Clozapine - An Antischiziphrenic Drug
In the quest for an antipsychotic drug to treat schizophrenia
that would combine low extrapyramidal side effects with high
effectiveness, a class of 'atypical' neuroleptics were
discovered. Kane et al(1994) defined 'atypical' in terms of a
lack of both extrapyramidal side effects and tardive
dyskinesia relative to typical antipsychotic drugs. Such
typical drugs include haloperidol and chlopromazine. Some
examples of the atypical class of neuroleptics include
risperidone, sertindole, remoxpride andclozapine (Kerwin,
1994). Clozapine is considered an ideal example of this class.
(Lieberman et al,1994) It is clozapine on which this report
will focus. In its entirety, this report will include the
primary treatment effects, side effects, chemistry, drug
interactions, neurotransmitters, and receptors affected.
Primary Treatment Effects Darla Gardner
Neuroleptics are
not curative rather they enable remission of the illness and a
reduction of symptoms to come more quickly (Kane et al, 1994).
In comparison with classic neuroleptics such as haloperidol,
clozapine has been shown to be superior in those patients with
treatment-refractory schizophrenia. Brenner et al (1990)
states that the percentage of schizophrenic patients who fit
into the treatment-refractory group is between 5% and 25%.
Treatment-refractory refers to those patients who had no relief
of symptoms, only partial relief of symptoms, or whose
extrapyramidal side effects became to great. It is clozapine's
effectiveness on treatment-refractory patients that has earned
it such wide acclaim. Studies have shown that one-third of
patients with schizophrenia improve dramatically; one-third of
patients derive significant benefit; and one-third fail to
respond at all to clozapine (Kerwin,1994).
The type of
patients in which clozapine should be used for is the subject
of much debate and controversy. Most research has concentrated
on treatment-refractory patients. One study by Broir etal
(1994) studied the effects of clozapine on outpatients with
schizophrenia. Some, however, believethat because of the life
threatening risk of agranulocytosis, the use of clozapine
should be limited toselect treatment-refractory patients (Kane
et al, 1988). Kerwin (1994) has stated that if not
foragranulocytosis clozapine would be the treatment of choice
for all schizophrenic patients. Despite this itstill should
only be used on those patients who fail to respond to other
neuroleptics. Those whobelieve that clozapine should no
longer be limited to treatment-resistant patients argue that
by doingfrequent blood tests the risk of fatal agranulocytosis
is greatly reduced (Breier et al, 1994). What isclear from
all arguments is the need for the doctor and patient to work
closely together in an effort toreduce agranulocytosis in both
treatment-refractory and in outpatients with less severe
schizophrenia. Positive Symptoms and Negative Symptoms
Positive symptoms of schizophrenia include such things as
hallucinations, thoughtdisorganization, hostility and
aggression. In most studies positive symptoms are determined
using theBrief Psychiatric Rating Scale, or BPRS, and the
Clinical Global Impression ,or CGI, scale. Overall,clozapine
has been shown effective in respect to positive symptoms in
patients who are resistant totreatment. There is also
evidence to support clozapines beneficial effects on patients
with much lesssevere schizophrenia (Breier et al, 1994).
In a study done by Leiberman et al (1994) BPRS and CGI scores
were compared intreatment-refractory patients at a baseline
and at weeks 3, 6, 12, 26, 39, 52, 65, 78, 91, and 104
ofclozapine treatment. Statistically significant changes from
the baseline were seen at each point over allfive factors of
the BPRS . The hostility/suspiciousness factor showed the
most improvement . Theresults of this study showed that
clozapine was effective in some but not all
treatment-refractorypatients. This study also was able to
isolate certain predictors of outcome. These will be
discussed infurther detail later.
In the study by Breier
et al (1994), as mentioned earlier, the BPRS was also used
indetermining clozapines efficacy. In this study, clozapine
was compared with haloperidol. The subjectswere outpatients
who had previously had at least partial recovery with other
neuroleptics. Resultsfound were consistent with those found
in the study by Leiberman et al (1994). Clozapine was found
tobe significantly superior to haloperidol for treating
positive symptoms as measured by the BPRS (Breieret al, 1994).
This study also found that clozapine was especially effective
in reducing BPRS hostilityscores.
Most agree that
clozapine is effective in treating positive symptoms. There
is little controversyor discrepancy in the research regarding
positive symptom reduction. This can not be said for
theeffectiveness of clozapine on negative symptoms such as
blunted effect, loss of motivation, slowedspeech, and slowed
body movement (Kane et al, 1994). Much of the controversy
that exists can beattributed to discrepancies in the
vocabulary describing negative symptoms of schizophrenia.
Someargue that the reduction of negative symptoms seen in
clozapine treated patients is merely secondary toa reduction
of positive symptoms and extrapyrimidial side effects (Breier
et al, 1994). It is maintainedthat extrapyrimidial symptoms
can mimic negative symptoms. Breier distinguishes between
deficit andnondeficit schizophrenia. Those who have deficit
schizophrenia exhibit very pronounced negativesymptoms that
are primary features of the illness. In nondeficit
schizophrenia, negative symptoms areconsidered secondary to
the illness. By making a distinction between the two types,
with clozapinetherapy it can be seen that there is a
significant difference in the reduction of negative symptoms
in thosepatients with non deficit schizophrenia (Breier et al,
1994). In deficit schizophrenia no difference wasfound when
comparing clozapine with haloperidol.
Lieberman et
al (1994) also concluded that improvements in negative
symptoms may be due toa reduction in secondary negative
symptoms. Secondary negative symptoms being defined as
thosethings that can be attributed to positive symptoms and/or
extrapyrimidial side effects. Theseconclusions are based on
the results that almost all of the improvement of negative
symptoms occurredtogether with improvements in positive
symptoms and extrapyrimidial side effects. Predictors of
Outcome The beneficial properties of clozapine seen in the
reduction of positive symptoms and to somedegree negative
symptoms of treatment-refractory patients and outpatients is a
tremendous step in thefield of neuroleptics. What still needs
to be remembered is that clozapine does not work in all
patientsand that a risk of agranulocytosis exists. Because of
these points, an important step for clozapine is toisolate
those variables that can help predict a patient's response to
clozapine. In any search such as this, there are two
types of variables to be considered: demographicvariables
such as age, race and gender, and clinical variables such as
psychopathology, age of onsetand duration of illness,
extrapyrimidial side effects, and tardive dyskinesia
(Leiberman et al, 1994). Leiberman et al (1994) found that the
usual advantage that female patients have with schizophrenia
wasnot there in the treatment-refractory group studied. In
fact females responded less well than their malecounterparts.
Admittedly, this effect was only a trend.
Poorer
response to treatment was also associated with a younger age
of onset. Those having ayounger age of onset may have a more
severe course of illness and a longer duration of
illness(Leiberman et al, 1994). The subtype, paranoid or
nonparanoid of schizophrenia may also be apredictor of
response to clozapine. Kane (1992) stated that the paranoid
subtype of schizophreniaresponded the best. This was also
found to be true by Leiberman et al in his 1994 study. How
thepatient responded to previous neuroleptics in terms of
extrapyramidal side effects has also been shownas a reliable
way to predict outcome to clozapine. Higher baseline levels
of extrapyrimidial sideeffects, shown using the Simpson-Angus
scale ratings, corresponded with better response to clozapine.
At the same time a greater decrease in the same scale was
related to better response (Leiberman et al,1994). Those
patients who on typical neuroleptics could not tolerate the
extrapyrimidial side effectsmay be prime candidates for the
beneficial effects of clozapine. In terms of biological
markers that could help in predicting outcome, Small et al
(1987) studiedthose who responded favorably to clozapine using
an EEG. In doing so he found that those whoresponded
favorably had higher EEG alpha amplitude in frontal and
temporal areas. Freidman et al(1991) used computerized
topography scans to indicate that those who had higher
degrees ofpre-frontal sulcal did not respond to clozapine
therapy. Being able to predict the response to clozapinewill
not only benefit doctors as they decide who to give this drug
to, but it may also help in the search todevelop more atypical
drugs.
REFERENCES
Breier, A., Buchanan, R.W., Kirkpatrick, B.,
et al (1994) Effects of clozapine on positive and
negativesymptoms in outpatients with schizophrenia. American
Journal of Psychiatry, 151:1, 20-25.
Brenner, H.D., Dencker,S.J., Goldstein, M.J., et al (1990)
Defining treatment refractoriness inschizophrenia.
Schizophrenia Bulletin, 16,551-562.
Friedman, L., Bastani, B., Ranirez, L.F., et al (1991)
Prefrontal sulcal prominence is inversely relatedto treatment
response to clozapine in schizophrenia. Schizophrenia
Research, 4, 317.
Kane, J. (1992) Clinical efficacy of
clozapine in treatment-refractory schizophrenia: an overview.
BritishJournal of Psychiatry, 160(suppl. 17), 41-45.
Kane, J. &
Freedman, H. (1994) Towards more effective antipsychotic
treatment. British Journal ofPsychiatry, 165(suppl. 25),
22-31.
Kane, J., Honingfeld, G., Singer, J. & Meltzer, H.
(1988) Clozapine for the treatment-resistantschizophrenic: a
double blind comparison with chlorpromazine. Archives of
General Psychiatry, 45,789-796.
Kerwin, R.W. (1994) The new
atypical antipsychotics: a lack of extrapyramidal side-effects
and newroutes in schizophrenic research. British Journal of
Psychiatry, 164, 141-148.
Lieberman, J.A., Safferman, A.Z.,
Pollack, S. et al (1994) Clinical effects of clozapine in
chronicschizophrenia: response to treatment and predictors of
outcome. American Journal of Psychiatry,151:12,
1744-1752.
Small. I.F., et al (1987) Computerized EEG profiles
of haloperidol, chlorpromazine, clozapine andplacebo in
treatment resistant schizophrenia. Clinical
Electroencephalography, 18, 124-135.
Side Effects
Colleen Cavallo
Clozapine is an atypical antipsychotic drug
which is primarily being used in the treatment ofrefractory
schizophrenia. This drug, unlike many of the standard
neuroleptic drugs, has not beenassociated with the development
of acute extrapyramidal symptoms or tardive dyskinesia
(Meltzer,1992). Clozapine has, however, been reported to have
certain side effects. Included in this list
areagranulocytosis, seizures, hypersalivation, cardiovascular
effects, gastrointestinal effects, urogenitialeffects,
hyperthermia, and weight gain.
Agranulocytosis is one of
the most commonly reported side effects associated with
clozapine. It is defined as a granulocyte count less than
500mm3 (Safferman, Lieberman, Kane, et al, 1995).
Clozapine-induced agranulocytosis causes a drop in white blood
cell count which can leave the patient'simmune system highly
vulnerable to infection. This could potentially lead to death
and therefore makesagranulocytosis very serious. Of the 185
cases of clozapine-induced agranulocytosis, Krupp andBarnes
(1989) found that the greatest risk of onset was between 4 and
18 weeks of treatment. Theyalso found that older and female
patients were at the greatest risk of developing
agranulocytosis. This isconsistent with research done by
Lieberman and Alvir (1992) who reported that it was within the
firstsix months of treatment was the greatest risk period for
the development of agranulocytosis. They alsofound that it
was higher among women and increased with age. Of their 1155
patients, 73 developedagranulocytosis, two of which resulted
in death. Lieberman (1992) has also described the history
offive patients of Jewish descent that developed
agranulocytosis. The onset was gradual in these casesand was
reversible in just over two weeks. This research has lended
some support that there might bea genetically determined
vulnerability to this effect.
Because of the risk of
agranulocytosis, white blood cell counts should be monitored
in patientstaking clozapine (Alvir et al, 1993). The
manufactures of clozapine have provided some guidelines forthe
management of a drop in WBC count and suggested watching for
signs of infection or fever. Themechanism which causes
agranulocytosis occurs has not yet been determined, but
evidence suggests animmune-mediated mechanism (Safferman,
Lieberman, Kane, 1995). Seizures are another possible side
effect. Haller and Binder (1990) found seizure risk to
bedosage related. None of their patients, with the exception
of one with a preexisting seizure disorder,experienced any new
seizure episodes and three of their patients seizures stopped
after their dosagewas reduced. Haller and Binder suggest
looking for other causes of seizures and to avoid
combiningclozapine with other drugs that reduce the seizure
threshold. Some guidelines to reduce the risk includeEEG and
monitoring blood level (Safferman, Lieberman, Kane et al,
1995). More common than agranulocytosis, is
granulocytopenia, which occurs when the granuloctyecount falls
below 1500/mm3. Granulocytopenia occurs in about 3% of the
patients taking clozapineand in most cases will occur within
the first eighteen weeks of treatment (Krupp and Barnes,
1992). The risk of granulocytopenia, just like
agranulocytosis, means that all patients receiving
clozapinetreatment should receive regular blood monitoring.
Sedation, dizziness and confusion are other CNSeffects that
have been reported (Lieberman, Safferman, Pollack, 1994).
Hypersalivation is an effect that occurs early in treatment
(Sandoz, 1990). Increase in salivationthat occurs most often
while the patients is sleeping and may continue for years
following the treatment(Safferman, Lieberman, Kane et al,
1995). Clonidine is sometimes effective in reducing it
(Graboski,1992). Although hypersalivation is quite frequent
during clozapine treatment, there are other adverseeffects
that may develop less often. These symptoms include dry
mouth, dry eyes and blurred vision(Leiberman, Safferman,
Pollack, 1994). One possible cardiovascular effect that
can occur during clozapine treatment is tachycardia,which is
an increase in the heart rate, usually 100 beats per minute or
more. Over time a tolerance maydevelop, but in many cases the
tachycardia will continue unless there is a reduction in
dosage(Safferman, Lieberman, Kane et al, 1995). Another side
effect is postural hypotension. This is adecrease in blood
pressure when a person stands up. Although a tolerance will
likely develop, posturalhypotension can be avoided by a low
initial dose of clozapine. The occurrence of hypertension
hasalso been reported. Patients with preexisting
cardiovascular disease should be monitored due to thechanges
that clozapine can produce. Respiratory side effects are
uncommon, but CNS depressants,such as benzodiazepines, should
be kept to a minimum never the less(Safferman, Lieberman,
Kane,1995).
The most common gastrointestinal side effect
is constipation. Lieberman, Safferman andPollack (1994) found
there to be a 53.3% likelihood of constipation difficulties
occurring at least onceduring treatment with their patients.
Less frequent gastrointestinal effects include nausea,
heartburn, andvomiting. Although mild, some liver function
abnormalities have also been reported (Kane et al, 1988).
Some urogental effects that have accompanied the use of
clozapine include incontinence,frequency of urgency
difficulties, hesitancy problems, and urinary retention.
Lieberman, Safferman,Pollack (1994) found 16.6% incontinence
and 33.3% increased frequency in urination in their patientsat
least once during the treatment period.
Clozapine-induced hyperthermia typically involves an increase
of one to two degreesFahrenheit, and ends over a few days of
continued treatment. Mild hypothermia is quite common.
Itoccurs in 87% of patients on clozapine and is just as
frequent as in other neuroleptics such achlorpromazine
(Safferman, Lieberman, Kane et al, 1995).
Weight gain is
another reported side effect of clozapine. In case reports by
Cohen, Chiles andMacNaughton (1990) six out of seven of their
patients treated with clozapine gained weight. Theweight
gained ranged from 8 to 69 pounds, with a mean of 24.7
pounds. Four of these patients beganclozapine treatment while
at their ideal weight range, but exceeded it while on
clozapine. This weightgaining effect is not clozapine
specific and occurs in other neuroleptics, such a
chlorpromazine(Safferman, Lieberman, Kane et al, 1995).
The side effects mentioned range in seriousness with the risk
of agranulocytosis in particular tobeing not a serious threat
like weight gain. What makes clozapine beneficial however, is
itsimprovement in positive symptoms, extrapyramidal function,
and tardive dyskinesia (Meltzer, 1992). This is different from
many of the drugs that have been previously used in the
treatment ofschizophrenia. More research findings will
determine the fate of clozapine treatment, however.
Stopp,Muller, Fuchs and Ruther (1992) and recent research
findings have shown that there is more reportedsedation and
higher body weight following clozapine treatment than with the
new anti-schizophreniadrug risperidone (Daniel, Goldberg,
Weinberger et al, 1996). Hopefully, the costs and benifits of
thisdrug will be measured further.
REFERENCES
Alvir, J.,
Lieberman, J., Safferman, A., Schwinner, J., & Schaaf, J.
(1993) Clozapine-inducedagranulocytosis: incidence and risk
factors in the United States. The New England Journal of
Medicine,329, 162-167.
Cohen, S., Chiles, J., MacNaughton, A.
(1990) Weight gain associated with clozapine. AmericanJournal
of Psychiatry. 147, 503-504.
Daniel, D., Glodberg, T.,
Wienberger, D., et al (1996) Different side effect profiles of
resperidone andclozapine in 20 outpatients with schizophrenia
or schizoaffective disorder: a pilot study. AmericanJournal of
Psychiatry. 153, 417-419.
Haller, E. & Binder, R. (1992)
Clozapine and seizures. American Journal of Psychiatry.
147,1069-1072.Krupp, P. & Barnes, P. (1992)
Clozapine-associated agranulocytosis: risk and aetiology.
BritishJournal of Psychiatry. 160(suppl. 17), 38-40.
Metzer, H.
(1992) Dimensions and outcome with clozapine. British Journal
of Psychiatry. 160(suppl.17), 46-53.
Naber, D., Hozbach, R.,
Perro, C. & Hippius, H. (1992) Clinical management of
clozapine patients inrelation to efficacy and side-effects.
British Journal of Psychiatry. 160(suppl. 17),
54-59.
Safferman, A., Lieberman, J., Kane, J., Szymanski, S., &
Kinon, B. Clozapine in Treatment-RefractorySchizophrenia in
Contemporary Issues in the Treatment of Schizophrenia.
American Psychiatric Press,Inc., 1996. pp337-351.
Stoppe, G.,
Muller, P., Fuchs, T. & Ruther, E. (1992) Life-threatening
allergic reaction to clozapine.British Journal of Psychiatry.
161, 259-261.
Physiological Side Effects
Evan Halpern
As was mentioned above clozapine despite its advantages over
other neuroleptic drugs, still hasan array of side effects.
There is a physiological reason for each of these side
effects, but to go into thephysiology of all the side effects
would go beyond the scope of this paper, instead I have chosen
todiscuss the physiology of some of the more interesting and
life threatening side effects of clozapine willbe discussed.
Agranulocytosis and granulocytopenia are the most life
threatening of the side effects. Peopleof the southern and
western regions of Finland have a much higher rate of
clozapine inducedagranulocytosis than do people of other
geographic locations. In 1977, De la Chapelle et al
conducteda study in the hopes of determining whether or not
there was an environmental or genetic cause foragranulocytosis
but no link could be found between the two.
Mason and
Fischer (1992) theorized that clozapine might be metabolized
into free radicalmetabolites by neutrophils and their
committed stem cell precursors (Shriqui & Nasrallah, 1995).
Such metabolites are toxic to these cells. This is known as
the FREE RADICAL THEORY. Acommitted stem cell is a precursor
that is committed to form a neutrophil. Its genetic code has
dictatedthat it will be a neutrophil and nothing else. These
cells go through stages of maturation changing tosome extent
with each cycle of cellular division. The cells that are
created from these originals,reproduce and differentiate into
different types of granulocyte cells and circulate throughout
the system. Because of the free radical theory, it was
suggested that agranulocytosis could be prevented
byadministration of either vitamins C or E, both of which are
antioxidants (Mason and Fischer, 1992). Pippenger et al
(1991) proposed that if free radical enzymes were augmented
with an enzymecofactor such as selenium, zinc or copper, that
agranulocytosis might be prevented altogether (Shriqui&
Nasrallah, 1995). If agranulocytosis is the most
dangerous, then drowsiness is certainly the most common
sideeffect. Drowsiness is thought to be caused by clozapines
antihistaminic (H1) or antiadrenergic (alpha1) properties
(Shriqui & Nasrallah, 1995). Both hyperthermia and
hypothermia are two side effects that seem to be clozapine
induced.(Shriqui & Nasrallah, 1995) The reasons for the
temperature disregulation is not known for sure, but ithas
been suggested that the hypothalamus is involved. (Guyton &
Hall, 1996)
Hypersalivation is thought to be induced
because of clozapines anticholinergic properties. Theamount
of salivary flow can be altered if certain receptors on the
salivary glands are stimulated. Included in the receptors
are the muscurinic, adrenergic and tachykinin P receptors
(Shriqui &Nasrallah, 1995). Weight changes may be due in
part to clozapines antihistiminic, and antiseritonergic
activity(Shriqui & Nasrallah, 1995). It is also thought that
neuroleptic blockade of dopamine in thehypothalamus may cause
the weight gain. It may be attributed to a stimulation of the
appetite centers inthis region (Palfai & Jankiewicz, 1996).
Another side effect of clozapine included neuroleptic
malignant syndrome (NMS). This is anabnormal fluxuation of
the temperature system. For instance, a person's body
temperature may go upwhen he or she is already too hot and
vice versa. This was an unexpected event due to
clozapineslack of affinity for D2 receptors (Shriqui &
Nasrallah, 1995). This has occurred in two patients, bothof
which had prior cases of NMS while taking other neuroleptic
drugs and both of which were takinglithium (Pope et al, 1986)
and carbamazepine (Muller et al, 1988). There have also been
cases ofNMS in which clozapine was the sole drug administered
to the patient.(Anderson and Powers, 1991;DasGupta and Young,
1991; D.M. Miller et al, 1991) There is evidence that
clozapine can induce an allergic reaction. In a case report
by Stoppe etal, (1988) a 69 year old woman previously treated
with a variety of anti-psychotic agents(zuclopenthixol,
flupenthixol, trifluoperazine, fluphenazine and haloperidol)
developed an asthmaticreaction three times following treatment
with clozapine. A skin test did not indicate
hypersensitivity toclozapine. It was suggested that the
patient developed a delayed hypersensitivity or a pseudo
allergicreaction to the clozapine. Grohmann et al (1989)
reported four other patients who collapsed withrespiratory
depression following clozapine. All of these patients were
taking benzodiazepinessimultaneously with clozapine at the
time of the respiratory collapse. (Gabriela Stoppe et al,
1992). Clozapine is known to have a high affinity for alpha 1
adrenergic receptors as well as histaminergic (H1)sites. When
administered to rats a 68% increase occurred in the number of
adrenergic receptor sites inthe forebrain (Ross J.
Baldessarini et al, 1992). Dizziness and syncope (a brief
loss of consciousness),two other central nervous system side
effects, are thought to be caused by orthostatic hypotension.
Tachycardia and postural hypotension are thought to occur
because of clozapines directvagolytic effects or an increase
in plasma norepinephrine or both (Picker et al, 1992). Drug
feveroccurs in about 5% of the patients taking clozapine.
The rise in temperature can increase the heart ratewhich is a
dangerous situation if the patient has severe heart disease to
begin with. (Guyton & Hall,1996) Seizures can occur with
clozapine (Baker and Conley 1991; Devinsky et al, ; Haller and
Binder1990; Leiberman et al, 1989; Povlsen et al, 1985;
Simpson and Cooper 1978). Other neuroleptics,as well as
clozapine, are known to cause seizures.
A review of the
various drugs and their effect, one may notice that the
administration ofphenothiazines to patients of schizophrenia
may increase catecholamines (a class of amine that
includessuch neurotransmitters as dopamine, norepinephrine and
epinephrine) (Carlson, 1994). Uponexamination of these
neurotransmitters, it can be seen that they have an affect on
a large number ofneurons in a widespread portion of the brain.
Seizures are caused by a massive CNS activation ofmany
reverberating pathways through the brain (Textbook of medical
physiology 9th edition) It ispossible that discrepancies in
the release of catecholamines, caused by clozapine itself
could trigger achain reaction causing seizures, especially if
the patient had a history of seizures. There are a number
of side effects that are due to clozapines interaction with
cholinergicreceptors. Constipation, which is another side
effect of clozapine, is due precisely to this interaction.
Clozapine is a anticholinergic drug (Bellak, L. 1979).
Because clozapine can cause blockage in thecholinergic
receptors (Palfai and Jankiewicz, 1996), smooth muscle causes
the bowels to function areslowed down and constipation is the
result. Other side effects incontinence, enuresis, frequency
orurgency difficulties occur because of muscarinic and
andrenergic transmission alterations. Lastly,
there are three reported cases of tardive dyskinesia out of
which two had questionableratings. When analyzing the latter
three cases it should be kept in mind that all three of them
had takentypical neuroleptics in the past. Before discussing
the possible causes of tardive dyskinesia, the readermust keep
in mind that one of clozapines most attractive features is
that unlike other neuroleptics, it (forthe most part) does not
cause extrapyramidal symptoms (EPS). In fact, it has been
used in high doses(500m 900 mg per day) to treat tardive
dyskinesia. It is theorized that by having more of an
affinityfor the D4 receptors clozapine allows the D2
receptors to essentially heal themselves thereby lesseningthe
symptoms.(Nami, 1996) Contrary to popular belief though,
clozapine does in fact occupy the D2receptors and can occupy
anywhere from 3863% of the receptors (Farde and Nordstrom,
1992). Itwas also found that clozapine, as well as occupying
some of the D2 also has an affinity for 5HT(serotonin) which
in turn seems in many cases to have an inhibitory effect on
the firing of dopamineneurons (Meltzer, 1992). This may be
the reason that the EPS are so rare in patients taking
clozapine. Clozapine has had dramatic effects on patients
with schizophrenia, but it is by no means awonder drug. The
positive aspect is the relative lack of extrapyramidal side
effects. The multitude ofside effects (agranulocytosis being
the most dangerous) make it a drug of considerable concern to
thosewho have to take it. In the latter potions of this
paper, such things as the side effects and the propertiesof
clozapine were discussed. In the next section, the chemistry
of clozapine and how it interacts withother drugs will be
brought forth in the hopes of providing a better understanding
of this atypical drugclozapine.
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Baldassarini,
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Bellak, L. Disorders of
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Bacon, 1994, pp.601.
Farde, Lars & Nordstrom, A.L. (1992) PET
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Company,1996, pp.914,593.
Kane, J. & Freeman, H. (1994) Towards
more effective antipsychotic treatment. British Journal
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Meltzer, H. (1992) The
importance of serotonin-dopamine interactions in the action of
clozapine.British Journal of Psychiatry, 160(suppl. 17),
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T. & Jankiewicz, H. Drugs and Human Behavior. Brown and
Burchmark Publishers, 1996,pp.256. Shriqui, M.L. & Nasrallah,
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AmericanPsychiatric Press, 1995, 339-352.Stoppe, G., Muller,
P., Fuchs, T. & Ruther, E. (1992) Life threatening allergic
reaction to clozapine.British Journal of Psychiatry, 161,
260.
Chemistry
Pedro Sousa
Clozapine is a tricyclic dibenzodiazepine
derivative,8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]
diazepine (Fleeger, 1994). Clozapine(C18H19ClN4) has a
molecular weight of 326.83 grams per mole. It is made up of
approximately 66.15% Carbon, 5.86% Hydrogen, 10.85% Chlorine,
and 17.14% Nitrogen by weight (Budavari,1996). Clozapine has a
melting point of 183-184 oC and is lethal in mice at a
concentration of 58mg/kg. Clozaril (clozapine) is a yellow,
crystalline powder, that is only slightly soluble in
water.(Reidenberg, 1996) Clozapine has a chemical
structure similar to that of loxapine. The unsubstituted
benzene ring isbelieved to be important for interactions at
the dopamine receptors (McEvoy, 1996). Thechloro-substituted
benzene ring , on the other hand, seems more necessary for
action at the muscarinicreceptors. Substitution of the
piperazine moiety of clozapine by an open carbon side chain
will generallylead to a loss of activity. One significant
variation of clozapine from other antipsychotic agents is its
central ring. Clozapinehas a seven- rather than a six-membered
central ring (McEvoy, 1996). Another variation ofimportance
is the spatial relationship between the piperazine moiety and
the chloro-substituted benzenering. The nonplanar nature of
the tricyclic nucleus of clozapine allows limited rotation of
the piperazinemoiety. Clozapine varies structurally from
loxapine by the presence of a diazepine rather than an
oxapinecentral ring in the core tricyclic ring system and by
the presence of a chlorine atom at position 8 insteadof 2 on
the core tricyclic ring system (McEvoy, 1996). This variation
in the position of the chlorineatom appears to be associated
with its distinct pharmacological profile and may be
responsible for thedrug's antimuscurinic activity.
Clozapine can be taken orally resulting in rapid absorption
of 90 to 95% via the gastrointestinaltract (Long, 1995-1996).
Food does not appear to affect either the rate or the extent
of absorption andthus clozapine may be administered with or
without food (Long, 1995-1996, Weiner, 1995). Due toextensive
hepatic first-pass metabolism by cytochrome P450IID6 however,
only about 27-50% of anorally administered dose reaches
systemic circulation unchanged (McEvoy, 1996, Mehta,
1995).Clozapine is almost completely metabolized prior to
excretion and only trace amounts of unchangeddrug are detected
in the urine and the feces (Long, 1995-1996). Approximately
50% of theadministered dose is excreted in the urine and 30%
in the feces as demethylated, hydroxylated andN-oxide
derivatives (Drug Facts & Comparisons, 1995). Pharmacological
testing has shown thedesmethyl metabolite to have only limited
activity, while the hydroxylated and N-oxide derivatives
wereinactive (Weiner, 1995). After absorption,
primarily in the small intestine, clozapine is transported to
the tissues via theblood supply. The distribution of
clozapine into the tissues is rapid and extensive. Clozapine
is onlyslightly soluble in water and can be found in the blood
supply approximately 95% bound to plasmaproteins (Long,
1995-1996).
The mean elimination half-life of clozapine
after a single 75 mg dose was 8 hours (range: 4-12hours),
compared to a mean elimination half-life, after reaching
steady state with 100 mg b.i.d. (twiceper day dosing), of 12
hours (range: 4-66 hours) (Reidenberg, 1996). Comparison of
single-dose tomulti-dose administration of Clozapine showed
that the elimination half-life increased significantly
aftermultiple dosing relative to that after single-dose
administration, suggestive of the possibility ofconcentration
dependent pharmacokinetics (Weiner, 1995).Drug Interactions
The potential risks of using clozapine in combination with
other drugs has not been evaluatedsystematically. However,
clinical experience and drug studies indicate that certain
potential druginteractions exist. The mechanism of
clozapine-induced agranulocytosis is unknown; however, the
possibility thatcausative factors may interact synergistically
to increase the risk and/or severity of bone marrowsuppression
warrants consideration. Therefore, clozapine should not be
used concomitantly with drugsknow to suppress bone marrow
function (i.e. carbamazepine) (Mehta, 1995). Marked
sedation and excessive salivation has been reported in
patients during concomitantadministration of clozapine and
benzodiazepines (i.e., diazepam, flurazepam, lorazepam)
(Grohmann,1989, Cobb, 1991,Fleeger 19940). Two patients had
given lorazepam for treatment of agitationbrought on by a
daily 100 mg dose of clozapine (Cobb, 1991). One of the
patients experiencedsedation, ataxia and salivation 95 minutes
after administration of 2 mg IM of lorazepam. The otherpatient
became lethargic, pale, drooling and ataxic the day after
three doses of lorazepam 1 mg orallyadministered over 24
hours. Both patients required the assistance of staff members
in order to walk.Four patients taking diazepam, florazepam or
lorazepam accompanying administration of clozapine,collapsed
and lost consciousness (Grohmann, 1989). A study performed on
8 schizophrenic patientsperformed by doctor William H.
Benefield, Jr., Pharm.D. et al at the University of Texas
alsoconcluded that concomitant treatment of patients with
clozapine and lorazepam resulted in moderate tosevere sedation
(Benefield, 1995). The patients were premedicated with
lorazepam 3 mg PO or IM inPeriod 1 before a 75 mg dose of
clozapine was administered in Period 2 of the study, followed
bytitrating to steady-state with a multiple dose regimen of
300 mg/day of clozapine. During 23 of 29AUCs, subjects
experienced moderate or severe sedation. Until more is known
about thispharmacodynamic interaction, patients should be
observed and vital signs monitored when clozapineand
benzodiazepines or any other psychotropic drug are taken
concurrently. Reduction in plasma concentrations of
clozapine and exacerbation of psychosis have beenreported in
patients receiving concomitant therapy with clozapine and
phenytoin (Miller, 1991).
Onepatient, a 29-year-old male was
receiving 200 mg of clozapine twice daily. When tonic-clonic
seizuresoccurred the dosage of clozapine was reduced and a
dose of 300 mg phenytoin was started. Acuteworsening of
psychotic symptoms occurred within 48 hours. The serum levels
of clozapine had beenreduced from 282.2 ng/ml and 295.9 ng/ml
to 56.2 and 48.7 ng/ml during concurrent
phenytoinadministration. In the same report another patient, a
29-year-old woman was also reported toexperience a dramatic
drop in clozapine plasma levels when a loading dose of
phenytoin 1200 mgfollowed by a maintenance dose of 300 mg
daily to treat tonic-clonic movements induced by
clozapinetreatment. Although the mechanism of this interaction
is not known, several theories have been suggested. Phenytoin
may increase clozapine metabolism via stimulation of the
hepatic cytochromeP-450 (microsomal) enzyme system and/or
displacement of clozapine from protein binding sights, or that
phenytoin may decrease absorption of clozapine from the GI
tract (McEvoy, 1996). Patientsbeing treated with clozapine in
whom phenytoin treatment is initiated should be monitored for
recurrentpsychosis and the clozapine dosage should be adjusted
accordingly. Another drug suspected of inducing hepatic
microsomal enzymatic metabolism of clozapine iscarbamazepine
(Muller, 1988, Raitasuo, 1993). A 76-year-old man with a
history ofbromperidol-induced neuroleptic malignant syndrome
(NMS) developed NMS 3 days after theaddition of clozapine to a
stable carbamazepine dose (Muller, 1988). Another patient, a
25-year oldschizophrenic man, had been receiving clozapine 800
mg daily and carbamazepine 600 mg daily forseveral months.
After discontinuation of carbamazepine therapy, the plasma
clozapine concentrationincreased from 1.4 to 2.4 mcmol/L
(therapeutic level, 1.1 mcmol/L) (Raitasuo, 1993).
Since clozapine is highly bound to serum proteins, the
administration of clozapine concomitantlywith other drugs
known to highly bound to protein (e.g. warfarin, digoxin) may
cause an increase in theplasma levels of either drug,
potentially resulting in adverse effects (Weiner, 1995).
Patients should bemonitored during the initiation of such a
concurrent treatment and the dose of each drug
adjustedaccordingly.
REFERENCES
Benefield, W. et al.
"Clozapine and lorazepam: prospective evaluation of
pharmacodynamicinteraction" (1995). [online]. Available:
http://www.UTA.edu: [1996 September].
Budavari, S., ed. The
Merck Index. 12th ed. White House Station: Merck Research
LaboratoriesDivision of Merck & CO., 1996.
Cobb CD. et al.
(1991) Possible interaction between clozapine and lorazepam
[letter]. AmericanJournal of Psychiatry, 148, 1606-1607.Drug
Facts & Comparisons. Facts & Comparisons Inc. 1995. CP/M-based
computer. compact disk.
Fleeger, C. A., ed. USP Ditionary.
Rockville: USP, 1994.Grohmann R., et al. (1989). "Adverse
effects of clozapine [letter]. Psychopharmacology.
99,101-104.
Long, P.W. (1995-1996). Internet Mental Health
[online]. Available: http://www.eb.com. [1996,September
13].McEvoy, G.K., ed. AHFS Drug Information. Bethesda: AHFS,
1996.Mehta, M., ed. PDR Guide to Drug Interactions Side
Effects Indications. Montvale: MedicalEconomics, 1995.Miller
D.D. (1991) Effect of phenytoin on plasma clozapine. Journal
of Clinical Psychiatry. 52, 23-25.Muller T., et al, (1988)
Neuroleptic malignant syndrome after clozapine plus
carbamazepine. Lancet, 2,8628-8627.
Reidenberg, M., ed.
Physicians Gen Rx. New York: Mosby, 1996.Raitasuo V., et al
(1993) Carbamazepine and plasma levels of clozapine [letter].
American Journal ofPsychiatry 150 (1), 169.
Weiner, B. ed.
PDR Generics. Montvale: Medical Economics, 1995.
Potential changes
Paula Reynolds
Schizophrenia, which is
classified with either positive or negative symptoms, may be
oftentreated with either classic neuroleptic or atypical
neuroleptic drugs. Because the atypical drugs havehad a known
effect on both types of symptoms, they have become the drugs
of choice for manyschizophrenic patients. Clozapine, like
many other atypical drugs, is often used because of
itsminimizing effect on the motor system and its impressive
antipsychotic effect. With this understanding,an attempt will
be made to explain the inhibitory and excitatory changes
within the neuronal systemsinvolving schizophrenia and come to
identify clozapine's influence on the brain.
The positive or negative symptoms of schizophrenia reflect an
over activity or inactivity in themesolimbic, mesocortical and
nigrostriatal areas in the brain. Clozapine works by
suppressing themesolimbic system, while it also allows the
dopamine neurons in the nigrostriatal areas to function
rathernormally. It is a combination of these three systems
working independently, as well asinterdependently, which
allows the onset of schizophrenia to occur and also allows
clozapine to havean extrapyramidal symptom free,
anti-psychotic effect. Transmitter Substance Addressed It
is important to briefly identify and give the history of a few
transmitter substances used bythese three systems. This will
hopefully help to explain the usefulness of clozapine and may
be neededas well in understanding the next section to come.
The mesolimbic, mesocortical and nigrostriatalsystems all use
dopaminergic neurons. Dopamine which is classified as a
monoamine. Carlson (1994)states that four chemicals that
belong to the family of compounds called monoamines are
epinephrine,norepinephrine, dopamine, and serotonin. The
similarity of the molecular structures of thesesubstances
causes some drugs to affect activity of all of the monoamines
to some degree. A subclass ofmonoamines, including
epinephrine, norepinephrine and dopamine, do not appear to
transmit specificinformation but serve to modulate the
function of widespread regions of the brain. Thus they act
asvolume controls increasing or decreasing activity of brain
function (Carlson,1994).
Dopamine produces both
excitatory and inhibitory post-synaptic potentials, depending
on thepost-synaptic receptors (Carlson,1994). Serotonin at
most synapses produces inhibitorypost-synaptic potentials and
is regulates sleep, arousal and pain. The interaction of
these two chemicalsplay a key role in helping to understand
schizophrenia. The combination leads to the coordination
andmodulation of the midbrain and dopamine function (Kapur &
Remington, 1996). Mesolimbic The mesolimbic system
incorporates the ventral tagmentum, nucleus accumbens,
amygdala,hippocampus and septum (J. Morgan, personal
communication, April 19, 1996.) Each of these areasuse axons
to bring synapse to a new area and are made up of groups of
nuclei. Dopamine has beenimplicated as a transmitter
substance that is involved in schizophrenia, a serious mental
disorder thatincludes hallucinations, delusions, and
disruption of normal, logical thought processes (Palfai
&Jankiewiez, 1996). These symptoms are associated with the
mesolimbic area. The ventral tagmentum,which is also a member
of the pleasure reinforcement circuit, reinforces stimuli by
activating neuronsand causing the release of dopamine in the
mesolimbic system (Carslson,1994). In schizophrenia,
thedopamine transmitter substance is at an over productive
state. This results in the limbic system, whichusually would
reinforce an emotional response or thought process seemingly
"fitting" the given situationor environment, being unable to
modulate or control activation of dopamine into the receptors.
According to Carlson, (1994) the reinforcement system must
perform two functions which are to detectthe presence of a
reinforcing stimulus and detect the neurons that produce
instrumental response. Assuming that this mechanism is correct
we can ask three major questions. What activates
dopamineneurons in ventral tagmentum? What role does release
of dopamine play in strengthening synapticconnection? Where
do synaptic changes take place?"
The ventral tagmentum
is marked as the beginning of the mesolimbic pathway
(Carlson,1994). The axons then travel through the medial
forebrain bundle and synapses at the amygdala, thehippocampus,
the septum and the nucleus accumbens. The amygdala is
essential for conditionedemotion response. The hippocampus is
involved in short term and long term memory. Finally,
thenucleus accumbens, plays a significant role in attention
and reinforcement.
It is important to understand that
the mesolimbic system dysfunction is represented by
thebehavioral dysfunction in schizophrenia and to move on to
the efficiency of clozapine in this system. Tounderstand the
effects of antipsychotic drugs on the functioning of midbrain
dopamine neurons, it isnecessary first to understand the way
these systems function in the absence of drugs (Bunney, 1992).
Clozapine works within the mesolimbic system to suppress the
activity of dopamine and to help soothebehavioral symptoms.
Its main objective, (as in all anti-psychotic drugs,) is to
access and occupydopamine receptor cites without stimulating
the post synaptic receptor or dopamine 4 receptor(Mrzljak et
al, 1996). In addition, this allows the "volume controller"
or excitatory potential to decreaseits firing rate, and
systematically decrease and/or help reinstate behavior
dependent synapses to anormative level. Mesocortical J.
Morgan (personal communication, April 4, 1996) explains that
the mesocortical systemincludes such nucleus as the ventral
tagmentum, thalamus, and the cingulate gyrus. This system is
in part responsible for instrumentally conditioned responses
(Carlson,1994). Themesocortical area which also begins in the
ventral tagmentum, is involved in motivation and reward(Kapur
& Remington, 1996). Just as the mesolimbic system is
multi-functional; the mesocortical system has the same
independent/interdependent functioning. For instance, Cohen &
Wan (1995) stated that"because the role of the thalamus in
modulating attention and behavior and integrating
perception,emotion, and cognition, it has been suggested for
more than sixty years that thalamic dysfunction mightexplain
the diverse perceptual, emotional, and cognitive symptoms as
well as the characteristicfragmentation of mental experiences
and behavior seen in schizophrenia (pg. 104)." The
cingulategyrus, located near the interior medial section of
the longitudinal fissure, appears to provide an area
ofmediation between decision-making processes of the frontal
cortex and the emotional functions of thelimbic system. The
stimulation of this area can produce feelings (Carlson,1994).
This area seems towork in combination with both the mesolimbic
and nigrostriatal systems. By seemingly balancing thephysical
actions of an individual versus their perception of the
sensory and thought processing in howthey wish to move, its
effectiveness and consequences are altered. The mesocortical
pathway starts atthe ventral tagmentum. It makes synapse in
the thalamus, prefrontal cortex, and the cingulate gyrus.
When dealing with the mesocortical area it is unclear exactly
what effect clozapine exhibits.Within this system it seems to
profoundly affect the thalamus (Cohen & Wan,1995). By this,
it is notnecessarily the excitatory or inhibitory changes
directly affecting the action of the thalamus, but theeffect
clozapine has on other areas may initially change the
behavioral aspects of schizophrenia. Asstated by Cohen & Wan,
(1995) These notions not only support a role for the thalamus
in mediatingschizophrenic symptoms but also may assume that
alleviation of symptoms involving schizophrenia mightwork in
part through effects on the thalamus. Clozapine could
hypothetically work in many ways. Suchproposals are, but of
course are not limited to: blocking or antagonizing dopamine
receptors in thalamusto suppress activity of the thalamus,
enhancing other transmitter substances allowing them to
regulatethe system, or affecting reuptake or autoreceptors in
dopaminergic and/or other neurons in themesocortical system
and affecting dopaminergic and/or other neurons in the
mesolimbic or otherneuronal systems. It is to be remembered
that these proposals are not being supported by any data
butare merely an attempt to begin to understand how these
systems may work individually orcooperatively. It is known,
however, that this area has a predominant amount of dopamine 1
receptorsand that clozapine has a lessened amount of occupancy
compared to old or classic neuroleptics(Nordstrom,1995).
Nigrostriatal The
nigrostriatal system incorporates the ventral tagmentum,
substantia nigra, nucleusaccumbens, basal ganglia and claudate
nucleus, including putamen and globus pallidus (J.
Morgan,personal communication, April 4, 1996). This system is
implicated in the motor movements includinginitiation and
cessation. This system controls all movement or non-movement
when an organism isinvolved in stimuli that reinforces an
emotionally conditioned response (Carlson,1994). The
ventral tagmentum, as similar to the mesolimbic,and
mesocortical is the beginning point forthis system. It then
send axons to the substantia nigra and to the rest of the
striatal system(Carlson,1994). The substania nigra then
projects to the claudate nucleus (namely the putamen andglobus
pallidus) and move on to basal ganglia. The basal ganglia is
essential for direct initiation andcessation of motor
movement. The motor nuclei of the basal ganglia including the
caudate nucleus,putamen and globus pallidus receive most of
its input from the primary motor cortex and the
substantianigra and reticular formation (Carlson,1994).
Activation or inhibition of the dopaminergic system in
thecentral nervous system has been implicated in the
pathophysiology of various neuropsychiatric disordersincluding
schizophrenia (Janowsky et al,1992). Simply stated, it is
because this system also usesdopamine, that it is inevitably
thrown into the mix. It also may lend itself to understanding
some of thebehavioral effects of schizophrenia, as well as
drug induced effects or side effects. This system when
represented with a lack of dopaminergic activity creates
extra-pyramidal sideeffects (Janowsky et al. 1992) This is
the one system that shows the astounding differences
betweenclassic neuroleptics and atypical neuroleptics.
Clozapine was found to be substantially more affectivethan
classic neuroleptics in displacing binding to glutamate
receptors in striatum (Graham &Kokkinidis,1993). Although
dopamine is also an important transmitter substance in all
three areas, thereceptor cites for dopamine are classified
into families that show predominant placing in very
distinctbrain areas (Kapur & Remington, 1996). The
nigrostriatal system has a major employment for thedopamine 2
receptors (Kapur & Remington,1996). In all three dopamine
systems, it is important tounderstand that clozapine works
extremely well in that it affects these systems due to its
high affinity tospecific receptor cites. For instance,
clozapine has a higher affinity for dopamine 4 receptors,
locatedin the mesolimbic system, but a very low affinity for
dopamine 2 receptors in the nigrostriatal system(Janowsky et
al, 1992). Because of such dynamics, clozapine can suppress
the activity in themesolimbic systems to alleviate behavioral
symptoms such as thought and emotional disorders, butleave the
motor movement and control virtually unaffected. Research by
Bunney (1992) has shownthat GABA injected in the substania
nigra after haloperidol (a classic neuroleptic, which inhibits
blocksD2 receptors) leads to a restoration of normal stimulus
induced levels of extrapyramidal functions. In asense, the
GABA inhibited the inhibition that haloperidol had on the
receptor cites and allowed motormovement to be reinstated.
In conclusion, it should be noted that clozapine seems to work
well in conjunction to these threesystems and is helping lead
the way to understanding the complicated pathways that
incorporate thedysfunction of dopaminergic systems. Although
much is still being investigated and improvements arebeing
discovered daily, the key in working with the brain is to
constantly remember that although eacharea, down to the cells
themselves, have an automatic, independent role, it is overall
still aninterdependent system. Each system while working
separately is simultaneously carrying out messagesand
receiving messages in other systems. This application to the
dysfunction of schizophrenia isconceptually easy to recognize
when following this model but it is a biological phenomenon
that stillkeeps us guessing.
REFERENCES
Bunney, B.S. (1992).
Clozapine: A hypothesized mechanism for its unique clinical
profile. BritishJournal of Psychiatry, 160 (17)
,17-21.Carlson, N. R. (1994). Physiology of Behavior. Boston:
Allyn and Bacon.
Cohen, B.M. & Wan, W. (1995). The thalamus
as a site of action of antipsychotic drugs. AmericanJournal
of Psychiatry, 153 (1),104-6.
Graham S. R. & Kokkinidis, L.
(1993). Clozapine inhibits limbic system kindling:
implication forantipsychotic action. Brain Research Bulletin,
30 (5-6), 597-605.
Janowsky, A., Neve, K.A., Kinzie,M.,
Taylor,B., dePaulis, T., & Belknap, J. K.
(1992)Extrastriataldopamine d2 receptors: distribution,
pharmacological characterization and region-specific
regulation byclozapine. Journal of Pharmacology and
Experimental Therapeutics, 261(3),1282-1290.
Kapur, S. &
Remington, G. (1996) Serotonin-dopamine interaction and its
relevance to schizophrenia. American Journal of Psychiatry.
153(4) , 466-473.
Morgan, J. [Lecture: pychobiology]. (1996).
Arcata,CA Humboldt State University. ` Mrzljak,L.,
Bergson,D., Pappy,M., Huff, R., Levenson, R., & Rakic-Goldman,
P. S. (1996) . Localization of dopamine d4 receptors in
gabaergic neurons of the primate brain. Nature,
381(6579),245-248.
Nordstom, A., Farde, L., Nyber, S., et al.
(1995) D1,d2 and 5-ht2 receptor occupancy in relation
toclozapine serum concentration: a pet study of schizophrenic
patients. American Journal of
Psychiatry,152(10),1444-1449.
Palfai, T. & Jankiewiez, H.,
(1997). Drugs and human behavior. Chicago: Brown &
Benchmark.
Receptors Involved in the Action of Clozapine
Karen Wilson
It has been shown that the site of action of the
typical neuroleptics is primarily on the D2dopamine receptors
in the brain. These drugs have been shown to block D2
receptors, while theatypical neuroleptics, such as clozapine
do not seem to have as much affinity for D2 receptors ( Kahnet
al, 1993). If clozapine does not have a high affinity for D2
receptors, but has been shown to beclinically effective, then
which receptors are affected by clozapine? Various studies
have tried toanswer this question in regard to clozapine.
Many studies have shown that the transmitter
substanceserotonin (5-HT) and some of its receptors (5-HT1c,
5-HT2, and 5-HT3) are affected by clozapine(Kahn et al, 1993).
Some studies have also shown that the D4 dopamine receptors
are also affectedby clozapine (Meltzer, 1992; Mrzljak et al,
1996; Pilowsky, 1992). A possible interaction between
thedopamine and serotonin systems may be involved in the
action of clozapine.
While clozapine does block the D2
receptors, it does not have as high an affinity for them asthe
typical neuroleptics do (Carlson, 1994). The percentages of
D2 receptors that are blocked byclozapine varies from study to
study. Some reported percentages are as follows: 40-60%;
38-63%(Meltzer, 1992; Nordstrom et al, 1995). Farde et al
(1992) used PET analysis to determine D1 andD2 occupancy in
patients treated with typical neuroleptics and clozapine. A
high D2 receptoroccupancy was found in patients treated with
typical antipsychotics (70-89%) while D2 receptoroccupancy in
those treated with clozapine was much lower (38-63%) (Farde et
al, 1992 ). D1occupancy in those treated with clozapine was
38-52%. Farde et al (1992) also found that in patientstreated
with typical neuroleptics, those that showed extrapyramidal
symptoms (EPS) had higher D2occupancy than those who didn't
show any side effects. They reported that the D2
receptoroccupancy of clozapine never reached the high D2
receptor occupancy of the classical neuroleptics. Farde et al
(1992) did not find a significant D1 receptor blockade to
account for the effects ofclozapine, but this does not rule
out the possibility that the D1 receptor was involved. They
report thatother studies have found that clozapine has
demonstrated similar affinities for D1 and D2 receptors. By
itself, the D1 receptor does not seem to have an effect, but
the combination of low D2 and high D1seems to be a unique
property of clozapine in relation to typical neuroleptics
(Farde et al, 1992) One of the possible actions of
clozapine is that it blocks certain 5-HT receptors in the
brain. The ability of clozapine to block 5-HT receptors in the
brain is not shared with other typicalneuroleptics (Kahn et
al, 1993). Kahn et al (1993) attempted to show that
clozapine's effects may bedue to action on 5-HT receptors,
specifically the 5-HT1c receptor. One of the ways in
whichclozapine has been shown to block 5-HT receptors is that
it appears to block the effects of certaindrugs that stimulate
5-HT receptors in rats (Kahn et al, 1993). Kahn et al (1993)
attempted to showthat patients who respond to clozapine have
an increased activity of 5-HT receptors. To show this
theyused what they called the 5-HT challenge paradigm. A 5-HT
agonist is administered and the effectscontrolled by 5-HT are
measured. In this case, the release of ACTH and prolactin
were measured,which are 5-HT mediated functions. Kahn et al
(1993) hypothesized that if 5-HT receptor functionwere
increased in those who benefited from clozapine, they would be
expected to show larger prolactinand ACTH response to the 5-HT
agonist. The 5-HT agonist used was
m-chlorophenylpiperazine(MCPP). The study showed that those
who respond to clozapine also had significantly higher
ACTHresponse. This suggests that 5-HT receptor function is
increased in clozapine responders (Kahn et al,1993). It was
also found that there was an increase in 5-HT1c and 5-HT2
receptor sensitivity in thosethat respond to clozapine. They
suggest tat clozapine is effective at least in part to the
blocking of 5-HTreceptors.
Pilowsky et al (1992) also
reports that clozapine's effectiveness is due to blocking of
5-HTreceptors, particularly 5-HT2 and 5-HT3 receptors. In a
survey of the literature on the interactionbetween 5-HT and
DA, Meltzer (1992) also reports a strong affinity of clozapine
for 5-HT2 receptorsas compared with D2 receptors. Meltzer
(1992) also reports other receptor blockade by clozapine atthe
D1and D4 receptors. The lower D2 affinity is probably why
patients on clozapine don't have EPSwhen taking the drug as
opposed to taking the more typical antipsychotics which do
produce EPS. Meltzer (1992) also notes that D1 receptor
blockade may also be important in the action of clozapine.
Meltzer (1992) reports that in a study done on rats, clozapine
appeared to act more like a D1antagonist than a D2 antagonist.
5-HT2 receptor blockade has been shown to modulate
nigrostriatalDA neurotransmission and this is a relevant
component to clozapine's action (Meltzer, 1992).
Meltzer(1992) reports that clozapine and another atypical,
fluperlapine were 23.2 and 49.7 times more potentat blocking
5-HT2 than D2. A review of the dopamine hypothesis in
schizophrenia by Davis et al (1991) notes thatclozapine has a
high affinity for D4 receptors and they also point out that
clozapine's affinity for D4receptors may suggest that
important differences among dopamine receptors may account for
someaspects of clozapine's atypicality. A study done by
Mrzljak et al (1996) also reports clozapine's highaffinity for
D4 receptors and also notes that clozapine's clinical
efficacy may be due to GABAmodulation by D4 receptors. This
effects may be due to blocking of D4 receptors in cortical
pyramidalcells where DA is inhibitory. Meltzer (1992) also
states that clozapine seems to have a high affinity forD4
receptors. Nordstrom et al (1995) attempted to show high
D1, low D2, and high 5-HT2 receptoroccupancy in patients
treated with clozapine. They used PET scans to examine the
receptor occupancyof clozapine. The ranges of receptor
occupancy were as follows: D1 occupancy for 11 patients
was33-59%; D2 occupancy for 16 patients was 20-67%; and 5-HT
occupancy in 5 patients was 84-94%. Nordstrom et al (1995)
report that D2 receptor blockade by clozapine was lower than
previouslyfound in patients treated with typical neuroleptics.
They hypothesize that D2 occupancy alone is not themechanism
of action of clozapine and that the combination of D1 and D2
blockade may result in theeffects of clozapine. Also noted by
Nordstrom et al (1995) is that 5-HT2 affinity is very high and
thecombination of high 5-HT2 occupancy with low D2 occupancy
may also result in the clinical efficacy ofclozapine. They
report that their results are consistent with others that high
5-HT2 occupancy ischaracteristic of clozapine during
treatment. Nordstrom et al (1995) note that the low D2
receptoroccupancy may be due to the limited range of doses of
clozapine that are clinically tolerable. They notethat higher
doses of clozapine may result in higher D2 receptor occupancy.
In summary, several receptors may be involved in the action
of clozapine. These receptorsinclude 5-HT1c, 5-HT2, 5-HT3,
D4, and to a smaller extent D1 and D2. The typical
neurolepticsseem to mostly have their effect by blocking D2
receptors. While clozapine does seem to show someaffinity for
D2 receptors, this affinity is much lower than with the
typical neuroleptics.
REFERENCES
Carlson, Neil R. (1994).
Physiology of Behavior, 5th Edition, Allyn and Bacon.
Davis,
K.L., M.D.; Kahn, R.S., M.D.; Ko, G., M.D.; and Davidson, M,
M.D.; (1991). Dopamine inschizophrenia: A review and
reconceptualization. American Journal of Psychiatry,
148:11,1474-1486.
Farde, Lars, M.D.; Nordstrom, Ann-Lena, M.D.;
Weisel, Frits-Axel, M.D.; Pauli, Stefan, M.D.; Halldin,
Christer, Ph.D.; Sedvall, Goran, M.D. (1992). Positron
emission tomographic analysis ofcentral D1 and D2 dopamine
receptor occupancy in patients treated with classical
neuroleptics andclozapine. Archives of General Psychiatry,
49, 538-544.
Kahn, Rene S., M.D.; Davidson, Michael, M.D.;
Siever, Larry, M.D.; Gabriel, Steven, Ph.D; Apter,Seth, Ph.D.;
Davis, Kenneth, L., M.D. (1993). Serotonin function and
treatment response to clozapinein schizophrenic patients.
American Journal of Psychiatry, 150, 1337-1342.
Meltzer,
Herbert, Y. (1992). The importance of serotonin-dopamine
interactions in the action ofclozapine. British Journal of
Psychiatry, 160, 22-29.
Mrzljak, L., Bergson, C., Pappy, M.,
Huff, R., Levenson, R., Goldman-Rakic, P.S. (1996)
Localization of dopamine D4 receptors in GABAergic neurons of
the primate brain. Nature, 381,245-247.
Nordstrom, Anna-Lena,
M.D.; Farde, Lars, M.D., Ph.D.; Nyberg, Svante, M.D., et al.
D1, D2, and5-HT2 receptor occupancy in relation to clozapine
serum concentrations: A PET study ofschizophrenic patients.
American Journal of Psychiatry, 152, 1444-1449.
Pilowsky,
L.S., Costa, D.C., Ell, P.J., et al. Clozapine, single photon
emission tomography, and theD2 dopamine receptor blockade
hypothesis of schizophrenia. The Lancet, 340,
199-202.
Conclusion
In summary, clozapine is an effective
treatment for schizophrenic patients that do not respond
toother neuroleptics. Upon initiation of treatment patients
should be monitored rigorously for the onset ofthe life
threatening side effects, agranulocytosis and
granuloctyopenia. The pharmocological mechanismthat brings
about these severe symptoms is not yet known. If severe onset
of such side effects shouldoccur, administration of clozapine
should be discontinued. Clozapine has not been
systematicallyevaluated for potential risks while using it in
combination with other drugs. It is known, however,
thatconcomitant administration of clozapine and benzodiazepam
may cause sedation, ataxia, and salivation. Care should also
be taken when clozapine is administered concurrently with
phenytoin or by other drugthat may affect metabolism by the
hepatic cytochrome P-450 enzyme system. Also, dosage should
bemonitored when clozapine is take with any other drug that
competes with it for its plasma proteinbinding sites. Further
research must be done in order for clozapine to be used on a
wider population ofschizophrenics such as outpatients. The
future of drug therapy resides not in clozapine but in
thoseatypical drugs that can be used in all schizophrenics not
just those who are treatment-refractory.
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