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