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