1. Antipsychotics: The Essentials Module 5 A Primer on Selected Antipsychotics
Flavio Guzmán, MD

2. About this module 13 antipsychotics will be studied Plan:
3 first generation antipsychotics
10 second generation antipsychotics
Plan:
Binding profile (highlights, not exhaustive)
Basic prescribing information
Main clinical features of each AP

3. About this module
All antipsychotics mentioned in this presentation are approved for the treatment of schizophrenia.

4. Antipsychotics Chlorpromazine (Thorazine) Ziprasidone (Geodon)
Haloperidol (Haldol)
Aripiprazole (Abilify)
Perphenazine ( Trilafon)
Iloperidone (Fanapt)
Clozapine (Clozaril)
Asenapine (Saphris)
Olanzapine (Zyprexa)
Lurasidone (Latuda)
Risperidone (Risperdal)
Paliperidone (INVEGA)
Quetiapine (Seroquel)

5. Chlorpromazine One of the first antipsychotics
Low potency FGA (high doses required for therapeutic effect)
Used as comparator for antipsychotic dose equivalence
Owens D. Meet the relatives: a reintroduction to the clinical pharmacology of ‘typical’ antipsychotics (Part 1). Advances in Psychiatric Treatment 2012

6. Chlorpromazine: binding profile
D2 antagonist
H1 antagonist
Alpha 1 antagonist
Muscarinic antagonist
5HT2A antagonist
Owens D. Meet the relatives: a reintroduction to the clinical pharmacology of ‘typical’ antipsychotics (Part 1). Advances in Psychiatric Treatment 2012

7. Chlorpromazine: prescribing facts
Dosage range:
mg/day
Current suggested dosing: mg/day
Dosage forms
Tablets: 10 mg, 25 mg, 50 mg, 100 mg, 200 mg
Capsules: 30 mg, 75 mg, 150 mg
Ampul: 25 mg/ml, 1ml, 2ml
Liquid: 10 mg/ 5 ml
Suppository 25 mg, 100 mg
Owens D. Meet the relatives: a reintroduction to the clinical pharmacology of ‘typical’ antipsychotics (Part 1). Advances in Psychiatric Treatment 2012

8. Chlorpromazine: Clinical Profile
Advantages
Long established use
High margin of safety
Sedative
Disadvantages
Tolerability less favorable than safety
Generally too sedative for long term use
Owens D. Meet the relatives: a reintroduction to the clinical pharmacology of ‘typical’ antipsychotics (Part 1). Advances in Psychiatric Treatment 2012

9. Haloperidol
High potency FGA
High risk of causing EPS
Available as LAI

10. Haloperidol: Binding Profile
Very high affinity for D2 receptors
Affinity for s receptors
No significant action for H1 and M receptors
Owens D. Meet the relatives: a reintroduction to the clinical pharmacology of ‘typical’ antipsychotics (Part 1). Advances in Psychiatric Treatment 2012

11. Haloperidol- Prescribing Facts
Dose range:
1-40 mg/day orally
Efficacy can be obtained with low doses (less than 5 mg/day).
Owens D. Meet the relatives: a reintroduction to the clinical pharmacology of ‘typical’ antipsychotics (Part 1). Advances in Psychiatric Treatment 2012

12. Haloperidol- Prescribing Facts
Dosage forms:
Scored tablets: 0,5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg.
Concentrate: 2 mg/ml
Solution: 1 mg/ml
Injection 5 mg/ml
LAI - Decanoate formulation:
50 mg haloperidol as 70.5 mg/ml haloperidol decanoate.
100 mg haloperidol as mg/ml haloperidol decanoate.
Stahl, S M. The Prescriber's Guide. 4thd ed. New York: Cambrigde University Press; 2011

13. Haloperidol: Clinical Profile
Advantages
Long established use
Very useful in psychiatric emergencies
Disadvantages
Very high liability to produce EPS
Perception of dosage higher of what pharmacology suggests
Owens D. Meet the relatives: a reintroduction to the clinical pharmacology of ‘typical’ antipsychotics (Part 1). Advances in Psychiatric Treatment 2012

14. Perphenazine Intermediate potency FGA
Served as active comparator in the CATIE trial

15. Perphenazine: Binding Profile
Intermediate affinity for D2 receptors
Significant a 1 antagonist action
H1 antagonist
Owens D. Meet the relatives: a reintroduction to the clinical pharmacology of ‘typical’ antipsychotics (Part 1). Advances in Psychiatric Treatment 2012

16. Perphenazine: Prescribing Facts
Dosage range:
12-24 mg/day
CATIE allowed up to 32 mg/day
16-64 mg/day in hospitalized patients
Dosage forms
Tablets: 2 mg, 4 mg, 8 mg, 16 mg
Injection: 5 mg/ml
Stahl, S M. The Prescriber's Guide. 4thd ed. New York: Cambrigde University Press; 2011

17. Perphenazine: Clinical Profile
Advantages
Long established use
High margin of safety
Better known through its use as active comparator in CATIE
Disadvantages
Short half-life ( 8-12 hours): ideally is best administered three times daily.
Potency and tolerability make easy for EPS to emerge undetected.
Owens D. Meet the relatives: a reintroduction to the clinical pharmacology of ‘typical’ antipsychotics (Part 1). Advances in Psychiatric Treatment 2012

18. Clozapine First of the SGAs Unique therapeutic benefits
Unique side effects profile

19. Clozapine: Binding Profile
High 5HT2A/D2 ratio
H1 antagonism
Muscarinic antagonism
a 1 antagonism
5HT2C antagonism
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008
Schatzberg, AF, Nemeroff, CB. The American Psychiatric Publishing Textbook of Psychopharmacology. 4th ed.American Psychiatric Publishing, 2009

20. Clozapine: Binding Profile
D3 and D4 antagonist
5HT1A partial agonist
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008
Schatzberg, AF, Nemeroff, CB. The American Psychiatric Publishing Textbook of Psychopharmacology. 4th ed.American Psychiatric Publishing, 2009

21. Clozapine: Prescribing Facts
Dosage range:
mg/day
In some cases: higher than 500 mg/day (risk of seizures)
Dosage forms:
Tablets: 12.5 mg, 25 mg (scored), 50 mg, 100 mg (scored)
Orally disintegrating tablets: 12.5 mg, 25 mg, 50 mg, 100 mg
Metabolized primarily by CYP1A2, with additional contributions by CYP2C19, CYP2D6 and CYP3A4
Stahl, S M. The Prescriber's Guide. 4thd ed. New York: Cambrigde University Press; 2011

22. Clozapine: Clinical Profile
Effective for treatment-resistant schizophrenia.
Reduces violence and persistent aggression in schizophrenia.
Long-term treatment associated with reduction of risk of suicidal behaviors.
Hennen J, Baldessarini RJ. Suicidal risk during treatment with clozapine: a meta-analysis. Schizophrenia research 2005
Conley RR, Buchanan RW. Evaluation of treatment-resistant schizophrenia. Schizophr Bull 1997

23. Clozapine – Adverse Effects Profile
One of the antipsychotics with the lowest EPS risk
One of the antipsychotics with the highest metabolic risk
Risk of agranulocytosis
Dose-dependent seizure risk
Can be very sedating
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008
Schatzberg, AF, Nemeroff, CB. The American Psychiatric Publishing Textbook of Psychopharmacology. 4th ed.American Psychiatric Publishing, 2009

24. Olanzapine SGA less “dirty” than clozapine.
Available in combination with fluoxetine: OFC
Dosage forms include parenteral formulations
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008
Schatzberg, AF, Nemeroff, CB. The American Psychiatric Publishing Textbook of Psychopharmacology. 4th ed.American Psychiatric Publishing, 2009

25. Olanzapine – Binding Profile
High 5HT2A/D2 ratio
H1 antagonist
Muscarinic antagonist
a 1 antagonist
5HT2C antagonist
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008
Schatzberg, AF, Nemeroff, CB. The American Psychiatric Publishing Textbook of Psychopharmacology. 4th ed.American Psychiatric Publishing, 2009

26. Olanzapine- Prescribing Facts
Dosage range:
10 – 20 mg/day
Dosage forms:
Tablets: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg
Orally disintegrating tablets: 5 mg, 10 mg, 15 mg, 20 mg
OFC capsule: 6 mg/ 25 mg, 6 mg /50 mg, 12 mg/25 mg, 12 mg/50 mg
IM formulation: 5 mg/ml, each vial contains 10 mg (available in some countries)
LAI: olanzapine pamoate: 150 mg, 300 mg, 210 mg, 405 mg
Stahl, S M. The Prescriber's Guide. 4thd ed. New York: Cambrigde University Press; 2011

27. Olanzapine – Clinical Profile
Olanzapine/fluoxetine combination was the first drug approved for bipolar depression.
Associated with less EPS than FGAs.
Weight gain is problematic with long term use.
Can be very sedating.
Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.