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The results suggest that the risk of agranulocytosis associated with clozapine may be overstated. They also appear to lend support to the 2015 decision by the Food and Drug Administration to lower the neutrophil count cutoff at which patients are required to discontinue Clozaril from 1500/mm3 to 1000/mm3.
Clozapine has been shown to be the drug of choice for treatment-resistant schizophrenia. Yet since its introduction, the drug has been linked to a risk for agranulocytosis, requiring regular blood monitoring, a disincentive to both clinicians and patients. Guidelines originally called for discontinuation of the medication when neutrophil counts dropped below 1500/mm. That was lowered to 1000/mm3 in 2015; in Europe and the U.K., the lower limit is still 1500/mm3.
Engilbert Sigurdsson, M.D., and colleagues at the University of Iceland and Landspitali University, Reykjavik, sought to analyze the risk of neutropenia and the progression to agranulocytosis in a sample of patients with schizophrenia in Iceland. In that country, providing blood samples at certain intervals is not required for dispensing clozapine. The patient sample included those who were taking clozapine and those who had never used the drug.
Searching the electronic health records of Landspitali, the National University Hospital of Iceland, they identified 201 patients with schizophrenia treated with clozapine and 410 patients with schizophrenia who had never taken clozapine. They identified patients who developed neutropenia/agranulocytosis through neutrophil counts in the databases. They also examined the frequency of neutrophil measurements.
Despite being monitored much less frequently, the rate of neutropenia overall was not significantly greater for patients on clozapine than for patients who had never used the medication. Only mild neutropenia (between 1500-1900/mm3) was more common in clozapine users, and none of those patients (n=24, or 12.8%) progressed to agranulocytosis. For moderate (1000-1400/mm3) and severe neutropenia (500-1000/mm3), the rate was actually higher among patients who had never been prescribed clozapine.
Sigurdsson and colleagues stated that the results support the safety of lowering the neutrophil-count cutoff for discontinuation of clozapine from 1500 to the U.S. standard of 1000/mm3. “This change would result in a much lower rate of clozapine discontinuation, and our findings suggest that the progression to agranulocytosis would remain a rare event,” they wrote.
For related information see the article, "Addressing Barriers to Clozapine Underutilization: A National Effort."
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