Diane McIntosh, BSc Pharmacy, MD, FRCPC Clinical … · FRCPC Clinical Assistant Professor,...
Transcript of 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
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
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
Neuroanatomy of FEAR
Adapted from Pierre Bleau, 2003
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
Neuroanatomy of FEAR
THREAT
DANGER
thalamus
Adapted from Pierre Bleau, 2003
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?
Neuroanatomy of FEAR
Adapted from Pierre Bleau, 2003
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
© 2009 K. Kjernisted
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
© 2009 K. Kjernisted
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
Post-Synaptic Projection Areas
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
+
© 2009 K. Kjernisted
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
Post-Synaptic Projection Areas
Depressed anxious state- Phasic reactivity in response to stress or threatening stimulus
Locus Ceruleus
Alpha-2 Somatodendritic
Autoreceptors
NE neuron
Alpha-2 Terminal Autoreceptors
NE Reuptake Transporter
α-2
α-2
α-2
α -1
α-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
+
© 2009 K. Kjernisted
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
Post-Synaptic Projection Areas
Tonic activity- After three or more weeks of NRI or SNRI
Locus Ceruleus
Alpha-2 Somatodendritic
Autoreceptors
NE neuron
Alpha-2 Terminal Autoreceptors
NE Reuptake Transporter
α-2
α-2
α-2
α -1
α-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
© 2009 K. Kjernisted
+ 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
Post-Synaptic Projection Areas
Locus Ceruleus
Alpha-2 Somatodendritic
Autoreceptors
NE neuron
Alpha-2 Terminal Autoreceptors
NE Reuptake Transporter
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
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
+ anxiolytic
Increased extracellular NE tonically
both potentially anxiolytic
© 2009 K. Kjernisted
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
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
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
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
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
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
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