characterized by positive and negative symptoms ◦ positive symptoms – those that can be...
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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”,
positive symptoms◦ majority of traditional “neuroleptics” reduce
positive symptoms
negative 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
traditional neuroleptics – chlorpromazine (Thorazine), haloperidol (Haldol)◦ ability to block “positive” symptoms – linked to
high well the drug binds to and blocks D2 receptors
DA theory for schizophrenia ◦ too much DA activity responsible for + symptoms◦ reduce DA activity, reduce positive symptoms
mesolimbic –◦ emotion, reward, may be responsible for +
symptoms
nigrostriatal –◦ motor movement, extrapyramidal motor system
degeneration associated with Parkinsons disease
parkinson like side effects◦ early on; see symptoms in virtually all
schizophrenics that were similar to PD extrapyramidal motor side effects
◦ motor induced akinesias – ◦ tardive dyskinesia –
avoid it by periodically changing meds; atypical neuroleptics?
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
risk of agranulocytosis (1%) requires weekly blood testing
only used for treatment resistant schizophrenia or those nontolerant to conventional antipsychotics (ie motor side effects)
risperidone (Risperdal) olanzapine (Zyprexa) quietiapine (Seroquel) aripiprazole (Abilify)
do not produce agranulocytosis
block 5HT2 receptors and ACh receptors
less motor side effects than traditional neuroleptics
appear able to reduce negative symptoms;
appear to be somewhat less sedating
at lower risk for producing tardive dyskinesia
improvement can be more rapid
not all are generic yet
reduction innoncompliance
weight gain-20 – 40 lbs average but can be much more!
still have anticholinergic side effects◦ dry mouth, memory problems, urinary retention
still have motor side effects tachycardia direct costs can be up to 100X greater than
typical neuroleptics
Disorders of mood found throughout history
unipolar or major depression
bipolar or manic depression
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
Neurochemical Theory◦ monoamine theory:
◦ supportive data
1. Reserpine
2. Drugs used to treat depression increase activity of NE and/or 5HT neurons
Pharmacologically◦ drugs have been available for ~ 40+ years
2 categories of drugs emerged about same time◦ 1. MAO inhibitors
2. tricyclic antidepressants
◦ 3rd group of drugs– more recent
◦ SSRI◦ SNRI
/
MAOI’s – MAO inhibitors◦ MAO – breaks down excess catecholamines
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)
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
Two types of MAO enzymes◦ MAOA and MAO B
reduced (although still an issue)
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
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)
Block reuptake of 5HT◦ selective serotonin reuptake inhibitor
Some patients do not respond well to first treatment
most take 3 - 4 weeks to exert significant therapeutic effects
◦ what does this suggest?
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
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
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