diane mcintosh, bsc pharmacy, md, frcpc clinical … · frcpc clinical assistant professor,...

Diane McIntosh, BSc Pharmacy, MD, FRCPC

Clinical Assistant Professor, University of British Columbia

2

Diane McIntosh has received research support, spoken for, or sits on advisory boards for the following companies:

Lundbeck, Pfizer, Sanofi, Servier, Shire, Astra Zeneca, Valeant, Otsuka, Eli Lilly, Bristol Myers Squibb, Janssen-‐Ortho, Sunovion

Conflict Disclosure Information

 Compare and describe the distinctive phenomenology and

burden of anxiety disorders.

 Describe the neurobiological origins and physiological

mechanisms of anxiety disorder.

 For a specific case or need, select and implement advances

in pharmacological and psychological treatments of anxiety

disorders.

Objectives

  Anxiety Disorders includes: -‐Separation Anxiety Disorder -‐Agoraphobia -‐Specific Phobias -‐Social Anxiety Disorder -‐Panic Disorder (and Panic Attack Specifier) -‐Generalized Anxiety Disorder -‐Substance/ Medication Induced Anxiety D/O -‐GMC -‐Unspecified

  New Categories: *Obsessive Compulsive and Related Disorders Includes BDD, Hoarding, Trichotillomania, Excoriation…

*Trauma and Stressor Related Disorders Includes PTSD, Reactive Attachment, Acute Stress Disorder, Adjustment Disorder

  Depression with anxious distress specifier (2+ anxiety sxs)

What’s New in DSM-‐5?

The most common anxiety disorder in children/adolescents is?

1.  Panic disorder

2.  Generalized anxiety disorder

3.  Specific phobia

4.  Social phobia

5.  Separation anxiety disorder

Question

The most common anxiety disorder in children/adolescents is?

1.  Panic disorder 1-‐3%

2.  Generalized anxiety disorder 2%

3.  Specific phobia 19%

4.  Social phobia 10%

5.  Separation anxiety disorder 3-‐8%

Question

  Anxiety disorders are the most common psychiatric disorders of childhood and adolescents.

  Onset for first or any anxiety disorder commonly in childhood   Lifetime prevalence in children and adolescents from Western countries is between 15-‐30%

  Many affected children are diagnosed with more than one anxiety disorder

  National Comorbidity Study:   31.9% lifetime prevalence for 13 to 18-‐year-‐olds for pure or comorbid anxiety disorder with some impairment or moderate symptom severity.

  8.3% with severe impairment and symptom severity

Childhood and Adolescent Anxiety

Epidemiology of Anxiety Disorders

Diagnosis Lifetime Prevalence

Total Lifetime

12 Month Prevalence

Median Age of Onset

Female/male

Panic+/- Ag 7.0/3.3 5.2 3.1 24

GAD 7.7/4.6 6.2 2.9 30

Ag+/- panic 3.2/2.0 2.6 1.7 20

Social Phobia 14.2/11.8 13 8.0 13

Specific phobia 17.5/9.9 13.8 10.1 7

OCD 3.6/1.8 2.7 1.3 19

PTSD 11.7/4.0 8.0 4.4 24

TOTAL 40.4/26.4 33.7 21.3

Kessler R et al Int J Methods Psychiatr Res. 2012 Sep;21(3):169-84. doi: 10.1002/mpr.1359. Epub 2012 Aug 1

Wittchen & Jacobi European Neuropsychopharm 2005, 15,357

Kessler R et al Int J Methods Psychiatr Res. 2012 Sep;21(3):169-84. doi: 10.1002/mpr.1359. Epub 2012 Aug 1

Identified Course Trajectories of Anxiety Disorders (n=907)

MONTH abc ab

J Clin Psychiatry 75:9 September 2014

Class 3: severe and chronic. Severity at baseline and follow up greatest

J Clin Psychiatry 75:9 September 2014

Course of illness best predicted by:   Age on onset   Having a partner   Mood disorder co-morbidity   History of childhood trauma

Panic with agoraphobia and SAD more likely class 3

  HARP (Harvard) 12 year follow-‐up (Bruce et al 2005):   Recurrence rates were about 60% for PD, 40% for social phobia and 45% for GAD

  Calkins et al 2009-‐ 65% recurrence rate at 3 year follow up

  Scholten 2012-‐ 24% of all remitted patients relapse in 2 years

  In several studies, there was a high rate of conversion to another anxiety disorder (33% for Scholten 2012)

Anxiety Disorders: Chronic/ Recurrent

  Greatest risk is higher level of disability and high anxiety sensitivity (fear of anxiety related sensations)

  Other risks:

  Residual symptoms

  Comorbid depression or another anxiety disorder

  Earlier age of onset

  Parental substance abuse

  Discontinuation of an antidepressant

Predictors of Recurrence

Scholten et al 2012

Which of the following is not correct?

1.  The most common psychiatric co-‐morbidity associated with bipolar disorder are anxiety disorders.

2.  The suicide rate for mood disorders is higher than the suicide rate for anxiety disorders.

3.  The most common co-‐morbidity associated with ADHD are anxiety disorders.

4.  Comorbid alcohol abuse has not been positively associated with the suicide risk of psychiatric disorders.

5.  Depressed and anxious patient have a greater risk of mortality associated with myocardial infarction.

Question

% Population Life-‐time Co-‐morbidity (Kessler R 1997)

Anxiety Disorder Lifetime Comorbidity GAD 91.3

Panic disorder 92.2

PTSD 81.0

Social phobia 81.0

Simple (specific) phobia 83.4

Agoraphobia 78.3

Any anxiety disorder 74.1

Fear Vs. Anxiety Occurs in anticipation or the presence of stimuli that threaten homeostasis

FEAR: -‐A response to a threat that is known, external, definite -‐Involves primitive structures including the Amygdala, Locus Ceruleus….

ANXIETY: -‐A response to a threat that is unknown, internal, vague

-‐May occur in the absence of a trigger -‐A more complex emotion, processed by higher level brain structures ( association cortex) -‐Excessive, unwarranted, inappropriate fear

Anxiety Disorders: Associated Fear

Disorder Focus of fear

Panic disorder Intolerance of physical feelings/ fear of death

Agoraphobia Intolerance of being unable to escape

Social anxiety Fear of being negatively evaluated

Specific phobia Fear of specific objects or situations

GAD Excessive and uncontrollable worry/ “What if…”

OCD Repetitive fearful unwanted thoughts +/-‐ rituals/ doing harm

PTSD Fear of re-‐experiencing traumatic event

  Genetic/Biological Vulnerability  Genes:

  Some specific gene associations

  Panic and GAD more closely related to each other than to specific phobias (Hettema Arch Gen Psych 2005)

  Epigenetics   Personality variables

  E.g. High trait anxiety or high anxiety sensitivity (Levy and Martin 1981)

  Bodily sensations related to anxiety are misattributed as a harmful experience causing more intense anxiety/fear

  Early behavioural inhibition (Biederman et al 1990)

  consistent tendency of some children to demonstrate fear and withdrawal in novel situations

The Origins of Anxiety

  Psychological Vulnerability  Life experiences  Latent inhibition: Exposure to a controlled stimulus before the conditioned and unconditioned stimulus are paired might decrease the amount of subsequent conditioning   E.g. Good early dentist experiences reduces likelihood you will develop fear if later there are bad dentist experiences. Lebow 1998, Kent 1997

 Vicarious Conditioning: Development of anxiety through observation (Cook 1985, Cook 1990)

  Sense of mastery and control over environment: leads to more rapid adaptation to anxiety provoking situations (Mineka 1996, Chorpita 1998)

The Origins of Anxiety II

  A neutral sensory stimulus: conditioned stimulus (CS)   a sound, light or odor or context

  Paired with a coinciding aversive stimulus :unconditioned stimulus (US)   E.g. a brief electric stimulus

  A memory is formed

  With subsequent exposure to the CS or conditioned context, a conditioned fear response (CR) is elicited   These responses involve autonomic components (like hypertension, tachycardia, and

hypoalgesia), an overall endocrine arousal, as well as species-‐specific defensive behaviors, such as freezing and flight

  Human subjects with anxiety disorders exhibit abnormalities in the acquisition and extinction of conditioned fear responses

Classical “Pavlovian” Conditioning

Unconditioned stimulus(US)

Conditioned Stimulus (CS)- often neutral

CS (sound) and US (shock) paired: rat has a fear response to the sound= Conditioned response (CR)

If sound occurs repeatedly without the shock, eventually the association between the two stimuli weakens =extinction

Memory Consolidation   The process whereby transient (short-‐term) memory shifts to a stable form (long-‐term memory).   This process requires gene expression and new protein synthesis

  Neuronal networks must be coordinated for memory consolidation to take place

  Long-‐term memories are not consolidated in a formal sense, but remain in a labile state, or become labile again after consolidation   All memories are susceptible to change and disruption after memory retrieval and require “re-‐consolidation”

  Transient synaptic modifications induced during fear conditioning become stabilized during fear memory consolidation   These processes can be altered in the course of fear memory extinction.

Experience Memory Consolidation

Long-term memory

Creating New Memories….

During consolidation, memories are labile or vulnerable….

“I remember when my son was born…”

Memory Re-consolidation: “He’s being a bit of a pain lately…” or “What a delightful child”

Altered long-term memory: “His birth was an awful experience” or “a delight”.

Memory Reconsolidation: Old Memories Become New Memories

Remembering past experiences triggers a process of re-consolidation, which requires the same molecular mechanisms as initial consolidation and memories are again labile….

Reconsolidation updates memories in light of new experiences

Reconsolidation-‐Extinction

If 10 minutes before extinction training, memory of blue box and shock is recalled (reactivated), the fear is replaced effectively during extinction-‐ memory is allowed to be re-‐consolidated

If both result in shock and only blue one is reactivated before extinction training, only the blue memory is reconsolidated as non-‐distressing and extinguished. Effect lasted a year.

= shock….

= shock

or

Schiller et al Nature 463 49-53 2010

Quickly developed fear response to blue box

Treatment for traumatic memories: giving extinction training to humans during the reconsolidation window effectively redefines fearful memories as safe

Development of fearful memories: determined before and after the traumatic event

1.  Genetic heritability

2.  Early childhood abuse a strong risk factor for all mood and anxiety disorders.

3.  Prevent encoding Psychological and pharmacological approaches to prevent the initial encoding of the trauma are under study.

4.  Impair consolidation Memories undergo a period of consolidation where they shift from a labile state to a more permanent state.

5.  Extinction The expression of traumatic memories is diminished by extinction

Repeated therapeutic exposures reduce or inhibit the fear memories over time.

Functional Neuroanatomy of Fear and Anxiety

Amygdala Thalamus

Peripheral receptor cells of exteroceptive

auditory,visual somesthetic

sensory systems

Single or

Multisynaptic pathways

Hippocampus

Orbitofrontal cortex

Periaqueductal gray

Locus ceruleus

Parabrachial

nucleus

Dorsal motor nucleus of the

Vagus

Lateral hypothalamus

Paraventricular nucleus of the hypothalamus

Fear-induced skeletal motor

activation

Facial expression of

fear

Fear-induced hyperventilation

Fear-induced

parasympathetic nervous system

activation

Fear-induced sympathetic

nervous system activation

Neuroendocrine

and neuropeptide

release

Fight or flight

response

Increase urination

defecation ulcers

bradycardia

Tachycardia increase BP

sweating piloerction pupil dilat

Hormonal

stress response

Visceral afferent

pathways Nucleus

Paragigantocellularis Olfactory sensory stimuli

Entirhinal

coertex

Cingulate gyrus

Afferent system Stimulus processing Efferent system

Fear and Anxiety Response Patterns

Striatum

Trigeminal nucleus

Facial motor nucleus

Primary sensory and Association Cortices

( Charney & Deutsch 1996 )

THREAT

Mr. HJ Simpson

Neuro-‐anatomy of Anxiety Disorders

AMYGDALA

Insula (cortex) Anterior Cingulate

Pre-frontal Cortex

Caudate Thalamus Brainstem (somatovisceral)

Hypothalamus

Hippocampus

Amygdalo-‐centric neuro-‐circuitry model of anxiety disorders

Note: OCD is distinct via cortico-striatal-thalamic circuit Britton and Rauch 2009

PROCESSING

Cortex (cingulate)

Amygdala

Hippocampus

_

_

Locus Ceruleus

+

THREAT

DANGER

thalamus

Neuroanatomy of FEAR

Adapted from Pierre Bleau, 2003

What’s my Thalamus?

  A relay centre between subcortical areas and the cortex

  Sensory impulses are transmitted through the thalamus.

  E.g.: Sensory information from the retina"lateral geniculate nucleus of the thalamus "projects to the primary visual cortex (occipital lobe)

  Process and relay sensory information

What’s a Thalamus?

  Most sensory input goes to the cortex, by-‐passing the amygdala

  Amygdala gets message from afferents first, via “neuronal express lane”

  The key region for the processing of aversive signals and fear learning   Sensory input to the amygdala may result in a

powerful fear reaction   Speed necessary for survival: Fight, flight or freeze

response

Thalamus "Amygdala

  Located in anterior temporal lobe

  Comprised of several nuclei divided in two or more subnuclei with distinct connectivity.   Subnuclei important in acquisition and the

extinction of conditioned fear:

  basolateral complex (BLA) – composed of 3 nuclei (LA, BL, BM), central nucleus (CE) and intercalated (ITC) cell masses

  The amygdala forms connections with cortex, striatum, some thalamic and hypothalamic nuclei, basal forebrain structures and brainstem nuclei

  Influences autonomic and motor control, memory formation and neuro-‐modulation

Amygdala

Martin E et al Psychiatr Clin N Am 32 (2009) 549–575 Physiol. Rev April 2010; 90(2): 419-463

PROCESSING

Cortex (Cingulate)

Amygdala

Hippocampus

_

_

Locus Ceruleus

+

THREAT

DANGER

thalamus



I see a bear! I hear a bear! RUN!!!

Creates a fear response that’s hard to control….it

feeds on itself and overrides reason

Amygdala as “Brain Hijacker”

There is a “lag time” between the urge to take action, and the action itself  0.25 seconds-‐ an eternity when it comes to the brain  Gives the opportunity to determine alternate interpretations for perceptions  Loud noise isn’t a bomb or the comment wasn’t meant to be hurtful

 An opportunity to alter behaviour

Can the hijacker be stopped???

Afferent pathways

PROCESSING

Pre-frontal Cortex


THREAT

DANGER

thalamus


  Slow, but lots of information

  Allows for more careful evaluation of the sensory input

  More options for response available other than just fear, fight, flight, freeze

  Consults the amygdala, but normally not overly influenced by the amygdala’s predictable fear response

Thalamus "Prefrontal Cortex

PROCESSING

PFC

Amygdala

Hippocampus

_

_

Locus

+

THREAT

DANGER

thalamus RUN!!!

I Like Bears! I know bears can KILL!!!

I need to get away, but how? I could climb a tree… Wait, bears can climb. Should I play dead? Make some noise?



I see a bear! I hear a bear!

The Hypothalamic-‐Pituitary Axis (HPA)

A major biological system involved in coordinating the body’s acute and chronic responses to stress

The HPA Stress-‐Response Cascade Stress Activated Neuropeptides

CRF from Hypothalamus

(PVN)

ACTH from Pituitary

GC from Adrenals

(-)

ADRENAL GLAND STRESS ACTIVATES

HPA

Glucocorticoids interact with GRs and MRs in PVN, amygdala, PFC

and hippocampus

Altered gene expression (transcription/ repression) Terminates

stress response

Long-term changes

Great Review! Neuroscience 283 (2014) 166–177

What is Corticotropin-‐Releasing Factor (CRF)?

  CRF from PVN of hypothalamus controls brain responses to stress

  CRF containing brain circuitry innervates widespread neurons   Brainstem, cortex and amygdala

  Responsible for “behavioural activation”   Increased EEG activity   Increased LC firing and plasma NA levels   Increased HR   Increased attention and arousal   Behaviours consistent with fear and anxiety   Less exploration in new environment   More acoustical startle

 There is hypersecretion of CRF in depressed and anxious patients.

Functional Neuroanatomy of Fear and Anxiety

Amygdala Thalamus

Peripheral receptor cells of exteroceptive

auditory,visual somesthetic

sensory systems

Single or

Multisynaptic pathways

Hippocampus

Orbitofrontal cortex

Periaqueductal gray

Locus ceruleus

Parabrachial

nucleus

Dorsal motor nucleus of the

Vagus

Lateral hypothalamus

Paraventricular nucleus of the hypothalamus

Fear-induced skeletal motor

activation

Facial expression of

fear

Fear-induced hyperventilation

Fear-induced

parasympathetic nervous system

activation

Fear-induced sympathetic

nervous system activation

Neuroendocrine

and neuropeptide

release

Fight or flight

response

Increase urination

defecation ulcers

bradycardia

Tachycardia increase BP

sweating piloerction pupil dilat

Hormonal

stress response

Visceral afferent

pathways Nucleus

Paragigantocellularis Olfactory sensory stimuli

Entirhinal

coertex

Cingulate gyrus

Afferent system Stimulus processing Efferent system

Fear and Anxiety Response Patterns

Striatum

Trigeminal nucleus

Facial motor nucleus

Primary sensory and Association Cortices

( Charney & Deutsch 1996 )

THREAT

Which is true regarding monoamines and anxiety:

1.  Stimulating 5HT1a receptors worsens anxiety.

2.  Medications that increase norepinephrine release from the locus

ceruleus worsens anxiety.

3.  The tonic release of norepinephrine reduces after a few weeks of

treatment with an SNRI

4.  Increasing serotonin can cause a reduction of NE and DA.

5.  Venlafaxine XR becomes an SNRI at 75mg. At lower doses venlafaxine

does not effect NE levels appreciably.

Question

Which is true regarding monoamines and anxiety:

1.  Stimulating 5HT1a receptors worsens anxiety.

2.  Medications that increase norepinephrine release from the locus

ceruleus worsens anxiety.

3.  The tonic release of norepinephrine reduces after a few weeks of

treatment with an SNRI

4.  Increasing serotonin can cause a reduction of NE and DA.

5.  Venlafaxine XR becomes an SNRI at 75mg. At lower doses venlafaxine

does not effect NE levels appreciably

Question

SSRI/SNRI blocks reuptake of 5HT   Reuptake blocked   5HT increases quickly in synaptic cleft   Post-‐synaptic 5HT2/5HT3 receptors overstimulated causing side effects   Side effects decrease over 1-‐3 weeks as 5HT2/5HT3 receptors de-‐sensitize

Post-Synaptic Projection Areas

Serotonergic Effects

5HT neuron

5HT Reuptake Transporter (SERT)

5HT1

a

5HT1a

5HT1a

Somatodendritic 5HT1a

Autoreceptors

5HT1d Terminal Autoreceptors

Raphe Nuclei

5HT

1d

5HT2

5HT1a

5HT3

-anxiolytic -antidepressant

-jitteriness -insomnia -sexual dysfnc

-nausea -headache

© 2009 K. Kjernisted

Depressed/Anxious: 5HT too low

A Serotonin Bomb SSRIs/SNRIs Increase serotonin everywhere

Increasing 5HT is antidepressant and anxiolytic

 But can also cause of side effects including nausea, sexual dysfunction, apathy, fatigue, cognitive fog

Creese I, Burt DR, Snyder SH Science 1976, 192:481-483. 2.Seeman P, Lee T, Chau-Wong M, Wong K Nature 1976, 261:717-719.

Role of Norepinephrine

Dampens noise Increases inhibition Inhibit distraction Engage and disengage from stimuli

Change focus to new stimuli

Executive operations

Locus ceruleus

Solanto. Stimulant Drugs and ADHD. Oxford; 2001.

  Executive Operations:   Judgment   Planning/organization   Problem solving   Critical thinking   Forward thinking   Working memory

Norepinephrine Tonic Activity vs. Phasic Reactivity

Tonic (steady-‐state) noradrenergic activity  Correlates with behavioral arousal at rest (awake, alert)  Relates to release of NE at the nerve terminal

Morilak DA, et al. International Journal of Neuropsychopharmacology ; 2004, 7: 193-218


Happy Line

Norepinephrine Tonic Activity vs. Phasic Reactivity

Phasic (stimulus-‐evoked) noradrenergic reactivity  Correlates with threat or stress-‐induced anxiety-‐like behavior +/or panic attack (noradrenergic neuron firing)

Morilak DA, et al. International Journal of Neuropsychopharmacology ; 2004, 7: 193-218


Happy Line

Happy Line

TONIC: TOO LOW

PHASIC: TOO HIGH

DEPRESSED AND ANXIOUS STATE

Tonic activity (exocytotic release) at rest is low   Basal firing rate low   Reuptake efficient   Extracellular NE low in PFC-‐ fatigue, somnolence, cognitive impairment


Depressed anxious state- Tonic activity; awake, alert, at rest, no threatening stimulus

Locus Ceruleus

Alpha-2 Somatodendritic

Autoreceptors

NE neuron

Alpha-2 Terminal Autoreceptors

NE Reuptake Transporter

α-2

α-2

α-2

αα -1

αα-2

α-2

SzaboT, Blier.P. Brain Research 2001; 922 : 9–20 Parini S Neuropsych Pharm. 2005; 30(6): 1048-1055 Morilak D, et al. Int J Neuropsychopharmacol 2004;7:193-218

+


ββ11

Depressed/Anxious: NE too low

Phasic reactivity (neuronal firing) very high in response to stress or threatening stimuli   Neuronal firing rate very high   Extracellular NE becomes very high-‐ anxiety, dysphoria, cognitive impairment


Depressed anxious state- Phasic reactivity in response to stress or threatening stimulus

Locus Ceruleus


Autoreceptors

NE neuron



α-2

α-2

α-2

α -1

α-2

α-2


+


β1

  Reuptake blocked; extracellular NE increases   Terminal α-‐2 receptors desensitize   Brakes taken off exocytotic release of NE §  Tonic activity (extracellular NE) is increased -‐ improved energy,attention,cognition


Tonic activity- After three or more weeks of NRI or SNRI

Locus Ceruleus


Autoreceptors

NE neuron



α-2

α-2

α-2

α -1

α-2

α-2



+ β1

  Reuptake remains blocked   Terminal α-‐2 receptors desensitized   Brakes off exocytotic release of NE   Increased NE at somatodendritic autoreceptors (which fail to desensitize) – brakes on neuronal firing


Locus Ceruleus


Autoreceptors

NE neuron



x

α-2

α-2

α-2

α -1

α-2

α-2

1) Attenuated phasic reactivity (decreased neuronal firing) 2) Downregulated excitatory post-synaptic ß receptors

Phasic reactivity- After three or more weeks of NRI or SNRI


+ anxiolytic

Increased extracellular NE tonically

both potentially anxiolytic


β1

Interaction of Norepinephrine and Performance

Locus Ceruleus Mediated Arousal

Adapted from: Aston-Jones G et al. Biol Psychiatry 1999; 46:1309-1320 [Aston-Jones pp1310a, 1313b, 1314a,Fig 4]

Task

Per

form

ance

Focused Attention: Creativity, Problem

Solving

Labile Attention: Fear,

Hyperarousal Inattentive

Drowsy

Courtesy Pierre Blier

Trivedi MH, Hollander E, Nutt D, Blier P. J Clin Psychiatry 2008; 69: 246-258

The 5HT Effect ü  SSRIs increase serotonergic neurotransmission BUT may lower NE and DA via agonism of 5HT2A and 5HT2C ü  Stimulating 5HT2A and 5HT2C in the PFC may result in fatigue, loss of interest, apathy, and cognitive dulling

Baseline lab investigations should be performed before initiation of pharmacological treatment

Regularly monitor weight changes and adverse effects of medication, including sexual dysfunction

Initial Physical Assessment of Patients with Anxiety

Baseline Lab Investigations

  Complete blood count (CBC)   Pregnancy test (if relevant)

  Fasting glucose   Urine toxicology for substance(?)

  Fasting lipid profile   Prolactin (if relevant)

  Electrolytes   Thyroid stimulating hormone

  Liver enzymes   Electrocardiogram (>40 years or if indicated)

  Serum bilirubin

  BUN, creatinine

Self-administered rating scales Clinician-administered rating scales

Depression, Anxiety, Stress Scale (DASS)

Hamilton Rating Scale for Anxiety (HAM-A)

Davidson Trauma Scale (DTS) Clinician administered PTSD scale-2 (CAPS-2)

Obsessive Compulsive Inventory (OCI) Treatment Outcome PTSD Scale (TOP-8)

Anxiety Sensitivity Index (ASI) Yale-Brown Obsessive Compulsive Scale (Y-BOCS II)

Social Phobia Inventory (SPIN) Liebowitz Social Anxiety Scale (LSAS)

Fear Questionnaire (FQ) Panic Disorder Severity Scale (PDSS)

Sheehan Disability Scale

GAD 7

Assess Baseline and Response to Therapy

n  Response defined as percentage reduction in symptoms. Usually 25-50% n  Remission should be goal of therapy for most cases. Often defined as loss of diagnostic status, a low

score on a disorder specific scale, and no functional impairment

CBT has been shown to have greatest effect size on which of the following?

1.  Acute stress disorder

2.  GAD

3.  OCD

4.  PTSD

5.  Social phobia

Question

  Books/ Manuals

  Self help

  Expert CBT

  Mindfulness

Psychological Treatment of Anxiety in Adults

Efficacy of CBT in Adult Anxiety Disorders

Hoffman S et al. J Clin Psych (2008) 69, 621- 632

Exposure • Encourage patients to face fears • Patients learn corrective information through experience • Extinction of fear occurs through repeated exposure • Successful coping enhances self-‐efficacy

Safety response inhibition

• Patients restrict their usual anxiety-‐reducing behaviors (e.g., escape, need for reassurance) • Decreases negative reinforcement • Coping with anxiety without using anxiety-‐reducing behavior enhances self-‐efficacy

Cognitive strategies

• Cognitive restructuring, behavioral experiments, and related strategies target patients’ exaggerated perception of danger (e.g., fear of negative evaluation in SAD) • Provides corrective information regarding the level of threat • Can also target self-‐efficacy beliefs

Arousal management

• Relaxation and breathing control skills can help patient control increased anxiety levels

Surrender of safety signals

• Patient relinquishes safety signals (e.g., presence of a companion, knowledge of the location of the nearest toilet) • Patients learn adaptive self-‐efficacy beliefs

Components of cognitive behavioral interventions

Summary of Psychological Treatment Strategies for Anxiety Disorders (Antony, Federici and Stein 2009)

Anxiety Disorder Well Established Strategies Preliminary/Mixed Support Panic Disorder and Agoraphobia Psychoeducation

Cognitive restructuring Interoceptive exposure In vivo exposure (Ag)

Breathing retraining Psychodynamic PRx Experiential PRx

Social Anxiety Disorder Psychoeducation Cognitive restructuring In vivo exposure Simulated exposure(role

plays) Social skills training

Applied relaxation training Virtual reality exposure Interpersonal PRx

Specific phobia In vivo exposure Applied tension (blood and

injury phobia)

Applied relaxation Virtual reality training

Generalized Anxiety Disorder Cognitive restructuring Progressive muscular

relaxation

Mindfulness and acceptance-‐based strategies

Exposure to worry related imagery

Problem-‐solving training Prevention of worry

behaviours Stimulus control strategies

(egg planned worrying sessions)

Obsessive-‐Compulsive Disorder Exposure and response prevention

Cognitive restructuring

Exposure in imagination

Posttraumatic Stress Disorder In vivo exposure Exposure in imagination Cognitive restructuring Progressive muscle

relaxation

Eye movement desensitization and reprocessing (EMDR)

Virtual reality training

NICE Guidelines (2011) GAD: Stepped Care Model

Sertraline recommended

Coordinated Anxiety Learning and Management (CALM) allowed choice of CBT, medication, or both   real-‐time web-‐based outcomes monitoring to optimize treatment decisions

  computer-‐assisted program to optimize delivery of CBT by non-‐expert care managers who assisted primary care clinicians in promoting adherence and optimizing medications.

Conclusion: CALM compared with usual care resulted in greater improvement in anxiety symptoms, depression symptoms, functional disability, and quality of care during 18 months of follow-‐up.

Delivery of Evidence-‐Based Treatment for Multiple Anxiety Disorders in Primary Care (n = 1004)

Roy-Byrne P et al, JAMA Oct 2010

Proportion Achieving Response and Remission From Baseline BSI-12 Score.

Roy-Byrne, P. et al. JAMA 2010;303:1921-1928

Copyright restrictions may apply.

  Guided self help

  Incorporation of Mindfulness and Acceptance Strategies

(Roemer & Orsillo, 2007)

  Addition of Motivation Enhancement Strategies

(Arkowitz, Westra, Miller, Rolnick.)

  Virtual reality based exposure

Advances in CBT for Anxiety

Enjoy Your Break….

Functional anatomy of normal and pathological sadness and anxiety

Martin E et al Psychiatr Clin N Am 32 (2009) 549–575 ACC- Anterior cingulate cortex PCC- Posterior cingulate cortex

Functional Neuroimaging of Anxiety: A Meta-Analysis of Emotional Processing in PTSD, Social Anxiety Disorder, and Specific Phobia

Etkin A & Wagar TD Am J Psychiatry 2007; 164:1476–1488

Neuropeptides in stress and psychopathology

Martin et al Psych Clin N Am 2009

MR Findings in Anxiety Disorders

Decreased hippocampus and medial prefrontal cortex volumes in

PTSD and GAD

Decreased cortico-striato-thalamo-striato- cortical

circuitry in patients with OCD

Decreased prefrontal cortex and

hippocampus activity in PTSD

Decreased NAA in striatum and anterior

cingulate cortex in OCD

Decreased medial temporal lobe volume

in PD

Increased amygdalar and hippocampal

activity in SAD and PD

Reduced NAA levels in R hippocampus may predict PTSD after trauma

Increased insula activity in patients

with PD

Increased Glu in SAD and OCD

Increased activity orbito-frontal cortex,

anterior cingulate cortex, and striatum

in OCD

Decreased GABA in anterior cingulate cortex and posterior occipital

cortex in GAD

Structural MR Imaging Diffusion-Tensor Image Functional MR Proton MR Spectroscopy

Agarwal N et al. Update on the Use of MR for Assessment and Diagnosis of Psychiatric Diseases Radiology: Volume 255: Number 1—April 2010

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