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 Onset
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 DA2 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 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