April 10, 2015
Elliott K. Lee MD, FRCP(C)
Staff Psychiatrist
Anxiety Disorders Clinic
Royal Ottawa Mental Health Centre

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Anxiety results from an unknown internal stimulus, or is inappropriate or excessive when compared to the existing external stimulus.
It is an expected, normal and transient response to stress; may be a necessary cue for adaptation and coping (future event)

Pathologic anxiety
1.
2.
Autonomy : i.e. Minimal/no recognizable environmental trigger
Intensity – exceeds tolerance capacity
3.
4.
Duration – persistent, not transient
Behaviour – impairs coping: results in disabling behavioural strategies – avoidance, withdrawal

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Physical symptoms:
- autonomic arousal – tachycardia, tachypnea, diaphoresis, diarrhoea, light headedness
Affective symptoms:
Mild edginess
Severe terror, feeling loss of control, dying
Behaviour
Avoidance, or compulsions (“compensatory”)
Cognitions – worry, apprehension, obsessions

Anxiety disorders are
Prevalent , real, serious, treatable
Anxiety disorders are not
Signs of personal weakness

Nutt et al. In: Handbook of Anxiety and Fear 2008

Neurophysiology
Psychodynamic formulation
Cognitive behavioural formulation

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Central noradrenergic system (NE): locus coeruleus (LC)– major source of brain’s adrenergic innervation. E.g. – stimulate LC – get panic attacks; block LC – decrease
Gamma Amino Butyric Acid (GABA) system
Especially – septohippocampal areas – mediate generalized anxiety, worry, vigilance
- BDZ bind to GABA receptors; reduce vigilance
Serotonergic system (5-HT)
Modulate above 2 systems – explains efficacy of multiple clinical interventions – SSRIs, SNRIs,
GABA agents, CBT

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Psychopharmaology for anxiety disorders is based on those neurotransmitter systems:
1) Norepinephrine
TCAs, Prazosin
2) GABA
Benzodiazepines, anticonvulsants
3) Serotonergic (5-HT) modulation
- SSRIs, SNRIs, TCAs

Limbic cortex
Nucleus accumbens
Orbitofrontal cortex
Amygdala
Hippocampus Ventral
Tegmental Area
Periaqueductal
Gray matter
Brain Stem

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State anxiety
An interruption of one’s emotional state
- become restless, agitated, and then may react/overreact to external stimuli
- high state anxiety is unpleasant – pts may seek out “adaptive” behaviours to alleviate this.
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Trait anxiety
“Stable aspect of personality”
- may worry all the time, even with
“normal stimuli”, then when there’s a real threatening stimuli – may worry even more

Panic
Disorder
OCD
GAD
SSRI or
SNRI
(8-12 wks)
PTSD
Social
Anxiety disorder

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Switch Drug
- Another SSRI/SNRI
- Alpha2Delta drug
- Clomipramine
- OCD
- Panic Disorder
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NB NEVER COMBINE
SSRI/SNRI with MAOI
SSRI + MAOI = DOA
(Serotonin Syndrome)
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Augment:
- Clonazepam (not SAD,
OCD, PTSD)
- Buspirone (SAD, GAD)
- Gabapentin/Pregabalin
- GAD
- Social phobia
- PTSD
- Pain
- Atypical Antipsychotic
- GAD, OCD, PTSD

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SSRIs
- Fluoxetine (Prozac)
- Paroxetine (Paxil)
- Sertraline (Zoloft)
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- Fluvoxamine (Luvox)
- Citalopram (Celexa)
- Escitalopram (Cipralex)
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SNRIs
- Venlafaxine (Effexor)
- Desvenlafaxine (Pristiq)
- Cymbalta (Duloxetine)
-Pain
NDRI
- Bupropion
(Wellbutrin, Zyban)
(Anxiety worse)
NRI
- Atomexetine (Strattera)
- Indicated for ADHD

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Focus on information processing and behavioural reactions
Faulty cognitionse.g. Overprediction of likelihood/degree of catastrophe
Attempts to neutralize anxiety – e.g. With avoidance, compulsive behaviour, paradoxically “lock in” or reinforce anxiety
►chronic arousal and anticipatory anxiety

Trigger
Reduced
Anxiety
Perception of
Danger
Cognitive restructuring
Beliefs &
Assumptions
Increased
Anxiety
- Escape
- Avoidance
- Safety behaviours
Exposure therapy

Single person sees attractive person
Automatic thoughts/Feelings:
I am foolish, I am incompetent, I am not loveable
Automatic thoughts/Feelings: that person is attractive, I am a good person. Maybe we can be a good match. Let’s find out
Behaviour: Initiate conversation*** Behaviour: RUN!
Reinforcement:
I have not dated; good people don’t like me; I am foolish, I am incompetent, I am not loveable
Reinforcement:
Attractive person seemed to enjoy talking to me. Maybe I have something to offer in a relationship

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Cognitive Behavioural Therapy (CBT) is based on these notions
Replace anxiogenic thoughts and behaviours with positive ones.
Anxiety Thought
• World is dangerous
• I am not competent
• I can not cope
Coping Thought
• World is safe
• I am competent
• I can cope

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Anxiety = threat to the ego; signals are elicited because current events have similarities
(symbolic or actual) to threatening developmental experiences (traumatic anxiety)
Object relations theorists emphasize the use of internalized objects to maintain affective stability under stress

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Generalized Anxiety Disorder
Panic Disorder
Agoraphobia
Specific Phobia
Social Phobia/Social Anxiety disorder
Generalized Anxiety Disorder
Anxiety Disorder Due to Another Medical
Condition or Substance-Induced Anxiety Disorder
Unspecified Anxiety Disorder
(Related: Obsessive compulsive and related disorders, trauma and stressor-related disorders)

Somers et al. Can J Psychiatry 2006

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9282 pts – english speaking
12 month prevalence of numerous psychiatric disorders
Any psychiatric disorder 26.2%
Any anxiety disorder 18.1%

10
5
Kessler et al. Arch Gen Psychiatry, 2005
Specific phobia
(8.7%)
Social phobia
(6.8%)
PTSD
(3.5%)
GAD
(3.1%)
Panic
(2.7%)
OCD
(1%)

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Persistent and irrational fear of certain objects or situations
Exposure provokes anxiety/panic response
Recognized as excessive or unreasonable
Phobic object/situation avoided or endured with intense anxiety or distress
Significant interference or marked distress
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Types: animals/insects, natural environment, blood/injury, situational, other

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Most common anxiety disorder
Marked and persistent fear of clearly discernible circumscribed objects or situations
Exposure almost invariably provokes anxiety
Fear is recognized as excessive or unreasonable
(though children may not )
Phobic stimulus is avoided, or tolerated with dread
Avoidance/fear leads to significant distress or interference with social/occ functioning
In children – should persist >6 m

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Biopsychosocial
- Bio
- Medications – generally not helpful.
BDZs – may provide some temporary relief
(e.g. For flying etc.)
Psychosocial
- Exposure therapy – has shown the most benefit
Novel methods
- internet based
- virtual reality

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Fear of social or performance situations due to anticipated scrutiny, humiliation or embarrassment
Exposure provokes anxiety/panic
Considered excessive or unreasonable
Situations avoided or endured with anxiety
Significant interference or suffering
Duration > 6 months
(Specify: performance only)

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Epidemiology:
- 6.8% of the population
- Onset - by age 11, 50% have symptoms;
- by age 20, 80% have symptoms
- I.E.- CHILDHOOD ONSET
- Children – may refuse to go to school;
- Associated with early drop out from school
- Selective mutism – highly likely becomes social anxiety disorder (severe variant)

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Etiology
-Familial, with recurrence risk ratio 2<x<6 i.e. Moderate heritability
(chromosome 16 implicated –NE transporter)
Consequences:
- Reduced work productivity
- Financial costs
- Reduced quality of life
Despite these issues – only half seek treatment, and usually after 15-20 years of suffering

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ALCOHOL /SUBSTANCE ABUSE/DEPENDENCE
- Strongly consider underlying social phobia in pts with a history of alcohol abuse/dependence
» ¼ of pts may have comorbid abuse
Parkinsons pts – may frequently develop social anxiety – suggesting striatal involvement

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Biopsychosocial approach
Bio –
SSRIs*
Escitalopram
SNRIs*
Venlafaxine
RIMAs+MAOIs AntiCon
Moclobemide
BDZs
Gabapentin Clonazepam
Fluvoxamine Phenelzine Pregabalin Alprazolam
Sertraline
Paroxetine
Citalopram
Fluoxetine
Divalproex
Topiramate
Bromazepam
1 st line: SSRI, SNRI, Pregabalin
2 nd line: BDZ, AntiCon, MAOI

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CBT - 12-15 sessions – lasting 50-90 minutes
(individual or group therapy)
Correcting distorted cognitions – e.g.
Everyone laughing at me – come up with alternative explanations
Exposure therapy – may be integrated in CBT
- e.g. Returning item, going to crowded mall
Social skills training
- making small talk, looking at tone, posture, active listening, assertiveness

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Epidemiology
- 3.1% of the population affected (F:M = 2:1)
- Onset
(median US age=31 yrs, but often childhood)
- 25% have onset by 20 yrs old
- 50% have onset b/w 20-47 yrs old
- >90% comorbidity
Kessler RC et al. Arch Gen Psychiatry, 2005

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Elderly –
- may be associated with social isolation, trauma, migration, illness in spouse, bereavement
- left untreated – may be associated with medical/psychiatric complications
- Cardio/cerebrovascular disease
- COPD
- Malnutrition
- Depression
- Dementia
- Alcohol abuse
Weisberg R.B. J Clin Psychiatry, 2009

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Etiology
- Multiple neurotransmitters likely involved
- 5-HT, NE, CCK
- Genetic factors likely involved
- Some twin studies – show 50% concordance rate in monozygotic twins, and 15% in dizygotic twins
- Behavioural, psychosocial factors involved

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Excessive, wide-spread and uncontrollable anxiety and worry (  6 months)
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Symptoms of tension and exhaustion (≥3/6)
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 restlessness, muscle tension, tiredness, irritability, insomnia, difficulty concentrating
(SICKEM – sleep, irritability, conc, keyed up/restless, energy, muscle tension)
NB – children only need ≥1
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Worry not confined to another Axis I disorder
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Significant distress or impairment
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Not due to the effects of substance of GMC

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Often – do not present with anxiety initially
- May be (somatic)
Pain
Fatigue
Sleep disturbances
Poor concentration
Depression
- Frequently associated with disabilities in work, education, and/or social interactions
Comorbidities common (>90%) – mood disorders, anxiety disorders, substance abuse

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Biopsychosocial approach
- Bio
SSRIs* SNRIs* TCAs
Escitalopram* Venlafaxine* Imipramine
Sertraline*
Paroxetine*
Citalopram
AntiCon
Pregabalin
BDZs
Lorazepam
Alprazolam
Bromazepam
Diazepam
1 st line: SSRI, SNRI x 8-12 wks, Pregabalin
2 nd line: BDZ, NDRI, Buspar, TCA

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CBT – most evidence for efficacy
Efficacy is comparable to pharmacologic therapy, but may have higher remission rates
Other therapies that may be effective:
- Short term psychodynamic therapy
- Interpersonal therapy

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Panic attacks (PA)
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Recurrent and unexpected, acute, time-limited symptoms (at least 4/13)
Not caused by substance or GMC
NB Panic attack ≠ Panic disorder (yet)
Anticipatory anxiety
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Concern about additional attacks, their implications and consequences or change in behaviour  1 month
(Agoraphobia)
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Avoidance/distress/anxiety in places or situations difficult to escape or get help in case of PA

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Panic attacks – may come from a dysfunction of the fear circuitry
Amygdala – central involvement
- Consists of several distinct nuclei in the brain
Very high comorbidity
- 50-60% may have comorbid major depressive disorder

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Yohimbine
Lactate
CO2
Caffeine
Isoproterenol
5HT agonists (fenfluramine, m-CPP)
Choleocystokinin (CCK-4, CCK-5)
Stimulants – nicotine, amphetamines

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Biopsychosocial approach
- Bio
SSRIs* SNRIs* TCAs
Escitalopram
Fluoxetine
Sertraline
Paroxetine
Citalopram
Fluvoxamine
Venlafaxine
AntiCon
Imipramine Gabapentin
Clomipramine Divalproex
BDZs
Lorazepam
Alprazolam
Diazepam
Clonazepam
1 st line: SSRI, SNRI
2 nd line: BDZ, NaSSA, TCA
3 rd line: Anticon, MAOI, Atypical Antipsych, RIMA, pindolol

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SSRI Benefits – may be seen within 1 wk;
- up to 6-8 wks
Continued benefits may be seen after 12 m
(e.g. BDZ treatment – maintenance for 3 years has been associated with benefit, though is not routinely indicated for long term use)
Treatment time of 8 -12 m is suggested, to prevent relapse risk.

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CBT – most evidence for efficacy
Efficacy is comparable to pharmacologic therapy, but may have higher remission rates
Other therapies that may be effective:
(BUT – INSUFFICIENT evidence to recommend)
- Psychodynamic therapy
- Eye Movement Desensitization and
Reprocessing (EMDR)

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Epidemiology
- 1% of population (F:M= 3:2)
- Onset – median age 19 yrs old, though can be childhood onset (NB – in childhood, F:M= 1:2)
- Children

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Etiology:
- Dysregulation of 5-HT*
- Genetics – significant
35% of 1 st degree relatives of OCD also have
OCD
- Neuroimaging studies
- show increased metabolism of frontal lobes, caudate and cingulum
- Behavioural, psychosocial factors involved

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Obsessions
 recurrent, persistent thoughts, urges or images experienced as intrusive and anxiety-provoking, distinct from excessive worry, attempted to be suppressed, ignored or neutralized
 contamination, harm/aggression, somatic, religious, sexual
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Compulsions
 repetitive, excessive behaviours or mental acts and rituals aimed to prevent or decrease anxiety/distress
 cleaning, checking, counting, repeating, arranging, hoarding

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Obsessions or compulsions are time consuming
(>1 hr/day ) or cause clinically significant distress
At some point – obsessions/compulsions are recognized as excessive or unreasonable
(may not occur in childhood)
Not due to medical condition/substance

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Obsessions – are distressing – e.g. Repeated thoughts about contamination
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Usual response – compulsion – a behaviour aimed at reducing the anxiety associated with obsession – e.g. wash hands – temporary relief from anxiety of obsession, but then obsession returns.
Egodystonic : i.e. “alien”, not within his/her control BUT – recognized as product of the mind
(i.e. Not thought insertion)

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Children - clinical features:
- Most frequent compulsion children
Handwashing (75%)
- Checking
- Sorting
May not be egodystonic – often brought by parents
Small subset (<5%) – ass with Gp A β-hemolytic streptococcal infection (scarlet fever, “strep throat”) abrupt onset, with motor abnormalities
= PANDAS
( P aediatric A utoimmune N europsychiatric D isorder A ss with S treptococcal infection)

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Elderly onset – more concerns about morality and washing rituals.
Comorbid issues with OCD
“Depressing BODY TAASTE”:
- Depressive disorder
- Body dysmorphic disorder
- Trichotillomania and other impulse control d/o
- Anxiety Disorders
- Autism
- Schizophrenia
- Tourette’s/Tic disorders
- Eating Disorders e.g. Anorexia nervosa

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Biopsychosocial
(NB lowest response rate to placebo among anxiety disorders)
- Bio
SSRIs*
Escitalopram
Fluoxetine
Sertraline
Paroxetine
Citalopram
Fluvoxamine
SNRIs*
Venlafaxine
TCAs
Clomipramine
IV Clomipramine
AntiCon
Gabapentin
Topiramate
1 st line: SSRI
2 nd line: Clomipramine, SNRI, NaSSA
3 rd line: Something else....antipsych, anticon, MAOI
AntiPsych
Risperidone
Olanzapine
Quetiapine
Haloperidol

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Dosages of meds e.g. SSRIs may need to be higher
Response may take 6 wks or longer
Most recommendations – suggest staying on treatment for 1-2 yrs (reduce relapse risk)

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Neurosurgical options
- deep brain stimulation
- anterior cingulotomy
- anterior capsulotomy,
- subcaudate tractotomy
- limbic leucotomy
Indicated for severe OCD, refractory to therapy/medications
40-60% of refractory pts may benefit

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CBT with Exposure Response Prevention (ERP)
- the most evidence for efficacy for treatment
Individual may be better than group
(individualization of treatment)
Adding CBT to pharmacological treatment may yield better long term outcomes

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Epidemiology – genetics, environment
♀>♂, usually 2:1. OCD the exception (1:1)
Look at Trigger:
1) Constant- GAD (6 months)
*Childhood onset
2) Groups of People – Social Phobia (6 months)
3) Parents – Separation
4) Objects/animals – phobia*** commonest
5) Trauma – PTSD (>1 month)
6) “Out of the Blue” – Panic (>1 month)
7) Contamination, “bad things happening”– OCD
NB: Egodystonic
Streptococcus possibility(PANDAs)

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Comorbidity: MAJOR DEPRESSIVE DISORDER (all)
- Social Phobia – Alcohol dependence
- OCD – Depressing BODY TAASTE
Neurotransmitters involved:
5-HT
(esp OCD )
NE GABA
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Structures: Amygdala
Amygdala

Panic
Disorder
OCD
PTSD
GAD
SSRI or
SNRI
Higher doses
(8-12 wks);
(BDZ short term except OCD)
OCD – Can also do neurosurgery
Pregabalin also 1 st line for SAD, GAD.
Social
Anxiety disorder

Panic
Disorder
OCD
PTSD
GAD
Social
Anxiety disorder
EMDR – Used with PTSD
CBT preferred over pharmacotherapy for children/adolescents

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Anxiety is common – we all experience this
Pathological anxiety can also be common, and is not a sign of personal weakness.
Important, but sometimes difficult to recognize.
There are significant biological underpinnings to anxiety disorders.
Psychological approaches are very effective.
Treatment can be very effective, but should be tailored to individual patients.
Use BIOPSYCHOSOCIAL approach.