Antipsychotics: The Essentials

Module 1: Introduction

1

Slide 1

Welcome to the first module of our course “Antipsychotics: The Essentials”. My name is Flavio Guzmán and in this first module I’d like to give you an introduction make your understanding of antipsychotics easier.

I’ve tried to compile the most critical and updated information, and present it in a way that is friendlier than textbooks. I hope this course helps you in your everyday practice.

Slide 2

Module 1 is an introduction to

preliminary definitions, classifications

and the history of antipsychotics.

In the first section I’ll summarize the history in drug research from the early 50’s to present. After that, I’ll describe terminology and classification for first as well as second generation antipsychotics.

Finally, I close this module by previewing some differences between first and second generation antipsychotics.

Antipsychotics: The EssentialsModule 1

Introduction

Flavio Guzmán, MDMental Health Teaching Hospital “Dr. Carlos Pereyra”

MendozaArgentina

Antipsychotics: The EssentialsModule 1

Introduction

Flavio Guzmán, MDMental Health Teaching Hospital “Dr. Carlos Pereyra”

MendozaArgentina

Outline• Antipsychotics History

– The discovery of chlorpromazine– Clozapine– Second Generation Antipsychotics

• First Generation Antipsychotics– Terminology– Classification

• Second Generation Antipsychotics– Terminology– List of agents

• Differences between FGAs and SGAs

Outline• Antipsychotics History

– The discovery of chlorpromazine– Clozapine– Second Generation Antipsychotics

• First Generation Antipsychotics– Terminology– Classification

• Second Generation Antipsychotics– Terminology– List of agents

• Differences between FGAs and SGAs

2

Slide 3

Antipsychotics history is relevant to our course objectives. The development of this class was a breakthrough for psychiatry and medicine in general. Learning how and when antipsychotics were discovered is critical to understand what to expect from present therapies.

Slide 4

Here in the picture you can see the two French psychiatrists that opened field of chlorpromazine research in psychiatry, Jean Delay and Pierre Deniker. They didn’t synthesize the molecule, but they were the first group to try its effectiveness as an antipsychotic.

Chlorpromazine was initially synthesized as an antihistamine, it was chosen for human investigation because it was mildly sedating. The sedative properties then led the French anesthesiologist Henri Laborit to use it in lytic cocktail to reduce autonomic response to surgical stress. Laborit persuaded many clinicians to try this drug for the treatment of a wide variety of other disorders. In this context; he encouraged Delay and Deniker, who then administered CPZ to schizophrenic patients. That was the beginning of the antipsychotics era. The introduction of the first antipsychotic drugs in the 1950s had a transformational impact. Psychiatric hospitals could for the first time, discharge a large number of patients who would otherwise have spent their lives in a hospital setting.

Antipsychotics history:Why is it important?

Antipsychotics history:Why is it important?

The Discovery of ChlorpromazineChlorpromazine as antihistaminic

Henri Laborit

• (Anesthesia)

Jean Delay and Pierre Deniker

• (1952, Schizophrenia)

The Discovery of ChlorpromazineChlorpromazine as antihistaminic

Henri Laborit

• (Anesthesia)

Jean Delay and Pierre Deniker

• (1952, Schizophrenia)

3

Slide 5

I think it’s interesting to see this chlorpromazine ad (Thorazine in the US). The company promoted the sedating properties as the major therapeutic goal, therapies at the time were focused only on the management of acute schizophrenia symptoms, such as psychomotor agitation.

In fact, you can read the benefit promoted: “ At the outset of treatment, Thorazine’s combination of antipsychotic and sedative effects provides both emotional and physical calming. Assaultive or destructive behavior is rapidly controlled”. Emotional quieting and psychomotor inhibition are part of the syndrome known as neurolepsis.

Slide 6

Between 1954 and 1975, about 15 antipsychotic drugs were introduced in the United States and about 40 all over the world. Development of new antipsychotics was paused from the late 70’s to late 80’s. As we’ll see in a minute, the

introduction of clozapine in 1989 opened the era of the “atypical” drugs.

Chlorpromazine Ad 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.

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.

4

Slide 7

The next milestone in antipsychotics history is the discovery of clozapine. This icon represents (maybe exaggerates) how clozapine beats other antipsychotics in the pharmacotherapy of treatment-resistant schizophrenia.

Slide 8

Clozapine was developed in 1961, clinical trials began in 1972, after that it was released in Europe under the trade name Leponex. Three years after, in 1975, the manufacturer voluntarily withdraw the drug from the market because of reports showing that clozapine was associated with a very serious

adverse effect, agranulocytosis. Fifteen years later, in 1989, clozapine was reintroduced following the landmark trial by Kane and cols. comparing clozapine with chlorpromazine in treatment-resistant schizophrenia. This and many other studies showed that clozapine was more effective against treatment-resistant schizophrenia than other antipsychotics.

ClozapineClozapine

Clozapine timeline

1961

• Clozapine synthesis

1972

• 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.

Clozapine timeline

1961

• Clozapine synthesis

1972

• 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.

5

Slide 9

After the findings of clozapine’s both therapeutic and adverse effects, the pharmaceutical industry started to concentrate efforts in developing new compounds that could replicate clozapine effectiveness without the need for blood monitoring. The result is a shift in prescription pattern from drugs such as haloperidol or chlorpromazine to

drugs such as risperidone, olanzapine, quetiapine among others. As you can see, this is clearly reflected in the chart, prescriptions of typical antipsychotics are illustrated in red, showing a steady decline over the years. Atypical antipsychotics use has risen dramatically since the early 90’s.

Slide 10

• Chlorpromazine discovery in 1952 was a breakthrough for psychiatry. • “Serendipity” in drug discovery implies the finding of one thing while looking for something else. This is the case of chlorpromazine, an antipsychotic was discovered while looking for an antihistamine.

• A new generation of drugs were approved after the development of clozapine.

Post- Clozapine Antipsychotics

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

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.

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.

6

Slide 11

The antipsychotics field is known for its complexity. There is constant research, both in developing new compounds and in understanding more about the dozens of agents already available in the market.

In this course we’ll use the classification proposed by the World Psychiatric Association, which recommends to classify antipsychotics in generations.

Slide 12

On the left I have listed the classic and commonly used terms, on the right the new terminology proposed by the World Psychiatric Association. Neuroleptics are the drugs that fall under the category of conventional antipsychotics, or typical antipsychotics. The new terminology calls them first generation

antipsychotics, this includes drugs such as chlorpromazine, haloperidol, fluphenazine, among others. The term “atypical antipsychotics” is the most commonly used for second generation antipsychotics. Based on their shared pharmacological properties, these drugs were also called dopamine-serotonin antagonists. Some researchers claim that drugs acting as dopamine partial agonists fall under a different category: third generation antipsychotics. At this time, the only FDA approved drug in this group is aripiprazole. During this course we’ll group aripiprazole with second generation agents, in module 2 we’ll study its mechanism of action as partial agonist.

Antipsychotics ClassificationAntipsychotics 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

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

7

Slide 13

I’ll begin this section by describing some aspects about the terminology and classification of first generation antipsychotics.

Slide 14

It’s useful to make clear some aspects regarding terminology . The terms neuroleptic, typical and atypical are commonly used in practice. It is interesting to understand their background and meaning. What is a neuroleptic? This is a term used to refer to first generation antipsychotics (such as

chlorpromazine or haloperidol) because of their ability to produce neurolepsis. The question that follows is: what is neurolepsis? Clinicians in the fifties described this syndrome, which has three main features: • Psychomotor slowing • Emotional queting • Affective indifference Psychiatrists at the time thought this syndrome was a reliable sign of antipsychotic efficacy. Nowadays, it is clear that these effects are not required for drugs to have therapeutic action. In fact, the presence of these symptoms predicts low treatment adherence.

First Generation Antipsychotics

• Terminology• Classification

First Generation Antipsychotics

• Terminology• Classification

Terminology: neuroleptics

Neuroleptic: term used for first generation (typical) antipsychotics because of their ability to produce neurolepsis.

Psychomotor slowing

Emotional quieting

Affective indifference

Neurolepsis

Stahl, S M. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. New York: Cambrigde University Press; 2008

Terminology: neuroleptics

Neuroleptic: term used for first generation (typical) antipsychotics because of their ability to produce neurolepsis.

Psychomotor slowing

Emotional quieting

Affective indifference

Neurolepsis

Stahl, S M. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. New York: Cambrigde University Press; 2008

8

Slide 15

There are two possible ways to classify first generation antipsychotics, in this slide we can see a classification based on chemical classes. The main classes include phenothiazines, thioxanthenes, dibenzoxazepines, butyrophenones and diphenylbutylpiperidines.

This full list is available as a PDF download so you can review it at your own pace. In the next 4 slides I will show you some relevant features of the phenothiazines and butyrophenones.

Slide 16

This slide shows the chemical characteristics common to all of the phenothiazines, they consist of a three-ring structure with different side chains joined at the nitrogen atom of the middle ring. The activity of the group can be affected by substitutions at positions 2 or 10. The phenothiazines are usually categorized into three classes based on substitutions at position 10, these

are: - Aliphatic - Piperidines - Piperazines These substitutions have important effects on the pharmacological characteristics of each phenothiazine.

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

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.

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.

9

Slide 17

Substituting an aliphatic side chain results in a drug with relatively low antipsychotic potency. Take a look at position 10 here in the chlorpromazine molecule, you can see the aliphatic side chain. At position 2 chlorpromazine has a chlorine atom. These agents tend to be sedating and to cause anticholinergic and hypotensive effects at their effective

doses.

Slide 18

This molecule, mesoridazine, is the result of the substitution of a piperidine ring at position 10. These drugs have similar potency and side effects when compared with the aliphatic phenothiazines.

Aliphatic - Chlorpromazine

• 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.

Aliphatic - Chlorpromazine

• 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.

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.

10

Slide 19

Most of the clinically useful butyrophenones have a piperidine ring attached to the tertiary amino group. Haloperidol is the representative drug for this class. Haloperidol and other butyrophenones tend to be potent D2 antagonists and have minimal

anticholinergic and autonomic effects.

Slide 20

A different way to classify first generation antipsychotics is by their potency. It’s important not to confuse potency with effectiveness. Potency refers to the dose required to achieve the desired therapeutic effect. For example, drug A is more potent than drug B if the therapeutic dose of drug A is 1mg, while the therapeutic dose of drug B is 10 mg.

This means that the lower the required dose, the more potent a drug is. In this table, first generation antipsychotics are classified in three levels: low, mid and high potency. Chlorpromazine is the pattern drug, so the other agents are compared to the effect of 100 mg of chlorpromazine. On the top of the table we have the drug with the lowest potency, chlorpromazine. The most potent antipsychotic is at the bottom, pimozide, as you can see 100 mg of chlorpromazine are equal to 2 mg of pimozide. Mid-potency antipsychotics include loxapine, perphenazine and molindone. Haloperidol, fluphenazine and pimozide are high potency antipsychotics with high risk of extrapyramidal symptoms.

Butyrophenones - Haloperidol

• 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.

Butyrophenones - Haloperidol

• 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 PotencyAgent Chlorpromazine

equivalence (mg)

Low Potency Chlorpromazine 100

Mid PotencyLoxapine 10

Perphenazine 10

Molindone 10

High PotencyHaloperidol 3

Fluphenazine 2

Pimozide 2

FGA Classification According to PotencyAgent Chlorpromazine

equivalence (mg)

Low Potency Chlorpromazine 100

Mid PotencyLoxapine 10

Perphenazine 10

Molindone 10

High PotencyHaloperidol 3

Fluphenazine 2

Pimozide 2

11

Slide 21 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.

Slide 22

Now I will describe some introductory ideas regarding second generation antipsychotics. Since I will give more details about this class of drugs in module 5, I’ll just outline some of the most relevant concepts, such as terminology and classification.

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.

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 AntipsychoticsSecond Generation Antipsychotics

12

Slide 23

As I described before, second generation antipsychotics are also known as “atypical” antipsychotics. What is an atypical antipsychotic? Originally, this term was used to describe a lower risk of EPS associated with clozapine use. Researchers found that at therapeutic doses, clozapine showed a much lower risk of extrapyramidal

symptoms such as tardive dyskinesia. Later, the use of this term was broadened to include: • Efficacy against negative and cognitive symptoms. • Lack of prolactin elevation. • Efficacy in treatment resistant patients. Currently, researchers argue that the addition of the features shown here in green have hampered antipsychotic drug research and that reframing the concept of atypicality could have a key role in the advance of this therapeutic field.

Slide 24

There are 10 antipsychotics approved

in the US market at this time. In this

table I’ve classified them according to

their approval date.

Clozapine was the parent drug of this group. Risperidone was approved in 1993 under the trade name Risperdal,

paliperidone and risperidone are the two second generation associated with risk of hyperprolactinemia. Olanzapine shares some chemical features with clozapine, including its high risk of inducing weight gain.

Terminology: “Atypical” antipsychoticsAtypical antipsychotics

Lower EPS risk

Efficacy against cognitive and

negative symptoms

Lack of prolactin elevation

Efficacy for treatment-

resistant patients

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)

Originally: Later broadened to include:

Terminology: “Atypical” antipsychoticsAtypical antipsychotics

Lower EPS risk

Efficacy against cognitive and

negative symptoms

Lack of prolactin elevation

Efficacy for treatment-

resistant patients

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)

Originally: Later broadened to include:

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)

Clozapine (Clozaril) Dibenzodiazepines 1989

Risperidone (Risperdal) Benzisoxazole 1993

Olanzapine (Zyprexa) Thienobenzodiazepines 1996

Quetiapine (Seroquel) Dibenzothiazepines 1997

Ziprasidone (Geodon) Benzisothiazolyls 2001

Aripiprazole (Abilify) Quinolinones 2002

13

Quetiapine is a sedating antipsychotic with lower liability of producing extrapyramidal symptoms, this makes it particularly useful for patients with Parkinson’s disease. Aripiprazole is a partial D2 agonist that shows low incidence of metabolic side effects.

Slide 25

Here are the remaining 4 antipsychotics, this is an artificial subdivision I made just to highlight the number of new drugs in a short period of time. Paliperidone is similar to risperidone, in fact it is a metabolite, 9 hydroxyrisperidone. Iloperidone is not structurally related

to risperidone and was approved in 2009. Asenapine was approved as a special sublingual formulation. Sublingual administration is essential because bioavailability is less than 2% if ingested. Lurasidone is the newest antipsychotic, it has antagonist properties at the 5HT7 receptors.

Slide 26

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

Drug Chemical Class Year Approved (FDA)

Paliperidone (Invega) Benzisoxazole 2006

Iloperidone (Fanapt) Piperidinyl-benzisoxazole 2009

Asenapine (Saphris) Dibenzo-oxepino pyrrole 2009

Lurasidone (Latuda) Benzisothiazol 2010

Second Generation Antipsychotics

Drug Chemical Class Year Approved (FDA)

Paliperidone (Invega) Benzisoxazole 2006

Iloperidone (Fanapt) Piperidinyl-benzisoxazole 2009

Asenapine (Saphris) Dibenzo-oxepino pyrrole 2009

Lurasidone (Latuda) Benzisothiazol 2010

Second Generation Antipsychotics

Key Points

• The concept of “atypicality” is not get completely defined.

• Ten second generation antipsychotics are available in the US market.

Key Points

• The concept of “atypicality” is not get completely defined.

• Ten second generation antipsychotics are available in the US market.

14

Slide 27

To close the introduction to antipsychotics I’d like to give you a preview on the main differences between first and second generation antipsychotics. Some of them will be explained in detail in the next modules, but it’s useful to have a general idea first.

Slide 28

Let’s see the differences regarding pharmacological profiles. First generation antipsychotics are D2 antagonists, they act on different regions such as mesolimbic, mesocortical, nigrostriatal and tuberoinfundibular pathways. Something worth noting is that both first and second generation antipsychotics have some degree of

D2 antagonism. D2 antagonism has proven to be responsible for antipsychotic efficacy. Besides D2 antagonism, first generation agents have effects on other receptors, such as muscarinic, adrenergic alpha 1 and histamine-1. Blockade of these receptors is related with their side effects profile. Second generation antipsychotics also block D2 receptors, but what makes them different from first generation agents is their ability to block 5HT2A receptors. As we saw in a previous slide, these drugs are also known as serotonin-dopamine antagonists. In fact, they have higher affinity for 5HT2a receptors than for D2 receptors.

Differences Between First and Second Generation Antipsychotics

Differences Between First and Second Generation Antipsychotics

Pharmacological profile

First Generation Antipsychotics

• D2 Antagonism

Second Generation Antipsychotics

• 5HT2A/D2 antagonism

Pharmacological profile

First Generation Antipsychotics

• D2 Antagonism

Second Generation Antipsychotics

• 5HT2A/D2 antagonism

15

Slide 29

There are important differences regarding adverse effects profiles. First generation antipsychotics are associated with higher risk of neurological side effects. Some of these include, tardive dyskinesia, extrapyramidal symptoms dystonia, among others. I’ve included this image depicting basal ganglia to highlight the effects

that first generation antipsychotics have on the nigrostriatal dopamine pathway. We’ll On the other hand, second generation antipsychotics gained popularity thanks to a lower risk of neurological side effects. Later, it was discovered that these drugs were associated with an increased risk of developing metabolic side effects: these include hyperglycemia, weight gain and dyslipidemia. This picture shows abdominal obesity, as a reminder of metabolic side effects.

Slide 30

One question matter of clinical debate is whether second generation antipsychotics are more effective than first generation antipsychotics. There are two important clinical trials that shed some light in this controversy. The first are the Clinical Antipsychotic Trials of Intervention effectiveness, funded by the National Institutes of

Mental Health. The other is the Cost Utility of The Latest Antipsychotics in Severe Schizophrenia, conducted in the UK and funded by the National Health Service. The results from these trials: - Show no evidence of benefit of second over first generation antipsychotics in the treatment

of negative symptoms of schizophrenia. - Clozapine has shown clear utility in treatment-resistant schizophrenia.

Adverse effects profile

First Generation Antipsychotics

• Higher risk of neurological side effects

Second Generation Antipsychotics

• Higher risk of metabolic side effects

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

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

16

References and further reading

Hippius H. A historical perspective of clozapine. The Journal of clinical psychiatry 1999;60 Suppl

12:22-3.

Shen WW. A history of antipsychotic drug development. Comprehensive psychiatry

1999;40:407-14.

Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of

Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of

Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.

American Psychiatric Publishing, 2010.

Stahl, S M. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical

Applications. 3rd ed. New York: Cambrigde University Press; 2008