Akademik Veri Yönetim Sistemi
World Psychiatric Association (WPA) International Congress, İstanbul, Türkiye, 12 Temmuz 2006, ss.323
Treatment of
clozapine induced late onset neutropenia with G-CSF and beta- glucan: Case
report
Gursoy NU¹ ,
Yildiz M¹, Ozer S¹, Yagcioglu EA¹, Haznedaroglu IC ²
¹ Department of Psychiatry, Faculty of Medicine, Hacettepe University,
Ankara, Turkey
² Department of Heamotolgy, Faculty of Medicine, Hacettepe University,
Ankara, Turkey
Clozapine is the
only medication with proven efficacy in treatment-resistant schizophrenia
(1). Despite its advantages, the use of
clozapine is restricted because of a relatively high incidence of potentially
life-threatening haematological complications. Incidence of clozapine induced
agranulocytosis (neutrophil count below 500/mm3) varies
between 0.4-0.8 % (2, 3). Neutropenia (neutrophil
count between 1,500 mm3 and 500/mm3) is also clinically important as it can be
an early sign of incipient agranulocytosis (6).
Although the risk of developing neutropenia is highest during the first
sixth months, a few cases of delayed neutropenia have been reported with prolonged
clozapine therapy as well (4, 5).
According to recommended guidelines immediate
discontinuation of clozapine is required and reinitiation is contraindicated
when either the white blood cell count falls below 3000 per mm3 or the absolute
neutrophil count falls below 1500 per mm3 (7). However many clinicians are
hesitant to discontinue a successful treatment despite well known risks
accompanied by clozapine. In addition serious problems such as a rapid and more
severe relapse of psychotic symptoms have been reported following the abrupt
switch from clozapine to the other antipsychotics (8,9). Accordingly efforts
are made to continue clozapine despite neutropenia (10). The authors present
here a case of clozapine-induced late onset neutropenia treated with G-CSF and
beta glucan.
The patient is a
54-year-old man with a 23-year history of schizophrenia (DSM-IV). He had been
treated with adequate doses of neuroleptics (haloperidol and chlorpromazine)
for more than ten years. Since the symptoms (auditory halucinations,
referential and persecutory delusions) were refractory to neuroleptics, the treatment was switched to olanzapine in
1999. Olanzapine (30 mg/day) provided only a moderate decrease in his psychotic
symptoms, thus clozapine treatment was initiated and titrated up to 600 mg/day
2 years ago. The hallucinations and delusions disappeared at the end of the
sixth month of clozapine treatment and substantial
improvement in his clinical situation was observed.
Hemogram was checked weekly for the first 4 months. Then
during the monthly follow-ups, his WBC counts ranged between 4000 and 10 000/mm3. On August 2005, 25 months after
initiation of clozapine, the patient’s white blood cell (WBC) count fell to
1900/mm3. Haematological testing and consultation
with Haematology Department, excluded all other plausible factors that could
result in neutropenia. No concomitant medication was reported, which might be
associated with neutropenia. Total WBC counts ranged between 1500-2000/mm3 in
the following days, with no fever, lethargy, sore throat or any other sign of
infection. After 5 days, clozapine was discontinued, and olanzapine 20
mg/day was instituted. Following the
replacement of clozapine by olanzapine,
his psychotic symptoms exacerbated and olanzapine was titrated up to 30
mg/day. After discontinuation of
clozapine, the WBC count did not return to normal limits within 3 weeks, and still
ranged between 500-2000/mm3 . The severe psychotic symptoms persisted as well. The symptomatic treatment of clozapine-induced
neutropenia was planned after consulting the Haematology Department and a
single dose of 300 mcg (4 mcg/kg) granulocyte colony-stimulating factor (G-CSF) was applied by subcutaneous injection and
daily oral beta-glucan therapy was initiated at the dose of 20 mg/day. Ten days later the total WBC count
was 7700/mm3.
As the
patient suffered from severe intervening psychotic symptoms and could not
maintain his occupational and household responsibilities despite 30 mg/day
olanzapine treatment, hospitalization and reinstitution of clozapine treatment
was planned. The patient was on beta-glucan therapy when clozapine was started
and titrated to 600 mg/day. Weekly total WBC counts were within normal limits during
one month hospitalization and follow-up. Psychotic symptoms disappeared after
six weeks of treatment and he returned to his former job again.
Discussion:
For
patients on clozapine, the period of highest risk of neutropenia and
agranulocytosis is during the first 6–18 weeks of treatment . Nonetheless it
has also been reported that the risk for developing agranulocytosis or
neutropenia persist for much longer periods (4,5). In the previous cases of delayed
neutropenia with prolonged clozapine therapy, the patients were using other atypical
or conventional psychotropic medications as well (12) which is not the case for
the patient presented here.
The decision
to discontinue clozapine is never easy. Particularly the physicians are
reluctant to terminate the clozapine therapy because of the former dramatic and
prolonged response achieved by clozapine, when an improvement is achieved for a prolonged time, and
the patients’ tolerance which was the case for the patient presented here. Clozapine is generally a last resort for
patients with complex symptomatologies, who were refractory to at least one
typical and one atypical antipsychotic which was again the case for this
patient. The usual recommendation is to discontinue clozapine and never
restart, but recently there have been several reports of patients who were able
to continue taking clozapine despite the occurrence of neutropenia. The therapeutic
options such as symptomatic treatment of neutropenia with lithium and
granulopoiesis-stimulating factors are used in order not to lose the
established stability with clozapine (10). These methods may be used when
rechallenging the neutropenia with clozapine, as well.
Granulocyte colony
stimulating factor (G-CSF) is a well-known
treatment for neutropenia of any cause. In
the case presented here, a G-CSF injection was applied due to the persistance
of low leukocyte counts, but since his psychotic symptoms exacerbated when he
was on olanzapine, reinstitution of clozapine treatment with oral beta-glucan
treatment was accomplished.
Beta-D-glucans,
usually referred to as beta-glucans, comprise a class of non-digestible
polysaccharides widely found in nature in such sources as oats, barley, yeast,
bacteria, algae and mushrooms. Beta-glucan may have hypocholesterolemic and
glucose-regulating activity. It also has putative immunomodulatory activity ( PDRdaki referanslar). The
immunomodulatory activity has been shown in tissue culture and in mice. It
appears to activate macrophages to release certain cytokines. Such activity, in
mice, has been found to be protective against bacterial infection. It is
unclear whether beta-glucan has immunomodulatory activity in humans.
In
animal studies beta-glucans are shown to enhance murine hematopoietic recovery following
bone marrow injury and the addition of glucan to cultures containing GM-CSF +
interleukin-3 or GM-CSF + stem cell
factor significantly augmented granulocyte-macrophage colony production above
baseline, suggesting an independent mechanism of action for glucans. Phase I
studies of beta-glucan are being conducted in childhood Hodgkin and non-
Hodgkin lymphoma and leukemia. To our
knowledge this is the first reported case of beta-glucan administration to a
patient with clozapine-induced neutropenia.
It is not easy to
clarify the relative contributions of G-CSF and beta-glucan to the elevation of
leukocyte count and hasten marrow recovery, ten days after the application and initiation,
respectively of both treatments. The persisting haematological stability of our
patient at the end of five months follow-up can’t be attributed solely to beta-
glucan for another reason, as well. There are reports (12) of clozapine
rechallenge after delayed neutropenia without combination with G-CSF and with
no return of haematological abnormalities.
Nevertheless beta-glucan
is a promising alternative therapeutic option for clozapine-induced neutropenia
as it is cheap, easy to administer and safe. Moreover it does not contain
protein so is free of G-CSF severe side effects such as allergic reactions.
In
patients with schizophrenia treated with clozapine, in addition to its possible
immunomodulatory activity, beta-glucan may also be helpful in glucose
regulation. Insulin resistance which is frequently associated with clozapine
treatment may account for hyperglycemia, glucose intolerance or overt diabetes
mellitus seen in these patients. Beta-glucan, like other sources of soluble
fiber may reduce post prandial hyperglycemia by slowing gastric emptying and
decrease insulin resistance.
This case is the first report of beta-glucan administration
for clozapine-induced neutropenia. Even it may not be used alone, beta-glucan
therapy may help by reducing the necessity of G-CSF administration during the
follow-up period and thereby avoiding the less common but serious side effects
of G-CSF, such as anaphylaxis or common side effects of it, such as bone pain
and spleen enlargement and decreasing treatment costs.
To prove its beneficial effects, studies
comparing beta-glucan and other treatments like G-CSF head to head or
beta-glucan combination with G-CSF and G-CSF alone are needed, though such
controlled trials would be very difficult to conduct due to the relatively low
incidence of clozapine-induced neutropenia/ agranulocytosis and because of
ethical considerations.
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