antipsychotics: the essentials€¦ · antipsychotics: the essentials module 5. a primer on...

Antipsychotics: The Essentials

Module 5: A Primer on Selected Antipsychotics

Antipsychotics: The Essentials Module 5. A Primer on Selected Antipsychotics

1

Slide 1

This is the last module, it´s a primer

on selected antipsychotics.

Slide 2

Before beginning with the discussion

of each drug, let me give you a

preview of how I’ve organized this

module.

I have selected 13 antipsychotics, 3

are first generation agents and 10 are

second generation agents. As you

may see, there is an emphasis on

second generation antipsychotics.

This is because prescribers are often

interested in knowing more about the new drugs they hear about.

Please keep in mind that first generation antipsychotics are still extremely valuable drugs,

especially for situations in which costs of new drugs may be prohibitive.

If you are interested in learning up-to-date detailed information about first generation

antipsychotics, I would recommend you to check a recent review published in Advances in

Psychiatric Treatment by Dr. Owens. You can look for the title it in the references slide.

The structure for each antipsychotic is the following:

- First we’ll study the most relevant features regarding binding profiles. These are just highlights

that often have clinical implications, we won’t go into exhaustive pharmacodynamic detail.

Antipsychotics: The EssentialsModule 5

A Primer on Selected Antipsychotics

Flavio Guzmán, MD

Antipsychotics: The EssentialsModule 5

A Primer on Selected Antipsychotics

Flavio Guzmán, MD

About this module

• 13 antipsychotics will be studied– 3 first generation antipsychotics

– 10 second generation antipsychotics

• Plan:– Binding profile (highlights, not exhaustive)

– Basic prescribing information

– Main clinical features of each AP

About this module

• 13 antipsychotics will be studied– 3 first generation antipsychotics

– 10 second generation antipsychotics

• Plan:– Binding profile (highlights, not exhaustive)

– Basic prescribing information

– Main clinical features of each AP


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Second, I’ll describe basic prescribing information, mainly dosage range and dosage forms.

Third, I’ll present main clinical features of each drug.

Slide 3

One last clarification: all

antipsychotics mentioned in this

presentation are approved for the

treatment of schizophrenia.

This means that when we reach the

clinical features part and discuss

approved indications I’ll be

mentioning additional uses besides

schizophrenia.

Slide 4

The list of antipsychotics we’ll study is

the following:

Chlorpromazine (Thorazine)

Haloperidol (Haldol)

Perphenazine ( Trilafon)

Clozapine (Clozaril)

Olanzapine (Zyprexa)

Risperidone (Risperdal)

Paliperidone (INVEGA)

Quetiapine (Seroquel)

Ziprasidone (Geodon)

Aripiprazole (Abilify)

Iloperidone (Fanapt)

Asenapine (Saphris)

Lurasidone (Latuda)

About this module

• All antipsychotics mentioned in this presentation are approved for the treatment of schizophrenia.

About this module

• All antipsychotics mentioned in this presentation are approved for the treatment of schizophrenia.

Antipsychotics

• Chlorpromazine (Thorazine)• Haloperidol (Haldol)• Perphenazine ( Trilafon)• Clozapine (Clozaril)• Olanzapine (Zyprexa)• Risperidone (Risperdal)• Paliperidone (INVEGA)• Quetiapine (Seroquel)

• Ziprasidone (Geodon)• Aripiprazole (Abilify)• Iloperidone (Fanapt)• Asenapine (Saphris)• Lurasidone (Latuda)

Antipsychotics

• Chlorpromazine (Thorazine)• Haloperidol (Haldol)• Perphenazine ( Trilafon)• Clozapine (Clozaril)• Olanzapine (Zyprexa)• Risperidone (Risperdal)• Paliperidone (INVEGA)• Quetiapine (Seroquel)

• Ziprasidone (Geodon)• Aripiprazole (Abilify)• Iloperidone (Fanapt)• Asenapine (Saphris)• Lurasidone (Latuda)


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Slide 5

Let´s begin with one of the oldest

antipsychotics, chlorpromazine. This

is a low potency first generation

antipsychotic, as you remember, this

means that high doses are required

for achieving therapeutic effect.

One of the reasons why

chlorpromazine is still relevant is that

it is used as comparator for

antipsychotic dose equivalence.

Slide 6

Let’s study its binding profile.

Chlorpromazine has antagonist action

at D2 receptors, this is linked to its

efficacy as an antipsychotic.

Regarding other receptors,

chlorpromazine is an antagonist at

histamine 1 receptors, alpha 1 and

muscarinic receptors.

Histamine 1 antagonism is linked to one the effects most typically associated with

chlorpromazine use: sedation.

Alpha 1 antagonism increases the risk of orthostatic hypotension, it’s important to keep in mind

this side effect especially in an acute setting.

Chlorpromazine also blocks 5HT2A receptors, but not as potently as second generation drugs.

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

Chlorpromazine

• One of the first antipsychotics

• Low potency FGA (high doses required for therapeutic effect)

• Used as comparator for antipsychotic dose equivalence


Chlorpromazine: binding profile

- D2 antagonist- H1 antagonist- Alpha 1 antagonist- Muscarinic antagonist- 5HT2A antagonist


Chlorpromazine: binding profile

- D2 antagonist- H1 antagonist- Alpha 1 antagonist- Muscarinic antagonist- 5HT2A antagonist



4

Slide 7

Chlorpromazine dosage ranges from

200 to 800 mg/day. Current

suggested dosing is between 400 and

600 mg/day.

Regarding dosage forms,

chlorpromazine is available as tablets

of 10, 25, 50, 100 and 200 mg.

As capsules of 30, 75, 150 mg

As ampul of 25 mg/ml, 1 ml and 2 ml.

As liquid drug 10 mg / 5ml.

And as suppository of 25 and 100 mg.

Slide 8

From a clinical perspective,

chlorpromazine as advantages and

disadvantages.

Among the advantages we can list:

Long established use.

High margin of safety.

Its sedative properties, this is an

advantage for acute patients.

The disadvantages include:

Tolerability is less favorable than safety.

Generally it’s too sedative for long term use.

Chlorpromazine: prescribing facts• Dosage range:

– 200-800 mg/day– Current suggested dosing: 400-600mg/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


Chlorpromazine: prescribing facts• Dosage range:

– 200-800 mg/day– Current suggested dosing: 400-600mg/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


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


Chlorpromazine: Clinical Profile

Advantages



• Sedative

Disadvantages

• Tolerability less favorable than safety

• Generally too sedative for long term use



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Slide 9

The next drug in our list is

haloperidol. This is a high potency

first generation antipsychotic that has

high risk of causing EPS, it is available

as long acting injection, which is an

advantage in terms of treatment

adherence for some patients

Slide 10

Haloperidol has a relatively simple

binding profile. It has very high

affinity for D2 receptors, this strong

D2 blocking property has a correlation

in terms of extrapyramidal symptoms.

It also has affinity for sigma receptors.

Haloperidol doesn’t have significant

affinity for histamine 1 or muscarinic

receptors, this makes it a drug with

low potential to cause sedation or anticholinergic effects.

Haloperidol

• High potency FGA

• High risk of causing EPS

• Available as LAI

Haloperidol

• High potency FGA

• High risk of causing EPS

• Available as LAI

Haloperidol: Binding Profile

- Very high affinity for D2 receptors

- Affinity for s receptors- No significant action for H1

and M receptors


Haloperidol: Binding Profile

- Very high affinity for D2 receptors

- Affinity for s receptors- No significant action for H1

and M receptors



6

Slide 11

Haloperidol has a wide dosage range,

from 1 to 40 mg/ day orally.

Brain imaging studies show that low

doses of haloperidol, less than 5

mg/day can occupy 80% of D2

receptors, this percentage of

occupancy is associated with clinical

efficacy.

Slide 12

Available dosage forms include:

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 141.04 mg/ml haloperidol decanoate

Haloperidol- Prescribing Facts

• Dose range:

– 1-40 mg/day orally

– Efficacy can be obtained with low doses (less than 5 mg/day).



• Dose range:

– 1-40 mg/day orally

– Efficacy can be obtained with low doses (less than 5 mg/day).



• 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 141.04 mg/ml haloperidol decanoate.

Stahl, S M. The Prescriber's Guide. 4thd ed. New York: Cambrigde University Press; 2011


• 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 141.04 mg/ml haloperidol decanoate.



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Slide 13

In clinical terms, the advantages of

haloperidol include:

- Long established use. Haloperidol

was approved in 1967, since then it

has been extensively used.

- It’s very useful in psychiatric

emergencies. The lack of alpha 1

antagonism makes it a drug with low

risk of causing orthostatic hypotension, which is an benefit for parenteral use.

The disadvantages:

- Because of its strong affinity for D2 receptors, it has very high liability to produce

extrapyramidal symptoms.

- The perception of dosage is higher of what pharmacology suggests.

Slide 14

Perphenazine is an intermediate

potency first generation drug that

served as active comparator in the

CATIE trial.

Haloperidol: Clinical Profile

Advantages


• Very useful in psychiatric emergencies

Disadvantages

• Very high liability to produce EPS

• Perception of dosage higher of what pharmacology suggests


Haloperidol: Clinical Profile

Advantages


• Very useful in psychiatric emergencies

Disadvantages

• Very high liability to produce EPS

• Perception of dosage higher of what pharmacology suggests


Perphenazine

• Intermediate potency FGA

• Served as active comparator in the CATIE trial

Perphenazine

• Intermediate potency FGA

• Served as active comparator in the CATIE trial


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Slide 15

Perphenazine has an intermediate

affinity for D2 receptors, compared to

haloperidol it’s a weaker D2

antagonist. It has significant alpha1

antagonist action and it’s also a

histamine 1 antagonist.

This pharmacological profile should

remind us of risk of orthostatic

hypotension and sedation.

Slide 16

The dosing range of Perphenazine

goes from 12 to 24 mg/day. Here we

can see two situations worth noting,

the CATIE trial allowed up to 32 mg/

day. Also in hospitalized patients, the

daily dose can range from 16 to 64

mg.

The dosage forms are tablets and an

injection.

There are available tablets of 2, 4, 8 and 16 mg.

The injection is a formulation of 5 mg/ml.

Perphenazine: Binding Profile

- Intermediate affinity for D2 receptors

- Significant a 1 antagonist action

- H1 antagonist


Perphenazine: Binding Profile

- Intermediate affinity for D2 receptors

- Significant a 1 antagonist action

- H1 antagonist


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


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



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Slide 17

From a clinical perspective, the

advantages of Perphenazine include:

Long established use

High margin of safety (remember its

wide dosage range)

The fact that we got to know it

better through its use as active

comparator in the CATIE trial.

We also need to consider its disadvantages:

- It has a short half-life: between 8 to 12 hours, ideally is best administered three times daily.

This can be problematic in terms of treatment adherence.

Its potency and tolerability make easy for extrapyramidal symptoms to emerge undetected.

Slide 18

We’ll move now to the second

generation drugs. Clozapine was the

first of the second generation

antipsychotics to be approved, it has

unique therapeutic benefits and a

unique side effects profile.

Perphenazine: Clinical Profile

Advantages



• 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.


Perphenazine: Clinical Profile

Advantages



• 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.


Clozapine

• First of the SGAs

• Unique therapeutic benefits

• Unique side effects profile

Clozapine

• First of the SGAs

• Unique therapeutic benefits

• Unique side effects profile


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Slide 19

This drug has a very complex

pharmacology. Because of the

reasons I mentioned earlier the

binding profile of clozapine has been

intensively studied.

I’ll refer to some of the most relevant

features, those that have implications

because of hypothetical mechanisms

of action or adverse effects.

Clozapine has a high 5HT2A/D2 ratio, this means despite being an antagonist for both receptors,

it has higher affinity for 5HT2A receptors.

The drug is also an antagonist at histamine 1, muscarinic and alpha 1 receptors. This is relevant

for potential side effects.

Antagonism at 5HT2C receptors has been associated to an increase in the risk of weight gain.

Slide 20

In addition, clozapine is an antagonist

at D3 and D4 receptors. Also, the drug

is a partial agonist at 5HT1A

receptors.

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

Clozapine: Binding Profile- High 5HT2A/D2 ratio- H1 antagonism- Muscarinic antagonism a 1 antagonism- 5HT2C antagonism


Clozapine: Binding Profile

- D3 and D4 antagonist- 5HT1A partial agonist


Clozapine: Binding Profile

- D3 and D4 antagonist- 5HT1A partial agonist



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Slide 21

The dosage range of clozapine goes

from 300 to 450 mg/day. In some

cases doses as high as 500 mg/day

can be used, we must remember that

seizure risk is dose dependent,

Dosage forms include tablets and

orally disintegrating tablets. Tablets

are available in presentations of 12.5

mg, 25 mg scored tablets, 50 mg, and

100 mg scored tablets.

Orally disintegrating tablets are available in formulations of 12.5, 25, 50 and 100 mg.

A pharmacokinetic fact worth noting is that clozapine is metabolized primarily by CYP1A2, with

additional contributions by CYP2C19, CYP2D6 and CYP3A4.

Slide 22

It’s important to take a moment to

identify the three clinical features

that make clozapine unique.

- The first is that clozapine is the only

antipsychotic that has proven

effective for treatment-resistant

schizophrenia. For a definition of

treatment-resistant schizophrenia I

would recommend you to check the

paper by Conley cited at the bottom of the slide.

The second concept is that clozapine reduces violence and persistent aggression in

schizophrenia.

Last, but definitely not least, long- term treatment is associated with reduction of risk of suicidal

behaviors.

Clozapine: Prescribing Facts• Dosage range:

– 300-450 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


Clozapine: Prescribing Facts• Dosage range:

– 300-450 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


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.

Conley RR, Buchanan RW. Evaluation of treatment-resistant schizophrenia. Schizophr Bull 1997

Hennen J, Baldessarini RJ. Suicidal risk during treatment with clozapine: a meta-analysis. Schizophrenia research 2005

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.

Conley RR, Buchanan RW. Evaluation of treatment-resistant schizophrenia. Schizophr Bull 1997

Hennen J, Baldessarini RJ. Suicidal risk during treatment with clozapine: a meta-analysis. Schizophrenia research 2005


12

Slide 23

Clozapine has a special adverse

effects profile.

- It’s one of the antipsychotics with

the lowest risk of causing EPS.

On the other hand, it’s one of the

antipsychotics with the highest

metabolic risk, the other is

olanzapine.

As we saw in the module on adverse effects, the risk of agranulocytosis requires periodic blood

monitoring.

It has a dose-dependent seizure risk.

Because of its antagonist effect at histamine 1 receptors it can be very sedating.

Slide 24

Olanzapine is a second generation

antipsychotic known to be less “dirty”

in pharmacodynamic terms than

clozapine.

It is available in combination with the

antidepressant fluoxetine as

olanzapine fluoxetine combination or

OFC.

Dosage forms include parenteral formulations.

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


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


Olanzapine

• SGA less “dirty” than clozapine.

• Available in combination with fluoxetine: OFC

• Dosage forms include parenteral formulations


Olanzapine

• SGA less “dirty” than clozapine.

• Available in combination with fluoxetine: OFC

• Dosage forms include parenteral formulations



13

Slide 25

Olanzapine has a binding profile

similar to clozapine, but it interacts

with less receptors.

It has a high 5HT2A/D2 ratio, like

clozapine it is an antagonist at

histamine 1, muscarinic, alpha 1 and

5HT2C receptors. Antagonist actions

at 5HT2C and histamine 1 receptors

are thought to be related to an

increased risk of weight gain.

Because of its affinity for alpha 1 receptors, olanzapine can cause in some cases orthostatic

hypotension. Since this drug is available as IM injection, we need to remember this side effect

to avoid combining it with benzodiazepines.

Slide 26

The dosage range of olanzapine goes

from 10 to 20 mg / day. There are

several dosage forms that include oral

and parenteral formulations.

Tablets are available in doses of 2.5,

5, 7.5, 10, 15 and 20 mg.

Orally disintegrating tablets: 5, 10, 15

and 20 mg

Oral fluoxetine combination of 6 mg of fluoxetine and 25 mg of olanzapine, 6 and 50 mg, 12 and

25 and 12 and 50 mg.

An IM formulation for use in acute settings: 5 mg per ml, each vial contains 10 mg. This

formulation is available in some countries.

A long acting injection of olanzapine pamoate: doses of 150, 300, 210, 405 mg

Olanzapine – Binding Profile- High 5HT2A/D2 ratio- H1 antagonist- Muscarinic antagonist a 1 antagonist- 5HT2C antagonist


Olanzapine – Binding Profile- High 5HT2A/D2 ratio- H1 antagonist- Muscarinic antagonist a 1 antagonist- 5HT2C antagonist


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


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



14

Slide 27

I’ve selected some interesting facts

about the clinical profile of

olanzapine:

Olanzapine/fluoxetine combination

was the first drug approved for

bipolar depression.

Olanzapine is associated with less EPS

than FGAs.

Weight gain is problematic with long term use. Olanzapine and clozapine are associated with

the highest risk of weight gain.

It can be a very sedating antipsychotic.

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.

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.

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