Transcript Schizophrenia and Antipsychotic Treatment

Schizophrenia and
Antipsychotic Treatment
Stacy Weinberg
3 April 2007
What is it?
•It is a severe, chronic, disabling brain disease
•Considered to have biological origins but exact unknown
•1% of population affected
•“Schizophrenia” – split mind
•Multiple personality disorder is not schizophrenia
•Psychosis is more accurate
•Severe mental illness where patient loses contact with
reality
•People have problems thinking and feeling but are aware
of their surroundings
Types
1. Catatonic Type
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Either in position or speech (imitating others)
Very rare
2. Disorganized Type
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Disturbance in behavior, speech, and thought
Flat affect, eccentric
3. Paranoid Type
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Delusions and auditory hallucinations
Cognitive functioning remains intact
4. Residual Type
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Have been previously diagnosed but no longer
show prominent symptoms; still have other
symptoms
5. Undifferentiated Type
Positive Symptoms
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Disturbances of thought processes
Delusions
Hallucinations
Erratic/extreme emotions
Very slow or fast movement, catatonia
Behavioral changes
Negative Symptoms
• Lack of interest/enjoyment in activities
• Low energy/motivation
• Blank facial expression, less facial
variability
• Inability to make or keep friends
• Difficulty initiating activities
• Social isolation
Causes - Dopamine Hypothesis
• Genetic aspect
• Most think it involves dopamine:
– Elevation of D2 monomers, decrease of
dimers
– Increased release of dopamine
• 2x higher
• When given amphetamine, 2x more
dopamine is released than control
Other Hypotheses
• Dopamine hypothesis not agreed on by
everyone
• Some think excitatory amino acids like
glutamate could play a role
– One type of glutamate receptor, NMDA:
NMDA antagonists (ex ketamine) can induce
psychotic symptoms in non-schizophrenic
patients
– Found increase of NMDA receptors in
postmortem studies of schizophrenic brains
Types of Drug Treatment
1. Typical Antipsychotics
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Dopamine antagonists
2. Atypical Antipsychotics
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5-hydroxytryptamine effect, also effect
dopamine
3. Combination Drugs
Typical
• Tend to produce Extrapyramidal side
effects:
– Parkinsonism – tremors, rigidity, slowness of
movement, temporary paralysis
– Dystonia – involuntary muscle contractions
– Akathisia – inability to resist urge to move
– Tardive dyskinesia – involuntary movements
of the mouth, lips, and tongue
• Chewing, puckering, grimacing, etc.
Typical - Phenothiazines
• Dopamine D2 receptor antagonists
• Chlorpromazine first developed from
promethazine, first tricyclic antihistamine
Promethazine
Chlorpromazine
Trifluoperazine
Haloperidol
• Butyrophenone
• Used in 1970s almost exclusively
• No anticholinergic effects – therefore used
in patients with delirium
Atypicals
• Atypicals do not induce EPSE
• Block D2 receptors and 5-HT seratonin
receptors (decreases EPSE)
• As opposed to typicals, these are more
loosely bound to D2 receptors
– Easier dissociation
– Shown that higher occupation of D2 receptors
by drug, higher incidence of EPSE
5-HT seratonin receptors
• Blocking 5-HT seratonin receptors decreases
negative symptoms and EPSE
– Mechanism is unknown
– Seratonin inhibits dopamine release
– Positive symptoms associated with
hyperdopaminergic condition in limbic lobe – more D2
receptors here, so D2 blocking prevails
– Negative symptoms associated with
hypodopaminergic condition in frontal lobe – more 5HT receptors here, so seratonin inhibits dopamine
release – stabilizes dopamine level
Clozapine
• First atypical (1990)
• Most dangerous atypical: risk of
agranulocytosis (severe decrease in WBC
count)
• Most effective in reducing EPSE, also in
reducing negative symptoms
– Increases Fos-positive neurons in the
prefrontal cortex (shown to affect negative
symptoms)
Risperidone
• Low doses needed
• Predominantly blocks D2, then 5-HT
– Does not exhibit multireceptor action
• Lacks anticholinergic activity – makes it
better for youth, elderly
• Problem – increases prolactin levels
(shouldn’t give to people with breast
cancer)
Olanzapine
• Zyprexa is number one antipsychotic in
sales (Eli Lilly)
• Exhibits multireceptor action
• Good for controlling mood symptoms
• Available in a wafer
• Problems: Sedation and
weight gain
Combinations
• Example is Symbyax
– Combination of olanzapine and fluoxetine
(Prozac)
– Can also treat bipolar disorder
• Combination of ziprasidone and clozapine
– Can be used to combat treatment resistance
• Combination of aripriprazole and clozapine