Transcript schizophrenia

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characterized by positive and negative
symptoms
◦ positive symptoms – those that can be observed;
ex. hallucinations
◦ negative symptoms – absence of normal behaviors –
lack of affect – “anhedonia”,
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positive symptoms
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negative symptoms
◦ majority of traditional “neuroleptics” reduce
positive symptoms
◦ majority of traditional “neuroleptics” have no
effect on negative symptoms
◦ originally thought that negative symptoms were
simply an indicator of brain damage
◦ current: atypical neuroleptics also appear to
reduce negative symptoms
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traditional neuroleptics – chlorpromazine
(Thorazine), haloperidol (Haldol)
◦ ability to block “positive” symptoms – linked to high
well the drug binds to and blocks D2 receptors
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DA theory for schizophrenia
◦ too much DA activity responsible for + symptoms
◦ reduce DA activity, reduce positive symptoms
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mesolimbic –
◦ emotion, reward, may be responsible for +
symptoms
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nigrostriatal –
◦ motor movement, extrapyramidal motor system
 degeneration associated with Parkinsons disease
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parkinson like side effects
◦ early on; see symptoms in virtually all
schizophrenics that were similar to PD
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extrapyramidal motor side effects
◦ motor induced akinesias –
◦ tardive dyskinesia –
 avoid it by periodically changing meds; atypical
neuroleptics?
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clozapine (Clozaril)
◦ works on positive and negative symptoms
◦ reduced motor side effects
◦ more selective at binding to DA R (and does not
bind as potently)
◦ also blocks ACh, histamine, 5HT
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risk of agranulocytosis (1%)
 requires weekly blood testing
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only used for treatment resistant
schizophrenia or those nontolerant to
conventional antipsychotics (ie motor side
effects)
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risperidone (Risperdal)
olanzapine (Zyprexa)
quietiapine (Seroquel)
aripiprazole (Abilify)
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do not produce agranulocytosis
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block 5HT2 receptors and ACh receptors
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less motor side effects than traditional neuroleptics
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appear able to reduce negative symptoms;
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appear to be somewhat less sedating
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at lower risk for producing tardive dyskinesia
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improvement can be more rapid
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not all are generic yet
reduction in
noncompliance
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weight gain20 – 40 lbs average but can be much more!
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still have anticholinergic side effects
◦ dry mouth, memory problems, urinary retention
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still have motor side effects
tachycardia
direct costs can be up to 100X greater than
typical neuroleptics
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Disorders of mood
found throughout history
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unipolar or major depression
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bipolar or manic depression
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Depression
◦ over 10% with ~ 5% (11,000,000) suffering from a
depressive episode in any given year
◦ untreated - 25 - 30% will attempt or commit suicide
◦ 2X greater prevalence in women than men
◦ estimated only ~ 50% receive specific treatment
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Neurochemical Theory
◦ monoamine theory:
◦ supportive data
1. Reserpine
2. Drugs used to treat depression increase activity of
NE and/or 5HT neurons
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Pharmacologically
◦ drugs have been available for ~ 40+ years
2 categories of drugs emerged about same time
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1. MAO inhibitors
 2. tricyclic antidepressants
◦ 3rd group of drugs– more recent
◦ SSRI
◦ SNRI
/
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MAOI’s – MAO inhibitors
◦ MAO – breaks down excess catecholamines
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Alters the metabolism of amino acid
tyramine
◦ foods high in tyramine include: aged cheeses,
wine, smoked fish, yeast products
◦ consumption of these can result in a
hypertensive crisis:
 severe headaches, heart palpitations. Flushing,
nausea, vomiting, stroke
◦ very long 1/2 life (2 weeks)
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Two types of MAO enzymes
◦ MAOA and MAO B
 maybe we can get more selective?
◦ Reversible MAO inhibitors
 don’t take as long to clear out of body
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Two types of MAO enzymes
◦ MAOA and MAO B
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reduced (although still an issue)
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Blocks reuptake of NE and 5HT
very widely used
fairly significant side effects
◦ mainly because they block ACh receptors
 blurred vision, dry mouth, urinary retention, irregular
heart rate, constipation, sexual dysfunction,
◦ effects on other NT
 sedation, weight gain
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Fluoxetine (Prozac) - first introduced in US in
1988
SSRIs have a more favorable side effect profile
than earlier antidepressants
relatively safe (esp in OD situations)
some controversy…...
(Celexa)
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Block reuptake of 5HT
◦ selective serotonin reuptake inhibitor
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Some patients do not respond well to first
treatment
most take 3 - 4 weeks to exert significant
therapeutic effects
◦ what does this suggest?
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1% incidence (lower than depression)
symptoms usually emerge during
adolescence or early adulthood
no sex differences in incidence
without effective treatment - ~ 20%
result in suicide
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Treatments
◦ oldest - lithium
 odd history lithium metal isolated in early 1800’s
 1940’s - replaced sodium chloride with lithium chloride
for hypertensive patients
 reintroduced to treat bipolar in 1970
◦ limitations of lithium
 effective dose and toxic dose are TOO close
 regular blood monitoring
◦ newer - carbamazepine (Tegretol) or valproic acid
(Divalproex)
 anticonvulsants