Clozapine hematologic

The seeds of this transformation were sown some years ago. The first so-called atypical antipsychotic, clozapine (Clozaril), was devised in the 1960s. Clozapine was used widely in Europe until a series of deaths from a toxic hematological (blood) side effect called agranulocytosis occurred in the mid-1970s. Clozapine resurfaced in the 1980s and was approved for use (under strict guidelines) in the United States in 1990. Since that time, several other atypical antipsychotics have been approved, and others loom on the horizon. 

Clozapine was the first atypical antipsychotic released in the United States. However, clozapine is associated with the risk of leukopenia and, potentially, lethal agranulocytosis. Because of these concerns, hematological monitoring during clozapine pharmacotherapy is required (Alphs and Anand, 1999). Due to these hematological risks, clozapine is indicated only for patients with treatment-resistant schizophrenia. The other atypical antipsychotics, risperidone, olanzapine, quetiapine, and ziprasidone, that are marketed in the United States can be used as first-line treatments for adults with schizophrenia. 

Hematological Agranulocytosis, leukopenia, neutropenia N/A Complete blood count with differential at baseline and if symptoms of infection, pallor, or bruising develop shortly after treatment initiation White blood counts weekly for 6 months, then every other week thereafter if treated with clozapine... 

TABLE 4-4. Guidelines for hematological monitoring of patients taking clozapine... 

Because of the potential for hematological and hepatic toxicity, carbamazepine should not be administered to patients with liver disease or thrombocytopenia or to those at risk for agranulocytosis. For this reason, carbamazepine is strictly contraindicated in patients receiving clozapine. Because of reports of teratogenicity, including increased risks of spina bifida (Rosa 1991), microcephaly (Bertol-lini et al. 1987), and craniofacial defects (Jones et al. 1989), carbamazepine is relatively contraindicated in pregnant women. Pretreatment evaluation should include a complete blood count and determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. 

Clozapine has been found effective in patients who did not improve during treatment with first-generation antipsychotics, and since the hematological side effects permit only its restricted use, this dmg has a unique indication for treatment- resistanf schizophrenia. Another unique indication for clozapine is the reduction in the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorders. The indications of clozapine and its two analogues, olanzapine and quetiapine, are summarized in Tab. 13.5. The US labels of these drugs served as the data source [62-64]. Clozapine and olanzapine, but not quetiapine, are available in intramuscular form, which is helpful in the treatment of acutely agitated patients with diagnoses as defined in Tab. 13.5. 

Clozapine and SSRIs are often used together, because depressive syndromes are common in patients with schizophrenia. Clozapine carries a relatively high risk of agranulocytosis, but this adverse effect is very rarely seen with SSRIs, although a case of possible fluoxetine-induced neutropenia has been described (SEDA-22, 15). Two cases in which the addition of paroxetine to clozapine was associated with neutropenia have been reported (11). The patients had been taking stable doses of clozapine for 6-12 months and had previously tolerated other SSRIs without adverse hematological consequences. In both cases the white cell count recovered when clozapine was withdrawn, although paroxetine was continued. 

According to the recommended guidelines by Novartis, neutropenia (a white blood cell count below 3.0 x 109/1 or an absolute neutrophil count below 1.5 x 109/1) during clozapine treatment is classified as being in the red-alert zone immediate withdrawal of clozapine is recommended and reinstitution prohibited. However, in some patients, this is not feasible, because of lack of effective alternatives to clozapine. In five patients who were maintained on clozapine despite red-alert zone neutropenia and two control patients who discontinued clozapine because of neutropenia, hematological and clinical progress was followed for more than 600 days (158). In all five patients, there were no additional episodes of neutropenia despite continued clozapine treatment. 

Data from an open study (n = 329) have suggested that patients aged 55-64 years may have a better response to clozapine than those aged 65 and older, but there were no significant differences between the two age groups in the number of patients remaining on clozapine therapy and the number in whom therapy was discontinued (n = 134) (223). The mean duration of clozapine therapy was 278 days. The most common adverse effects that required withdrawal were sedation (n = 12), hematological adverse effects (n = 7), and cardiovascular adverse effects (n = 6). 

Peacock L, Gerlach J. Clozapine treatment in Denmark concomitant psychotropic medication and hematologic monitoring in a system with liberal usage practices. J Clin Psychiatry 1994 55(2) 44-9. 

Lamarque V. Effets hematologiques de la clozapine bilan de l experience internationale. [Hematologic effects of clozapine a review of the international experience.] Encephale 1996 22(Spec No 6) 35-6. 

Jungmn U, Albers M, Woggon B. Increased risk of hematological side-effects in psychiatric patients treated with clozapine and carbarn azepine Pharmacopsychiatry (1993) 26,262. 

Hematologic Lithium increases bone marrow neutrophil production, protects bone marrow hemopoietic stem cells after exposure to anticancer drugs or radiation, and increases platelet count [71 ]. These effects suggest several potential uses in medicine, such as concomitant use in patients who have clozapine-induced neutropenia. 

Hematologic Agranulocytosis, leukopenia, and neutropenia associated with clozapine have been extensively studied and discussed [SED-15, 829 SEDA-32, 97]. 

Immunologic Leukocytosis. A case is described of a 23-year-old man with paranoid schizophrenia who had previously developed clozapine-induced leukopenia, and who presented with olanzapine-associated leukopenia and thrombocytopenia, in which treatment with lithium at 600mg/day, allowed olanzapine to be restarted without recurrence of hematologic abnormalities [115 ]. 

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