Schizophrenia

1. Schizophrenia Paul M. Moran Maverick Miller Leslie Radka Jennifer Schmid Michael Ball Cheryl Rosario

2. Background • 1% Prevalence • 10-15% take their own lives • Within first 10yrs of diagnosis • Onset • Late teens to early 20’s • Early treatments relied on Antipsychotics • There were however many adverse effects • Early 1990’s pharmacological breakthroughs allowed for a more functioning lifestyle in society

3. Background • It is believed that Schizophrenia must be treated in a multifaceted treatment • While medication is the first line treatment counseling, social and family services should be provided for proper treatment of patients • Further developments in pharmacological treatments should increase functioning of patients in society by reducing side effects with more selective drugs

4. Etiology • Schizophrenia is a misregulation of information in the brain • Many different NT pathways are hypothesized to be involved in the biological basis of the disorder • Genetics may be an important role • The environment may trigger a possible genetic predisposition

5. Etiology • Despite years of research there is no consensus on a single etiology for this disorder

6. Symptoms • Schizophrenia has been broken down into two sets of symptoms • Positive and Negative • Positive Symptoms • Hallucinations • Delusions • Disorganized Speech, Behavior and Movements • Increase in goal directed activity • Illogical thoughts

7. Negative Symptoms • Blunted Affect • Impaired emotional responsiveness • Apathy • Loss of motivation and interest • Social withdrawal

8. Atypical vs Traditional • Traditional Antipsychotics only alleviate the positive symptoms • Atypical drugs however treat both the positive and negative symptoms • Lower extrapyrimidal effects • Act on 5HT2 as well as D2 • More expensive

9. Role of Dopamine • Original theory proposed that an over activation of DA led to schizophrenic symptoms • More recently it has been hypothesized that • Positive symptoms are caused by an over activation of specific DA pathways • Negative symptoms arise from and under activation of different DA pathways

10. Role of Dopamine • DA subtypes • DA1 receptors • DA1, D1B • DA2 receptors • D2, D3 and D4 • DA1 and DA2 exert opposite actions on intracellular mechanisms • Traditional view of antipsychotics were that they antagonize D2 and D4 receptors • The problem with these drugs were that they caused Parkinson like symptoms, tardive dyskinesias and may worsen negative symptoms

11. Atypical Antipsychotics • There is no agreement on what biological actions define atypical antipsychotics • These drugs are thought to block D2 receptors • Have a possible effect on D1, 5HT2 or adrenergic receptor blockade • Some are thought to effect D3 and D4 • Problem with atypicals is that their action on D2 receptors also may cause side effects involving movement disorders

12. Serotonin Involvement • Observations of psychedelic drugs psilocybin and LSD • Cause a state similar to schizophrenia • These drugs are 5-HT agonist • 5-HT antagonism may have therapeutic efficacy

13. Serotonin Involvement • Serotonin’s exact mechanisms of action are unclear • Autopsy results show reduced 5HT2 receptors in the prefrontal cortex • PET studies of living schizophrenics have not confirmed these findings • Studies show a possibility of serotonin-glutamate interaction • Drug-induced serotonin blocking limits glutamate release

14. Glutamate Hypothesis • NMDA over activity leads to an excessive excitatory neurotransmission in the fontal cortex • This damages cortical neurons which causes degeneration

15. Summary of Theories • Overall • DA is considered to be involved with the positive symptoms • Glutamate is considered to be involved with the negative symptoms

16. Drug Classifications • Standard, classical, traditional • Phenothiazines are the prototypical agents • New generation or atypical • Clozapine, risperidone, olanzapine, sertindole, quetiapine and ziprazadone • Advantages • Theputically effective without causing neuroplectic syndrome • Help relive negative symptoms and cognitive dysfunctions

17. Phenothiazines • Widely used • Least expensive

18. Pharmacokinetics • Absorbed unpredictably and erratically through the GI tract • Dose decisions commonly made by trial and error • Oral is still most common • Rapid distributed once in bloodstream • 24-48hr half life • Slowly metabolized in liver • Bind extensively to tissue • Causing slow elimination • May be responsible for slow rate of reoccurrence of psychotic episodes

19. Pharmacological Effects • Blocks D2 receptors • Ach, 5HT, Histamine and NE receptors • Limbic system • Brain Stem • Basal Ganglia • Hypothalamus-Pituitary

20. Side Effects and Toxicity • High Potency Phenothiazapines • Fluphenazine, Trifluphenazine, Perphenazine • Cause less sedation • Fewer anticholergenic side effects • Less postural hypertension • More extrapyrimydal side effects • Low Potency Phenothiasapines • Chlorpromazine, Thioridazine • Used when sedation is desirable • Also when Anticholinergic side effects limit compliance • Often combined with benzodiazapines

21. Tolerance and Dependence • Rarely abused • No tolerance • No physical or psychological dependence • Stopping treatment can either result in relapse or withdrawal

22. Haloperidol • First therapeutic alternative to Phenothiasazines • Similar effects of phenothiasazines • Produces sedation • Reduces initiative, anxiety and activity • Well absorbed orally • Slow rate of metabolism and excretion • Acts on D2 receptors • Few side effects • Does produce Parkinson like effects

23. Atypical Antipsychotics • Molindone • Resembles 5HT • Relation to 5HT therapeutic effect is unknown • Resembles traditional antipsychotics • Mechanism of action, efficacy, side effects • Moderate sedation • Increased motor activity • Possibly euphoria

24. Loxapine • Similar in structure to atypicals • Actions differ little from traditional effects • Antipsychotic, antiametic and sedative properties • Causes abnormal motor movements • Good absorption, metabolism and excretion

25. Clozapine • Used to treat treatment resistant schizophrenics • Clinically superior to traditional drugs • Relieves much of the negative symptoms • Lacks many extrapyramidal effects • Less of a cognitive inhibitor • Clozapine may cause a loss of white blood cells but it reduces suicide rates

26. Pharmacokinetics • Varied absorption rates among patients • Well absorbed orally • Metabolitic half life 9-30hrs • Peak plasma levels 1-4hrs • Metabolized by the liver into 2 active metabolites • Blood levels must be monitored to ensure proper dosing

27. Pharmacodynamics • High binding affinity for DA, Seretonin1c, seretonin2, alpha1, muscaranic and histamine • Low rate of binding to D2 receptors • Blocks 5HT2 at higher levels

28. Side Effects and Toxicity • Sedation • 40% of patients • Can affect compliance • Bed time dosing may help compliance • Weight gain • 80% of patients • Persistant • Reason not known • Withdrawal • Delusions, hallucinations, hostility, paranoid reaction, nausea, vomit, diarraheachachacha, headache, restlessness, agitation, confusion, sweating

29. Other Concerns • Expensive • Due to blood monitoring

30. Risperidone • Potent inhibitor of D2 and 5HT2 • Pharmacokinetics • Orally administered • Rate of metabolism varies • 3hr half life • Active metabolite 9-hydroxy-risperidone • Half life 22hrs • Considered a first-line treatment for schizophrenia • High efficancy • Safe • Few detrimental effects on memory • Minimal extrapyramidal side effects • Other side effects • Agitation, anxiety, insomnia, headache, nausea, extrpyramidal side effects (only at high doses)

31. Olanzapine • Structurally related to clozapine • Blocks many receptors, but dopamine and serotonin interaction are thought to be responsible for therapeutic effect • Pharmacokinetics • Well absorbed orally • Peak plasma levels at 5 to 8 hours • Elimination half-life 27-38 hours • Overall effectiveness • improvements in both positive and negative symptoms • Studies seem to show better results with less severely impaired patients • Also used in bipolar

32. Sertindole • 5-HT2, D2, and alpha1-adrenoreceptors antagonist • Treats both positive and negative symptoms • Minimal extrapyramidal side effects • Reduced sedative effects due to no affinity for histamine receptors • Half-life 60 hours to 95 hours • Can lead to severe cardiac arrythmias

33. Quetiapine (Seroquel) • 5-HT2/D2 receptor antagonst • Half life 7hrs • Two or more daily doses needed • Greater affinity for 5HT2 than D2 • Separates the antipsychotic action from the extrapyramidal side effects • Reduces expression of glutamate receptor mRNA

34. Ziprasidone • Similar in effect to Haloperidal • Weight gain is negliable • Inactive byproducts • Poorly absorbed orally • Unique actions on receptors • Blocks 5HT2 and D2 • Agonist at 5HT1a • May cause an antidepresant function

35. Amisulpride • Yet to be released • D2 and D3 subtypes blocked in limbic system but not in Basal Ganglia • Twice as selective for D3 than D2 • Low doses blocks presynaptic receptors increasing DA • Higher doses it antagonizes DA • At these doses it has efficacy for negative symptoms • Low incidence of extrapyramidal side effects • No affinity for 5HT which is unusual for Atypical