1. Schizophrenia and Antipsychotic Treatment Stacy Weinberg 3 April 2007

2. What is it? It is a severe, chronic, disabling brain disease Considered to have biological origins but exact unknown 1% of population affected “Schizophrenia” – split mind Multiple personality disorder is not schizophrenia Psychosis is more accurate Severe mental illness where patient loses contact with reality People have problems thinking and feeling but are aware of their surroundings

3. Types 1.Catatonic Type Either in position or speech (imitating others) Very rare 2.Disorganized Type Disturbance in behavior, speech, and thought Flat affect, eccentric 3.Paranoid Type Delusions and auditory hallucinations Cognitive functioning remains intact 4.Residual Type Have been previously diagnosed but no longer show prominent symptoms; still have other symptoms 5.Undifferentiated Type

4. Positive Symptoms Disturbances of thought processes Delusions Hallucinations Erratic/extreme emotions Very slow or fast movement, catatonia Behavioral changes

5. Negative Symptoms Lack of interest/enjoyment in activities Low energy/motivation Blank facial expression, less facial variability Inability to make or keep friends Difficulty initiating activities Social isolation

6. Causes - Dopamine Hypothesis Genetic aspect Most think it involves dopamine: –Elevation of D2 monomers, decrease of dimers –Increased release of dopamine 2x higher When given amphetamine, 2x more dopamine is released than control

7. Other Hypotheses Dopamine hypothesis not agreed on by everyone Some think excitatory amino acids like glutamate could play a role –One type of glutamate receptor, NMDA: NMDA antagonists (ex ketamine) can induce psychotic symptoms in non-schizophrenic patients –Found increase of NMDA receptors in postmortem studies of schizophrenic brains

8. Types of Drug Treatment 1.Typical Antipsychotics Dopamine antagonists 2.Atypical Antipsychotics 5-hydroxytryptamine effect, also effect dopamine 3.Combination Drugs

9. Typical Tend to produce Extrapyramidal side effects: –Parkinsonism – tremors, rigidity, slowness of movement, temporary paralysis –Dystonia – involuntary muscle contractions –Akathisia – inability to resist urge to move –Tardive dyskinesia – involuntary movements of the mouth, lips, and tongue Chewing, puckering, grimacing, etc.

10. Typical - Phenothiazines Dopamine D2 receptor antagonists Chlorpromazine first developed from promethazine, first tricyclic antihistamine ChlorpromazinePromethazineTrifluoperazine

11. Haloperidol Butyrophenone Used in 1970s almost exclusively No anticholinergic effects – therefore used in patients with delirium

12. Atypicals Atypicals do not induce EPSE Block D2 receptors and 5-HT seratonin receptors (decreases EPSE) As opposed to typicals, these are more loosely bound to D2 receptors –Easier dissociation –Shown that higher occupation of D2 receptors by drug, higher incidence of EPSE

13. 5-HT seratonin receptors Blocking 5-HT seratonin receptors decreases negative symptoms and EPSE –Mechanism is unknown –Seratonin inhibits dopamine release –Positive symptoms associated with hyperdopaminergic condition in limbic lobe – more D2 receptors here, so D2 blocking prevails –Negative symptoms associated with hypodopaminergic condition in frontal lobe – more 5- HT receptors here, so seratonin inhibits dopamine release – stabilizes dopamine level

15. Clozapine First atypical (1990) Most dangerous atypical: risk of agranulocytosis (severe decrease in WBC count) Most effective in reducing EPSE, also in reducing negative symptoms –Increases Fos-positive neurons in the prefrontal cortex (shown to affect negative symptoms)

16. Risperidone Low doses needed Predominantly blocks D2, then 5-HT –Does not exhibit multireceptor action Lacks anticholinergic activity – makes it better for youth, elderly Problem – increases prolactin levels (shouldn’t give to people with breast cancer)

17. Olanzapine Zyprexa is number one antipsychotic in sales (Eli Lilly) Exhibits multireceptor action Good for controlling mood symptoms Available in a wafer Problems: Sedation and weight gain

18. Combinations Example is Symbyax –Combination of olanzapine and fluoxetine (Prozac) –Can also treat bipolar disorder Combination of ziprasidone and clozapine –Can be used to combat treatment resistance Combination of aripriprazole and clozapine