Olanzapine agranulocytosis with

Some explanations of the lower risk of agranulocytosis have been advanced after an in vitro cytotoxicity study (209). Like clozapine, olanzapine is oxidized to a reactive nitrenium ion by HOC1, the major oxidant produced in activated neutrophils. However, the olanzapine-reactive metabolite has a lower propensity to cause toxicity to human neutrophils, monocytes, and HL-60 cells than the reactive clozapine nitrenium ion. The lower toxic potential of the olanzapine reactive metabolite, in conjunction with the lower therapeutic plasma concentrations of olanzapine compared with clozapine, may help to explain this difference between the drugs. 

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. 

Aripiprazole Blockade of 5HT2A receptors > blockade of D2 receptors Some a blockade (clozapine, risperidone, ziprasidone) and M-receptor blockade (clozapine, olanzapine) variable receptor blockade (all) Schizophrenia—improve both positive and negative symptoms bipolar disorder (olanzapine or risperidone adjunctive with lithium) agitation in Alzheimer s and Parkinson s (low doses) major depression (aripiprazole) Toxicity Agranulocytosis (clozapine), diabetes (clozapine, olanzapine), hypercholesterolemia (clozapine, olanzapine), hyperprolactinemia (risperidone), QT prolongation (ziprasidone), weight gain (clozapine, olanzapine)... 

Clozaril (Clozapine), for example, can cause agranulocytosis (a potentially lethal suppression of white blood cells by the bone marrow). Parkinsonian symptoms and weight gain occur with risperidone (Risperdal) and olanzapine (Zyprexa). In addition, quetiapine (Seroquel) has been associated with an increased incidence of cataracts. 

In three cases of leukopenia with olanzapine, a reduction in dose was followed by normalization of the leukocyte count and allowed continued treatment (210). Two of the patients had a previous history of neutropenia and agranulocytosis associated with typical neuroleptic drugs and the third developed neutropenia for the first time while taking olanzapine. 

Olanzapine-induced blood disorders have been reviewed and compared with clozapine-induced agranulocytosis... 

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). 

Finkel B, Lerner A, Oyffe I, Rudinski D, Sigal M, Weizman A. Olanzapine treatment in patients with typical and atypical neuroleptic-associated agranulocytosis. Int Clin Psychopharmacol 1998 13(3) 133-5. 

Another atypical agent, olanzapine, also is associated with lower rates of EPS and TD and is not associated with a high risk for agranulocytosis (Tollefson et al. 1997). In a multisite study, EPS and dyskinesia occurred in a smaller percentage of patients of African descent who took olanzapine (4%) than in similar patients who took haloperidol (22%) (Tran et al. 1999). In addition, significant ethnic differences in movement-disordered events were seen with haloperidol therapy but not with olanzapine therapy. 

Thus, valproate is often used to reduce the risk for clozapine-induced seizures. Carbamazepine can potentially increase the risk for development of agranulocytosis when coadministered with clozapine, so this combination should be avoided. Carbamazepine increases renal clearance of olanzapine by about 45% and reduces its half-life by about 20%. To date, no pharmacokinetic interactions have been reported between aripiprazole and valproate. 

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