Pharmacology
Section 10
Neuroleptic Drugs.
Marta Jóźwiak-Bębenista
Department of Pharmacology
Medical University of Lodz
Pharmacology
Section 10
Neuroleptic Drugs.
Marta Jóźwiak-Bębenista
Department of Pharmacology
Medical University of Lodz
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)