Download Psychopharmacology

Schizophrenia
• Individuals with schizophrenia have many different
symptoms
– Including
•
•
•
•
hearing voices
Unrealistic beliefs
Disorganized communication
Often need to be hospitalized
• Schizophrenia is a chronic condition
– Drugs or environmental toxins can cause acute psychosis
– Despite therapy about 30% of people with schizophrenia spend
a significant portion of their lives in mental hospitals
• About 1-1.5% of the population will suffer from
schizophrenia
– 2-3% will suffer from less severe symptoms that do not meet the
diagnostic criteria
Symptoms of schizophrenia
• Symptoms usually begin
during late teenage years
and early twenties
– can occur in childhood
• Affects men and women
equally
• Clear gender difference in
onset
• Men more likely to get the
disease early in life
• Women more likely to get
the disease later in life
No defining cluster of symptoms
• Schizophrenia is a thought disorder
– Illogical thinking
– Lack of reasoning
– Inability to recognize reality
• Specific symptoms are quite variable for
each individual
• Disturbance of perception (hallucinations)
are common
– Usually auditory
Symptoms of schizophrenia
• Sometimes the voices can be familiar like a
parent or spouse
• Sometimes unrecognized
– Foreign agents
• Radio transmitter in head
• Voices of angels
• Often the voices are critical, demanding, or
accusatory
• Sometimes can direct the person to perform
destructive behaviors
Symptoms of schizophrenia
• Recently researchers have imaged the brain during
hallucinations
• Some consistent findings are
– Usually left cerebral hemisphere is more activated
• Typical language hemisphere
– Most active areas are in the audio linguistic association cortex
• Rather than primary cortex
– Consistent with the internally generated nature of the experience
– Some have hypothesized that auditory hallucinations are like
“inner speech”
• But Broca’s area is often not activated
• Wernicke’s area is usually activated
– Electrical stimulation of this area can cause hallucinations in a healthy
individual
Symptoms of schizophrenia
Symptoms of schizophrenia
• During visual hallucinations
– Activation of visual association cortex
• Interestingly there is also often deep brain
activity
– Including thalamus and limbic system
– Probably contributes to the emotionality of the
experience
Symptoms of schizophrenia
• Bizarre delusions (false beliefs) are also
common
• Delusions of persecution
– People are spying on them
– Planning to do them harm
• Delusions that one’s thoughts are being
broadcasted to others
• Delusion that thoughts are from an outside
source
– Often outer space
Symptoms of schizophrenia
• Emotional disturbances are also common
• Emotions might be absent
– Flattened affect
– Monotone voice
• Emotions may be inappropriate to the situation
– Laughing or smiling when discussing a tragic event
• Can sometimes have unpredictable changes in
mood
Symptoms of schizophrenia
• People with schizophrenia are frequently
withdrawn
– Preoccupied with their own thoughts or delusions
• Often don’t perform everyday activities like
maintain personal hygiene
• Often have motor disturbances
– Inappropriate or bizarre postures
– Stereotyped movements
• Twirling hair
• Rocking or pacing
• Some forms of schizophrenia (particularly
paranoid) can lead to agitation and violence
Diagnosis
• Diagnosis is not simple
– No two individuals show identical patterns
– Nor is there a single symptom that all people
with schizophrenia share
– Symptoms can increase and decrease over
time
• Some believe that schizophrenia
represents a cluster of disorders rather
than a single disorder
• Historically schizophrenia was categorized into
subtypes
– Catatonic
• Alternating periods of immobility and excited agitation
– Can be completely unable to move
– May flail about – pace in a frenzy
• Extreme resistance – won’t respond to any attempt to be
moved or speak
• Mimicking speech (echolalia) or movement (echopraxia)
– Paranoid
• Delusions of grandeur or persecution
• Auditory hallucinations
• Hebephrenic also known as disorganized
– emotional responses can often seem strange or
inappropriate to the situation.
– Inappropriate facial responses may be common
– behavior is sometimes described as 'silly', such as
inappropriate laughter
– Complete lack of expressed emotion is sometimes
seen
– indifference, anhedonia (the lack of pleasure),
– avolitiion (a lack of motivation).
• Undifferentiated
– Doesn’t fit the criteria of the other subtypes
• Another classification scheme refers to positive and
negative symptoms of schizophrenia
• Positive symptoms (too much)
–
–
–
–
Delusions
Hallucinations
Disorganized speech
Bizarre behavior
• Patients with primarily positive symptoms tend to be
older when they get the disease
– Appear relatively normal in younger years
– Respond well to conventional antipsychotic medications
• Block Dopamine receptors
– Symptoms escalate with drugs that enhance dopamine
• Negative symptoms (too little)
–
–
–
–
–
–
•
•
•
•
•
Reduced speech (alogia)
Flattened affect
Loss of initiative and motivation (avolition)
Social withdrawal
Loss of ability to derive pleasure in life (anhedonia)
Intellectual impairment
Tend to show early onset of some symptoms
Long course of progressive deterioration
Resistant to classical antipsychotics
Newer atypical antipsychotics can help
Evidence that neurodegeneration may play a role
Pharmacological treatment has revolutionized treatment of schizophrenia
• Prior to advent of drug treatment there were few
options for patients with schizophrenia
– Restrained in hospitals
– Shock and insulin induced seizures
– Prefrontal lobotomy
• Since the advent of 1950s
– Hospitalization began to decline
– Concided with the drug chlorpromazine (thorazine)
18.2 Treatment of the mentally ill
Preclinical Models of Schizophrenia
• Schizophrenia is primarily a thought disorder
• Difficult to develop animal models
• Stimulant models of schizophrenia
– High doses of stimulants have been used to model
schizophrenia
– Amphetamine and cocaine can cause psychosis in humans
• Paranoid delusions
• Stereotyped, compulsive behaviors
• Visual and auditory hallucinations
– Trained clinicians can have difficulty distinguishing
– If patients with schizophrenia take amphetamines their
symptoms get worse
– Amphetamine induced psychosis responds to the same drugs
used to treat schizophrenia
• In animals high doses of amphetamines
– Cause stereotyped sniffing, licking, gnawing
• Known as amphetamine-induced stereotypy
– Similar to repetitive motions in schizophrenia
• Amphetamine-induced stereotypy is a
classic screening device for antipsychotics
• Another animal model that is used is blockade of
apomorphine-induced motor activity
• Apomorphine is a dopamine agonist that causes
increased activity in rats.
• It has been shown that drugs that reduce apomorphine
induced running are consistently effective antipsychotics
• Researchers usually compare the dose that will block
apomorphine activity (related to therapeutic effect)
– With dose that will produce catalepsy (related to locomotor side
effects)
• The farther apart those two dose response curves are
the more likely the drug will be effective without
producing motor side effects
PCP-induced psychosis
• PCP-induced psychosis
– Original observation in humans serves as the basis for the dopamineglutamate hypothesis of schizophrenia
– The symptoms of high doses of PCP include
• Disorientation, Muteness, Cognitive impairments
– Can sometimes cause paranoid delusions
• Motor symptoms
– Agitation, Grimacing, Rigidity, Catalepsy, Tremors
– Again – closely resembles schizophrenia
– Repeated use of PCP can cause long-lasting psychotic symptoms
• PCP has also been used as animal model of schizophrenia
• What is interesting about this model is that it can cause both positive
and negative symptoms
• Remember that PCP antagonizes glutamate in addition to causing
increases in DA activity
Prepulse inhibition of startle model
• Prepulse inhibition of startle (PPI)
• People with schizophrenia seem to have
difficulty screening out irrelevant information
• One theory is that because they fail to screen
out this information they become bombarded by
stimuli
– Leading to sensory overload
– Fragmented thinking
– Thought disorder
PPI
• Here’s how it works
– Normally a loud noise
causes a strong startle
response
– However, if a quieter
noise occurs just prior
to the loud noise the
startle response is
reduced
• Prepulse can occur 30500 ms before
• It is too weak to
produce startle itself
PPI
• The startle response is a
simple reflex, however the
inhibition of this reflex involves
a complex neuroanatomical
circuit
– Including
• Limbic cortex, striatum,
globus pallidus, Pontine
reticular formation
– All of these brain areas show
abnormalities in patients with
schizophrenia
• Thus, it is not surprising that
patients with schizophrenia
show diminished PPI
PPI
• PPI has several advantages that make it
an appealing animal model
– It is a simple measurement (startle reflex)
which produces reliable results
– All mammals including primates exhibit PPI
and do not require training to show it
• In humans they often measure eyeblink
• In rats they often measure whole-body flinch
PPI
• PPI is disrupted by systematic administration of
dopamine agonists.
– Like apomorphine
• PPI is reinstated by dopamine receptor-blocking
antipsychotic drugs
– Including the atypical antipsychotics (like clozapine)
– Because these drugs reinstate PPI at clinically relevant doses it
further validates this method as a treatment screening device
• Positive correlation
– Drugs that treat schizophrenia at low doses reinstate PPI at low doses
» High = high
» See next slide
Box 18.2 Animal Model—Prepulse Inhibition of Startle (Part 3)
• PPI is also disrupted by
– systematic exposure to serotonergic agonists
– Glutamate antagonists
– Surgical manipulation of the cortical-striatal-pallidalpontine circuit
• This parallels structural and functional
abnormalities that have been identified in
schizophrenic patients
• Thus, this model may allow researchers to study
unique aspects of the pathology of
schizophrenia
PPI
• Another reason the PPI model is very appealing is
because it responds to genetic and environmental
manipulations
• Genetically distinct strains of rats differ in how
responsive they are to dopaminergic modulation of PPI
– Rats bred for apomorphine sensitivity or lack of sensitivity show
more and less inhibition of PPI respectively
– This may be useful as a model for how genes might code for DAinduced gating disruption
• Which may provide insight into susceptibility to schizophrenia
• Developmental influences can have effects as well
– Isolation stress early in life can reduce PPI
• This effect is reversed by antipsychotic drugs.
Classic Neuroleptics and atypical antipsychotics
• Drugs used to treat schizophrenia are
called antipsychotic drugs or neuroleptics
• Commonly divided into two classes
– Traditional neuroleptics
– Second generation (atypical) antipsychotics
• No drug is consistently better than any
other, but an individual may be responsive
to a particular drug
Traditional Neuroleptics
• Chlorpromazine (thorazine) was the first
neuroleptic to be used in psychiatry
• By making slight changes to the chemical
structure many neuroleptics have been
created
– See Figure 18.4 for a listing
Pharmakokinetics of traditional neuroleptics
• The traditionally neuroleptics are traditionally given orally
– Sometimes given IM for patients that are unable or unwilling to
take the drug
• The drugs are distributed throughout the body with the
highest concentrations in the liver and lungs
– Binding to inactive sites like blood proteins and fats is common
• Release from these sites is slow
• Leading to a very slow rate of elimination
– Metabolism is also quite slow
• Metabolites can be found in the urine many months after termination
of treatment
• Thus, the half life is quite long (11-58 hours)
– Only a single dose is needed per day
Effectiveness of traditional neuroleptics
• As we mentioned earlier the introduction of neuroleptics
dramatically improved the treatment of schizophrenic
patients
• Works for a significant number of the patient population
–
–
–
–
Reduce symptoms
Decrease average hospital stay
Calm agitated patients
Open up patients that are more withdrawn
• just a few doses can eliminate hyperexcitability or manic
behaviors
• Positive symptoms such as delusions, hallucinations,
and disordered thinking gradually improve over several
weeks
• Negative symptoms are more resistant
Effectiveness of traditional neuroleptics
•
Law of thirds
– One third of patients treated
respond well
– One third of patients show
significant improvement but may
relapse from time to time
– One third of patients don’t
respond well
• Some fail to respond at all
• This category may represent a
large portion of the homeless
population in the US
•
Following initial recovery
antipsychotics are prescribed to
prevent relapse
– The drugs do have side effects
– so often patients fail to continue
treatment
• When the antipsychotics were introduced in the 1950s scientists had
no idea how they worked
– chlorpromazine was administered as a treatment for severe vomiting
and as a sedative for presurgical patients
• One thing that was noticed was that there was a connection
between improved symptoms and Parkinson’s like motor problems
• By the early 1960s the biochemical nature of Parkinson’s disease
was beginning to be understood.
– deficiency in the DA releasing neurons of the midbrain.
• This led to the development of Parkinson’s drugs
– Also provided insight to the mechanism of neuroleptics
• positive effects seemed to be due to decreasing DA function
• L-Dopa treatment could lead to psychotic symptoms in Parkinson’s patients
• It is now know that
the effectiveness of
neuroleptics is
correlated with their
ability to antagonize
DA
– binding effectiveness
(x-axis)
• dose at which 50% of
receptors are bound
– therapeutic dose (yaxis).
• Neuroleptics also bind
to serotonin
receptors, but there is
no clear relationship
between binding
effectiveness (x-axis)
and therapeutic dose
(y-axis).
• You probably recall that there are many subtypes of DA
receptors
– The typical neuroleptics block the D2 receptor to varying
degrees.
• D2 receptors occur both postsynaptically and
presynaptically as autoreceptors.
– so again (like with depression) we have a complex interaction of
systems
• it takes several weeks for neuroleptics to reach full
effectiveness.
– thus, like with depression, it is likely that it is synaptic changes
related to DA turnover and effectiveness that contribute to the
positive effects
The traditional neuroleptics have significant side effects
• The effect of the traditional neuroleptics on the D2 receptors likely
leads to the significant side effects that these drugs have.
• Parkinsonism
–
–
–
–
–
classic antipsychotics cause a movement disorder
tremors
akinesia (slowing or loss of movement)
muscle rigidity
akathesia (feeling of discomfort in the legs)
• hard to sit still
• One way to treat Parkinson’s disease is to reduce acetylcholine
activity
– Thioridazine is an antipsychotic that also has anticholinergic action
• making it less likely to cause Parkinsons
– sometimes antipsychotics are prescribed along with an anticholinergic
drug
• Tardive dyskinesia
– stereotyped involuntary
movements
– particularly of the face and
jaw
• lip smacking, lateral jaw
movements, tongue
movements
– also uncontrolled
movements of arms and
legs.
• clip
– Incidence of Tardive
Dyskinesia goes up
dramatically with chronic
treatment
• Neuroendocrine effects
–
–
–
–
–
breast enlargement and tenderness
decreased sex drive
lack of menstruation
increased prolactin levels (can lead to lactation)
inhibition of growth hormone release
• problem for medicating adolescents
– weight gain
• neuroleptic malignant syndrome
–
–
–
–
fever
rigidity
altered consciousness
autonomic nervous system instability
• rapid heart rate
• blood pressure fluctuations
– can be fatal
• additional side effects
– can have anticholinergic effects
•
•
•
•
dry mouth
blurred vision
constipation
difficulty in urination
– can have antiadrenergic effects
• dizziness
• fainting
atypical antipsychotics
• atypical antipsychotics
– fewer motor system side-effects
• selective D2 receptor antagonists
– sulpiride, raclopride, remoxipride
– bind specifically to D2 and D3 receptors
• thus, fewer ANS side-effects and less sedation
• broad-spectrum antipsychotics
– block a broader spectrum of receptors.
– clozapine
• weak affinity for D1 and D2
• high affinity for D4
• substantial affinity for serotonin, muscarinic, and histamine
receptors
• blocks apomorphine hyperactivity, but no catalepsy
– not more effective for postive symptoms than typical neuroleptics
• can be effective in patients that don’t respond to traditional
medications
– also can reduce negative symptoms
• can take 5 months of treatment to be fully effective
– not known why
– The idea here is that increased activity at say D4 or serotonin
sites can compensate for some of the D2 effects.
• clozapine
– has side effects
• increased likelihood of seizures
• weight gain
• cardiovascular problems
– one side effect is particularly dangerous
• can cause agranulocytosis
– decrease in granulocytes
» a type of white blood cell
– infections of skin and throat and lungs can occur
• Risperidone (risperdal)
– broad spectrum antipsychotic that doesn’t have the
risk for agranulocytosis
• Dopamine stabilizers
– aripiprazole (Abilitat)
• Dopamine partial agonist
– binds to DA receptors
– produces less effect than DA itself
• in the presence of a lot of DA
– antagonist
• in the presence of little DA
– agonist
– by reducing too much DA activity positive symptoms
may be reduced
– by increasing DA activity in areas where little activity
is occuring negative symptoms may be reduced
– Has fewer side effects than many of the drugs
Neurochemical models of schizophrenia
• DA imbalance hypothesis
– too little DA function in mesocortical neurons
• negative symptoms
• impaired thinking
• due to impaired prefrontal cortex activity
– too much DA activity in mesolimbic neurons
• positive symptoms
18.17 Schematic representation of the neurodevelopmental model of schizophrenia
• Neurodevelopmental
model of schizophrenia
(Weinberger, 1987)
• Negative symptoms are
associated with reduced
frontal lobe function
– resemble the symptoms of
patients that have had
frontal lobe lesions
• frontal lobotomy
• Positive symptoms are
the result of decreased
inhibitory feedback from
the frontal cortex to limbic
sites.
• What causes the damage
– heredity
• runs in families
• closer the family member the more likely
• monozygotic twins = about 50%
18.15 Lifetime risks of developing schizophrenia
• developmental errors?
– genetic vulnerability increases chance of perinatal brain development
errors
• perhaps disrupted pruning in prefrontal cortex
– viral infection during second trimester of pregnancy increases risk of
schizophrenia
– other delivery complications are also associated with increased risk
• oxygen deprivation
• maternal drug use
• malnutrition
• Why doesn’t it show up until after puberty
– Frontal cortex is not fully developed until late teens, early twenties
– increased limbic activity at puberty
• taxes the social and inhibitory systems?