Medical Sciences Bulletin Contents
Reprinted from the February 1994 issue of Medical Sciences Bulletin, published by Pharmaceutical Information Associates, Ltd.
Schizophrenia is one of the most devastating and expensive of all illnesses, costing society billions of dollars annually, not to mention incalculable suffering by patients and their families. It afflicts approximately 2 million Americans and accounts for 25% of hospital beds and an enormous proportion of the nations chronically homeless population. Some 15% to 30% of schizophrenics are resistant to all treatments, and an estimated 70% respond only partially to drug therapy and remain too afflicted to work or lead a normal life.
Clozapine and agranulocytosis: is the risk worth the benefit?
ABCâs TV movie Out of Darkness is the story of an Atlanta mother who battled schizophrenia for 18 years and then found clozapine (Clozaril/Sandoz). The drug released her from the paranoia and psychosis of this devastating illness. Sandoz had almost nothing to do with making the movie but is making the most of what has been called a "public relations windfall," with press releases, posters to support groups, a grant to the National Alliance for the Mentally Ill (to expand its toll- free hotline for 3 days after the movie was shown), and the sponsorship of TV interviews with the director of a schizophrenia clinic and three patients taking clozapine.
There is no question that clozapine is a remarkable drug. This dibenzodiazepine antipsychotic is superior to traditional antipsychotic drugs for the treatment of refractory schizophrenia and causes fewer dopamine-related side effects (parkinsonism, dystonia, tardive dyskinesia, and elevated prolactin levels). About one third of patients treated will show a significant response to clozapine therapy. For the first time in decades, many are capable of normal thought processes. Like the woman in the TV movie, they can claim that clozapine has led them out of darkness. Unfortunately, clozapine can also cause a fatal agranulocytosis. Patients receiving the drug must undergo weekly blood tests to monitor for agranulocytosis. Lab tests cost from $300 to $3000 a year, the drug itself costs more than $4000 a year, and the total is beyond the reach of most patients.
Just how risky is clozapine therapy? Clozapine appears to induce two different types of neutropenia. The first is mild to moderate neutropenia (absolute neutrophil count 500- 1500/mm^3) that occurs in 1.5% to 2% of patients and may result from destruction of neutrophils in blood or spleen (myeloid maturation continues in the marrow). Recovery is rapid, occurring within 3 to 7 days of drug withdrawal. Patients remain asymptomatic. The second type of neutropenia is agranulocytic (absolute neutrophil count less than 500/mm^3) and occurs in 0.8% of patients treated for 1 year. These patients are at risk of sepsis. Recovery takes 14 to 22 days. Some patients go on to agranulocytosis even when clozapine is withdrawn before the neutrophil count drops below 1500. Toxicity appears confined to maturing myeloid cells. The hematopoietic colony stimulating factors (CSF) -- granulocyte CSF and granulocyte-macrophage CSF -- have been used to increase proliferation and differentiation of myeloid precursors. Gerson et al. reported that granulocyte CSF reduced the period of agranulocytosis from a mean of 16 days to 8 days when given within 48 hours of the onset of clozapine-induced agranulocytosis. (Gerson SL et al. Lancet. 1992; 340: 1097.)
Clozapine may also cause mild eosinophilia (counts reaching 4000/mm^3 or higher), chronic leukocytosis (sometimes with low-grade fever), and severe lymphopenia (fewer than 600 lymphocytes/mm^3, sometimes with fever and diarrhea). It is thought that clozapine, its metabolites, or both stimulate expression of various hematologic growth factors, both stimulatory and inhibitory. Because of these hematologic effects, weekly monitoring is required. In the United States, 70,000 patients have received clozapine, and 7 have died of agranulocytosis. However, the safety record is improving. The drug is not given to patients with white blood cell counts below 3500/mm^3 or neutrophil counts below 1500/mm^3 (e.g., patients with benign neutropenia or human immunodeficiency virus infection, and cancer patients requiring lowers neutrophil counts below 1500/mm^3). (Gerson SL. N Engl J Med. 1993; 329: 204-205.)
Recently Alvir et al. evaluated data from 11,555 patients who received clozapine between February 1990 and April 1991. Agranulocytosis developed in 73 patients, with fatal infections in two. Agranulocytosis occurred within 3 months after treatment started in 61 cases. The cumulative incidence was 0.8% at 1 year and 0.91% at 18 months. The risk of agranulocytosis increased with age and was higher in women. The investigators suggest that less frequent monitoring is possible after 6 months, because the incidence of agranulocytosis at this point is no greater than with many other drugs. (Alvir J et al. N Engl J Med. 1993; 329: 162-167.) When considering the risk (and the price) of clozapine therapy versus the benefits, patients and their families have to decide how important it is to try taking those first steps out of darkness.
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