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COMPARATIVE EFFICACY OF HALOPERIDOL AND RISPERIDONE: A REVIEW

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Pakistan Journal of Pharmacology
Vol.24, No.2, July 2007, pp.55-64

COMPARATIVE EFFICACY OF HALOPERIDOL

AND RISPERIDONE: A REVIEW
SHAHIDA PERVEEN AHMED, AFSHAN SIDDIQ,
SADIA GHOUSIA BAIG AND RAFEEQ ALAM KHAN
Department of Pharmacology, Faculty of Pharmacy
University of Karachi, Karachi-75270, Pakistan
ABSTRACT:
Psychosis is a mental state of illness in which person is detached from reality. Psychosis
is of many form, including; Hallucinations, Delusions, thought insertion, withdrawal,
block broadcasting, lack of insight etc. Different theories suggest that the cause of
psychotic illness may be, inherited, problem in brain, neurochemical imbalance, anxiety
or stress, any combination of the above, using drugs [e.g., cannabis, Lysergic acid
diethylamide (LSD)], infections (e.g., menningitis), brain tumours (cancer), epilepsy,
head injuries. Psychosis has been shown to respond well to treatments such as anti-
psychotic medication, and more recently cognitive-behavioural therapy has been
suggested as working well. Family and group therapies are often found to give successful
results in certain individuals. Haloperidol is a psychotropic agent indicated for the
treatment of schizophrenia. It also exerts sedative and antiemetic activity. Haloperidol
has actions at all levels of the central nervous system-primarily at subcortical levels as
well as on multiple organ systems. Risperidone is a novel antipsychotics, it is a uniquely
balanced serotonin/dopamine antagonist (SDA) that offers considerable advantages in the
first-line treatment of schizophrenia. This review examines the efficacy of haloperidol
versus risperidone.

Keywords: Psychosis, Scizophrenia, Antipsychotic, Mania, Major-bipolar disorder,

Cognition.

INTRODUCTION and brief psychotic disorder. However, other

Psychosis
Psychosis comprises a cluster of medical
symptoms, but a precise and universally
accepted definition has been elusive. The most
restrictive definition is limited to symptoms of
delusions or hallucinations – the hallucinations
occurring in patients who lack insight into
their illness. A broad definition can include
psychiatric manifestations such as the positive
symptoms of schizophrenia like disorganized
speech or catatonic behavior. The term
psychosis can conceptually include the loss of
ego boundaries or a gross impairment in
reality testing.
disorders can present with psychotic
symptoms, including bipolar disorder and
depression with psychotic features, substance-
induced psychosis, medical illness such as
neurological disorders like Parkinson’s disease
and with environmental circumstances e.g., in
the intensive care unit (ICU). ICU psychosis
can occur in some patients due to a variety of
situations: post-surgical anesthesia, waking up
with numerous intravenous lines in place,
noises in the ICU area, the constant flow of
staff, and an unfamiliar environment for that
could result in agitation and other psychotic
symptoms (Wallace, 2001; Sato et al., 2006
and Krakoski et al., 2006).

Psychotic symptoms are a defining feature Antipsychotic Drugs

of schizophrenia, schizophreniform disorder, Antipsychotics drugs have been the
schizoeffective disorder, delusional disorder, mainstay of the treatment for psychosis since

Correspondence: Email: drshahidaperveen@hotmail.com; siddiq.afshan@gmail.com

56 Comparative Efficacy of Haloperidol and Risperidone: A Review
chlorpromazine’s discovery in the mid-1950s
and its record of achievement earned in
clinical application during use in the early
1960s. From 1960s to 1989, anti-psychotics
drugs were effective in treating psychotic
symptoms in psychiatric disorders, but had
numerous adverse side effects, most notably
extra pyramidal side effects (EPS). The food
and Drug Administration’s (FDA) approval of
clozapine started a new era of developing anti-
psychotics drugs with fewer EPS.
Agents prior to 1989 can be classified as
“conventional” or “typical” anti-psychotics;
those approved after that date are termed
“atypical” anti-psychotics (Lee et al., 1997 and
Stollberger et al., 2005).
Behavioral Effects in Humans:
When administered acutely, anti-
psychotics produce profound effects in
psychotic individuals, including patients with
schizophrenia, acute mania, and others
displaying agitation, aggression or paranoia.
Soon after administration individuals become
less agitated, restless, aggressive and
impulsive without becoming excessively
sedated. Initiative and interest in the
environment may be reduced, in addition to
displays of emotion or effect. However, while
there may be drowsiness and some slowness in
response to external stimuli, subjects are easily
aroused, capable of giving appropriate answers
to direct questions, and seem to have intact
intellectual functions. Because of the dramatic
tranquilizing effect of these drugs in
individuals without schizophrenia, this
calming of acute psychosis is less selective
than the long-term effects (Wallace, 2001;
Zuidema et al., 2006 and Sato et al., 2006).
With continuous administration of the
anti-psychotics more selective effects on
psychosis emerge. Following two to six weeks
of administration, hallucinations, delusions,
and disorganized thinking tend to diminish or
disappear. Although negative symptoms are
less likely to be affected than positive
symptoms, patients displaying social with-
drawal may sometimes become more respon-
sive and communicative. Anti-psychotics
drugs are therefore not simply tranquilizers,
decreasing the ability of psychotic individuals
to express their disturbances, but instead
appear to somewhat selectively reverse many
of the symptoms of schizophrenia. Anti-
psychotics do not cure schizophrenia, they
simply alleviate symptoms. Since schizo-
phrenia is a lifetime disorder, treatment with
anti-psychotics typically continues throughout
the lifetime of the patient (Krakowski et al.,
2006; Molina et al., 2004 and Spanarello et al.,
2005).
Although anti-psychotics have produced
important benefits in the treatment of mental
illness, they are also associated with
significant side effects. Acutely, these drugs
may produce extra pyramidal symptoms,
movement problems similar to Parkinson’s
disease. With long-term use these drugs may
produce, in some individuals, a disturbing
movement disorder known as tardive
dyskinesia. Tardive dyskinesia is characterized
by stereotypical, repetitive, involuntary
movements of the mouth and tongue, trunk,
and extremities. These symptoms are typically
seen after two years or more of anti-psychotic
drugs use and symptoms sometime persist
indefinitely after discontinuation of the
medication. Secondary medications are often
administered with anti-psychotics to decrease
the potential for the development of tardive
dyskinesia (Ritchie et al., 2003 and Tarazi et
al., 2003).
Haloperidol:
Haloperidol is a butyrophenone derivative
with anti-psychotic properties that has been
considered particularly effective in the
management of hyperactivity, agitation, and
mania. Haloperidol is an effective neuroleptic
and also possesses anti-emetic properties; it
has a marked tendency to provoke extra
pyramidal effects and has relatively weak
alpha-adrenolytic properties (Savaskan et al.,
2005). It may also exhibit hypothermic and
anorexiant effects and potentiate the action of
barbiturates, general anesthetics, and other
CNS depressant drugs. The mechanism of
Ahmed et al.
action of haloperidol has not been entirely
elucidated, but has been attributed to the
inhibition of the transport mechanism of
cerebral monoamines, particularly by blocking
the impulse transmission in dopaminergic
neurons (Alvarez and Skowronski, 2003; Karl
et al., 2006; Ali et al., 2003; Kirkwood and
Givone, 2003 and Zimbroff, 2003). Peak
plasma levels of haloperidol occur within 2 to
6 hours of oral dosing and about 20 minutes
after i.m. administration. The mean plasma
(terminal elimination) half-life has been
determined as 20.7 ± 4.6 (SD) hours, and
although excretion begins rapidly, only 24 to
60% of ingested radioactive drug is excreted
(mainly as metabolites in urine, some in
faeces) by the end of the first week, and very
small but detectable levels of radioactivity
persist in the blood and are excreted for
several weeks after dosing. About 1% of the
ingested dose is recovered unchanged in the
urine. Haloperidol is indicated in the
management of manifestations of acute and
chronic psychosis, including schizophrenia
and manic states. It may also be of value in the
management of aggressive and agitated
behavior in patients with chronic brain
syndrome and mental retardation and in the
symptomatic control of Gilles de la Tourette’s
syndrome (Zykov et al., 2005; Andrezina et
al., 2006 and Kennedy et al., 2003), Comatose
states and CNS depression due to alcohol or
other depressant drugs; severe depressive
states; previous spastic diseases; lesions of the
basal ganglia; Parkinson’s syndrome, except in
the case of dyskinesias due to levodopa
treatment; sensitivity to haloperidol; senile
patients with pre-existing Parkinson-like
symptoms. Safety and effectiveness in young
children have not been established; therefore,
haloperidol is contraindicated in this age
group. Safety for use in pregnancy and
lactation has not been established; do not
administer to women of childbearing potential
or nursing mothers unless, in the opinion of
the physician, the expected benefits of the drug
outweigh the potential hazard to the fetus or
child. Haloperidol is excreted in breast milk
(Fredriksson & Archer, 2006; Diav-Citrin et
al., 2005).
57
Haloperidol has been reported to interfere
with the anticoagulant properties of
phenindione in an isolated case, and the
possibility should be kept in mind of a similar
effect occurring when haloperidol is used with
other anticoagulants. Haloperidol may
antagonize the action of epinephrine and other
sympathomimetic agents and reverse the blood
pressure-lowering effects of adrenergic-
blocking agents, such as guanethidine.
Enhanced CNS effects may occur when
haloperidol is used in combination with
methyldopa. Haloperidol inhibits the metabo-
lization of tricyclic antidepressants, thereby
increasing plasma levels of these drugs. This
may result in increased tricyclic antidepressant
toxicity (anticholinergic effects, cardiovascular
toxicity, lowering of seizure threshold)
(Krieger et al., 2004).
When prolonged Carbamazepine treat-
ment is added to haloperidol therapy, this
results in a significant reduction of haloperidol
plasma levels. Therefore, during combination
treatment, the haloperidol dose should be
adjusted, when necessary. After stopping
Carbamazepine, it will be necessary to reduce
the dosage of haloperidol. Haloperidol may
impair the antiparkinson effects of levodopa. If
an antiparkinson agent is used concomitantly
with haloperidol, both drugs should not be
discontinued simultaneously, since extra-
pyramidal symptoms may occur due to the
slower excretion rate of haloperidol. When
haloperidol is used to control mania in cyclic
disorders, there may be a rapid mood swing to
depression. The antiemetic action of
haloperidol may obscure signs of toxicity due
to over dosage of other drugs or mask the
symptoms of some organic diseases, such as
brain tumor or intestinal obstructions. Severe
neurotoxicity (rigidity, inability to walk or
talk) may occur in patients with thyrotoxicosis
who are also receiving anti-psychotic
medication, including haloperidol. Neuroleptic
drugs elevate prolactin levels; the elevation
persists during chronic administration.
Although disturbances such as galactorrhea,
amenorrhea, gynecomastia, and impotence
have been reported, which are presumed to be
58 Comparative Efficacy of Haloperidol and Risperidone: A Review
linked to elevated prolactin levels (Savaskan et
al., 2006, Besag and Berry, 2006).
Neuromuscular (extrapyramidal) effects
such as Parkinson-like symptoms, akathisia,
dyskinesia, dystonia, hyperreflexia, rigidity,
opisthotonos, and, occasionally, oculogyric
crisis are the most frequently reported side
effects associated with the administration of
haloperidol. Headache, vertigo and cerebral
seizures have also been reported. The
extrapyramidal reactions are usually dose
related in occurrence and severity and, as a
rule, tend to subside when the dose is reduced
or the drug is temporarily discontinued.
However, considerable interpatient variability
exists, and, although some individuals may
tolerate higher than average doses of
haloperidol, severe extra pyramidal reactions,
necessitating discontinuation of the drug, may
occur at relatively low doses. Administration
of an antiparkinson agent is usually, but not
always, effective in preventing or reversing
neuromuscular reactions associated with
haloperidol (Galili et al., 2000; Balestrieri et
al., 2000).
As with all anti-psychotic agents, tardive
dyskinesia may appear in some patients on
long-term therapy or may appear after drug
therapy has been discontinued. The risk
appears to be greater in elderly patients on
high dose therapy, especially females. The
symptoms are persistent and in some patients
appear to be irreversible. The syndrome is
characterized by rhythmical, involuntary
movements of the tongue, face, mouth or jaw
(e.g., protrusion of tongue, puffing of cheeks,
puckering of mouth, chewing movements).
Sometimes these may be accompanied by
involuntary movements of extremities. There
is no known effective treatment for tardive
dyskinesia; antiparkinsonism agents usually do
not alleviate the symptoms of this syndrome. It
is suggested that all anti-psychotic agents be
discontinued if these symptoms appear. It has
been reported that fine vermicular movements
of the tongue may be an early sign of the
syndrome and if the medication is stopped at
that time the syndrome may not develop.
Tardive dystonia, not associated with the
above syndrome, has been reported. Tardive
dystonia is characterized by delayed onset of
choreic or dystonic movements, is often
persistent, and has the potential of becoming
irreversible (Balestrieri et al., 2000; Luft,
Taylor, 2006, Schneider et al., 2006 and
Alvarez, Skowronski, 2006)
Insomnia, depressive reactions, and toxic
confusional states are the more common
effects encountered. Drowsiness, lethargy,
stupor and catalepsy, confusion, restlessness,
agitation, anxiety, euphoria, and exacerbation
of psychotic symptoms, including hallucina-
tions, have also been reported (Harvey et al.,
2004, Hassaballa and Balk, 2003)
Tachycardia, hypertension and ECG
changes including prolongation of the QT
interval and ECG pattern changes compatible
with the polymorphous configurations of
torsades de pointes have been reported.
Hypotension has occurred, but severe
orthostatic hypotension has not been reported.
However, should it occur, supportive
measures, including i.v. vasopressors such as
norepinephrine, may be required. Epinephrine
should not be used, since haloperidol may
block the vasoconstrictor effects of this drug.
Dry mouth, blurred vision, urinary
retention, incontinence, diaphoresis and
priapism have been reported. The overall
incidence of significant hematologic changes
in patients on haloperidol has been low.
Occasionally there have been reports of mild
and usually transient leukopenia and
leukocytosis, decreases in blood cell counts,
anemia, and a tendency toward lymphomono-
cytosis. Agranulocytosis has rarely been
reported with the use of haloperidol, and then
only in association with other medication.
Impairment of liver function (jaundice or
hepatitis) has been reported rarely. One case of
photosensitization is known and isolated cases
of idiosyncratic cutaneous involvement have
been observed.
Ahmed et al. 59

Other untoward effects encountered 5HT1C, 5HT1D, and 5HT1A receptors, weak
include peripheral edema, hypocholestero- no affinity (Ki of 620 to 800 nM) for the
lemia, alopecia, laryngospasm, bronchospasm dopamine D1 and haloperidol-sensitive sigma
and increased depth of respiration and stasis site, and to affinity (when tested at
pneumonia. Hyperammonemia has been concentrations >10-5M) for cholinergic
reported in a 5½ year old child with muscarinic or α1 and α2 adrenergic receptors
citrullinemia, an inherited disorder of (Marek et al., 2003, Aghajanian and Marek,
ammonia excretion, following treatment with 2000).
haloperidol. Table 1
The relative in vitro binding profiles of
As with other neuroleptic drugs, a (haloperidol)
symptom complex sometimes referred to a
neuroleptic malignant syndrome (NMS) has Receptor Haloperidol Risperodone
been reported. Cardinal features of NMS are D1 36.0 50.0
hyperpyrexia, muscle rigidity, altered mental D2 7.5 4.0
status (including catatonic signs), and evidence D3 2.7 6.7
of autonomic instability (irregular pulse or D4 23.0 7.0
blood pressure). Additional signs may include 5-HT2A 55.0 0.76
elevated CPK, myoglobinuria (rhabdomyoly- 5-HT2C 2100.0 14.0
sis), and acute renal failure. NMS is Alpha 1 18.0 1.7
potentially fatal, requires intensive symp- Alpha 2 2000.0 2.3
tomatic treatment and immediate disconti- H1 >1000.0 110.0
nuation of neuroleptic treatment. Hyperpyrexia Muscarinic 5500.0 6500.0
and heat stroke, not associated with the above
symptom complex, have also been reported Risperidone is well absorbed. Risperidone
(Gerbershagen et al., 2001; Reeves et al., is extensively metabolized in the liver by
2001; Magdalan et al., 2004; Lee et al., 1997). cytochrome P450IID6 to a major active
metabolite, 9-hydroxyrisperidone, which is the
Risperidone predominant circulating specie, and appears
Risperidone is a relatively new anti- approximately equi-effective with risperidone
psychotics that is a potent antagonist at 5-HT2a with respect to receptor binding activity (A
and D2 receptors. It is the most potent second minor pathway is N-dealkylation).
serotonin/dopamine antagonist available today. Consequently, the clinical effect of the drug
It also demonstrates relatively high affinity for results from the combined concentrations of
alpha1 and H1 receptors but low affinity for risperidone plus 9-hydroxyrisperidone. Plasma
beta-adrenergic or muscarinic receptors (Table concentrations of risperidone, 9-hydroxy-
1). Preclinical studies indicate that while ridperidone, and risperidone plus 9-hydro-
risperidone is approximately equipotent to xyrisperidone are dose proportional over the
haloperidol at D2 antagonism, it is several dosing range of 1 to 16 mg daily (0.5 to 8 mg
times less potent than haloperidol at inducing bid). The relative oral bioavailability of
catalepsy (McDonald et al., 2003). risperidone from a tablet was 94% when
compared to a solution. Food does not affect
Risperidone is a selective monoaminergic either the rate or extent of absorption of
antagonist with high affinity (Ki of 0.12 to 7.3 risperidone. Thus, risperidone can be given
nM) for the serotonin type 2 (5H2T), dopamine with or without meals. The absolute oral
type 2 (D2), O1 and O2 adrenergic, and H1 bioavailability of risperidone was 70%. The
histaminergic receptors. Risperidone anta- enzyme catalyzing hydroxylation of
gonizes other receptors, but with lower risperidone to 9-hydroxy-risperidone is cyto-
potency. Risperidone has low to moderate chrome P450IID6, also called debrisoquin
affinity (47 to 253 nM) for the serotonin hydroxylase, the enzyme responsible for
60 Comparative Efficacy of Haloperidol and Risperidone: A Review
metabolism of many neuroleptics, anti-
depressants, antiarrhythmics, and other drugs.
Cytochrome P450IID6 is subject to genetic
polymorphism. Following oral administration
of solution or tablet, mean peak plasma
concentrations occurred at about 1 hour. The
apparent half-life of risperidone was 3 hours in
extensive metabolizers and 20 hours in poor
metabolizers. Steady-state concentrations of
risperidone are reached in 1 day in extensive
metabolizers and would be expected to reach
steady state in about 5 days in poor
metabolizers (Aghajanian and Marek, 2000;
Zhou et al., 2006).
Risperidone is indicated for the
management of the manifestations of
psychotic disorders. The antipsychotics
efficacy of risperidone was established in
short-term (6 to 8 weeks) controlled trials of
schizophrenic inpatients (Kontaxakis et al.,
2006). The effectiveness of risperidone in
long-term use, that is, more than 6 to 8 weeks,
has not been systematically evaluated in
controlled trials. Therefore, the use of
risperidone for extended periods should
periodically re-evaluate the long-term useful-
ness of the drug for the individual patient
(Klebovich et al., 2005).
The interactions of risperidone and other
drugs have not been systematically evaluated.
Given the primary CNS effects of risperidone,
caution should be used when risperidone is
taken in combination with other centrally
acting drugs and alcohol (Poewe, 2005).
Because of its potential for inducing
hypotension, risperidone may enhance the
hypotensive effects of other therapeutic agents
with this potential.
Risperidone may antagonize the effects of
levodopa and dopamine agonists.
Chronic administration of Carbamazepine
with risperidone may increase the
clearance of resperidone.
Chronic administration of clozapine with
risperidone may decrease the clearance of
risperidone.
Fluoxetine may increase the plasma
concentration of the anti-psychotic
fraction (risperidone plus 9-hydroxy-
risperidone) by raising the concentration
of risperidone, although not the active
metabolite, 9-hydroxyrisperidone.
In vitro studies indicate that risperidone is
a relatively weak inhibitor of cytochrome
P450IID6. Therefore, risperidone is not
expected to substantially inhibit the clearance
of drugs that are metabolized by this
enzymatic pathway. However, clinical data to
confirm this expectation are not available.
Overdose:
Acute risperidone over-dosage with
estimated doses ranging from 20 to 300mg and
reported signs and symptoms are resulting
from an exaggeration of the drug’s known
pharmacological effects (i.e., drowsiness and
sedation, tachycardia and hypotension, and
extrapyramidal symptoms). One case,
involving an estimated overdose of 240 mg,
was associated with hyponatremia, hypo-
kalemia, prolonged QT, and widened QRS.
Another case, involving an estimated overdose
of 36mg, was associated with a seizure
(Magdalan et al., 2004 and Lee et al., 1997).
Another acute over-dosage with estimated
doses of up to 360 mg, the most frequently
reported signs and symptoms are those
resulting from an exaggeration of the drug’s
known pharmacological effects (i.e.,
drowsiness, sedation, tachycardia, and hypo-
tension). Other adverse events reported which
were temporally, (but not necessarily causally)
related to risperidone overdose, include
prolonged QT interval, convulsions, cardio-
pulmonary arrest, and rare fatality associated
with multiple drug overdose (Aichhorn et al.,
2006 and Llerena et al., 2004).
It is recommended that responding
patients be continued on risperidone, but at the
lowest dose needed to maintain remission.
Patients should be periodically reassessed to
determine the need for maintenance treatment
(Silke et al., 2002).
Ahmed et al.
DISCUSSION
Among patients with clinically stable
chronic schizophrenia or schizoaffective
disorder, the risk of relapse was significantly
lower during treatment with risperidone than
during treatment with haloperidol. The benefit
with risperidone was substantial. The means of
the modal daily doses of risperidone (4.9mg)
and haloperidol (11.7mg) were similar to those
used in clinical practice (Nyberg et al., 1999).
The relapse rate among subjects receiving
haloperidol (39.9 percent) was similar in
magnitude to that found previously among
patients receiving conventional anti-psychotic
agents (Glick et al., 2006).
The reduced risk of relapse with
risperidone could be due to that drug’s
superior efficacy, better tolerability, or both.
Patients who received risperidone had both
early and late improvements in symptoms
overall, as well as an amelioration of extra-
pyramidal symptoms. In contrast, patients
receiving haloperidol had a slight worsening of
both psychotic and extrapyramidal symptoms
(Hertel, 2006 and Nyberg et al., 1999). These
findings are similar to those previously
reported for an eight-week comparative trial of
risperidone and haloperidol. Another trial the
rate of relapse, was similar in the two
treatment groups (Halbreich and Kahn, 2003).
Improvements in cognition or other symptoms
of schizophrenia produced by risperidone but
not well assessed by the positive and negative
syndrome scale may also have contributed to
the reductions in the rate of relapse. Receptor
profiles and mechanisms of action vary among
atypical anti-psychotic agents. Therefore, other
agents should be assessed individually with
regard to their ability to prevent relapses (Fe-
Bornstein et al., 2002; Kirkwood and Givone,
2003).
Extrapyramidal side effects can occur
with risperidone treatment. However, in
clinical trials patients treated with risperidone
experienced much fewer EPS than those
treated with haloperidol. The use of
antiparkinsonian medication (to alleviate EPS)
61
reflects the finding with significantly fewer
patients treated with risperidone requiring anti-
parkinsonian medication compared to halo-
peridol (Garver, 2006).
RESULT
Risperidone is at least as (and possibly
slightly more) effective than atypical anti-
psychotics drugs (chiefly haloperidol). It has a
low incidence of EPS and may be more
acceptable to patients with schizophrenia.
Whether risperidone offers any advantages
over the other atypical anti-psychotics is yet to
be established (Kirkwood and Givone, 2003;
Conley and Kelly, 2002; Glick et al., 2006).
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