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

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

Antipsychotics history: Why is it important?

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

Chlorpromazine Ad

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;40:407-14.

Clozapine

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.

Post- Clozapine Antipsychotics Abbot, A Schizophrenia: The drug deadlock| Nature 468, 158-159 (2010)

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.

Antipsychotics Classification

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;16:488-501

First Generation Antipsychotics Terminology Classification

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

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

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.

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.

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.

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.

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

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.

Second Generation Antipsychotics

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 8:197-202, 2009)

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

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

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

Differences Between First and Second Generation Antipsychotics

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

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

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