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Anxiety Disorders. Five principle categories of anxiety disorders Generalized Anxiety Disorder (GAD) Panic Disorder (Panic Attacks) Phobias Post Traumatic Stress Disorder (PTSD) Obsessive Compulsive Disorder (OCD) . Generalized Anxiety Disorder. Anxiety has no real focus

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anxiety disorders
Anxiety Disorders
  • Five principle categories of anxiety disorders
    • Generalized Anxiety Disorder (GAD)
    • Panic Disorder (Panic Attacks)
    • Phobias
    • Post Traumatic Stress Disorder (PTSD)
    • Obsessive Compulsive Disorder (OCD)
generalized anxiety disorder
Generalized Anxiety Disorder
  • Anxiety has no real focus
  • Anxiety can be present for most of the day
  • Chronic anxiety
    • Persists for months or years
  • One of the more common anxiety disorders
    • Estimated 5% of population between 15 and 45 will suffer
panic attacks
Panic Attacks
  • Panic attack
    • A panic attack is characterized by all of the effects of the fear reaction in the absence of a threatening stimulus
    • Strong sympathetic effects
      • Shortness of breath, heart pounding, chest pain, choking, fear of losing control, fear of dying
    • Can occur without warning
    • Also can occur in a situation that previously elicited an attack
panic disorder
Panic disorder
  • Panic disorder
    • When panic attacks recur
      • Usually begins in the late twenties
      • Can last for many years
      • Experience both panic attacks and anxiety
        • Anticipatory anxiety
          • Fear of having an attack in an unsafe/embarrasing situation
      • This anticipatory anxiety can lead to agoraphobia
        • Fear of public places
  • Well documented genetic predisposition for panic disorder.
    • Higher concordance rate in monozygotic compared to dizygotic twins
    • Parents often have also diagnosed
panic disorder6
Panic disorder
  • Stimuli related to autonomic nervous system activity can cause panic attacks in those with the disorder
    • Injection of lactic acid (produced by muscle exertion)
    • Caffeine
    • Yohimbine (α2-adrenergic receptor agonist)
  • Indicates that perhaps those with panic disorder have a hypersensitive ANS
  • Also provide tools for studying panic disorder
phobias
Phobias
  • Irrational fears
    • toward a specific object or situation
    • Individual recognizes that it is irrational
  • Interferes with normal lifestyle
  • Phobias are influenced at least partially by culture
    • Chinese pa-leng
      • Morbid fear of being cold
  • Behavioral therapies can be very effective
    • Systematic desensitization
    • Flooding
  • Medications rarely used
post traumatic stress disorder ptsd
Post traumatic stress disorder (PTSD)
  • This is a severe and chronic emotional disorder that occurs after experiencing a traumatic event
    • war, disaster, assault, auto accident, rape
  • Symptoms include
    • Nightmares and unwanted recurring memories (flashbacks)
    • Sleep issues
    • Increased reactivity to stimuli related to the stress event
    • Avoidance of stimuli related to the stress event
    • Numbing of general emotional response
      • Feel detached from others
      • Fail to experience full range of emotions
        • Diminished interest in life activities
      • Can have sudden outbursts of irritability
slide9
PTSD
  • Symptoms continued
    • Higher probability of
      • Attempting suicide
      • Marital problems
      • Depression
      • Feelings of guilt and anger
  • Prevalence estimates vary from 1-10% in the U.S.
    • Depends on type of trauma
      • Personal attack – 3%
      • Natural disaster – 4-16%
      • War veterans – 30%
      • Rape victims – 50%
      • Tortured prisoners of war – 50-75%
slide10
There appears to be a genetic component to vulnerability to PTSD
    • Concordance rates in twin studies
    • Family histories
      • Those that develop PTSD are likely to have a family history of pschopathology
  • Children who have parents with PTSD have an increased risk for PTSD
    • Also tend to have lower-than-normal cortisol levels.
    • This may be a marker for increased risk
      • Opposite of what we talked about for depression
        • Depression = increased cortisol
      • May reflect a hyper sensitive feedback loop
        • Thus, the HPA axis is considered to be hypersensitive to any form of stimulation
obsessive compulsive disorder
Obsessive compulsive disorder
  • OCD is characterized by recurring, persistent, intrusive thoughts
    • Obsessions
      • Contamination, violence, sex, religion
  • Also repetitive rituals that seem to be an attempt to relieve the anxiety generated by these obsessive thoughts
    • Compulsions
      • May be directly related to the obsessive idea
        • Hand washing
      • May be completely unrelated to obsession, but patient feels compelled to act or there may be disastrous consequences
        • Counting cracks in sidewalk
        • Jumping through doorways
        • Chewing food at least 100 times
  • As you saw in the film these rituals are recognized by the patient as inappropriate and irrational
    • Feel compelled to act; almost as if against their will
slide15
OCD is considered an anxiety disorder because of the intense anxiety the patients feel if they do not perform the compulsion
  • Some researchers speculate that the disorder may be a motor disorder
    • Many of the compulsions resemble species-typical behaviors of other animals
      • Grooming, nest building, defensive behavior
        • Brelands “misbehavior of organisms”
          • OCD racoon?
          • tried to train to place coins in piggy bank
      • Perhaps these repetitive acts are innate traits that are being inadequately inhibited by the cortex
slide16
OCD is also often comorbid with other movement disorders
    • Tourette’s syndrome
    • Sydenham’s chorea
      • Saint Vitus’ dance
    • Parkinson’s Disease
  • Each of these diseases involve uncontrolled movement
  • Each of these diseases involve the function of the basal ganglia
neurobiological model of ocd
Neurobiological model of OCD
  • Abnormalities in a neural loop that includes
    • basal ganglia, frontal lobe, thalamus, and anterior cingulate
  • CT scans show abnormalities in caudate
    • An area that allows us to sequence elaborate behaviors
neurobiological model of ocd18
Neurobiological model of OCD
  • PET scans show increased activity in the basal ganglia and frontal lobes
  • Pharmacotherapy with SSRIs or cognitive behavior therapy decreases activity in the caudate, anterior cingulate, orbitofrontal cortex, and thalamus
  • Arrow in figure indicates caudate
neurobiological model of ocd19
Neurobiological model of OCD
  • Neurosurgery can be very effective (50-70%)
    • destroy the anterior cingulate
    • or sever the connection between the frontal cortex and subcortical areas
      • including basal ganglia and thalamus
animal models of anxiety
Animal models of anxiety
  • Light-dark crossing test
    • Two compartment box
      • One side is brightly lit
      • Other side is dark
    • Count crossings back and forth
  • Antianxiety drugs can lead to more crossings and more time spent in lit side
animal models of anxiety21
Animal models of anxiety
  • Elevated plus maze
    • Cross shaped maze raised above the ground
    • 2 closed arms and 2 open arms
  • Measure time spent in closed vs. open
    • Antianxiety drugs can cause increased time spent on open arms
animal models of anxiety22
Animal models of anxiety
  • Water-lick suppression test
    • Train water deprived rats to lick from the tip of a metal drinking spout
    • During test every 20 licks causes a mild tongue shock
    • This causes suppression of the lick response compared to animals that do not receive tongue shocks
    • Antianxiety drugs cause reduced lick suppression
slide23
Conditioned response suppression
    • Very similar to water-lick suppression
    • First train rats that a warning stimulus (tone or light) predicts foot shock.
    • Then train rats to barpress for RF (could be food or water)
    • When the warning stimulus is presented while the animal is barpressing they will suppress responding
      • Conditioned response suppression
    • Anxiolytic drugs reduce this suppression
drugs for treating anxiety
Drugs for treating anxiety
  • Drugs used to treat anxiety are known as anxiolytics
  • CNS depressants
    • Include barbiturates, benzodiazepines, and alcohol
    • All of these drugs reduce neuron excitability making GABA more effective
barbiturates
Barbiturates
  • Barbiturates
  • Oldest sedative hypnotic
  • Three types
    • Ultrashort-acting barbiturates
      • Highly lipid soluble
      • Readily penetrate the brain
      • IV admin. can put a person to sleep in 10-20 seconds
      • Consciousness returns in 20-30 minutes
barbiturates26
Barbiturates
  • Short/intermediate-acting
    • Moderately lipid soluble
    • Take longer to reach significant brain levels
    • Likely to produce relaxation and sleep in 20-40 minutes
      • Lasts 5-8 hours
    • This group is most likely to be prescribed for insomnia
    • Also likely to be abused
barbiturates27
Barbiturates
  • Long-acting
    • Poor lipid penetration
    • Onset takes an hour or more
    • Effects last for 10-12 hours
    • Useful for treating seizure disorders
barbiturates29
barbiturates
  • Side effects
    • Abnormal sleep patterns
      • Barbiturates induce sleep, but it is not a normal restful sleep
      • Reduce the amount of REM
      • Cause REM rebound
    • Cognitive side effects
      • Mental clouding
      • Loss of judgment
      • Slowed reflexes
    • Higher doses
      • Intoxication
      • Staggering
      • Jumbled speech
    • Coma and death due to respiratory failure can occur at 10-20 times the therapeutic dose
      • Extremely dangerous if combined with alcohol
barbiturates30
barbiturates
  • Metabolic tolerance occurs with repeated use
    • Increased liver enzymes
  • Pharmacodynamic tolerance also occurs
    • CNS neurons adapt to the presence of the drug
    • Mood changes and sedation show greatest and most rapid tolerance
    • The lethal respiratory depressant action of the drug does not show tolerance at all.
  • Thus, the therapeutic index declines with repeated use.
barbiturates32
Barbiturates
  • Produce significant physical dependence
    • Potentially fatal rebound excitability withdrawal syndrome similar to that of alcohol
  • Illicit use
    • The short/intermediate acting barbiturates are popular on the street
      • Seconal, nembutal, and amytal
benzodiazepines
benzodiazepines
  • Pharmacologists were looking for better anxiolytics because of barbiturates
    • high incidence of side effects
    • Rapid tolerance
    • Great abuse potential
  • The benzodiazepines were introduced in 1960
    • Have replaced prescription of barbiturates
benzodiazepines34
Benzodiazepines
  • The first benzodiazepine was chlordiazepoxide (librium)
    • Reduced anxiety without producing excessive sedation
    • Low incidence of tolerance
    • Less severe withdrawal syndrome
    • Very safe therapeutic index.
  • Now there are many benzodiazepines
    • Including
      • Diazepam (valium)
      • Oxazepam (serax)
      • Flurazepam (dalmane)
benzodiazepines35
Benzodiazepines
  • All BDZs have a common molecular structure and similar mechanism of action
  • Like barbiturates the choice of a BDZ for a particular therapeutic situation depends on the speed of onset and duration of action
  • The duration of action is determined by
    • 1) differences in the method of biotransformation
    • 2) extent of redistribution to inactive locations
      • Skeletal muscle
      • fat
benzodiazepines36
Benzodiazepines
  • Long-acting BDZs
    • Undergo several metabolic steps which produce multiple active metabolites that can have very long half lives
      • 60 hours or more.
  • Short-acting BDZs
    • Are metabolized in one step into inactive metabolites
benzodiazepines37
Benzodiazepines
  • BDZs cannot be used for deep anesthesia
    • Can be used for presurgical anesthesia during which patient is conscious but less aware
      • Also quite relaxed
  • Also commonly used before major dental work
  • Some of the BDZs can cause anterograde amnesia.
    • This is considered useful when used for surgical treatments
    • Some forms of BDZs have been used as date rate drugs
      • Flunitrazepam (Rohypnol)
        • Combined with alcohol
          • Impairs judgment
          • Causes sedation
          • Causes amnesia
        • Govt. has classified as a schedule 1
benzodiazepines38
Benzodiazepines
  • BDZs produce anxiety relief
    • Relieve subjective as well as physical symptoms
    • Does so with less side effects like mental clouding and motor incoordination
    • The mild sedation that initially occurs decreases with repeated use
    • There is little tolerance to the antianxiety effects
  • Some of the BDZs are used as sleeping aids (hypnotics)
    • There are issues with sleeping pills
benzodiazepines39
Benzodiazepines
  • Advantages of BDZs over other sedative hypnotics
    • Safer
      • Hard to overdose unless taken with another depressant (like alcohol)
      • Do not increase number of liver enzymes
        • Reduced tolerance and fewer effects on the metabolism of other drugs
    • Lower probability of physical dependence and abuse
      • Though a much milder form of physical dependence (compared to barbiturates) does occur
  • There are now partial BDZ agonists
    • Imidazenil, etizolam, abecarnil, bretazenil
    • Bind to BDZ receptor but produce a smaller effect
      • Likely to reduce anxiety with fewer side effects
second generation anxiolytics
Second-generation anxiolytics
  • Buspirone (BuSpar)
    • Unlike sedative-hypnotics it does not enhance GABA function
    • Acts as a partial agonist at 5-HT1A receptors
    • Onset of effectiveness is long
      • Several weeks of daily use
        • Like antidepressants probably relies on compensatory mechanism
          • Probably down regulation of 5-HT receptors
  • Decreases anxiety
    • But has a bigger effect on cognitive aspects rather than physical symptoms
  • Has fewer side effects
  • Little to no potential for abuse or physical dependence
  • Also no rebound withdrawal syndrome
antidepressants for anxiety
Antidepressants for anxiety
  • SSRIs
    • Are often used to treat OCD
  • TCAs and MAO-Is
    • Are often used to GAD, panic disorder, and sometimes phobic disorders
nuerochemical basis of benzodiazepines and barbiturates
Nuerochemical basis of Benzodiazepines and barbiturates
  • The Barbiturates and BDZs work on the GABAA receptor.
  • You probably recall that this is a Cl- channel.
  • There is a spot for GABA to bind
  • There are also spots for Barbiturates and BDZs
slide44
BDZs increase the affinity of GABA for its receptor site
    • This makes the Cl- channel open more often leading to inhibition
    • Do not affect the channel in the absence of GABA
  • Barbiturates also increase the affinity of GABA for its receptor site
    • But increase the duration that the Cl- channel remains open rather than number of openings
    • can open Cl- channels in the absence of GABA
      • Perhaps that is why they are more dangerous
the neurobiology of anxiety
The neurobiology of anxiety
  • The amygdala has long been viewed as the brain area that mediates fear reactions
  • Lesioning amygdala prevents the acquisition of conditioned emotional response
    • CS-light --> US-shock = UR –fear
      • CS-light = CR-fear
  • Humans with damage to the amygdala have difficulty recognizing the fearful facial expression
  • Many anxiolytic drugs have effects if injected directly into the amygdala
  • The prefrontal cortex appears to exert inhibitory control over the more primitive limbic system response
    • This allows us to make more appropriate responses to modern anxiety
      • Rather than just “fight or flight”
role of gaba in anxiety
Role of GABA in anxiety
  • We have already discussed the fact that barbiturates and BDZs increase the effectiveness of GABA and are effective anxiolytics
  • Local administration of GABA or muscimol (GABA agonist) into the amygdala is anxiolytic
  • BDZs adminstered directly into the amygdala is also anxiolytic
  • However, BDZs can reduce anxiety even after destruction of the amygdala
    • So there must be multiple pathways.
    • Nevertheless GABA clearly seems to be involved
natural bdz receptor ligands
Natural BDZ receptor ligands
  • Natural ligands for BDZ receptors?
    • The BDZ receptors occur in high concentrations in the amygdala and other portions of the limbic system that regulates the fear response
    • There are endogenous inverse agonists that bind to the BDZ receptor and produce opposite actions of the drugs we have discussed
    • The β-carbolines and diazepam binding inhibitors are two classes of these inverse agonists
      • Cause extreme anxiety and sense of panic when administered to humans
slide51
These inverse agonists are presumed to uncouple the GABA receptors form the Cl- channels so that GABA is less effective.
    • This would lead to increased membrane excitability
slide53
Other natural ligands for the BDZ receptor have also been identified
  • The endozepines appear to act as BDZ receptor agonists
    • And, thus, may serve as natural anxiety-reducing agents
  • In animal studies of anxiety in conflict situations (like lick suppression test) some animals are more anxious and some are more laid back
    • More emotional animals have shown to have fewer BDZ receptors in several brain areas
  • In patients with panic disorder, PET scans show less BDZ binding, particularly in portions of the frontal lobe.
    • Thus, GABA may not be able to prevent the panic attacks…too few binding sites.
17 19 pet scans of a control subject left panel and a patient with panic disorder right panel
17.19 PET scans of a control subject (left panel) and a patient with panic disorder (right panel)
slide55
GABA is the major inhibitory NT throughout the nervous system
  • Changes in GABA modify several other NTs
    • Including
      • NE
      • 5-HT
      • CRF
      • DA
  • The changes in the interactions of these NTs particularly in the locus coeruleus and amygdala probably modulate normal anxiety
  • But disruption in this system probably leads to anxiety disorders
  • Your book goes into quite a bit more depth about how these systems interact, but I am going to leave it at that.
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