1. Antipsychotics: The Essentials Module 1 Introduction
Flavio Guzmán, MD
Mental Health Teaching Hospital “Dr. Carlos Pereyra”
Mendoza
Argentina

2. Outline Antipsychotics History First Generation Antipsychotics
The discovery of chlorpromazine
Clozapine
Second Generation Antipsychotics
First Generation Antipsychotics
Terminology
Classification
List of agents
Differences between FGAs and SGAs

3. Antipsychotics history: Why is it important?

4. The Discovery of Chlorpromazine
Chlorpromazine as antihistaminic
Henri Laborit
(Anesthesia)
Jean Delay and Pierre Deniker
(1952, Schizophrenia)

5. Chlorpromazine Ad

6. Development of antipsychotic drugs after chlorpromazine
1952
Chlorpromazine
1957
Perphenazine
1967
Haloperidol
1972
Fluphenazine
1978
Thioridazine
Shen WW. A history of antipsychotic drug development. Comprehensive psychiatry 1999;40:

7. Clozapine

8. Clozapine timeline 1975 1989 1961 1972 Clozapine synthesis
Clinical trials begin
1975
Reports of agranulocytosis
Withdrawal by manufacturer
1989
Reintroduction to market
Hippius H. A historical perspective of clozapine. The Journal of Clinical Psychiatry 1999;60 Suppl 12:22-3.

9. Post- Clozapine Antipsychotics
Abbot, A Schizophrenia: The drug deadlock| Nature 468, (2010)

10. Key points
Chlorpromazine discovery in 1952 was a breakthrough for psychiatry.
“Serendipity” in drug discovery implies the finding of one thing while looking for something else.
A new generation of drugs were approved after the development of clozapine.

11. Antipsychotics Classification

12. Classic and commonly used terms Proposed new terms (WPA)
Neuroleptics
(conventional antipsychotics, typical antipsychotics)
First generation antipsychotics
Atypical antipsychotics (serotonin-dopamine antagonists)
Second generation antipsychotics
Dopamine partial agonists
(Aripiprazole)
Third generation antipsychotics
Mailman RB, Murthy V. Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? Current pharmaceutical design 2010;16:

13. First Generation Antipsychotics
Terminology
Classification

14. Terminology: neuroleptics
Neuroleptic: term used for first generation (typical) antipsychotics because of their ability to produce neurolepsis.
Neurolepsis
Psychomotor slowing
Emotional quieting
Affective indifference
Stahl, S M. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. New York: Cambrigde University Press; 2008

15. Chemical Classification of FGAs
Aliphatic
Chlorpromazine
Promazine
Triflupromazine
Piperidines
Thioridazine
Mesoridazine
Piperacetazine
Piperazines
Trifluoperazine
Fluphenazine
Perphenazine
Acetophenazine
Prochlorperazine
Phenothiazines
Thiothixene
Chlorprothixene 
Thioxanthenes
Loxapine
Dibenzoxazepines
Haloperidol
Droperidol
Butyrophenones
Pimozide
Diphenylbutylpiperidines

16. Phenothiazines Aliphatic Piperidines Piperazines Phenothiazines
Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

17. Aliphatic - Chlorpromazine
Piperidines
Piperazines
Phenothiazines
Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

18. Piperidines - Mesoridazine
Aliphatic
Piperidines
Mesoridazine
Piperazines
Phenothiazines
Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

19. Butyrophenones - Haloperidol
Droperidol
Butyrophenones
Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

20. FGA Classification According to Potency
Agent
Chlorpromazine equivalence (mg)
Low Potency
Chlorpromazine
100
Mid Potency
Loxapine 10
Perphenazine
Molindone
High Potency
Haloperidol 3
Fluphenazine 2
Pimozide

21. Key points
First generation antipsychotics are commonly classified according to chemistry and potency.
High potency agents (haloperidol) have a higher risk of extrapyramidal symptoms.
Low potency drugs (chlorpromazine) are more sedating and show a higher risk of hypotension and anticholinergic effects.

22. Second Generation Antipsychotics

23. Terminology: “Atypical” antipsychotics
Originally:
Later broadened to include:
Efficacy against cognitive and negative symptoms
Lack of prolactin elevation
Efficacy for treatment-resistant patients
Lower EPS risk
Currently in debate
(Gründer G, Hippius H, Carlsson A. The “atypicality” of antipsychotics: a concept re-examined and re-defined. Nature Rev Drug Disc 8: , 2009)

24. Second Generation Antipsychotics
Drug
Chemical Class
Year Approved (FDA)
Clozapine (Clozaril)
Dibenzodiazepines
1989
Risperidone (Risperdal)
Benzisoxazole
1993
Olanzapine (Zyprexa)
Thienobenzodiazepines
1996
Quetiapine (Seroquel)
Dibenzothiazepines
1997
Ziprasidone (Geodon)
Benzisothiazolyls
2001
Aripiprazole (Abilify)
Quinolinones
2002

25. Second Generation Antipsychotics
Drug
Chemical Class
Year Approved (FDA)
Paliperidone (Invega)
Benzisoxazole
2006
Iloperidone (Fanapt)
Piperidinyl-benzisoxazole
2009
Asenapine (Saphris)
Dibenzo-oxepino pyrrole
Lurasidone (Latuda)
Benzisothiazol
2010

26. Key Points The concept of “atypicality” is not yet completely defined.
Ten second generation antipsychotics are available in the US market.

27. Differences Between First and Second Generation Antipsychotics

28. Pharmacological profile
First Generation Antipsychotics
D2 Antagonism
Second Generation Antipsychotics
5HT2A/D2 antagonism

29. Adverse effects profile
First Generation Antipsychotics
Higher risk of neurological side effects
Second Generation Antipsychotics
Higher risk of metabolic side effects

30. Are SGAS more effective than FGAs?
No evidence of benefit of SGAs over FGAs in the treatment of negative symptoms of schizophrenia
Clozapine has shown clear utility in treatment-resistant schizophrenia