Antipsychotic Drugs

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Chapter 13
Antipsychotic Drugs
Russell Crowe in A Beautiful Mind
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Names Antipsychotic Narcoleptic Clasping
the neuron refers to effects on movement
similar to Parkinsons disease. More commonly
used in Europe. Antipsychotic effect is not
achieved through narcoleptic effect. Major
tranquilizer as opposed to minor tranquilizer
(benzodiazepines). Refers to sedating property,
but is not a stronger version of minor
tranquilizer. Antipsychotic effect is not
achieved through sedation.
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Typical antipsychotics were developed before
1975, they have Parkinsonian side effects and are
only effective against positive
symptoms. Atypical antipsychotics were developed
after 1990. They have minimal parkinsonian
effects and are effective against both positive
and negative symptoms.
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Psychosis Schizophrenia split between thought
and emotion.
Diagnostic criteria for Schizophrenia A.
Characteristic symptoms Two (or more) of the
following, each present for a significant portion
of time during a 1-month period (or less if
successfully treated) (1) delusions (2)
hallucinations (3) disorganized speech (e.g.,
frequent derailment or incoherence) (4) grossly
disorganized or catatonic behavior (5) negative
symptoms, i.e., affective flattening, alogia, or
avolition Note Only one Criterion A symptom is
required if delusions are bizarre or
hallucinations consist of a voice keeping up a
running commentary on the person's behavior or
thoughts, or two or more voices conversing with
each other.
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Criteria for Manic Episode DSM - IV A. A distinct
period of abnormally and persistently elevated,
expansive, or irritable mood, lasting at least 1
week (or any duration if hospitalization is
necessary). B. During the period of mood
disturbance, three (or more) of the following
symptoms have persisted (four if the mood is only
irritable) and have been present to a significant
degree (1) inflated self-esteem or
grandiosity (2) decreased need for sleep (e.g.,
feels rested after only 3 hours of sleep) (3)
more talkative than usual or pressure to keep
talking (4) flight of ideas or subjective
experience that thoughts are racing (5)
distractibility (i.e., attention too easily drawn
to unimportant or irrelevant external stimuli)
(6) increase in goal-directed activity (either
socially, at work or school, or sexually) or
psychomotor agitation (7) excessive involvement
in pleasurable activities that have a high
potential for painful consequences (e.g.,
engaging in unrestrained buying sprees, sexual
indiscretions, or foolish business investments)
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History
Henri Labroit French Military surgeon Tested
antihistamine, promethazine and chlorpromazine as
a cure for Surgical shock. Chlorpromazine induced
artificial hibernation (sedating effect).
Labroit suggested it might calm agitated
psychotic patients.
Better than that, it reduces psychotic symptoms
and was marketed in 1953 as Largactil or Thorazine
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Pharmacokinetics
Routes of administration Oral when used as an
antipsychotic - except where the sedating effect
is needed in agitated patients Depot injection
where compliance is a problem Parenteral when
used as presurgical anesthetic Absorption
absorbed from digestive system, Cross barriers
readily, much protein binding Distributed to
body fat Excretion. entirely metabolized,
released slowly from body fat. Half-life 11-58
hrs Can be taken once a day
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Neurophysiology
Dopamine hypothesis schizophrenia is caused by
an excess of dopamine activity in the brain.
In the 1970s it was noted that the clinical
potency of a drug was correlated with its
affinity for D2 receptors
Philip Seeman
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Dopamine systems in the brain
Mesolimbic DA system from the VTA to the Nucleus
Accumbens and frontal cortex - Reward system and
schizophrenia Nigrostriatal system from the
Substantia Nigra to the basal ganglia. -
extrapyramidal motor system.
Antipsychotic drugs block DA receptors in both
systems and therefore Parkinsonian symptoms are
side effects.
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Dopamine Hypothesis today
Drugs like amphetamine and cocaine cause
psychotic behavior, but so do other drugs like
PCP and LSD suggesting that serotonin and NMDA
receptors for glutamate are involved as
well. Drugs that block DA receptors block
psychotic behavior, but there is a delay in
effectiveness of antipsychotic drugs suggesting
an adaptation in a brain mechanism
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Nigrostriatal effects
Parkinsons Disease is a result of depletions in
DA in the Nigrostriatal system
Causes intentional tremor and difficulty
initiating movement
How can you suppress DA activity in the MDS
without blocking DA activity in the NS system?
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Typical and Atypical Antipsychotics
Typical antipsychotics have a high affinity for
D2 receptors. Atypical antipsychotic drugs have
high affinity for D3 and D4 receptors and low
affinity for D2 receptors. D3 receptors are found
in the n. acc. And D4 receptors in the cortex
amygdala and hippocampus. There are few D3 and D4
receptors in the motor system.
Atypicals also have a higher affinity for the
5HT2A receptor than the D2 receptor while
typicals have a lower affinity for the 5HT2A
receptor than the D2 receptor. This has the
effect of counteracting the D2 blockade in the
motor system
See next slide
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The lower the number, the greater the effect
Blockade of serotonin receptors also causes
diminished response of glutamanergic neurons in
the cortex. (oppostie effect of LSD). This may
reduce hallucinations
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Atypical antipsychotic drugs are also more
effective in treating the negative symptoms of
schizophrenia like alogia and avoilition.
Other neurotransmitters known to be involved are
acetylcholine, histamine, GABA, and NE. Different
drugs have different profiles if relative
activity of different transmitters.
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Effects on the Body
Parkinsonian symptoms (40 on typical
antipsychotics) Dulled expression on the face
rigidity and tremor in the limbs weakness in
the extremities very slow movements akathesia
(20 percent on typical antipsychotics)
uncontrolled inner restlessness, constant
compulsive movement,
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Tardive Dyskinesia repetitive, involuntary,
purposeless movements. Features of the disorder
may include grimacing, tongue protrusion, lip
smacking, puckering and pursing of the lips, and
rapid eye blinking. Rapid movements of the arms,
legs, and trunk may also occur. Impaired
movements of the fingers may appear as though the
patient is playing an invisible guitar or piano.
Patients with Parkinson's disease have difficulty
moving, while patients with tardive dyskinesia
have difficulty not moving. (Wikipedia
discussion) May not go away when drug is
withdrawn (Tardive) Occurs about 30 of the time
after long term high dose use of all
antipsychotic drugs with the exception of
clozapine. Sensitization of the extrapyramidal
motor system
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Other Effects on the Body
Poor temperature regulation Seizures Reduced food
intake Skin pigmentation Anticholinercic effects
like blurred vision, dry mouth and
constipation Agranulocytosis suppression of
bone marrow activity in 1-2 of patients on
clozapine Requires constant monitoring of
blood. Little effect on sleep. Very safe drugs
with a high LD50
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Subjective effects
Tiredness, lethargy, (like moving through
molasses) Confused thinking clumsiness Akathesia
causes rustiness, anxiety and irritability you
feel restless and want to move, but you cannot
move easily. Not a pleasant experience
Compliance problems.
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Performance
Attention and cognitive performance deficits with
acute administration. Tolerance after 2
weeks. Results variable Some recent studies show
an improvement in cognition in schizophrenics
after using antipsychotic drugs.
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Effects on nonhumans
Decrease in activity Plastic immobility
narcoleptic effect show movie.
Blocks avoidance without blocking escape
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Dissociation and Discrimination
Dissociation has been demonstrated in rats. Not
well discriminated large doses are required and
more training needed Will generalize to other
antipsychotics, but not to antidepressants or any
other class of drugs Clozapine does not
generalize to haloperidol or chlorpromazine.
Tolerance There is no tolerance to the
therapeutic effect. Withdrawal very mild and
rarely reported. May be due to slow rate of
excretion
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Self-administration Not positive reinforces
never self-administered Monkeys learn to avoid
infusions of chlorpromazine Never abused in
humans Compliance a problem with non
hospitalized patients and relapses frequently
occur Less problem with atypical antipsychotic
drugs
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Harmful effects Movement disorders Typical
antipsychotics cause prolactin release in males
and inhibit sexual performance and interest. In
females there maybe abnormal menstrual cycles and
infertility.
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Other Therapeutic effects Antiemetic Huntings
Chorea Torettes syndrome Hiccoughs Stuttering
DTs Psychotic behavior caused by psychomotor
stimulants and hallucinogens
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Greymatter video