Pharmacology

Section 10

Neuroleptic Drugs.

Marta Jóźwiak-Bębenista

Department of Pharmacology

Medical University of Lodz

martia1@tlen.

pl

Neuroleptic Drugs

Neuroleptic Drugs

=

=

antischizophrenic

antischizophrenic

drugs, antipsychotic

drugs, antipsychotic

drugs or major

drugs or major

tranquilizers

tranquilizers

Schizophrenia

Schizophrenia

What is the difference

What is the difference

?

?

PSYCHOSIS

PSYCHOSIS

Psychosis is a thought disorder characterized by

Psychosis is a thought disorder characterized by

disturbances of reality and perception, impaired

disturbances of reality and perception, impaired

cognitive functioning, and inappropriate or

cognitive functioning, and inappropriate or

diminished affect (mood).

diminished affect (mood).

Psychosis denotes many mental disorders.

Psychosis denotes many mental disorders.

SCHIZOPHRENIA

SCHIZOPHRENIA

Schizophrenia is a particular kind of psychosis characterized

Schizophrenia is a particular kind of psychosis characterized

mainly by a clear sensorium but a marked thinking

mainly by a clear sensorium but a marked thinking

disturbance.

disturbance.

Schizophrenia

Schizophrenia



Schizophrenia is characterized

Schizophrenia is characterized

by profound disruption in

by profound disruption in

cognition and emotion, affecting

cognition and emotion, affecting

the most fundamental human

the most fundamental human

attributes: language, thought,

attributes: language, thought,

perception, affect, and sense of

perception, affect, and sense of

self

self

Prevalence of

Prevalence of

schizophrenia

schizophrenia



1.1%

1.1%

population over the age of 18

population over the age of 18



51 mln

51 mln

people worldwide suffer from

people worldwide suffer from

schizophrenia

schizophrenia

12 million

12 million

people in China (a rough

people in China (a rough

estimate

estimate

based on the population)

based on the population)

8.7 million

8.7 million

people in India (a rough

people in India (a rough

estimate

estimate

based on the population)

based on the population)

2.2 million

2.2 million

people in USA

people in USA

285,000

285,000

people in Australia

people in Australia

Over

Over

280,000

280,000

people in Canada

people in Canada

Over

Over

250,000

250,000

diagnosed cases in Britain

diagnosed cases in Britain

Etiology of Schizophrenia

Etiology of Schizophrenia

Idiopathic

Idiopathic

Biological Correlates

Biological Correlates

1)

1)

Genetic Factors

Genetic Factors

2)

2)

Neurodevelopmental

Neurodevelopmental

abnormalities.

abnormalities.

3)

3)

Environmental stressors.

Environmental stressors.

The risk of getting

The risk of getting

schizophrenia

schizophrenia

Dopamine Theory of

Dopamine Theory of

Schizophrenia

Schizophrenia

Many lines of evidence point to

Many lines of evidence point to

the aberrant increased activity of

the aberrant increased activity of

the dopaminergic system as being

the dopaminergic system as being

critical in the symptomatology of

critical in the symptomatology of

schizophrenia.

schizophrenia.

Dopaminergic system

Dopaminergic system

There are

There are

4

4

major pathways for the dopaminergic

major pathways for the dopaminergic

system in the brain:

system in the brain:



The m

The m

esolimbic pathway

esolimbic pathway

from substantia nigra to limbic system

from substantia nigra to limbic system

,

,

functions

functions

of memory, emotion, arousal, and pleasure

of memory, emotion, arousal, and pleasure



The

The

mesocortical pathway

mesocortical pathway

from substantia nigra to neocortex

from substantia nigra to neocortex

,

,

cognition,

cognition,

social behavior, planning, problem solving,

social behavior, planning, problem solving,

motivation, and reinforcement in learning

motivation, and reinforcement in learning



The n

The n

igrostriatal pathway

igrostriatal pathway

from the substantia nigra to the striatum,

from the substantia nigra to the striatum,

coordination of involuntary movement

coordination of involuntary movement



The t

The t

uberoinfundibular pathway

uberoinfundibular pathway

from the hypothalamus to the pituitary gland,

from the hypothalamus to the pituitary gland,

secretion of certain hormones

secretion of certain hormones

(

(

prolactin

prolactin

)

)

THE DOPAMINERGIC SYSTEM

THE DOPAMINERGIC SYSTEM

Catecholamines

Catecholamines

Tyrosine

Tyrosine





Tyrosine hydroxylase

Tyrosine hydroxylase

L-

L-

Dopa

Dopa





Dopa decarboxylase

Dopa decarboxylase

Dopamine (DA)

Dopamine (DA)





Dopamine

Dopamine





hydroxylase

hydroxylase

Norepinephrine (NE)

Norepinephrine (NE)

(Noradrenaline)

(Noradrenaline)

Phenylethanolamine-

Phenylethanolamine-





-N-methyltransferase

-N-methyltransferase

Epinephrine (EPI)

Epinephrine (EPI)

(Adrenaline)

(Adrenaline)

Dopamine Synapse

DA

L-DOPA

Tyrosine

Tyrosine

Dopamine receptors

Dopamine receptors



D

D

1

1

, D

, D

5

5

dopamine receptors

dopamine receptors

-

-





cAMP by

cAMP by

activation of adenylyl cyclase

activation of adenylyl cyclase

D

D

1

1

– putamen, nucleus acumbens

– putamen, nucleus acumbens

D

D

5

5

– hypothalamus, hippocampus

– hypothalamus, hippocampus



D

D

2

2

, D

, D

3

3

, D

, D

4

4

dopamine receptors

dopamine receptors

-

-





cAMP

cAMP

by inhibition of adenylyl cyclase, inhibits

by inhibition of adenylyl cyclase, inhibits

Ca

Ca

2+

2+

channels and open K

channels and open K

+

+

channels

channels

D

D

2

2

– caudate–putamen, nucleus

– caudate–putamen, nucleus

acumbens

acumbens

D

D

3

3

– frontal cortex, medulla, midbrain

– frontal cortex, medulla, midbrain

There are at least five subtypes of
receptors:

The dopamine hypothesis

The dopamine hypothesis

(1):

(1):



Most antipsychotic drugs strongly

Most antipsychotic drugs strongly

block postsynaptic D2 receptors in

block postsynaptic D2 receptors in

the CNS (meso-limbic system)

the CNS (meso-limbic system)



Drugs that increase dopaminergic

Drugs that increase dopaminergic

activity aggravate schizophrenia and

activity aggravate schizophrenia and

produce psychosis

produce psychosis

de novo

de novo



Increased dopamine receptor

Increased dopamine receptor

density has been found

density has been found

post mortem

post mortem

in brains of schizophrenics

in brains of schizophrenics

The dopamine hypothesis

The dopamine hypothesis

(2):

(2):



PET has shown increased dopamine

PET has shown increased dopamine

receptor density in schizophrenics

receptor density in schizophrenics



Successful treatment of

Successful treatment of

schizophrenics changes the amount

schizophrenics changes the amount

of homovanilinic acid – metabolite of

of homovanilinic acid – metabolite of

dopamine in

dopamine in

cerebrospinal fluid,

cerebrospinal fluid,

plasma and urine.

plasma and urine.

SCHIZOPHRENIA

SCHIZOPHRENIA

Dysfunction of DA-

ergic system:

•

Hyperactivity of

DA system

(

mesolimbic

pathway)

•

Hypo-activity in

frontal cortex

(

mesocortical

pathway)

•

Dysfunction of
5-HT, GABA and
glutamate –ergic
systems

Onset of schizophrenia

Onset of schizophrenia



Onset - early

Onset - early

adulthood, between

adulthood, between

the ages of 15 and 25.

the ages of 15 and 25.



Men tend to develop

Men tend to develop

schizophrenia slightly

schizophrenia slightly

earlier (16 – 25 years

earlier (16 – 25 years

old) than women (25 –

old) than women (25 –

30

30

years old).

years old).



The average age of

The average age of

onset is 18 in men and

onset is 18 in men and

25 in women

25 in women

The Course of Schizophrenia



Early intervention and early use of new

Early intervention and early use of new

medications lead to better medical outcomes for

medications lead to better medical outcomes for

the individual

the individual



The earlier someone with schizophrenia is

The earlier someone with schizophrenia is

diagnosed and stabilized on treatment, the

diagnosed and stabilized on treatment, the

better the long-term prognosis for their illness

better the long-term prognosis for their illness



Teen suicide is a growing problem and teens

Teen suicide is a growing problem and teens

with schizophrenia have approximately a 50%

with schizophrenia have approximately a 50%

risk of attempted suicide

risk of attempted suicide



Anti-psychotic medications are the generally

Anti-psychotic medications are the generally

recommended treatment for schizophrenia !!!

recommended treatment for schizophrenia !!!



If medication for schizophrenia is discontinued,

If medication for schizophrenia is discontinued,

the relapse rate is about 80 percent within 2

the relapse rate is about 80 percent within 2

years. With continued drug treatment, only

years. With continued drug treatment, only

about 40 percent of recovered patients will

about 40 percent of recovered patients will

suffer relapses.

suffer relapses.

Outcomes of schizophrenia

Outcomes of schizophrenia

After 30 years of diagnosed

After 30 years of diagnosed

schizophrenia

schizophrenia



25%

25%

Completely Recover

Completely Recover



35%

35%

Much Improved, relatively

Much Improved, relatively

independent

independent



15%

15%

Improved, but require

Improved, but require

extensive support network

extensive support network



10%

10%

Hospitalized, unimproved

Hospitalized, unimproved



15%

15%

Dead (Mostly Suicide)

Dead (Mostly Suicide)

Symptoms of

Symptoms of

schizophrenia (1):

schizophrenia (1):



Positive

Positive

appear to reflect an excess or distortion of normal

appear to reflect an excess or distortion of normal

functions:

functions:

* delusions

* delusions

(paranoid, reference, somatic, delusions of

(paranoid, reference, somatic, delusions of

grandeur)

grandeur)

* halucinations

* halucinations

(visual, auditory, tactile, olfactory,

(visual, auditory, tactile, olfactory,

gustatory)

gustatory)

* disorganized speech

* disorganized speech

= „word salad”

= „word salad”

*disorganized or catatonic behavior

*disorganized or catatonic behavior



Negative

Negative

appear to reflect a diminution or loss of normal

appear to reflect a diminution or loss of normal

functions:

functions:

* lack of emotion

* lack of emotion

* low energy

* low energy

* affective flattening

* affective flattening

* low motivation

* low motivation

*inappropriate social skills

*inappropriate social skills

* alogia

* alogia

The terms "positive" and

The terms "positive" and

"negative" may be confusing.

"negative" may be confusing.

They should not be interperated

They should not be interperated

as "good" and "bad" symptoms.

as "good" and "bad" symptoms.

Symptoms of

Symptoms of

schizophrenia (2):

schizophrenia (2):



Cognitive

Cognitive



disorganized thinking

disorganized thinking



slow thinking

slow thinking



difficulty in understanding

difficulty in understanding



poor concentration

poor concentration



poor memory

poor memory



difficulty with expressing thoughts

difficulty with expressing thoughts



difficulty with integrating thoughts,

difficulty with integrating thoughts,

feelings and behavior

feelings and behavior

Symptoms of

Symptoms of

schizophrenia (3):

schizophrenia (3):



Disorganized symptoms (?)

Disorganized symptoms (?)

* thought disorder

* thought disorder

* confusion

* confusion

* disorientation

* disorientation

* memory problems

* memory problems

Disorganized symptoms may reflect an underlying

dysfunction common to several psychotic disorders,

rather than being unique to schizophrenia.

Schizophrenia

Schizophrenia

•

Active phase

Hallucinations

and delusions

are prominent

symptoms

•

Residual phase

U.S. diagnostic criteria for

U.S. diagnostic criteria for

schizophrenia (1)

schizophrenia (1)



A. Characteristic symptoms: ≥2

A. Characteristic symptoms: ≥2

during a 1-month period

during a 1-month period

:

:

delusions

delusions

halucinations

halucinations

disorganized speech

disorganized speech

disorganized behavior

disorganized behavior

negative symptoms

negative symptoms

U.S. diagnostic criteria for

U.S. diagnostic criteria for

schizophrenia (2)

schizophrenia (2)



Only

Only

one

one

Criterion A symptom is

Criterion A symptom is

required if delusions are bizarre or

required if delusions are bizarre or

hallucinations consist of a voice

hallucinations consist of a voice

keeping up a running commentary

keeping up a running commentary

on the person’s behavior or

on the person’s behavior or

thoughts, or two or more voices

thoughts, or two or more voices

conversing with each other.

conversing with each other.

U.S. diagnostic criteria for

U.S. diagnostic criteria for

schizophrenia (3)

schizophrenia (3)



B. Social/occupational dysfunction

B. Social/occupational dysfunction

work

work

interpersonal relations

interpersonal relations

self-care

self-care



C. Duration

C. Duration

continuous signs of the disturbance

continuous signs of the disturbance

persist for

persist for

at least 6 months

at least 6 months

, including

, including

1 month of symptoms from Criterion A

1 month of symptoms from Criterion A

and prodromal symptoms)

and prodromal symptoms)

U.S. diagnostic criteria for

U.S. diagnostic criteria for

schizophrenia (4)

schizophrenia (4)



D. Schizoaffective and mood disorder

D. Schizoaffective and mood disorder

exclusion

exclusion

no major depressive, manic or mixed

no major depressive, manic or mixed

episodes have occurred with the active-

episodes have occurred with the active-

phase symptoms

phase symptoms



E. Substance/general medical condition

E. Substance/general medical condition

exclusion

exclusion



F. Relationship to a pervasive

F. Relationship to a pervasive

developmental disorder

developmental disorder

Types of schizophrenia

Types of schizophrenia



Paranoid schizophrenia

Paranoid schizophrenia



Disorganized schizophrenia

Disorganized schizophrenia

(hebephrenic)

(hebephrenic)



Catatonic schizophrenia

Catatonic schizophrenia



Residual schizophrenia

Residual schizophrenia



Schizoaffective disorder

Schizoaffective disorder



Undifferentiated schizophrenia

Undifferentiated schizophrenia

Neuroleptic drugs

Neuroleptic drugs

ANTI-

PSYCHOTIC

DRUGS

TYPICAL

NEUROLEPTICS

ATYPICAL

NEUROLEPTICS

PHENOTHIAZINE

S

THIOXANTHENES

BUTYRO-

PHENONES

BENZISOXAZOLE

S

DIBENZO-

DIAZEPINES

Phenothiazines

Phenothiazines



Chlorpromazine

Chlorpromazine



Fluphenazine

Fluphenazine



Prochlorperazine

Prochlorperazine



Promethazine

Promethazine



Thioridazine

Thioridazine

Other groups of typical

Other groups of typical

neuroleptics

neuroleptics



Thioxanthene

Thioxanthene

Thiothixene

Thiothixene



Butyrophenone

Butyrophenone

Haloperidol

Haloperidol

Typical neuroleptics –

Typical neuroleptics –

mechanism of action

mechanism of action

Mechanisms of Action of

Mechanisms of Action of

Antipsychotics

Antipsychotics

conventional
antipsychotic
s



D2 receptor blockade of postsynaptic in
the mesolimbic pathway

atypical
antipsychotic
s



D2 receptor blockade of postsynaptic
in the mesolimbic pathway to reduce

positive symptoms;



enhanced dopamine release and 5-HT

2A

receptor blockade in the mesocortical

pathway to reduce negative symptoms;



other receptor-binding properties may
contribute to efficacy in treating

cognitive symptoms, aggressive
symptoms and depression in
schizophrenia

Atypical neuroleptics

Atypical neuroleptics



Benzisoxazoles

Benzisoxazoles

Risperidon

Risperidon

Ziprasidon

Ziprasidon



Dibenodiazepines

Dibenodiazepines

Clozapine

Clozapine

Quetiapine

Quetiapine

Olanzapine

Olanzapine

Atypical neuroleptics -

Atypical neuroleptics -

mechanism of action

mechanism of action

What is the clinical

What is the clinical

difference between older

difference between older

and newer drugs?

and newer drugs?



New antipsychotic drugs has been

New antipsychotic drugs has been

shown to be more effective than older

shown to be more effective than older

ones for treating negative symptoms

ones for treating negative symptoms

Actions of neuroleptic

Actions of neuroleptic

drugs (1)

drugs (1)



Dopamine receptor

Dopamine receptor

all, particularly: haloperidol, fluphenazine,

all, particularly: haloperidol, fluphenazine,

thiothixene

thiothixene



Muscarinic receptor

Muscarinic receptor

thioridazine, chlorpromazine

thioridazine, chlorpromazine







- Adrenergic receptor

- Adrenergic receptor

chlorpromazine

chlorpromazine



Serotonin receptor

Serotonin receptor

risperidone, clozapine

risperidone, clozapine



H1 - Histamine receptor

H1 - Histamine receptor

promethazine, chlorpromazine

promethazine, chlorpromazine

Actions of neuroleptic

Actions of neuroleptic

drugs (2)

drugs (2)



Antipsychotic actions:

Antipsychotic actions:

reduce the halucinations

reduce the halucinations

reduce spontaneous physical

reduce spontaneous physical

movement

movement

Occur after 4 – 6 weeks of treatment

Occur after 4 – 6 weeks of treatment



Extrapyramidal effects:

Extrapyramidal effects:

Parkinsonian symptoms

Parkinsonian symptoms

akathisia

akathisia

tardive dyskinesia

tardive dyskinesia

Actions of neuroleptic

Actions of neuroleptic

drugs (3)

drugs (3)



Antiemetic effect

Antiemetic effect

(exept

(exept

thioridazine)

thioridazine)



Antimuscarinic effect:

Antimuscarinic effect:

blurred vision, dry mouth, sedation,

blurred vision, dry mouth, sedation,

confusion, inhibition of GI and

confusion, inhibition of GI and

urinary smooth muscle

urinary smooth muscle



Other effects:

Other effects:

hypotension, lightheadness

hypotension, lightheadness



Neuroleptic drugs are not curative

Neuroleptic drugs are not curative

and

and

do not eliminate the fundamental

do not eliminate the fundamental

thinking disorder, but often do

thinking disorder, but often do

permit the psychotic patient to

permit the psychotic patient to

function in a supportive environment

function in a supportive environment

Therapeutic uses

Therapeutic uses



Schizophrenia

Schizophrenia



Other psychosis

Other psychosis



Schizoaffective disorders

Schizoaffective disorders



Delirium

Delirium



Prevention of severe nausea and vomiting

Prevention of severe nausea and vomiting

(vertigo, motion sickness, cancer chemo- and

(vertigo, motion sickness, cancer chemo- and

radiotherapy)

radiotherapy)



Tranquilizers

Tranquilizers



In combination with narcotic analgesics for

In combination with narcotic analgesics for

treatment of chronic pain with severe

treatment of chronic pain with severe

anxiety

anxiety



Intractable hiccups

Intractable hiccups

Pharmacokinetics

Pharmacokinetics



Neuroleptics are absorbed after

Neuroleptics are absorbed after

oral

oral

administration

administration



Pass through blood – brain barrier

Pass through blood – brain barrier



Bind well to plasma proteins, highly

Bind well to plasma proteins, highly

lipid-soluble

lipid-soluble



Are metabolized in liver by

Are metabolized in liver by

P-450

P-450

system

system

Adverse effects (1)

Adverse effects (1)

Acute

•

Acute dystonia

Medium- term

•

Akathisia

•

Parkinsonism

Chronic

•

Tardive
dyskinesia

•

Tardive dystonia



Neurologic effects due to D2 receptor

Neurologic effects due to D2 receptor

blockade

blockade

Acute dystonia

Acute dystonia

Fixed muscle postures

with spasm:

•

clenched jaw

muscles

•

protruding tongue

•

opisthotonos

•

torticollis

•

oculogyric crisis

(mouth open, head

back, eyes staring

upwards)

In the beginning of
treatment
Common in young males
Treatment with
anticholinergic drugs
(procyclidine 5-10mg or
benztropine i.m or i.v)

Akathisia

Akathisia

•

motor restlessness

•

affect lower limb

•

very distressing to
the patient

•

Treatment –
reduction of the
drug dose.

Parkinsonism

Parkinsonism

•

induced by blockade

of D2 receptors in

the striatum !!!

•

appear after a few

days to weeks

Treatment:

•

anticholinergic drugs

(e.g procyclidine)

•

reduction of dose

•

switching to an

atypical antipsychotic

Tardive dyskinesia

Tardive dyskinesia

orofacial dyskinesia -lip
smacking and tongue
rotating.

Tardive

Tardive

dystonia

dystonia

specific

movements of the
head, neck and trunk.

There is no effective treatment !!! They are
irreversible

.

Appear after months to years of drug
treatment

Clozapine

Clozapine

and

and

Risperidone

Risperidone

have a low potential for

have a low potential for

causing extrapyramidal symptoms and lower risk of

causing extrapyramidal symptoms and lower risk of

tardive dyskinesia

tardive dyskinesia

Adverse effects

Adverse effects

(2)

(2)

:

:



Anticholinergic effects

Anticholinergic effects

due to muscarinic blockade

due to muscarinic blockade

:

:

loss of accomodation, dry mouth,

loss of accomodation, dry mouth,

blurred vision,

blurred vision,

constipation, urinary retention

constipation, urinary retention



Ortostatic hypotension

Ortostatic hypotension

due to

due to





-adrenergic blockade

-adrenergic blockade



Neuroendocrine adverse effects

Neuroendocrine adverse effects

due to D2 blockade

due to D2 blockade

in the

in the

t

t

uberoinfundibular pathway

uberoinfundibular pathway

:

:

Amenorrhoea-galactor

Amenorrhoea-galactor

r

r

hoea

hoea

Infertility

Infertility

Impotence

Impotence

,

,

Failure to ejaculate

Failure to ejaculate



Drowsiness

Drowsiness



Weight gain

Weight gain

,

,



Urticaria, dermatitis, rashes, dermal photosensitivity

Urticaria, dermatitis, rashes, dermal photosensitivity

Adverse effects of

Adverse effects of

clozapine

clozapine



Bone marrow suppression

Bone marrow suppression



Cardiovascular side effects

Cardiovascular side effects



Diabetes

Diabetes

Adverse effects of

Adverse effects of

chlopromazine

chlopromazine



Cholestatic jaundice

Cholestatic jaundice

Neuroleptic Malignant

Neuroleptic Malignant

Syndrome

Syndrome



Precise pathophysiology unknown –

Precise pathophysiology unknown –

deranged dopaminergic function ?

deranged dopaminergic function ?



It is an idiosyncratic reaction that

It is an idiosyncratic reaction that

appears from a few days to weeks

appears from a few days to weeks

after beginning treatment, but can

after beginning treatment, but can

occur anytime.

occur anytime.



The mortality –

The mortality –

20%

20%

in untreated

in untreated

(

(

bromocriptine

bromocriptine

– D1/D2 agonist;

– D1/D2 agonist;

dantrolene

dantrolene

– sceletal muscle relaxant;

– sceletal muscle relaxant;

supportive treatment)

supportive treatment)

Neuroleptic Malignant

Neuroleptic Malignant

Syndrome

Syndrome

(NMS)

(NMS)



Hyperthermia

Hyperthermia



Muscle rigidity

Muscle rigidity



Autonomic instability

Autonomic instability



Fluctuating consciousness

Fluctuating consciousness



Mortality due to renal failure caused

Mortality due to renal failure caused

by rhabdomyolysis.

by rhabdomyolysis.

Interactions

Interactions

of

of

neuroleptics

neuroleptics



Additive effects:

Additive effects:

sedatives

sedatives





- adrenoreceptor – blocking drugs

- adrenoreceptor – blocking drugs

anticholinergic drugs

anticholinergic drugs

quinidine-like action (

quinidine-like action (

thioridazine,

thioridazine,

ziprasidone)

ziprasidone)

Contraindications

Contraindications



Alcohol abuse

Alcohol abuse



Seizure disorders (

Seizure disorders (

Chlorpromazine

Chlorpromazine

)

)



Epilepsy

Epilepsy



Agranulocytosis (

Agranulocytosis (

Clozapine

Clozapine

)

)

Neuroleptics o

Neuroleptics o

verdose

verdose



Rarely fatal

Rarely fatal



Drowsiness proceeds to coma, with

Drowsiness proceeds to coma, with

intervening period of agitation

intervening period of agitation



Increased muscular excitability may

Increased muscular excitability may

lead to convulsions

lead to convulsions



Decreased deep tendon reflexes

Decreased deep tendon reflexes



Ventricular tachyarrhythmias

Ventricular tachyarrhythmias



Gastric lavage !!!

Gastric lavage !!!

Dosage of neuroleptic

Dosage of neuroleptic

drugs

drugs



Antipsychotics may be given in

Antipsychotics may be given in

divided daily doses initially while

divided daily doses initially while

effective dosage level is being sought.

effective dosage level is being sought.



2 or more episodes of schizophrenia –

2 or more episodes of schizophrenia –

therapy for 5 years

therapy for 5 years



Fluphenazine

Fluphenazine

and

and

haloperidol

haloperidol

i.m.

i.m.





slow release drugs (up to 3 weeks)

slow release drugs (up to 3 weeks)