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CANADIAN JOURNAL OF PSYCHIATRY
Vol. 33
Ottawa, Canada, October 1988
No.7
Carbamazepine in Psychiatry: A Review*
M.
ISRAEL, M.D. 1 AND
P.
BEAUDRY, M.D. 2
.patients reported in the literature were noted to show
positive effects on mood and behavior during treatment
of their seizure disorder with carbamazepine. Although
most of the studies reviewed at the time were
uncontrolled clinical trials, seven of the studies were
double-blind placebo controlled.
In the early 1970's two groups of Japanese
investigators (2,3) began to publish the results of open
clinical trials suggesting a positive effect of carbamazepine in the treatment of bipolar affective disorder.
Takezaki and Hanaoka (2) noted moderate to marked
improvement in 7 out of 10 bipolar patients and in 6 out
of 10 patients with symptomatic mania. Okuma (3) and
his collaborators described an anti manic effect in 55% of
90 cases treated with carbamazepine. These studies were
followed by double-blind placebo controlled studies
comparing carbamazepine to neuroleptics (4) and to
placebo (5) which confirmed the antimanic effects of
carbamazepine. In a multi-institutional cooperative
study carried out in Japan carbamazepine was compared
to chlorpromazine in a double-blind design on a series of
63 acutely manic bipolar patients (4). Moderate to
marked improvement was noted in 70% of the patients
treated with carbamazepine versus 60% in the
chlorpromazine treated group. Ballenger and Post (5) in
a double-blind placebo controlled study demonstrated a
partial to marked response in 5 of 9 manic patients (4 of
the 9 patients showed a marked response). A recent
review of both American and Japanese studies has
suggested that 153 of 254 patients (60%) reported in the
literature have responded to carbamazepine when treated
during an acute manic episode (6).
Controlled studies also suggest that carbamazepine
exerts a prophylactic effect against both manic and
depressive episodes (3,7,8). Okuma et al. (3) in an open
clinical trial with 51 bipolar patients found a prophylactic
effect for carbamazepine of 71% for manic episodes and
64% for depressive episodes. In a later study by the same
group of investigators (3) the prophylactic efficacy of
carbamazepine was explored using a double-blind
placebo controlled design. A group of 22 bipolar patients
(12 in the carbamazepine group and 10 in the placebo
group) were followed for one year. The results revealed
60% moderate to marked efficacy in the carbamazepine
group versus 22.2% in the placebo group. Similarly, Post
et al. (8) followed a group of 7 rapidly cycling patients
and noted a significant reduction in the number of manic
and depressive episodes with carbamazepine treatment.
Carbamazepine is a tricyclic compound structurally
related to imipramine that has been used since the 1960's
for the treatment of trigeminal neuralgias and then
approved as an anticonvulsant in the U.S. in 1974. In the
last decade the use ofcarbamazepine has been expanded
to include the treatment ofcertain disorders ofmood and
behaviour. In this paper possible clinical applications of
carbamazepine in psychiatry are reviewed along with its
pharmacokinetic and pharmacodynamic profile. Also
discussed are adverse reactions and drug interactions
which are relevant to its use.
arbamazepine is an imino stilbene with a tricyclic
chemical structure similar to the antidepressant
C
imipramine.
has been used by neurologists since the
It
early 1960's for the treatment of trigeminal neuralgia and
epilepsy. It is especially effective in the treatment of
clinical and experimental seizures of the temporal lobe
and limbic system. Amelioration of affect, cognitive
performance and initiative and social behavior was also
observed by neurologists in 50% of their patients treated
with carbamazepine. These findings prompted studies on
the efficacy of carbamazepine in the treatment of mental
disorders. This paper will: (i) review the possible clinical
applications of carbamazepine in psychiatry; (ii) discuss
its pharmacokinetic and pharmacodynamic profile; and
(iii) describe the adverse reactions and drug interactions
often reported with its use.
1. Clinical Applications of Carbamazepine in Psychiatry
Use of Carbamazepine in Affective Disorders
It is through its increasing usage in the treatment of
temporal lobe epilepsy that the psychotropic effects of
carbamazepine began to be recognized. In an extensive
review summarizing 40 studies, Dalby (1) noted that most
studies reporting on the anticonvulsant effects of
carbamazepine also mentioned a psychotropic effect of
this agent. Approximately 50 percent of the 2,500
*Manuscript received October 1986: revised July 1987.
I Assistant Professor, Department of Psychiatry, McGill University;
Staff Psychiatrist, Allan Memorial Institute, Montreal, Quebec
2Assistant Professor, Department of Psychiatry, McGill University;
Staff Psychiatrist, Clinical Psychopharmacology Unit, Allan Memorial
Institute, Montreal, Quebec.
Address reprint requests to: Dr. M. Israel, Allan Memorial Institute,
1025 Pine Avenue West, Montreal, Quebec H3A lAI
Can. J. Psychiatry Vol. 33, October 1988
577
578
CANADIAN JOURNAL OF PSYCHIATRY
The authors also reported a reduction in the severity and
duration of episodes.
Finally, a recent study has provided some preliminary
data suggesting that carbamazepine also possesses some
acute antidepressant efficacy (9). In a double-blind offon-off study with 35 treatment resistant depressed
patients, Post et al. (9) reported at least a mild
improvement in 57% of their sample with more
substantial improvement in 34%. Of those depressed
patients who did respond to carbamazepine, those who
were more severely depressed at the initiation of
treatment tended to respond better. Also noted was a
nonsignificant trend towards better response to
carbamazepine in bipolar versus unipolar depressed
patients. Although the design of this study adequately
controlled for placebo responders, the authors
themselves acknowledge that spontaneous remissions
could not effectively be ruled out among the responders.
Most of the responders in this study did not relapse upon
discontinuation of carbamazepine and the investigators
did not have the opportunity to rechallenge patients in a
second drug trial. Clearly further studies need to be
carried out before the antidepressant efficacy of
carbamazepine can be adequately evaluated.
It is of interest to note that to date most of the patients
studied were initially poor or non-responders to lithium
carbonate. This would suggest that lithium and
carbamazepine act via different mechanisms of action.
Furthermore, in several studies carbamazepine was
added to other agents including neuroleptics, tricyclic
antidepressants and lithium. Nevertheless, some studies
have demonstrated clinical efficacy using carbamazepine
alone (4,7,8). Finally, there is little data available on
direct comparisons between lithium and carbamazepine.
Two recent studies in fact report contradictory findings.
Lerer et al. (10) reported preliminary findings suggesting
that carbamazepine is not as effective as lithium in the
treatment of acute mania. In their study 15 manic
patients were assigned randomly to treatment with either
carbamazepine or lithium for 4 weeks using a "double
placebo" system (8 received carbamazepine + placebo
and 7 lithium + placebo). Their results indicate that
carbamazepine was not as effective as lithium in
attenuating the manic syndrome and that overall there
was little therapeutic benefit in the patients treated with
carbamazepine. A possible explanation for their negative
findings is that unlike previous researchers, they did not
use patients who were previously refractory to lithium or
who were rapid cyclers. In contrast, Placidi et al. (11)
compared carbamazepine to lithium in the acute and
prophylactic management of patients with major
affective, schizo affective or schizophreniform psychoses
in a three year prospective double-blind randomized
trial. They studied 83 patients (42 received carbamazepine and 41 received lithium) and found that both drugs
were effective in two-thirds of patients. Furthermore, the
two drugs appeared comparable in most outcome
measures except for a significantly higher dropout rate
Vol. 33, No.7
for patients with mood-incongruent psychotic features
who were treated with lithium. Both drugs also appeared
more effective in preventing excited rather than
depressive symptoms. Thus, their findings suggest that
carbamazepine is as effective as lithium in the treatment
of the full spectrum of psychoses with affective
components.
In general, when antimanic effects of carbamazepine
are noted they tend to occur within the first week of
treatment. The hyperactive, aggressive and excitable
aspects of the manic syndrome seem to respond more
rapidly than the psychotic components (6). The onset of
antidepressant effects also seems to lag behind that of the
antimanic effects, often requiring several weeks before
improvement is noted. However, improvement in sleep is
generally evident within the first week in both manic and
depressed patients. Finally, there is general agreement
that the more manic and psychotic the patient, the greater
the likelihood of a therapeutic response to carbamazepine. In addition it appears that those patients with rapid
or continuous manic depressive cycles are those most
likely to respond to carbamazepine (6).
Use of Carbamazepine in Aggressive and
Non-Affective Psychosis
There are several reports on the treatment of aggressive
behavior and non-affective syndromes. Most of these are
open studies demonstrating the efficacy of carbamazepine in treating aggression in schizophrenics (12-14),
schizoaffectives (15), personality disorders (14) and
organic brain syndromes (14,15). Hakola and Laulumaa
(12) described 8 schizophrenic women in a maximum
security ward with histories of violent episodic outbursts
who responded to the addition of carbamazepine to their
neuroleptic regimen. All women had non-specific EEG
abnormalities as well as irritative activity with focal
tendencies in 3 cases and without focal tendencies in 4
cases. Treatment with carbamazepine resulted in almost
complete disappearance of violent behavior in all 8
patients. In 4 patients the specific schizophrenic
symptoms were also markedly decreased. Luchins (13)
described 7 patients (6 schizoaffective, 1 mixed
personality disorder) with normal EEGs who received
carbamazepine in an off-on-off design in addition to their
neuroleptic regimen. A significant decrease in the
number of aggressive episodes was noted during
carbamazepine treatment as compared to before or after
the treatment. The same author in a later study (14) found
no difference when comparing the efficacy of
carbamazepine in decreasing the frequency of aggressive
episodes in 8 violent patients with abnormal EEGs versus
11 violent patients with normal EEGs. A few controlled
studies have also been conducted in this area (16,17).
Neppe (16) carried out a 15 week double-blind placebo
controlled crossover study on 11 patients with mixed
diagnoses (8 were schizophrenics). All patients had nonspecific temporal lobe abnormalities on EEG and in all
cases carbamazepine was again added to the pre-existing
October, 1988
CARBAMAZEPINE IN PSYCHIATRY
neuroleptic regimen. Significant improvement was noted
in 8 patients. Furthermore, a reduction in the frequency
and severity of aggression was noted in the 6 patients who
exhibited aggressiveness. Finally, Klein et al. (17)
compared carbamazepine and haldol to placebo and
haldol in patients with excited schizophrenic or affective
psychosis in a controlled double-blind design. Twentythree patients received carbamazepine and haldol
whereas 20 patients received placebo and haloperidol.
Carbamazepine was found to be superior to placebo and
equally effective in schizophrenic or affective psychoses
as measured by percentage of improvement over baseline
on the Brief Psychiatric Rating Scale (BPRS). All the
patients who improved had normal EEGs. Furthermore,
15 of 18 BPRS symptoms improved, and items which did
not depend on activity (for example, unusual thought
content) improved as much as those that did.
Some studies have specifically reported a beneficial
effect of carbamazepine in the treatment of episodic
dyscontrol syndromes (18-20). Some of the patients
reported showed definite EEG abnormalities. For
example, Tunks (18) described a 24 year old woman with
episodic dyscontrol syndrome characterized by
intermittent aggressive outbursts associated with
dysphoria which disappeared when carbamazepine was
added to her treatment regimen (primidone and
chlorpromazine). The patient also had non-specific EEG
abnormalities. Gardner and Cowdry (20) recently studied
the effects of carbamazepine on behavioral dyscontrol in
11 women with borderline personality disorder. Using a
double-blind crossover trial, they found significantly less
severe behavioral dyscontrol with carbamazepine than
with placebo. EEG studies were not carried out in their
patients.
Although the results of the above studies suggest a
potential use for carbamazepine in non-affective
psychiatric disorders, the small number of patients, the
paucity of controlled studies and the tendency to
combine patients with different psychiatric diagnoses
make the interpretation of results difficult. In addition, in
all studies mentioned carbamazepine was always used as
an adjunct to other psychotropic drugs although many
authors report a reduction in the dosage of other drugs
when carbamazepine was added to the treatment
regimen. Finally, the presence of EEG abnormalities in
some of the patients studied adds another dimension that
requires experimental clarification. For instance, in
order to demonstrate a specific effect of carbamazepine
on aggressivity unrelated to its anticonvulsant effect,
more rigorous electrophysiological studies other than
standard surface EEGs would need to be performed.
Similarly, studies would have to differentiate between the
proposed mood stabilizing effects of carbamazepine and
specific effects on violent or psychotic behavior. The data
presented so far deals with a small group of selected
heterogeneous patients who mainly share the characteristic of being refractory to all conventional treatments and
who therefore make such distinctions difficult. It is
579
therefore not surprising that some studies also report
negative findings. For example, Dalby (21) noted a
paradoxical worsening of aggression in response to
carbamazepine in a small number of patients with brain
damage and/ or mental retardation. Stevens (22) also
reported on 2 schizophrenics who markedly worsened
when carbamazepine was added to their treatment
regimen.
2. Pharmacokinetic and Pharmacodynamic Profile
Pharmacokinetics
Carbamazepine is rapidly absorbed after oral intake.
Peak plasma concentrations are reached within 2 to 6
hours with considerable individual variations.
Carbamazepine is approximately 75% bound to
plasma proteins whereas its active metabolite carbamazepine 1O,1l-epoxide is 50% bound. Carbamazepine is
metabolized in the liver and may induce its own
metabolism. The initial half-life of the parent compound
ranges from 25 to 65 hours while the steady state half-life
ranges from 12 to 17 hours. Thus, after 2 to 3 weeks of
treatment serum levels usually decrease, as a result of
induction of hepatic enzymes, and it may be necessary to
increase the dose in order to maintain therapeutic drug
levels. The half-life of the active metabolite is in the range
of 5 to 8 hours. Given the half-life at steady states,
carbamazepine must be used in divided doses (usually
b.i.d. or t.i.d. depending on the overall dose).
Carbamazepine is metabolized by the liver to its active
metabolite carbamazepine 1O,1l-epoxide. There is then
further metabolism to carbamazepine 10,Ll-dehydroxide
and subsequent conjugation with glucoronic acid. Less
than 1% is recovered in the urine as a parent compound
or metabolite.
Pharmacodynamics
Mechanisms of Actions
In both clinical and experimental settings, carbamazepine has been shown to have a relatively greater limbic
than cortical anticonvulsant effect (23,24). Carbamazepine has been demonstrated to suppress after-discharges
and spontaneously induced seizure discharges preferentially in limbic areas over other cortical areas (24-26).
Carbamazepine also suppresses seizures kindled in limbic
areas by repetitive subthreshold electrical stimulation
(25-27). The postulated role of the limbic system in the
regulation of emotion has led some researchers to suggest
that the efficacy of carbamazepine in the treatment of
affective disorders may well be mediated via its
preferential effect on limbic structures (24).
The effect of carbamazepine on various neurotransmitters has been extensively reviewed and will be
summarized below. To date, it appears that carbamazepine's mechanism of action is largely nonspecific as it
affects several neuronal systems.
Noradrenergic Effects
Carbamazepine has been found to be a noradrenergic
reuptake blocker although it is relatively a weaker
580
CANADIAN JOURNAL OF PSYCHIATRY
inhibitor of reuptake when compared to imipramine (28).
The fact that unlike other antieonvulsants carbamazepine seems to exert an effect on catecholamine systems
has led some investigators to suggest that the action is
implicated in carbamazepine's psychotropic effect rather
than mediating its anticonvulsant action (29,30). Other
studies, however, have shown that depletion of
norepinephrine with 6-hydroxydopamine decreases the
anticonvulsant efficacy of carbamazepine (31).
Effects on Dopaminergic Systems
The effects of carbamazepine on the dopaminergic
system have been extensively studied and reviewed (32).
The data collected to date suggests that carbamazepine
acts through mechanisms other than the blockade of
dopaminergic receptors. In contrast to neuroleptics
carbamazepine: (i) does not tend to produce extrapyramidal side effects such as parkinsonism or tardive
dyskinesia; (ii) does not cause substantial increases in
plasma prolactin; (iii) does not increase homovanillic
acid (HV A) levels in human cerebrospinal fluid (CSF)
although it decreases probenicid-induced accumulation
of HVA; (iv) does not increase firing of dopaminergic
neurons in the substantia nigra; and (v) does not block
stimulant induced psychomotor activity. Furthermore,
carbamazepine does not appear to block dopamine
receptors as measured directly by displacement of [3H]spiroperidol. The data therefore suggest that carbamazepine may decrease dopamine turnover but unlike
neuroleptics it does not act via blockade of dopamine
receptors.
Effects on GABA
Carbamazepine has been reported to decrease GABA
turnover (33). This effect could reflect a functional
increase in GABA activity, a property shared by other
anticonvulsants such as valproic acid. It is also of interest
to note that lithium and propranolol also decrease
GAB A turnover. Thus, the action of carbamazepine on
GABA may be potentially related to both its
psychotropic and anticonvulsant effects. It must be
noted, however, that carbamazepine was not shown to
affect CSF GABA levels in bipolar patients who
responded to the drug (34).
Effects on Benzodiazepine Receptor Sites
There is now evidence to suggest that the "peripheraltype" benzodiazepine receptor is functionally involved in
the anticonvulsant effect of carbamazepine (35). This
receptor, although originally described in the periphery,
is also known to be localized in central structures
including olfactory bulb, hippocampus and cortex.
Carbamazepine, however, does not seem to act at the
central benzodiapezine site and is not associated with
tolerance or withdrawal effects. The implication of these
findings on the psychotropic effects of carbamazepine
remain to be elucidated.
Vol. 33, No.7
Adenosine Receptor Effects
Carbamazepine is reported to be a potent agent in
displacing binding of specific adenosine antagonists and
agonists (36). Carbamazepine has been shown to share
many properties with adenosine antagonists (37). The
data suggests that carbamazepine's effects on the
adenosine receptors is not critical to its anticonvulsant
activity but may well be related to its other clinical effects.
It has also been proposed that the effects of
carbamazepine on the noradrenergic system may be
linked to its action on adenosine (38).
Serotonergic Effects
Carbamazepine has not been found to alter basal levels
of 5HlAA in the CSF of affectively ill patients (39).
However, it has been found that carbamazepine, unlike
other anticonvulsants, increased plasma levels of
tryptophan. In the context of the postulated role of the
serotonergic system in affective disorders this finding
may reflect a relationship between carbamazepine's
psychotropic action and the serotonergic system.
Cholinergic Effects
Researchers have found that carbamazepine increased
acetylcholine levels in rat striatum while choline levels
were decreased (40).
Effects on Cyclic Nucleotides
Carbamazepine inhibits accumulation of cyclic AMP
induced by many stimuli (38). Basal levels of cyclic AMP
or cyclic GMP remained unchanged in affectively ill
patients treated with carbamazepine (41). However, it
was noted that probenecid-induced accumulation of
cyclic AMP and cyclic GMP were significantly decreased
during carbamazepine treatment. These findings are of
interest because of the postulated role of cyclic
nucleotides in both affective illness and seizure disorders
as well as the proposed role of lithium's effect on
adenylate cyclase activity in its mechanism of action.
Endocrine Effects
Carbamazepine induces escape from dexamethasone
suppression (42,43). Carbamazepine also increases
urinary free cortisol in both normal volunteers (44) as
well as in depressed patients with normal baseline levels
of urinary free cortisol (43). It has been suggested that the
effects of carbamazepine on cortisol may be mediated via
its effects on somatostatin (38). Carbamazepine has been
observed to significantly decrease somatostatin in CSF.
Since somatostatin has been shown to inhibit CRFmediated secretion of ACTH, a decrease in somatostatin
would result in removal of ACTH inhibition and
therefore in cortisol hypersecretion. Somatostatin has
also been reported to be decreased in untreated depressed
patients. The implication of the above findings on the
mechanism of action of carbamazepine awaits further
research.
October, 1988
CARBAMAZEPINE IN PSYCHIATRY
In contrast to lithium, carbamazepine has been noted
to have an antidiuretic effect. Several studies suggest that
carbamazepine may actually act directly at the
vasopressin receptor (reviewed in 38,45). Carbamazepine
has been successfully used in the treatment of central
diabetes insipidus (46). It is not yet clear, however,
whether a relationship exists between carbamazepine's
effects on vasopressin and its mechanism of action as an
anticonvulsant or psychotropic agent.
Finally, carbamazepine has been demonstrated to
decrease circulating levels of T 3 and T 4 with altering levels
of TSH. Furthermore, it has been found tht the decreases
in peripheral thyroid hormones were significantly greater
in carbamazepine responders when compared to nonresponders (47). This finding led investigators to suggest
that carbamazepine's effects on thyroid hormones may
be related to its therapeutic efficacy. The exact
mechanism, however, remains to be elucidated and
would represent a worthwhile goal for future research.
3. Adverse Reactions and Drug Interactions
Adverse Reactions
According to clinical experience approximately 25% of
patients receiving carbamazepine experience adverse
reactions (3,48). Most untoward effects subside within
one week or after a reduction in dosage. Adverse
reactions can be minimized by starting with small doses
and increasing the amount gradually. Adverse reactions
in psychiatric patients appear to be similar to those
encountered in epileptic and pain patients. The most
commonly reported adverse effects include nausea,
drowsiness, dry mouth, vertigo, ataxia and diplopia.
These effects tend to be mild and transient and if they
persist, tend to remit when drug dosages are decreased.
Dermatologic reactions are reported to occur in 8-15%
of patients treated with carbamazepine (6,48,49). These
range from mild exanthems to more serious lesions such
as Stevens-Johnson syndrome, exfoliative dermatitis and
toxic epidermic necrolysis. It is recommended that the
drug be discontinued if dermatologic reactions occur as
they may represent early signs of more serious toxicity.
Although rare, hepatic toxicity has also been
associated with carbamazepine treatment (49), cholestatic jaundice, hepatocellular jaundice and abnormal
liver function tests accompanied by immune complexes
have been reported (49). In some patients elevation of
liver enzymes will be transient. However, it is
recommended that baseline liver function tests (including
serum bilirubin, alkaline phosphatase, SGOT, SGPT
and lactate dehydrogenase) be obtained and that
symptoms such as nausea, vomiting, anorexia and fever
be immediately investigated. Routine monitoring ofliver
function tests is also recommended with discontinuation
of the drug if persistent elevation of liver enzymes is noted
or if the patient becomes symptomatic.
As a result of its antidiuretic action, hypnotremia has
also been reported in both psychiatric and nonpsychiatric populations treated with carbamazepine (45).
581
In a recent study, a significant incidence of hyponatremia
was reported in 12 patients treated with carbamazepine
when compared to placebo (45). Furthermore, a higher
risk was noted with older patients as well as in patients
with higher serum drug levels. It is currently estimated
that self-induced water intoxication can occur in 3 to 4%
of hospitalized psychiatric patients (50). Thus, these
patients would constitute a population at risk for the
development of clinically significant water intoxication if
treated with carbamazepine. It is therefore advisable to
obtain a serum sodium determination in any patient who
drinks large quantities of water or who develops
unexplained alterations in central nervous sytem
functioning while on carbamazepine.
A wide range of hematological effects have been
reported as a result of treatment with carbamazepine.
These include transient leukopenia, eosinophelia,
leucocytosis, reticulocytosis, thrombocytopenia purpura,
agranulocytosis, macrocytic anemia and aplastic anemia.
A 1983 review of carbamazepine induced hematological toxicity reported 22 cases of aplastic anemia and 15
cases of agranulocytosis some of which were lethal (51). It
must be noted that the link between carbamazepine and
the severe hematological effects in many of the cases was
obscured by the use of polypharmacy as well as by the
presence in some cases of severe underlying illnesses.
Although most of the cases reviewed to date occurred in
non-psychiatric populations, recent studies have noted
the occurrence of fatal hematological effects in
psychiatric patients (52). At present the estimated
incidence of carbamazepine induced aplastic anemia
and/ or agranulocytosis is 1 in 20,000 to 40,000 patients
(51).
A transient decrease in the white count can be expected
in many patients during the first few weeks of treatment
(53). In patients with low or below normal pretreatment
white counts, leukopenia may result. There is general
agreement in the literature that in most patients white
blood cell counts will tend to return to baseline over time
(usually within I month). In a recent review of
carbamazepine-induced leukopenia it was found that
94% of the cases were over 45, suggesting that age may be
a factor (54).
Since most cases of aplastic anemia have occurred
early in carbamazepine treatment it is generally
recommended that a complete blood count with
differential be obtained weekly for the first 2 to 3 months
and then every 3 months for the next 2 to 3 years. Table I
(6) summarizes current recommended guidelines for
discontinuation of carbamazepine. In addition patients
must also be advised to immediately contact their
physician ifthey develop fever, sore throat, mouth ulcers,
easy bruising, petechia, purpura or bleeding from
mucous membranes.
Drug Interactions
With the increasing use of carbamazepine in the
treatment of psychiatric disorders, reports have emerged
582
CANADIAN JOURNAL OF PSYCHIATRY
Table I
Recommended Guidelines for CBZ Discontinuation
WBC total
Neutrophils
Erythrocytes
Hematocrit
Hemoglobin
Platelets
Reticulocytes
Serum iron
<
<
<
<
<
<
<
>
4000jcu mm
1500jcu mm
4,000,000jcu mm
32%
11.0 gjdl
100,000jcu mm
0.3%
150ugjdl
on the potential interactions between carbamazepine and
other psychotropic drugs. Clinical reports have suggested
that synergistic effect may exist between carbamazepine
and lithium in the treatment of patients with bipolar
disorders (55,56) and in violent behavior (57).
Neurotoxicity has also been observed when carbamazepine is combined with lithium (58). This observation,
however, was made on 5 patients, all of whom had at least
one other risk factor such as concurrent medical or
neurological illness. In all cases, signs of neurotoxicity
remitted after the discontinuation of one of the drugs.
Interactions have also been described between
carbamazepine and neuroleptics. Specifically, delirium
developed in one patient when carbamazepine was added
to a regimen of haloperidol and thioridazine which
remitted when the neuroleptics were discontinued (59). A
similar syndrome was later described in a patient who
was treated with only haloperidol and carbamazepine
(60). Carbamazepine has also been reported to lower
haloperidol plasma levels which may in some cases result
in a deterioration of clinical status (61,62). This effect is
thought to be mediated via a carbamazepine-induced
increase in the metabolism of haloperidol (62).
Carbamazepine induces the microsomal enzymes and
can therefore accelerate the metabolism of any drug that
is metabolized by this system, including phenytoin,
warfarin and doxycycline (63). Similarly, carbamazepine
induces its own metabolism resulting in decreased serum
levels, usually 2 to 3 weeks after the initiation of
treatment.
There have also been several case reports of
carbamazepine toxicity when it is co-administered with
the monoamine oxidase inhibitor isoniazid (64-66). It is
proposed that the interaction is mediated by isoniazidinduced inhibition of microsomal enzymes resulting in a
rise in carbamazepine blood levels. However, no toxicity
was reported when tranylcypromine was co-administered
with carbamazepine in one patient (67). Until further
studies are done documenting the potential interaction
between monoamine oxidase inhibitors and carbamazepine, it is recommended that these drugs be administered
concomitantly only at moderate doses and that blood
levels of carbamazepine be monitored weekly in the first
month of therapy.
Vol. 33, No.7
Dosage and Blood Level Monitoring
It is best to start with low doses with small increments
in order to minimize adverse effects and maximize
patient compliance. It is recommended to start treatment
with doses of 200 mg daily or twice daily and then to
gradually increase the dose by 200 mg increments every
few days. Most patients will require an average of 1000
mg daily in divided doses, although many patients
respond to 400 to 600 mg per day. A few patients have
required up to 2200 mg per day. However, it is not
recommended to use high doses unless some response is
seen with lower doses.
A close relationship does not exist between therapeutic
response and carbamazepine blood levels. Therapeutic
responses tend to occur in the range of 6 to 12 ugml which
corresponds to the range used for the treatment of
epilepsy. A closer correlation may exist between levels of
carbamazepine 10,11- epoxide, in both plasma and CSF,
and the degree of clinical response (68).
Conclusions
Although there is growing evidence for a role of
carbamazepine in the treatment of certain psychiatric
disorders, further research is required before specific
indications for its use can be established. To date the
evidence does suggest that carbamazepine may represent
a potential alternative in the treatment of selected cases of
manic-depressive illness. This evidence is of special
significance in light of the growing recognition that as
many as 20 to 30% of patients with manic- depressive
illness fail to respond to lithium carbonate or are unable
to tolerate its side effects. In fact, the literature suggests
that rapid cyclers and those who are initially more manic
and psychotic tend to respond most favorably to
carbamazepine. Nevertheless, carbamazepine should not
be used as a first line drug in the treatment of manicdepressive illness. One possible exception may be those
patients with a history of seizures or paroxysmal
discharges on EEG. In such cases carbamazepine may be
preferable to lithium or neuroleptics because of the
associated risk of lowering the seizure threshold.
The data for the antidepressant effects of carbamazepine are less conclusive and additional controlled trials
are necessary before its efficacy can be accurately
estimated. However, carbamazepine should still be
considered as an alternative for those patients who are
refractory to more established antidepressants. In
addition, carbamazepine may be useful in treating
patients with violent outbursts whose aggressiveness
cannot be controlled with neuroleptics.
Finally, although much attention has been focused on
the potentially lethal side effects of carbamazepine, these
tend to be rare and it must be remembered that
carbamazepine has been used relatively safely for many
years in the treatment of nonpsychiatric disorders. It is,
however, important to remember that carbamazepine
has not yet been approved by the Food and Drug
Administration (FDA) or the Health Protection Board
October, 1988
CARBAMAZEPINE IN PSYCHIATRY
(HPB) for its application in psychiatric disorders. As
carbamazepine remains an investigational drug in
psychiatry it is recommended that patients be informed
of this fact with the concomitant provision of
information regarding the benefits and anticipated risks
associated with its use. Preferably the information
provided to the patient and the patient's written consent
should be well documented in the chart. Special care
should also be taken to document any adverse reactions
along with their course and treatment.
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Resume
La carbamazepine est un compose tricyclique relie par
sa structure a l'imipramine, qui a ere utilise depuis les
annees 60 pour Ie traitement de la nevralgie essentielle du
trijumeau et qui a ete approuve aux Etats- Unis comme
anticonvulsivant en 1974. Depuis la demiere decennie, on
se sert aussi de ce medicament pour Ie traitement de
certains troubles de l'humeur et du comportement. Dans Ie
present article, les auteurs examinent certains usages
possibles de la carbamazepine en psychiatrie ala lumiere
de ses caracteristiques pharmacokinesiques et pharmacodynamiques. lis discutent enfin des reactions negatives et
des interactions medicamenteuses reliees ace medicament.
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