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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 l.jpg
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)


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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


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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


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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


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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


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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


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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


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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%


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  • 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



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Obsessive compulsive disorder offspring of Holocaust survivors

  • 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


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17.5 Occurrence of OCD symptoms (Part 1) offspring of Holocaust survivors


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17.5 Occurrence of OCD symptoms (Part 2) offspring of Holocaust survivors


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  • 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


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  • OCD is also often comorbid with other movement disorders anxiety the patients feel if they do not perform the compulsion

    • 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


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Neurobiological model of OCD anxiety the patients feel if they do not perform the compulsion

  • 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


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Neurobiological model of OCD anxiety the patients feel if they do not perform the compulsion

  • 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


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Neurobiological model of OCD anxiety the patients feel if they do not perform the compulsion

  • 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


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Animal models of anxiety anxiety the patients feel if they do not perform the compulsion

  • 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


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Animal models of anxiety anxiety the patients feel if they do not perform the compulsion

  • 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


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Animal models of anxiety anxiety the patients feel if they do not perform the compulsion

  • 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


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  • Conditioned response suppression anxiety the patients feel if they do not perform the compulsion

    • 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


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Drugs for treating anxiety anxiety the patients feel if they do not perform the compulsion

  • 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


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Barbiturates anxiety the patients feel if they do not perform the compulsion

  • 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


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Barbiturates anxiety the patients feel if they do not perform the compulsion

  • 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


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Barbiturates anxiety the patients feel if they do not perform the compulsion

  • Long-acting

    • Poor lipid penetration

    • Onset takes an hour or more

    • Effects last for 10-12 hours

    • Useful for treating seizure disorders


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barbiturates anxiety the patients feel if they do not perform the compulsion

  • 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


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barbiturates anxiety the patients feel if they do not perform the compulsion

  • 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.


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17.9 Margin of safety anxiety the patients feel if they do not perform the compulsion


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Barbiturates anxiety the patients feel if they do not perform the compulsion

  • 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


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benzodiazepines anxiety the patients feel if they do not perform the compulsion

  • 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


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Benzodiazepines anxiety the patients feel if they do not perform the compulsion

  • 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)


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Benzodiazepines anxiety the patients feel if they do not perform the compulsion

  • 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


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Benzodiazepines anxiety the patients feel if they do not perform the compulsion

  • 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


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Benzodiazepines anxiety the patients feel if they do not perform the compulsion

  • 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


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Benzodiazepines anxiety the patients feel if they do not perform the compulsion

  • 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


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Benzodiazepines anxiety the patients feel if they do not perform the compulsion

  • 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


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Second-generation anxiolytics anxiety the patients feel if they do not perform the compulsion

  • 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


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Antidepressants for anxiety anxiety the patients feel if they do not perform the compulsion

  • SSRIs

    • Are often used to treat OCD

  • TCAs and MAO-Is

    • Are often used to GAD, panic disorder, and sometimes phobic disorders


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Nuerochemical basis of Benzodiazepines and barbiturates anxiety the patients feel if they do not perform the compulsion

  • 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


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  • BDZs increase the affinity of GABA for its receptor site anxiety the patients feel if they do not perform the compulsion

    • 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


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The neurobiology of anxiety anxiety the patients feel if they do not perform the compulsion

  • 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”





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Role of GABA in anxiety 3)

  • 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


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Natural BDZ receptor ligands 3)

  • 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


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17.18 The anxiety-producing receptors form the Cl- channels so that GABA is less effective.b-carbolines are inverse agonists at the BDZ receptor


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  • 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.


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17.19 PET scans of a control subject (left panel) and a patient with panic disorder (right panel)


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  • 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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