Download Psychopharmacology

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 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 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 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 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
• 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 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
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
– 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
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 2)
• 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
– 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 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 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 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 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 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 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 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
• 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
• 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 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
– Effects last for 10-12 hours
– Useful for treating seizure disorders
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
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.
17.9 Margin of safety
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 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
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
• 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 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 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
– 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 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 (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
• 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 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
• 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 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 2)
17.16 The amygdala coordinates components of emotion (Part 3)
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 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 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
• 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)
• 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.