schizophrenia

1. schizophrenia • 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”,

2. treatment options • 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

3. traditional neuroleptics • 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

4. DA pathways • mesolimbic – • emotion, reward, may be responsible for + symptoms • nigrostriatal – • motor movement, extrapyramidal motor system • degeneration associated with Parkinsons disease

5. problems with traditional neuroleptics • 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?

6. 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

7. problems with clozapine • risk of agranulocytosis (1%) • requires weekly blood testing • only used for treatment resistant schizophrenia or those nontolerant to conventional antipsychotics (ie motor side effects)

8. some other atypicals • risperidone (Risperdal) • olanzapine (Zyprexa) • quietiapine (Seroquel) • aripiprazole (Abilify)

9. other atypical neuroleptics • 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

10. negative side of the atypicals • 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

11. What are affective disorders? • Disorders of mood • found throughout history • unipolar or major depression • bipolar or manic depression

12. 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

13. Characteristics of Depression

14. Neurochemical Theory • monoamine theory: • supportive data 1. Reserpine 2. Drugs used to treat depression increase activity of NE and/or 5HT neurons

15. How do we treat depression? • 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 /

16. How do these work? • MAOI’s – MAO inhibitors • MAO – breaks down excess catecholamines

18. Limitations of classic MAO inhibitors • 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)

19. Future of MAO inhibitors • 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

20. Future of MAO inhibitors • Two types of MAO enzymes • MAOA and MAO B • reduced (although still an issue)

21. Tricyclic antidepressants • 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

23. SSRIs • 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…...

24. (Celexa)

25. How do SSRIs work? • Block reuptake of 5HT • selective serotonin reuptake inhibitor

26. Current problems that still exist with pharmacotherapy of depression • Some patients do not respond well to first treatment • most take 3 - 4 weeks to exert significant therapeutic effects • what does this suggest?

27. Bipolar • 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

28. Bipolar disorder • 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

29. Newer treatments • newer - carbamazepine (Tegretol) or valproic acid (Divalproex) • anticonvulsants