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Anxiety Disorders • Five principle categories of anxiety disorders – Generalized Anxiety Disorder (GAD) 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 • Anxiety can be present 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 attack – A panic attack is characterized by all of 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 – When panic attacks recur • Usually begins in 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 disorder • Stimuli related to autonomic nervous system activity can cause panic attacks 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 (α 2 -adrenergic receptor agonist) • Indicates that perhaps those with panic disorder have a hypersensitive ANS • Also provide tools for studying panic disorder

Phobias • Irrational fears – toward a specific object or situation – Individual recognizes 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) • This is a severe and chronic emotional disorder 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

PTSD • Symptoms continued – Higher probability of • • Attempting suicide Marital problems 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%

 • There appears to be a genetic component to vulnerability to PTSD – • 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

17. 4 Average blood cortisol levels in several groups of offspring of Holocaust survivors 17. 4 Average blood cortisol levels in several groups of offspring of Holocaust survivors

Obsessive compulsive disorder • OCD is characterized by recurring, persistent, intrusive thoughts – Obsessions 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

17. 5 Occurrence of OCD symptoms (Part 1) 17. 5 Occurrence of OCD symptoms (Part 1)

17. 5 Occurrence of OCD symptoms (Part 2) 17. 5 Occurrence of OCD symptoms (Part 2)

 • OCD is considered an anxiety disorder because of the intense anxiety the • 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

 • OCD is also often comorbid with other movement disorders – Tourette’s syndrome • 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 • Abnormalities in a neural loop that includes – basal 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 OCD • PET scans show increased activity in the basal ganglia 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 OCD • Neurosurgery can be very effective (50 -70%) – destroy 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 • Light-dark crossing test – Two compartment box • One 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 anxiety • Elevated plus maze – Cross shaped maze raised above 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 anxiety • Water-lick suppression test – Train water deprived rats to 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

 • Conditioned response suppression – Very similar to water-lick suppression – First train • 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 used to treat anxiety are known as anxiolytics 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 • Oldest sedative hypnotic • Three types – Ultrashort-acting 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

Barbiturates • Short/intermediate-acting – Moderately lipid soluble – Take longer to reach significant brain Barbiturates • Short/intermediate-acting – Moderately lipid soluble – Take longer to reach significant brain levels – Likely to produce relaxation and sleep in 2040 minutes • Lasts 5 -8 hours – This group is most likely to be prescribed for insomnia – Also likely to be abused

Barbiturates • Long-acting – Poor lipid penetration – Onset takes an hour or more Barbiturates • Long-acting – Poor lipid penetration – Onset takes an hour or more – Effects last for 10 -12 hours – Useful for treating seizure disorders

barbiturates • Side effects – Abnormal sleep patterns • Barbiturates induce sleep, but it 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 therapeutic dose • Extremely dangerous if combined with alcohol

barbiturates • Metabolic tolerance occurs with repeated use – Increased liver enzymes • Pharmacodynamic 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, therapeutic index declines with repeated use.

17. 9 Margin of safety 17. 9 Margin of safety

Barbiturates • Produce significant physical dependence – Potentially fatal rebound excitability withdrawal syndrome similar 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 • Pharmacologists were looking for better anxiolytics because of barbiturates – high incidence 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

Benzodiazepines • The first benzodiazepine was chlordiazepoxide (librium) – Reduced anxiety without producing excessive 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)

Benzodiazepines • All BDZs have a common molecular structure and similar mechanism of action 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

Benzodiazepines • Long-acting BDZs – Undergo several metabolic steps which produce multiple active metabolites 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

Benzodiazepines • BDZs cannot be used for deep anesthesia – Can be used for 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

Benzodiazepines • BDZs produce anxiety relief – Relieve subjective as well as physical symptoms 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

Benzodiazepines • Advantages of BDZs over other sedative hypnotics – Safer • Hard to 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 • Buspirone (Bu. Spar) – Unlike sedative-hypnotics it does not enhance GABA Second-generation anxiolytics • Buspirone (Bu. Spar) – Unlike sedative-hypnotics it does not enhance GABA function – Acts as a partial agonist at 5 -HT 1 A 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 • SSRIs – Are often used to treat OCD • TCAs 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 • The Barbiturates and BDZs work on the 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 also spots for Barbiturates and BDZs

 • BDZs increase the affinity of GABA for its receptor site – This • 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 amygdala has long been viewed as the brain 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”

17. 16 The amygdala coordinates components of emotion (Part 1) 17. 16 The amygdala coordinates components of emotion (Part 1)

17. 16 The amygdala coordinates components of emotion (Part 2) 17. 16 The amygdala coordinates components of emotion (Part 2)

17. 16 The amygdala coordinates components of emotion (Part 3) 17. 16 The amygdala coordinates components of emotion (Part 3)

Role of GABA in anxiety • We have already discussed the fact that barbiturates 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 ligands for BDZ receptors? – The BDZ receptors 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

 • These inverse agonists are presumed to uncouple the GABA receptors form the • These inverse agonists are presumed to uncouple the GABA receptors form the Clchannels so that GABA is less effective. – This would lead to increased membrane excitability

17. 18 The anxiety-producing b-carbolines are inverse agonists at the BDZ receptor 17. 18 The anxiety-producing b-carbolines are inverse agonists at the BDZ receptor

 • Other natural ligands for the BDZ receptor have also been identified • • 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 17. 19 PET scans of a control subject (left panel) and a patient with panic disorder (right panel)

 • GABA is the major inhibitory NT throughout the nervous system • Changes • 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.