1) Identify Genes Associated with Developmental Risk: e.g., FKBP5
Modeling Fear Disorders Pre-existing Sensitivity (gene + environment)
Learning of Fear (Traumatic event)
Consolidation of Fear Hours – days following event
Expression of Fear Memories, Nightmares, Flashbacks
Avoidance, Sympathetic Response, Startle
Extinction Diminished response to cues Over time
Generalization Recruitment of Non-associated cues
Sensitization Increased Fear With repeated exposure
Discrimination Fear is limited to specific trauma cue
PTSD
+ -
recovery
2) Identify New Risk Pathways: Convergent Genomics e.g., PACAP
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PACAP is a central stress regulator
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Examining PACAP peptide levels in Humans
Ressler et al., Nature, 2011
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ADCYAP1R1 risk allele is associated with increased amygdala activation (and decreased amygdala-hippocampal
connectivity) when viewing fearful faces (N=49)
Jennifer Stevens
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Potential Role for PAC1 / PACAP in stress + estrogen response
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1) Identify Genes Associated with Developmental Risk: e.g., FKBP5
Modeling Fear Disorders Pre-existing Sensitivity (gene + environment)
Learning of Fear (Traumatic event)
Consolidation of Fear Hours – days following event
Expression of Fear Memories, Nightmares, Flashbacks
Avoidance, Sympathetic Response, Startle
Extinction Diminished response to cues Over time
Generalization Recruitment of Non-associated cues
Sensitization Increased Fear With repeated exposure
Discrimination Fear is limited to specific trauma cue
PTSD
+ -
recovery
2) Identify New Risk Pathways: Convergent Genomics e.g., PACAP 3) Enhance Extinction
e.g., target plasticity
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NMDA blockade prevents extinction, while an NMDA agonist (D-cycloserine – DCS)
enhances Extinction
Pre-extinction test Post-extinction test
Walker, Ressler, et al., J Neurosci, 2002
Given systemically or Intra-amygdala
30 lights
160
140
120
100
80
60
40
20
0
saline
*
30 lights DCS
star
tle a
mpl
itude
0
10
20
30
40
50
60
70
Incr
easi
ng F
EAR
60 lights vehicle
60 lights AP5
Falls, et al. J Neurosci, 1992
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-70 -60 -50 -40 -30 -20 -10
0
1 2 3 4 9 14 19
Virtual Floor
Placebo D-cycloserine
Ressler, et al (2004) Arch Gen Psychiatry
Red
uctio
n in
Fea
r
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NMDA Receptor Enhancer IMPROVES Psychotherapy (extinction) across Anxiety Disorders
Social Anxiety Obsessive – Compulsive PTSD / Panic
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grin1
bdnf
cnr1
cck
Modulating Fear through Circuitry Modulation
Chhatwal et al., Nature Neurosci, 2008 Choi et al., PNAS, 2010
Gafford et al., PNAS, 2012 Andero et al., Science Transl Med, 2013
Jasnow et al., J Neurosci, 2013 Parsons et al., Nature Neurosci, 2013
Thy-1
Tac2/Nk3
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LA
BL
BM
CeL
CeM
ITCd
ITCv
IITC
Rationally Designed Therapies Based on Amygdala Biology
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BM
ITC
CeL CeM
CS
US
FEAR
LA GRP ?
BL
Thy1 Extinction ? Fear On
Marker Function
Parv Inhibitory SST Inhibitory FoxP2 ITC-Extinction MOR ITC-Extinction CRF Fear On? PKCd Fear Off Tac2 Fear On
Select Neuronal Populations in Amygdala
VP Excitatory
Rationally Designed Therapies Based on Amygdala Biology
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Optogenetically activating the Thy-1 neurons inhibits CeM output
Jasnow et al., 2013, J Neurosci
CaMKIIα Thy-1-YFP Merged
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Training Test Blocks of 2
* * * * * *
*
B
Optogenetically activating the Thy-1 neurons in vivo inhibits fear consolidation
B
* * *
*
B Extinction Ext. Retention
Jasnow, Ehrlich, Rainnie et al., 2013, J Neurosci
and enhances extinction
Take home: If we can target the ‘Fear Off’ neurons
specifically, it would create a novel and powerful new way to treat fear-related disorders.
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1) Identify Genes Associated with Developmental Risk: e.g., FKBP5
Modeling Fear Disorders Pre-existing Sensitivity (gene + environment)
Learning of Fear (Traumatic event)
Consolidation of Fear Hours – days following event
Expression of Fear Memories, Nightmares, Flashbacks
Avoidance, Sympathetic Response, Startle
Extinction Diminished response to cues Over time
Generalization Recruitment of Non-associated cues
Sensitization Increased Fear With repeated exposure
Discrimination Fear is limited to specific trauma cue
PTSD
+ -
recovery
2) Identify New Risk Pathways: Convergent Genomics e.g., PACAP 3) Enhance Extinction
e.g., target plasticity
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MANY OTHER STUDENTS & VOLUNTEERS
Donald Rainnie, PhD Barbara Rothbaum, PhD
Michael Davis, PhD NIMH (MH069884,
MH071537) NSF, Burrough’s Wellcome
Fund, NARSAD, ADAA, HHMI
The Grady Trauma Project Bekh Bradley, PhD Tanja Jovanovic, PhD Allen Graham Angelo Brown Rickey Gillespie, MD, PhD Joe Cubells, MD, PhD Ebony Glover, PhD Negar Fani, PhD Dorthie Cross Mokdad, PhD Alex Rothbaum Abigail Powers, PhD
Yerkes Fear Neurobiology Lab Brian Dias, PhD Raul Andero, PhD Georgette Gafford, PhD Dennis Choi, PhD Genetics of PTSD Elisabeth Binder, MD, PhD Kristie Mercer, MPH Alicia Smith, PhD Kimberly Kerley Lynn Almli, PhD
Psychopharmacology Friday, September 28 – Sunday, September 30, 2012
The Westin Copley Place
39th Annual Psychopharmacology Conference Thursday – Sunday, October 22– 25, 2015
The Westin Copley Place MGHCME.ORG
Massachusetts General Hospital Department of Psychiatry
Presents
39th Annual Psychopharmacology
Conference
THURSDAY-SUNDAY, OCTOBER 22-25, 2015 THE WESTIN COPLEY PLACE
BOSTON, MA