Treatment of Clozapine Induced Late Onset Neutropenia with G-CSF and Beta Glucan: Case Report”


Özer S.

World Psychiatric Association (WPA) International Congress, İstanbul, Turkey, 12 July 2006, pp.323

  • Publication Type: Conference Paper / Summary Text
  • City: İstanbul
  • Country: Turkey
  • Page Numbers: pp.323
  • Hacettepe University Affiliated: Yes

Abstract

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

 

Introduction   

  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.

 

Case

 

  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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