Anxiety Disorders Association of Canada

Social Anxiety Disorder Guidelines Stéphane Bouchard, Ph.D. John Walker, Ph.D. Pierre Bleau, M.D, FRCP

Overview of the symposium 1. Brief review of basic concepts in social anxiety disorder. 2. Epidemiology of social anxiety disorder. 3. Neurobiology of social anxiety disorder. 4. Psychology of social anxiety disorder. 5. Pharmacological treatment of social anxiety disorder. 6. Psychotherapeutic treatment of social anxiety disorder. 7. ADAC/ACTA Guidelines.

1. Brief review of basic concepts

Social Phobia / Social Anxiety Disorder Fear of scrutiny, negative evaluation by others or fear of humiliation and embarrassment

Social Anxiety Disorder (Social Phobia) • Marked fear of performance or social interaction situations. • Excessive fear of scrutiny or negative evaluation. • Fear of acting in a way (or showing anxiety symptoms) that will be humiliating or embarrassing. • Results in avoidance or endurance with distress. DSM-IV summarized

Social Phobia “Subtypes” Generalized

Nongeneralized (discrete, specific)

O O

O O

“Most” social situations (DSM IV) - performance - interactional

O O O O

Overlaps with avoidant personality disorder - 80-90 %

Most Most probably probably more more on on aa continuum continuum of of severity severity (quantitative) (quantitative) rather rather than different entities (qualitative). Stein et al., 2000. than different entities (qualitative). Stein et al., 2000.

1 or 2 social situations Usually performance writing in front of others eating in front of others telephone public speaking

Signs and Symptoms: Cognitive Symptoms • Fear of negative evaluation or disapproval • Negative evaluation of one’s own performance • Perfectionist standards • Expectations that others will be critical • Expectations that social situations will go badly (trigger bad habit or poor social skills) • Post-mortem thoughts

Signs and Symptoms: Physical Symptoms • • • • • • • • •

Blushing Stuttering or stammering Sweating Gastrointestinal symptoms (embarrassing) Dry mouth Palpitations Trembling Urgency of micturition Panic attacks

Signs and Symptoms: Behavioral Symptoms • Avoidance of difficult social situations • Being in situations but not participating (speaking) • Use of alcohol in social situations • Non-verbal behaviour – eye contact, shaking hands, interpersonal distance • Relying on family and friends • Leave the situation

Examples of feared social situations Social Interaction

Performance

• Going to a party

• Public speaking

• Lunch with peers

• Meeting new people

• Dating

• Fear of eating, drinking or writing in public

• Asking a teacher for help • Speaking to a boss at work • Asking a salesclerck for help • Asking for directions

• Fear of using a public washroom • Fear of using a telephone in public • Playing an instrument, sports • Entering a room

Differential Diagnosis Vs Other Anxiety Disorders Characteristics of social anxiety disorder are: • Childhood or adolescent onset • Impairment restricted to social situations • Blushing (Not present in Panic Attacks) • Unique cognitions (such as fear of scrutiny by others) (Different from fear to become fool) • No improvement with TCA

Rating Scales for Social Anxiety Disorder Clinician-Administered Scales Evaluation Rating Scale Clinical Severity

Clinical Global Impression (CGI) for Severity of Illness Liebowitz Social Anxiety Scale Clinical Global Improvement Hamilton Rating Scale for Anxiety Hamilton Rating Scale for Depression Social Anxiety and Distress Scale

Functional Disability

Sheehan Disability Scale Mini International Neuropsychiatric Interview (MINI) Duke Brief Social Phobia Scale Global Assessment of Functioning

Specificity Non-specific Specific Non-specific Non-specific Non-specific Specific Non-specific Non-specific Specific Non-specific

Rating Scales for Social Anxiety Disorder (Cont’d) Patient Self-Administered Scales Evaluation Rating Scale

Specificity

Clinical Severity

Social Phobia Inventory (SPIN)

Specific

Fear Questionnaire

Specific

Functional Disability

Liebowitz Disability Self-Rating Scale

Specific

Quality of Life

WHO Quality of Life - 100

2. Epidemiology of social anxiety disorder

Presentation lead by: John R. Walker, Ph.D. University of Manitoba

THE EPIDEMIOLOGY OF SOCIAL PHOBIA John R. Walker, Ph.D. University of Manitoba

Why is epidemiology important?

Why is epidemiology important? Informs us about the impact of a problem on the problem on the population as a whole. Knowledge of prevalence helps in planning service, education, and research. Research on risk factors helps in our understanding of etiology. Basis for developing and evaluating preventative procedures and public health practices

Lifetime Social Fears In Young People (EDSP, Munich – Ages 14-24) Situation

Lifetime Rate

Eating or drinking in public

4.4%

Writing while someone watches

2.2%

Participating in social events

4.6%

Performance/test situations

18.2%

Public speaking

13.2%

Talking with/to others Any social fear (from these questions)

6.4% 27.3%

Lifetime Rates of Social Phobia Location

Rate

Age, Study

Winnipeg

7.1%

18+, Stein et al, 1994

USA (NCS)

13.3%

15-54, Kessler et al, 1994

Ontario (OHS)

6.7%

15-64, Boyle et al, 1996

EDSP, Munich

7.3%

14-24, Wittchen et al, 1999

Alberta/Winnipeg

7.2%

16+, Stein et al, 2000

Paris

7.3%

18+, Pelissolo et al, 2000

Canadian Community Health Survey (2003) Females, 12 Month Prevalence Disorder

Age 15-24

Age 25-64

Overall

Social Phobia

6.2%

3.4%

3.4%

Panic Disorder

3.3%

2.2%

2.1%

Agoraphobia

1.2%

1.2%

1.1%

Maj. Depression

8.2%

5.8%

5.5%

Canadian Commun. Health Survey (2003) Males, 12 Month Prevalence Disorder

Age 15-24 Age 25-64

Overall

Social Phobia

3.3%

2.7%

2.5%

Panic Disorder

1.2%

1.2%

1.1%

Agoraphobia Maj. Depression

0.4% 4.3%

3.5%

3.4%

What are the causes of anxiety and depressive disorders? • • •

Biological / genetic factors? Conditioning or learning? Adverse experiences during childhood? • Life stress close to the time of onset?

Genetics of Social Anxiety Disorder Kendler’s study of female twin pairs Concordance rates of: - 15.3% for dizygotic pairs - 24.4% for monozygotic pairs - Heritability index of 30%

Childhood Adversity and SAD Ontario Health Survey (Chartier, Walker, Stein, 2001) Adverse Experience Juvenile Justice Involvement Child-welfare involvement Running away from home Lack of close adult relationship Marital conflict – parents Parental history of mental disorder Severe physical abuse Severe sexual abuse

O.R. 1.82 2.70 3.40 2.63 1.82 2.13 2.54 1.72

Childhood Adversity and SAD - 2 Ontario Health Survey (Chartier, Walker, Stein, 2001)

Adverse Experience - School

O.R.

Special education before grade 9

2.97

Special education after grade 9

2.71

Failing a grade before grade 9

1.99

Dropping out of high school

2.08

Social phobia is often the first disorder in the history for individuals with comorbid disorders Magee et al (1996)

What about childhood?

Concept of Behavioral Inhibition Jerome Kagan (1984, 1988) • Generally shy demeanour • Tendency to approach new situations with restraint, avoidance, and distress • Measured in different ways from infancy to early school years • Moderate levels of stability • Consistent Inhibition related to later anxiety

Early Developmental Stages of Psychopathology Study • • • • •

Munich Germany Ages 14 – 24 Baseline interview and follow up 20 or 40 months afterward Parents also provided some information First interview covered 12 month and lifetime, follow up interviews covered intervening time

Early Developmental Stages of Psychopathology Study • Longitudinal design allows an evaluation of risk of future disorders among individuals who have one disorder at the start of the follow up period • Previously most of the data available have been from cross sectional studies where researchers must rely on the accuracy of retrospective reports. • Are retrospective reports influenced by today’s mood? OR, is there under reporting of past experiences?

Social Anxiety Disorder and Risk of Major Depression (Stein et al., 2001) Baseline Diagnosis

Depressive Disorder Over Follow-up

No Mental Disorder

8%

Odds Ratio

SAD – No Depression

24%

3.5

Depression – No SAD

25%

3.8

Depression + SAD

44%

8.7

Social Anxiety Disorder and Risk of Major Depression (Stein et al., 2001) • Presence of both social anxiety disorder and depression was also related to increased severity of depression (number of symptoms, presence of suicide attempts, duration) • Other anxiety disorders likely follow a similar pattern • May not be a causal relationship, third factor may be involved

Selected Risk Factors For Anxiety and Depressive Disorders (Wittchen et al., 2000) Risk Factor

Depression

SAD

GAD Panic Agora

Edu. Probs.

1.7

2.7

Early Sep.

2.0

2.4

Parent Alc.

1.4

Parent Dep. Behav. Inhib.

2.1

3.6 2.3

2.7

2.4

Parent Anx. 1.9

2.2

10.0

6.4

Specific Phobia

1.4 2.3

2.4

1.6

10.0

18

4.2

Important Research Questions • Can we intervene early to reduce the impact? • Will prevention or early intervention applied to anxiety problems reduce other disorders? • What prevention approaches could be considered? • How cost effective would various intervention programs be?

Desirable Characteristics for Prevention Approaches • Community and school based rather than clinic based • Reaching out to families rather than waiting for referrals • Non stigmatizing – of children and of parents • Support parents in their role rather than blaming • Use change agents who will be available at the community level • Highly structured program to facilitate dissemination • Based on sound knowledge of child development

Social Phobia Why the Strong Interest? • Most common anxiety Disorder • Early age of onset • High rates of comorbidity • Significant personal morbidity • High financial burdon • Treatable although underrecognized

3. Neurobiology of social anxiety disorder

Presentation lead by: Pierre Bleau, M.D. McGill University

Psychobiology of FEAR Amygdala Central Nucleus

Central Central Gray Gray

Lateral Lateral Hypothalamus Hypothalamus

Paraventricular Paraventricular Nucleus Nucleus

Reticulo Reticulo pontis pontis

Freezing Freezing Blood Blood Pressure Pressure

Adapted Adapted from from LeDoux LeDoux .. The The Emotional Emotional Brain. Brain. 1996. 1996.

Stress Stress Hormones Hormones

Startle Startle Reflex Reflex

Conditioning of the Anxiety/Fear Response Fear conditioning – Coincidences between stimuli that trigger the fear response and the activation of the amygdala are connected together through hardening of synapses in the basolateral nucleus of the amygdala. These are arguably the formation of ‘emotional memories’

LeDoux J. Biol Psychiatry 1998; McKernan & Shinnick-Gallagher Nature 1997; Davis M Biol Psychiatry 1998

Sensory Sensory Cortex Cortex

Rhinal Rhinal (transitional) (transitional) Cortex Cortex (memories) (memories)

(memories (memories and and contexts) contexts)

(objects) (objects)

Sensory Sensory Thalamus Thalamus

Hippocampus Hippocampus

AMYGDALA

(stimulus (stimulus features) features)

Medial Medial Prefrontal Prefrontal (extinction) (extinction)

FEAR (responses (responses and and experiences) experiences) Adapted from LeDoux. The Emotional Brain. 1996.

Conditioning of the Anxiety/Fear Response Avoidance conditioning – Dysphoric experiences associated with the activation of the fear/anxiety responses are avoided. This involves prefrontal cortical and limbic interconnections

LeDoux J. Biol Psychiatry 1998; McKernan & Shinnick-Gallagher Nature 1997; Davis M Biol Psychiatry 1998

Sensory Sensory Cortex Cortex

Rhinal Rhinal (transitional) (transitional) Cortex Cortex (memories) (memories)

Hippocampus Hippocampus (memories (memories and and contexts) contexts)

Sensory Sensory Thalamus Thalamus

AMYGDALA

(stimulus (stimulus features) features)

FEAR (responses (responses and and experiences) experiences)

Adapted from LeDoux. The Emotional Brain. 1996.

Medial Medial Prefrontal Prefrontal (extinction) (extinction)

Conditioning of the Anxiety/Fear Response Contextual conditioning – Stimuli associated with cues that trigger the fear anxiety response result in increased vigilance. This involves declarative memory circuits mediated through the hippocampus

LeDoux J. Biol Psychiatry 1998; McKernan & Shinnick-Gallagher Nature 1997; Davis M Biol Psychiatry 1998

Sensory Sensory Cortex Cortex (objects) (objects)

Sensory Sensory Thalamus Thalamus (stimulus (stimulus features) features)

Rhinal Rhinal (transitional) (transitional) Cortex Cortex (memories) (memories)

Hippocampus Hippocampus (memories (memories and and contexts) contexts)

AMYGDALA

Medial Medial Prefrontal Prefrontal (extinction) (extinction)

FEAR (responses (responses and and experiences) experiences)

Adapted from LeDoux. The Emotional Brain. 1996.

Increased Amygdala Response to Angry/Fearful Faces in Normals: Impact of Short vs. Long Allele of the Serotonin Transporter Gene (SERT) Amygdala Responses: Group > 1 Group

Short Allele SERT Hariri et al. Science 2002:297:400-403

Long Allele SERT

Non -Stressed Non-Stressed

Stressed

Stress results in decreased dendritic branching of neurons in the CA3 region of the hippocampus Woolley CS, Gould E, Frankfurt M, McEwen BS. J Neurosci. 1990(Dec);10(12):4035-4039

Normal

Normal Survival and Growth

Stress

Antidepressants

↑ Glucocorticoids ↓ BDNF

↑ Serotonin and NE ↑ BDNF ↓ Glucocorticoids

Atrophy/Death of Neurons

↑ Survival and Growth

Other Neuronal Insults: Genetic Factors

Hypoxia-Ischemia Hypoxia-Ischemia Hypoglycemia Hypoglycemia Neurotoxins Neurotoxins Viruses Viruses

BDNF = brain-derived neurotrophic factor; NE = norepinephrine. Duman RS, et al. Arch Gen Psychiatry. 1997;54:597-606.

Neurobiology of Anxiety Cognitive Conspiracies Afférent pathways

Efferents pathways

PROCESSING

Adapted from Charney and Deutsch 1996

Neurobiology of Anxiety Cognitive Functions

Cognitive conspiracies

Cingulate g. _

Afférent pathways

Amygdala __ Hippocampus

PROCESSING Adapted from Charney and Deutsch 1996 And from Gray’s theory 1982, 2000

Neurobiology of Anxiety Cognitive Functions

Cognitive conspiracies

Cingulate g.

_

Afférent pathways

Amygdala __ Hippocampus

PROCESSING Adapted from Charney and Deutsch 1996 And from Gray’s theory 1982, 2000

Neurobiology of Anxiety Cognitive Functions

Cognitive conspiracies

Cingulate g.

_

Afférent pathways

Amygdala __ Hippocampus

PROCESSING Adapted from Charney and Deutsch 1996 And from Gray’s theory 1982, 2000

Neurobiology of Anxiety Cognitive Functions

Cognitive conspiracies

Cingulate g.

_

Afférent pathways

Amygdala __ Hippocampus

PROCESSING Adapted from Charney and Deutsch 1996

Neurobiology of Anxiety Lateral Lateral Hypothalamus Hypothalamus

Cognitive Functions

Cognitives conspiracy

Dors.Motor Dors.Motor N. N. Vagus Vagus Nucleus Nucleus Ambiguus Ambiguus

Cingulate g.

Parabrachial Parabrachial Nucleus Nucleus

Ventral Ventral Tegmental Tegmental Area Area

_

Locus Locus Ceruleus Ceruleus

Afférent pathways

Amygdala __

Dorso-lateral Dorso-lateral Tegmental Tegmental N N

N. N. Reticularis Reticularis Pontis Pontis Caudalis Caudalis

Hippocampus

Central Central Grey Grey or or Striatum Striatum Trigiminal, Trigiminal, Facial Facial N N

PROCESSING Paraventricular Paraventricular N N (Hypothal.) (Hypothal.) Adapted Adapted from from Charney Charney and and Deutsch Deutsch 1996 1996

Neurobiology of Anxiety Lateral Hypothalamus

Cognitive Functions

Cognitives conspiracy

Dors.Motor N. Vagus Nucleus Ambiguus

Parabrachial Nucleus

Cingulate g.

Ventral Tegmental Area

_

Afférent pathways

Locus Ceruleus

Amygdala

Dorso-lateral Tegmental N

__ N. Reticularis Pontis Caudalis

Hippocampus

Central Grey or Striatum Trigiminal, Facial N

PROCESSING Adapted from Charney and Deutsch 1996

Paraventricular N (Hypothal.)

Neurobiology of Anxiety Lateral Lateral Hypothalamus Hypothalamus

Sympathetic Sympathetic Activation Activation

Dors.Motor Dors.Motor N. N. Vagus Vagus Nucleus Nucleus Ambiguus Ambiguus

Parasympathetic Parasympathetic Activation Activation

Parabrachial Parabrachial Nucleus Nucleus

Increased Increased Respiration Respiration

Ventral Ventral Tegmental Tegmental Area Area Locus Locus Ceruleus Ceruleus

Activation Activation of of Dopamine Dopamine Noradrenaline Noradrenaline

Dorso-lateral Dorso-lateral Tegmental Tegmental N N

Acetylcholine Acetylcholine

N. N. Reticularis Reticularis Pontis Pontis Caudalis Caudalis

Increased Increased Reflexes Reflexes

Central Central Grey Grey or or Striatum Striatum

Cessation Cessation of of Behavior Behavior or or Flight Flight

Trigiminal, Trigiminal, Facial Facial N N

Mouth Mouth open, open, jaw jaw movements movements

Paraventricular Paraventricular N N (Hypothal.) (Hypothal.)

ACTH ACTH Release Release

Adapted from Charney and Deutsch 1996

Neurobiology of Anxiety Lateral Hypothalamus

Sympathetic Activation

Dors.Motor N. Vagus

Parasympathetic

Nucleus Ambiguus

Activation

Parabrachial Nucleus

Increased Respiration

Ventral Tegmental Area

Activation of Dopamine

Locus Ceruleus

Noradrenaline

Dorso-lateral Tegmental N

Acetylcholine

N. Reticularis Pontis Caudalis

Increased Reflexes

Central Grey or Striatum

Cessation of Behavior or Flight

Trigiminal, Facial N

Mouth open, jaw movements

Paraventricular N (Hypothal.)

ACTH Release

Adapted from Charney and Deutsch 1996

Neurobiology of Anxiety Lateral Lateral Hypothalamus Hypothalamus

Sympathetic Sympathetic Activation Activation

Dors.Motor Dors.Motor N. N. Vagus Vagus Nucleus Nucleus Ambiguus Ambiguus

Parasympathetic Parasympathetic Activation Activation

Parabrachial Parabrachial Nucleus Nucleus

Increased Increased Respiration Respiration

Ventral Ventral Tegmental Tegmental Area Area Locus Locus Ceruleus Ceruleus

Activation Activation of of Dopamine Dopamine Noradrenaline Noradrenaline

Dorso-lateral Dorso-lateral Tegmental Tegmental N N

Acetylcholine Acetylcholine

N. N. Reticularis Reticularis Pontis Pontis Caudalis Caudalis

Increased Increased Reflexes Reflexes

Central Central Grey Grey or or Striatum Striatum

Cessation Cessation of of Behavior Behavior or or Flight Flight

Trigiminal, Trigiminal, Facial Facial N N

Mouth Mouth open, open, jaw jaw movements movements

Paraventricular Paraventricular N N (Hypothal.) (Hypothal.)

ACTH ACTH Release Release

Adapted from Charney and Deutsch 1996

Neurobiology of Anxiety Lateral Lateral Hypothalamus Hypothalamus

Sympathetic Sympathetic Activation Activation

Tachycardia,BP Tachycardia,BP elevation elevation

Dors.Motor Dors.Motor N. N. Vagus Vagus

Parasympathetic Parasympathetic

Urination, Urination, defecation, defecation, Bradych. Bradych.

Nucleus Nucleus Ambiguus Ambiguus

Activation Activation

Ulcers Ulcers

Parabrachial Parabrachial Nucleus Nucleus

Increased Increased Respiration Respiration

Respiratory Respiratory Distress Distress

Ventral Ventral Tegmental Tegmental Area Area

Activation Activation of of Dopamine Dopamine

Behavioral Behavioral && EEG EEG

Locus Locus Ceruleus Ceruleus

Noradrenaline Noradrenaline

Arousal Arousal

Dorso-lateral Dorso-lateral Tegmental Tegmental N N

Acetylcholine Acetylcholine

Increased Increased vigilance vigilance

N. N. Reticularis Reticularis Pontis Pontis Caudalis Caudalis

Increased Increased Reflexes Reflexes

Startle Startle response response

Central Central Grey Grey or or Striatum Striatum

Cessation Cessation of of Behavior Behavior or or Flight Flight

Freeze Freeze or or Flight Flight

Trigiminal, Trigiminal, Facial Facial N N

Mouth Mouth open, open, jaw jaw movements movements

Facial Facial expression expression of of Fear Fear

Paraventricular Paraventricular N N (Hypothal.) (Hypothal.)

ACTH ACTH Release Release

Cortisol Cortisol (Stress (Stress response) response)

Adapted Adapted from from Charney Charney and and Deutsch Deutsch 1996 1996

Neurobiology of Anxiety Lateral Lateral Hypothalamus Hypothalamus

Sympathetic Sympathetic Activation Activation

Tachycardia,BP Tachycardia,BP elevation elevation

Dors.Motor Dors.Motor N. N. Vagus Vagus

Parasympathetic Parasympathetic

Urination, Urination, defecation, defecation, Bradych. Bradych.

Nucleus Nucleus Ambiguus Ambiguus

Activation Activation

Ulcers Ulcers

Parabrachial Parabrachial Nucleus Nucleus

Increased Increased Respiration Respiration

Respiratory Respiratory Distress Distress

Ventral Ventral Tegmental Tegmental Area Area

Activation Activation of of Dopamine Dopamine

Behavioral Behavioral & & EEG EEG

Locus Locus Ceruleus Ceruleus

Noradrenaline Noradrenaline

Arousal Arousal

Dorso-lateral Dorso-lateral Tegmental Tegmental N N

Acetylcholine Acetylcholine

Increased Increased vigilance vigilance

N. N. Reticularis Reticularis Pontis Pontis Caudalis Caudalis

Increased Increased Reflexes Reflexes

Startle Startle response response

Central Central Grey Grey or or Striatum Striatum

Cessation Cessation of of Behavior Behavior or or Flight Flight

Freeze Freeze or or Flight Flight

Trigiminal, Trigiminal, Facial Facial N N

Mouth Mouth open, open, jaw jaw movements movements

Facial Facial expression expression of of Fear Fear

Paraventricular Paraventricular N N (Hypothal.) (Hypothal.)

ACTH ACTH Release Release

Cortisol Cortisol (Stress (Stress response) response)

Adapted Adapted from from Charney Charney and and Deutsch Deutsch 1996 1996

P P H H E E N N O O T T Y Y P P E E O O F F A A N N X X II E E T T Y Y

Neurobiology of Anxiety Lateral Lateral Hypothalamus Hypothalamus

Sympathetic Sympathetic Activation Activation

Tachycardia,BP Tachycardia,BP elevation elevation

Dors.Motor Dors.Motor N. N. Vagus Vagus

Parasympathetic Parasympathetic

Urination, Urination, defecation, defecation, Bradych. Bradych.

Nucleus Nucleus Ambiguus Ambiguus

Activation Activation

Ulcers Ulcers

Parabrachial Parabrachial Nucleus Nucleus

Increased Increased Respiration Respiration

Respiratory Respiratory Distress Distress

Ventral Ventral Tegmental Tegmental Area Area

Activation Activation of of Dopamine Dopamine

Behavioral Behavioral & & EEG EEG

Locus Locus Ceruleus Ceruleus

Noradrenaline Noradrenaline

Arousal Arousal

Dorso-lateral Dorso-lateral Tegmental Tegmental N N

Acetylcholine Acetylcholine

Increased Increased vigilance vigilance

N. N. Reticularis Reticularis Pontis Pontis Caudalis Caudalis

Increased Increased Reflexes Reflexes

Startle Startle response response

Central Central Grey Grey or or Striatum Striatum

Cessation Cessation of of Behavior Behavior or or Flight Flight

Freeze Freeze or or Flight Flight

Trigiminal, Trigiminal, Facial Facial N N

Mouth Mouth open, open, jaw jaw movements movements

Facial Facial expression expression of of Fear Fear

Paraventricular Paraventricular N N (Hypothal.) (Hypothal.)

ACTH ACTH Release Release

Cortisol Cortisol (Stress (Stress response) response)

Adapted Adapted from from Charney Charney and and Deutsch Deutsch 1996 1996

P P H H E E N N O O T T Y Y P P E E O O F F A A N N X X II E E T T Y Y

Functional Neuroanatomy of Fear and Anxiety Fear Fear and and Anxiety Anxiety Response Patterns Response Patterns

(( Charney Charney & & Deutsch Deutsch 1996 1996 )) Cingulate Cingulate gyrus gyrus

Primary Primary sensory sensory and and Association Association Cortices Cortices Striatum Striatum Periaqueductal Periaqueductal gray gray

Orbitofrontal Orbitofrontal cortex cortex Peripheral Peripheral receptor receptor cells cells of of exteroceptive exteroceptive auditory,visual auditory,visual somesthetic somesthetic sensory sensory systems systems

Multisynaptic Multisynaptic pathways pathways

Thalamus Thalamus

uss aam mppu c o c p o H Hiippp inaall EEnnttirirhhin ccooeerrtteexx

Olfactory Olfactory sensory sensory stimuli stimuli

Afferent Afferent system system

Visceral Visceral afferent afferent pathways pathways

Fight Fight or or flight flight response response

Trigeminal Trigeminal nucleus nucleus Facial Facial motor motor nucleus nucleus

Single Single or or

Fear-induced Fear-induced skeletal skeletal motor motor activation activation

Facial Facial expression expression of of fear fear

Amygdala Amygdala

Locus Locus ceruleus ceruleus

Nucleus Nucleus Paragigantocellularis Paragigantocellularis

Stimulus Stimulus processing processing

Parabrachial Parabrachial nucleus nucleus

Fear-induced Fear-induced hyperventilation hyperventilation

Dorsal Dorsal motor motor nucleus nucleus of of the the Vagus Vagus

Fear-induced Fear-induced parasympathetic parasympathetic

Lateral Lateral hypothalamus hypothalamus

Paraventricular Paraventricular nucleus nucleus of of the the hypothalamus hypothalamus

nervous nervous system system activation activation Fear-induced Fear-induced sympathetic sympathetic nervous nervous system system activation activation

Neuroendocrine Neuroendocrine and and neuropeptide neuropeptide release release Efferent Efferent system system

Increase Increase urination urination defecation defecation ulcers ulcers bradycardia bradycardia Tachycardia Tachycardia increase increase BP BP sweating sweating piloerction piloerction pupil pupil dilat dilat Hormonal Hormonal stress stress response response

Neurobiology of Social Anxiety Disorder

Biology of Social Phobia Generalized

• Central dopaminergic involvement ? • Central serotonergic dysregulation?

Nongeneralized

• Peripheral autonomic mediation

Social Anxiety Disorder Spectrum-Continuum “Normal” Shy Performance - Social Anxiety Disorder Generalized - Social Anxiety Disorder Avoidant Personality Disorder

Age At Onset of Social Anxiety Disorder In Subjects Without Agoraphobia or Simple Phobia 30

(N=106)

Number of Subjects

25 20 15 10 5 0 0-5 6-10 11-15 16-20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75

Age (years) Schneier 1992

Serotonergic Function in SAD Knutson, Knutson, 1998 1998

SSRI SSRI treatment treatment

Increased Increased sociability sociability in in healthy healthy controls controls

Various Various studies studies

SSRI SSRI treatment treatment

Beneficial Beneficial effect effect in in Patients with SAD Patients with SAD

Hollander, Hollander, et et al. al. 1998 1998

m -CPP challenge m-CPP challenge (partial -HT agonist) (partial 55-HT agonist)

Significantly Significantly greater greater cortisol cortisol response response vs. vs. controls controls

Tancer Tancer,, 1993 1993

Fenfluramine Fenfluramine challenge challenge

Increase Increase in in cortisol cortisol Response Response

Moskowitz Moskowitz et et al. al. 2001 2001

Tryptophan Tryptophan Challenge Challenge

Increased Increased sociability sociability in in healthy healthy controls controls

Arbell Arbell et et al, al, 2003 2003

55-HTTPRL -HTTPRL polymorphism polymorphism

Association Association between between shyness shyness and and ll allele allele

Kang Kang Seob Seob Oh, Oh, 2003 2003

55-HTTPRL -HTTPRL polymorphism polymorphism

higher higher proportion proportion of of the the ll allele allele in in SAD SAD patients patients

Stevens Stevens et et al, al, 2004 2004

55-HTT -HTT binding binding

greater greater binding binding potential potential in patients with SAD in patients with SAD

Nutt Nutt et et al, al, 2004 2004

TRP TRP depletion depletion

Reverse Reverse SSRI SSRI treatment treatment

Neurobiology of SAD Serotonergic systems – Increased 5HT associated with dominant social status associated with affiliative behavior – Decreased 5HT associated with subordinant status

Moskowitz, et al 2001

Moskowitz DS, Pinard G, Zuroff DC, Annable L, Young SN The effect of tryptophan on social interaction in everyday life: a placebo-controlled study.Neuropsychopharmacology 2001 Aug;25(2):277-89

Neurobiology of SAD Dopaminergic systems – Modulates approach behavior – Reduces dopaminergic function in patients with SAD • Reduced striatal dopamine reuptake binding • Reduced D2 receptor binding density Tiihonen J, Kuikka J, Bergstrom K, Lepola U, Koponen H, Leinonen E. Dopamine reuptake site densities in patients with social phobia. Am J Psychiatry 1997 Feb;154(2):239-42

Tiihonen, et al 1997. Schneier FR, et al. Am J Psychiatry. 2000;157:457-459.

Evidence for dopaminergic dysfunction • Atypical antipsychotic olanzapine is effective in social anxiety disorder monotherapy (Barnett et al, 2003) • High rates of social anxiety disorder in patients with Parkinson’s Disease (Stein et al, 1990) • Healthy subjects with a detached personality show lower density of the dopamine D22 receptors (Laakso et al, 2000; Farde et al, 1997)

D2 Density and Personal Detachment in Normal Subjects 70

Detachment

60 50 40 30 20 15

25 35 D2-receptor density (pmol ml-1)

45

Individual values (n = 24) for D2-dopamine-receptor density plotted against KSP detachment scores. To adjust for the effect of gender, the scores were transformed to T scores using normative data. The T scores have a mean (± s.e.m.) of 50 (±10) in the normal population. Farde L, et al. Synapse. 1997;25:321-325.

Dopamine Transporter

4 hr after 185 MBq 123I-ß-CIT.

24 hrs after 185 MBq 123I-ß-CIT

and 20 mg paroxetine

Dopamine transporter binding in the basal ganglia of SAD patients and controls

β− CIT binding ratio

10

8

* 6

4

2 Stevens et al, 2004

Controls

Patients

D2 Receptor Binding Potential [1231] IBZMbinding potential ml/gr

200

P