ANXIETY DISORDERS

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ANXIETY DISORDERS
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OVERVIEW

• Symptoms of anxiety disorders
• Co-morbidity with other disorders
• Diagnostic Criteria
• Gender Differences
• Genetic Studies

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Cont

• Generalized Anxiety Disorder
• Panic Disorder
• Phobias Social
• Obsessive Compulsive Disorder

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ANXIETY DISORDERS

• Panic Disorder with or without Agoraphobia
• Agoraphobia
• Specific Phobia
• Social Phobia
• Obsessive-Compulsive Disorder (OCD)
• Posttraumatic Stress Disorder (PTSD) (NEXT CLASS)
  
• Acute Stress Disorder
• Generalized Anxiety Disorder (GAD)

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PANIC ATTACKS

• Discrete period of intense fear or discomfort in
  which 4 or more of the following symptoms occur
  and peak within 10 minutes
• Accelerated heart rate
• Sweating
• Trembling or shaking
• Shortness of breath

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Cont

• Feeling of choking
• Chest pain or discomfort
• Nausea or abdominal distress
• Dizzy, unsteady, lightheaded, or faint
• Feelings of unreality or depersonalization
• Fear of losing control
• Fear of dying
• Numbness
• Chills or hot flushes

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ANXIETY

• Fear real, immediate danger
• Anxiety general or diffuse emotional reation
  out of proportion
• Worry uncomfortable sequence of negative,
  emotional thoughts/images future threats

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PHOBIAS

• Persistent and irrational
• Very specific object and/or situation
• Avoidance
• or experiences intense anxiety
• Can cause serious impairments in occupational and
  social activities

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AGORAPHOBIA

• fear of marketplace (or places of assembly)
• More intense with distance from familiar place or
  signals of safety
• Panic attacks
• fear of fear
• Aware of internal bodily sensations that may
  signal onset of attach

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OCD

• Obsessions repetitive, unwanted, intrusive
  cognitive events
• intrusiveness diminished control
• Compulsions
• cleaning checking
• ensure safety of self and others

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CO-MORBIDITY

• Various symptoms overlap greatly
• 50 with one anxiety disorder meet criteria for
  another
• Mood Disorders
• panic disorders with or without agoraphobia
• agoraphobia
• OCD

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Cont

• Substance Abuse
• 40 patients with substance abuse also meet
  criteria for at least one anxiety disorder
• Patients with agoraphobia self-medication?
• What about GAD?

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DIAGNOSTIC CRITERIA

• Panic Attack worry about additional attacks
• Agoraphobia comfort or security
• Specific Phobia cued fear unreasonable
• Social Phobia performance
• GAD excessive worry that is difficult to control
• OCD must recognize that OC are unreasonable

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GENDER DIFFERENCES

• Women are more likely to suffer from anxiety
  disorders
• No differences in
• Social phobias
• OCD

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GENETIC STUDIES

• Family studies
• twice as common in first-degree relatives
• high rate of panic disorder in first-degree
  relatives
• patients with panic disorder or GAD relatives
  have high risk of panic disorder, but not GAD
• OCD high rates of anxiety disorders, but not
  necessarily OCD

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Cont

• Twin Studies
• MZ panic disorder, all phobias, OCD
• not for GAD, agoraphobia, animal phobias, or
  social phobia
• Conclusion genetic predisposition for anxiety
  disorders
• Environmental cues for specific disorders?

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GAD Overview

• GABA/Benzodiazepine
• Norepinephrine
• Serotonin
• CCK
• CRH HPA Axis
• Autonomic Functions
• Neuroimaging
• Pharmacotherapy

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GABA/Benzodiazepine

• Benzodiazepine affects action of GABA at GABA
  receptors also binds to GABA receptors
• produce inhibitory postsynaptic potentials
• anxiolytic ex. Valium
• lower number of binding sites for BZ
• BZs increase in number of receptors
• reduced sensitivity of receptors

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NOREPINEPHRINE

• sympathetic nervous system fight flight
• decreased receptor sensitivity
• reduced binding sites/receptor
• ...however not all studies show abnormalities
• challenges to show receptor sensitivities changes
• long-term adaptation?

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SEROTONIN

• overactivity of serotonin initially decrease
  then overcompensation
• stimulating postsynaptic receptors anxiety
• agonists hostility anxiety in GAD
• reduced serotonin in CSF

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CCK

• animal models CCK agonists antagonists
• may interact with other systems
• serotonin
• locus coeruleus activity
• CCK-like compound (pentagastrin) panic attacks
• panic attacks and GAD?

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CRH HPA Axis

• CRH brain regions anxiety fear
• ex. amygdala
• activates locus coeruleus norepinephrine
• links between stress anxiety?
• dexamethasone suppression test
• little evidence of link

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AUTONOMIC FUNCTION

• reduced skin conductance, increased respiration,
  increased blood pressure, and reduced heart rate
  variability
• diminished flexibility?
• links to stress?
• prolonged time for recovery
• reduced heart rate variability

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NEUROIMAGING

• PET Study elevated metabolism in occipital,
  temporal, and frontal lobes
• reduced basal ganglia metabolism
• increased cerebellar metabolism
• after BZ treatment cortical lobes, limbic
  system, and basal ganglia
• control group anxiety scores related to activity
  in limbic system basal ganglia

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PHARMATHERAPY

• 1. Benzodiazepines
• most effective for autonomic symptoms
• 2. Azapirones
• serotonin partial agonist
• fewer withdrawal symptoms
• 3. Antidepressants
• drug of choice

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PANIC DISORDER OVERVIEW

• Neuroanatomy
• Serotonin
• Norepinephrine
• GABA/Benzodiazepine

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NEUROANATOMY

• earliest neuroanatomical circuit Gray 1988
• septohippocampal brain circuit brain stem,
  limbic system, prefrontal cortex
• drugs brain stem
• Cognitive Behavioral Therapy prefrontal cortex

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NEUROIMAGING

• PET studies exaggerated asymmetry
• internally cued alarm systems
• SPECT studies also exaggerated asymmetry
• hippocampus frontal cortex

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SEROTONIN

• rostral serotonin system
• enhanced or diminished?
• Medial vs. Dorsal Raphe Nuclei
• Medial limbic system prefrontal cortex
  modulation of fear anxiety?
• Dorsal many areas cognitive motor components?

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Cont...

• Medial RN Dorsal RN
• SSRIs highly effective by enhancing serotonin
  levels
• unclear how serotonin is abnormal

Locus Coeruleus
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NOREPINEPHRINE

• role of locus coeruleus
• outputs to amygdala, BNST, entorhinal cortex,
  PVN, PAG, lateral hypothalamus
• input from medulla
• input mediated by glutamate, CRH, and substance P
• contains numerous GABA receptors

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Serotonin Norepinephrine?

• SSRI decreases NE global improvement
• increasing NE increases symptoms
• no correlations between serotonin
  norepinephrine metabolites
• but correlation in healthy volunteers

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GABA/Benzodiazepine

• therapeutic effects
• BZ challenge study reduced sensitivity of
  receptors
• BZ-R antagonists anxiogenic
• creates panic in patients, but not in healthy
  volunteers
• altered set point?

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Cont...

• reduced BZ binding in occipital, temporal, and
  frontal cortices
• PET generalized reduction in binding
• orbitofrontal cortex and right insula
• specific effects in amygdala
• basolateral nucleus vs central nucleus

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BEYOND LC/NE...

• LC activity inconsistent results
• high NE metabolites causes panic attacks, but
  only in subgroup
• very variable results with agonists antagonists
• role in arousal and anticipatory anxiety?
• indirect role in some symptoms?

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SOCIAL PHOBIA OVERVIEW

• Autonomic Nervous System
• Respiratory Function
• Neuroimaging
• Neuroendocrine Function
• Social Dominance as a model
• Serotonin
• Dopamine

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Cont...

• Non-generalized vs generalized
• also known as social anxiety disorder

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AUTONOMIC NS

• excessive heart rate in certain situations
• public speaking non-generalized vs generalized
• higher levels of NE before and after behavioral
  challenge
• not replicated sympathetic vs parasympathetic
  nervous systems?
• little research has been done

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RESPIRATION

• CO2 sensitivity is social phobia
• patients are sensitive to panic-provoking effects
  of CO2
• patients with GAD, OCD, and animal
  specific-phobias

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NEUROIMAGING

• MRI abnormal cell membrane composition
• SPECT dopamine binding is reduced in basal
  ganglia in generalized social phobia
• high rates in Parkinsons patients

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NEUROENDOCRINE

• normal dexamethasone suppression and cortisol
  levels
• shy children
• elevated levels of cortisol
• not into adulthood no relation to social phobia

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SOCIAL DOMINANCE

• animal model
• social status in baboons altered HPA axis
• subordinate baboons hypercortisolemia
• not model of social phobia, but consequences of
  being socially phobic
• IGF-1 lower stature linked to social phobia

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Cont Social Affiliation

• roles of oxytocin vasopressin
• Pathways from the hypothalamus to VTA may be
  critical for integrating social information with
  reward pathways..
• social phobia is not rewarding?
• Evaluating risks and benefits of social
  affiliation?
• But look at symptoms

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SEROTONIN

• neuroendocrine challenges
• only effects on serotonin system
• serotonin agonist increase in cortisol
• social dominance serotonin agonist increases
  social status
• responsive to SSRIs

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DOPAMINE

• MOAIs are effective, but not tricyclics
• PET abnormalities in dopamine system
• D2-receptor binding in putamen is related to
  avoidant personality traits

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OCD OVERVIEW

• Neuroimaging
• Glutamate Serotonin

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NEUROIMAGING

• abnormalities in striatum
• increased OCD behaviors are present in patients
  with basal ganglia disorders
• increased activity in caudate nucleus related to
  severity of illness
• conflicted findings

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Cont...

• MRI some studies show changes in caudate nuclei
  volumes
• related to different methodologies
• children vs adult OCD patients
• abnormalities in all pediatric patients
• reduced striatal volumes related to symptom
  severity

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Cont...

• striatal-prefrontal cortex pathways
• impairment in ability to inhibit
  context-inappropriate emotional responses
• lesions of anterior cingulate cortex
• MRI no generalized differences, but specific
  differences in orbitofrontal cortex

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Cont...

• Thalamus
• partial thalamotomy
• increased metabolic rates regional cerebral
  blood flow
• response to treatment
• increased thalamic volumes maturation rates

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Conclusion.

• Abnormalities in prefrontal cortex - striatal -
  thalamic circuitry
• specific reversal by treatment with SSRIs
  normalization of thalamus

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SEROTONIN GLUTAMATE

• interaction between these neurotransmitters
• caudate nucleus glutamate
• inhibition of serotonin by glutamate
• reduction in caudate glutamatergic concentrations
  related to severity
• higher relative levels are related to treatment
  response (SSRIs)

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PRESENTATION FORMAT

• before presentations symptoms, prevalence
  epidemiology, etc.
• one person 15 minutes
• two people 30 minutes
• hand in
• list of 10 references
• three questions for exam

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AUTISM SCHIZOPHRENIA

• a good review article on neurobiology of autism
  background
• primary sources different types of experiments
  being done
• ex. With NTs levels being measured, receptors

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PERSONALITY DISORDERS

• review of neurobiology neuroanatomy not too
  many details
• drugs used to treat several examples
• comorbidity how underlying neurobiological
  deficits are the same between disorders

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DRUG ADDICTION

• describe neural circuit for dependence
• tolerance, sensitization, and withdrawal take an
  example of a drug
• specific drugs how it affects behavior
• classical conditioning describe generally and
  then how heroin can be conditioned

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GENERAL POINTS

• Do not just list studies integration
• can give some details on specific studies
  regarding methodology if interesting
• Remember goal is to teach how these factors
  affect BEHAVIOR and SYMPTOMS.