Our study presents the first report to our knowledge describing rates of leucopenia and agranulocytosis among persons receiving clozapine by race in a large cohort. We show that significantly more African American patients (5.3%) discontinue clozapine due to leucopenia than Caucasians (2.4%). In fact, this was the only reason that differed between the racial groups other than the category of unknown reasons. It is possible that the some of the undocumented reasons (unknown), which were higher in African Americans, may have also been leucopenia cases. It appeared that African American men may be at the greatest risk for discontinuation, and this is supported by other literature describing lower normal WBC counts occurring in African American men compared with women.8
Also of interest was that no cases of agranulocytosis occurred in African Americans either representing higher vigilance and higher discontinuations by clinicians in WBCs that start to drop or a lower incidence of the true occurrence of agranulocytosis which is possibly genetically mediated. Thus, most likely, many African American patients were discontinued unnecessarily due to the benign ethnic neutropenia present in this racial group.
Previous work by our group and others has described disparities in clozapine treatment in African Americans relative to Caucasians.7
While the reasons for this continued disparity remain unclear, it may be mediated in part by guidelines for WBC monitoring. Values greater than 3500/mm3
are required before clozapine treatment can be initiated. Yet, many African Americans exhibit benign ethnic neutropenia, in which the lower ranges of their WBC fall within the red alert zone.8–12
This could potentially lead to underprescribing of clozapine or its unnecessary discontinuation in African American patients.
It is important to note that low baseline WBCs have not been associated with agranulocytosis among clozapine patients, and agranulocytosis does not occur more frequently in African Americans.10
In fact, evidence suggests that patients continuing treatment in the red alert zone appear to maintain their WBCs or have their WBCs recover in most instances following a drop below the threshold.13
Patients with morning pseudoneutropenia have also been maintained successfully on clozapine with no risk for agranulocytosis.14
As such, recent publications have challenged the prescribing guidelines in minority patients. In fact, some have argued in favor of creating different treatment recommendations for minority groups now that a body of data has been established detailing the risk of agranulocytosis.9,11
Additionally, Novartis has recently revised their prescribing guidelines in the United Kingdom and Canada to include special consideration for patients with benign ethnic neutropenia.11
Despite these observations, acknowledgments, and changes in labeling in other countries, a change to current recommendations for African Americans in the United States has not yet occurred.
As we have observed, the risk for leucopenia can occur at any point during treatment. On the other hand, agranulocytosis occurs primarily in the first 18 weeks with 87.5% of cases developing the blood dyscrasia during this timeframe with the mean time to occurrence of 68 days. Others have also reported that the highest incidence occurs in the 3rd month of treatment.15
It is unknown if the African Americans who developed leucopenia would have progressed to agranulocytosis. Our study is limited by the fact that actual documentation of WBCs was not available; however, guidelines from CAMP required that leucopenia cases (<3000/mm3
) be discontinued from clozapine, and this reason was documented in the electronic database.
This study suggests the need for further research on the appropriateness of the clozapine WBC guidelines for African Americans. Recent labeling changes in other countries underscore the possibility that modification of prescribing recommendations for clozapine in the United States may reduce racial disparities and encourage greater use of clozapine in African American populations.