Agranulocytosis, clozapine-induced

Corzo, D., et al., "The Major Histocompatibility Complex Region Marked by HSP and HSP70-2 Variant is Associated with Clozapine-induced Agranulocytosis in Two Different Ethnic Groups," Blood, 86, 3835-3840 (1995). 

Clozapine Myeloproliferative disorders uncontrolled epilepsy history of clozapine-induced agranulocytosis or severe granulocytopenia should not be used with other agents having a well-known potential to cause agranulocytosis or suppress bone marrow function. 

Alvir JM, Lieberman JA, Safferman AZ, et al Clozapine-induced agranulocytosis incidence and risk factors in the United States. N Engl J Med... 

Barnas C, Zwierzina H, Hummer M, et al Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis a case report. J Clin Psychiatry 53 245-247, 1992... 

Nielsen H Recombinant human granulocyte colony-stimulating factor (rhG-CSF filgrastim) treatment of clozapine-induced agranulocytosis. J Intern Med 234 529-531, 1993... 

Initially, the mortality rate from clozapine-induced agranulocytosis was about 40%, but it has decreased by more than half. Now, while the mortality rate of agranulocytosis complicated by infection is still 40%, without infection, it is approximately 15%. In U.S. clinical trials, the incidence is about one per 100, but because this outcome is based on only 1,000 patients, it may not be an accurate estimate. It is notable that some who developed clozapine-induced agranulocytosis were later able to tolerate other antipsychotics without a recurrence, again implying a different underlying mechanism. 

Gerson SL, Gullion G, Yeh H-S, et al. Granulocyte colony-stimulating factor for clozapine-induced agranulocytosis. Lancet 1992 340 1097. 

Lithium has beneficial granulocytopoietic effects (35-37). For example, lithium carbonate (800-900 mg/day) effectively corrected neutropenia due to chemotherapy or radiotherapy in over 85% of 100 cancer patients (38). The potential benefit and possible risks of using lithium to treat clozapine-induced neutropenia/agranulocytosis have been reviewed (39). 

Blier P, Slater S, Measham T, Koch M, Wiviott G. Lithium and clozapine-induced neutropenia/agranulocytosis. Int Clin Psychopharmacol 1998 13(3) 137-40. 

Clozapine-induced agranulocytosis Human leukocyte antigen variants Association SEDA-26, 60... 

Immune-mediated mechanisms of clozapine-induced agranulocytosis have been reviewed in the context of agranulocytosis in a 46-year-old woman (140). Immune and toxic mechanisms have also been explored in patients taking clozapine, three who developed agranulocytosis, seven who developed neutropenia, and five who were asymptomatic. There was no evidence of antineutrophil antibodies in the blood of patients shortly after an episode of clozapine-induced agranulocytosis, and an antibody mechanism... 

Table 1 Reported incidences of clozapine-induced agranulocytosis ...

Increased apoptosis of neutrophils has been reported in a 45-year-old woman with clozapine-induced agranulocytosis (142). Withdrawal of clozapine and treatment with granulocyte colony-stimulating factor led to normalization of the blood neutrophil count within 3 weeks. 

Some of the genetic aspects of clozapine-induced agranulocytosis have been evaluated (143). Polymorphisms of specific clozapine metabolizing enzyme systems were determined in 31 patients with agranulocytosis and in 77 without. Genotyping of a recently discovered G-463 A polymorphism of the myeloperoxidase gene and CYP2D6 showed no evidence of an association. 

Lithium can be used in combination with clozapine, and in these patients the possibility of inducing leukocytosis and increasing the total leukocyte count and the granulocyte count has been considered (SEDA-20, 50). Lithium has even been used to prevent clozapine-induced neutropenia (SEDA-22, 59) (162). It has also been used in a patient with clozapine-induced neutropenia and in another with complete agranulocytosis in both cases lithium increased the neutrophil count to within the reference range within 6 days (163). In the patient who had neutropenia, clozapine was restarted in the presence of lithium and the neutrophil count did not fall thereafter. Five other patients who took combined clozapine and lithium had a significant improvement with this... 

Loeffler S, Fehsel K, Henning U, Fischer J, Agelink M, Kolb-Bachofen V, Klimke A. Increased apoptosis of neutrophils in a case of clozapine-induced agranulocytosis. Pharmacopsychiatry 2003 36 37—41. 

Dettling M, Sachse C, Muller-Oerlinghausen B, Roots I, Brockmoller J, Rolfs A, Cascorbi I. Clozapine-induced agranulocytosis and hereditary polymorphisms of clozapine metabolizing enzymes no association with myeloperoxidase and cytochrome P4502D6. Pharmacopsychiatry 2000 33(6) 218-20. 

Lieberman JA, Yunis J, Egea E, Canoso RT, Kane JM, Yunis EJ. HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch Gen Psychiatry 1990 47(10) 945-8. 

Dettling M, Schaub RT, Mueller-Oerlinghausen B, Roots I, Cascorbi I. Further evidence of human leukocyte antigen-encoded susceptibility to clozapine-induced agranulocytosis independent of ancestry. Pharmacogenetics 2001 11(2) 135-41. 

Horacek J, Libiger J, Hoschl C, Borzova K, Hendrychova I. Clozapine-induced concordant agranulocytosis in monozygotic twins. Int J Psychiatry Clin Pract 2001 5 71-3. 

Patel NC, Dorson PG, Bettinger TL. Sudden late onset of clozapine-induced agranulocytosis. Ann Pharmacother 2002 36(6) 1012-5. 

Marcos F, Solano F, Arbol F, Caballero L, Maldonado G, Lopez P, Duran A. Clozapine-induced agranulocytosis. SN 2000 5 27-9. 

Prolonged granulocytopenia due to olanzapine occurred in a 39-year-old woman after clozapine withdrawal (217). In contrast, two patients with severe clozapine-induced granulocytopenia and agranulocytosis were successfully treated with olanzapine in a dose greater than 25 mg/ day (218). Furthermore, a 65-year-old man who had previously developed leukopenia and neutropenia, first with clozapine and then also with risperidone, took olanzapine (20 mg/day for 2 years with only a transient reduction in leukocyte and neutrophil (but not erythrocyte or platelet) counts) during a flu-like illness (219). 

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