 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 in noncompliance

 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 % 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 ◦ 3 rd 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 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