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Is clozapine induced neutropenia caused by a decreased cytokine release?
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Is clozapine induced neutropenia caused by a decreased cytokine release? Spemer-Unterweger, B. 1, Gaggl, S.2, Barnas, C.H. 1, Herold, M. 2, Fleischhacker, W.W} and Geissler, D. 3 Departments of 1Psychiatry and 2Internal Medicine, Innsbruck University Clinics, Innsbruck, Austria 3State Hospital Klagenfurt, Klagenfurt, Austria Key words: Clozapine; Agranulocytosis; Cytokines In searching for mechanisms involved in the pathophysiology of clozapine induced blood dyscrasia we performed in vitro studies using microagarcultures as well as liquid cultures for hematopoietic progenitor cells. Normal peripheral blood mononuclear cells (MNC) were incubated in the presence of lineage specific growth factors. Progressively increasing concentrations of clozapine (0-100 ~tg/ml) were added to the cultures. Supematants of agar cultures were harvested on day 14 and analysed for cytokine content by immunological assays. The agar pellicle was fixed, dried and stained and colony formation was evaluated. MNC liquid cultures were also incubated in the presence of clozapine (0-100 ~tg/ml) and were harvested after 2, 12, 24, 48 and 72 hours. Time course of neopterin and GM-CSF release was analysed. Although there was a slight decrease of colony formation in the presence of clozapine a biologically relevant suppression could not be found. These findings seem to indicate, that the pathogenetic mechanism of clozapine induced blood dyscrasia is not related to a direct cytotoxic effect. There was a strictly dose dependent suppression of GM-CSF and neopterin. This was observed in microagarcultures as well as in liquid cultures. This might be a hint towards a clozapine induced impairment of cytokine release which could contribute to an immunological process that causes neutropenia and agranulocytosis.
Hematologic side effects of clozapine
Hummer, M., Barnas, C., Kurz, M., Oberbauer, H. and Fleischhacker, W.W. Innsbruck University Clinics, Dept. of Psychiatry, A-6020 Innsbruck, Austria Key words: Clozapine; Side effects; Neutropenia Hematological side effects are frequently reported to be induced by the atypical antipsychotic clozapine. Blood dyscrasias as agranulocytosis or neutropenia are of considerable clinical relevance. Agranulocytosis, for instance, a potentially letal form of these side effects occurs at an incidence rate of 1-2%. Neutropenia can either be a harmless transient phenomenon or an early sign of incipient agranulocytosis. We have defined neutropenia as less than 2000 neutrophil granulocytes/mm3. In an analysis of our clozapine drug monitoring program we have evaluated the data of 68 patients receiving clozapine for the first time. Eleven out of these patients developed neutropenia as defined above. Neutrophil granulocytes dropped to 290 and 660/mm 3 in two patients, both recovered after the discontinuation of clozapine. One patient with a granulocyte count of 1800/ram 3 was stopped because regular WBC monitoring was not possible. Eight patients demonstrated a completely reversible transient decrease of gnmulocytes during ongoing clozapine administration. This amounts to a cumulative incidence
Is clozapine induced neutropenia caused by a decreased cytokine release? Spemer-Unterweger, B. 1, Gaggl, S.2, Barnas, C.H. 1, Herold, M. 2, Fleischhacker, W.W} and Geissler, D. 3 Departments of 1Psychiatry and 2Internal Medicine, Innsbruck University Clinics, Innsbruck, Austria 3State Hospital Klagenfurt, Klagenfurt, Austria Key words: Clozapine; Agranulocytosis; Cytokines In searching for mechanisms involved in the pathophysiology of clozapine induced blood dyscrasia we performed in vitro studies using microagarcultures as well as liquid cultures for hematopoietic progenitor cells. Normal peripheral blood mononuclear cells (MNC) were incubated in the presence of lineage specific growth factors. Progressively increasing concentrations of clozapine (0-100 ~tg/ml) were added to the cultures. Supematants of agar cultures were harvested on day 14 and analysed for cytokine content by immunological assays. The agar pellicle was fixed, dried and stained and colony formation was evaluated. MNC liquid cultures were also incubated in the presence of clozapine (0-100 ~tg/ml) and were harvested after 2, 12, 24, 48 and 72 hours. Time course of neopterin and GM-CSF release was analysed. Although there was a slight decrease of colony formation in the presence of clozapine a biologically relevant suppression could not be found. These findings seem to indicate, that the pathogenetic mechanism of clozapine induced blood dyscrasia is not related to a direct cytotoxic effect. There was a strictly dose dependent suppression of GM-CSF and neopterin. This was observed in microagarcultures as well as in liquid cultures. This might be a hint towards a clozapine induced impairment of cytokine release which could contribute to an immunological process that causes neutropenia and agranulocytosis.
Hematologic side effects of clozapine
Hummer, M., Barnas, C., Kurz, M., Oberbauer, H. and Fleischhacker, W.W. Innsbruck University Clinics, Dept. of Psychiatry, A-6020 Innsbruck, Austria Key words: Clozapine; Side effects; Neutropenia Hematological side effects are frequently reported to be induced by the atypical antipsychotic clozapine. Blood dyscrasias as agranulocytosis or neutropenia are of considerable clinical relevance. Agranulocytosis, for instance, a potentially letal form of these side effects occurs at an incidence rate of 1-2%. Neutropenia can either be a harmless transient phenomenon or an early sign of incipient agranulocytosis. We have defined neutropenia as less than 2000 neutrophil granulocytes/mm3. In an analysis of our clozapine drug monitoring program we have evaluated the data of 68 patients receiving clozapine for the first time. Eleven out of these patients developed neutropenia as defined above. Neutrophil granulocytes dropped to 290 and 660/mm 3 in two patients, both recovered after the discontinuation of clozapine. One patient with a granulocyte count of 1800/ram 3 was stopped because regular WBC monitoring was not possible. Eight patients demonstrated a completely reversible transient decrease of gnmulocytes during ongoing clozapine administration. This amounts to a cumulative incidence