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Clozapine use has been notably lower in African American patients than in Caucasians. It has been suggested that lower normal ranges for white blood cell (WBC) counts in African Americans, known as benign ethnic neutropenia, may account partially for the disparity. We examined the rates of leucopenia and agranulocytosis as reasons for discontinuation of clozapine in a sample of 1875 patients with schizophrenia treated in the State of Maryland. Between 1989 and 1999, 5.3% (31/588) of African Americans and 2.4% (31/1287) of Caucasians discontinued clozapine treatment due to leucopenia (chi square = 10.35, df = 1, P = 0.001). No African American patients developed agranulocytosis while 8 Caucasian patients (0.62%) developed this blood dyscrasia. Discontinuations due to leucopenia occurred throughout treatment. Discontinuations due to agranulocytosis occurred primarily in the first 18 weeks (7/8; 87.5% patients with agranulocytosis). It is likely that African Americans had clozapine discontinued unnecessarily due to benign ethnic neutropenia. We concur with recent recommendations to acknowledge differences in WBC values in African Americans and to modify prescribing guidelines or formally acknowledge benign ethnic leucopenia like in other countries in order to facilitate greater use of clozapine in these patients.
Approximately 1.5 million people in the United States suffer from schizophrenia, and between 20–30% of these patients are unresponsive to first-line antipsychotic therapy. Clozapine is the only antipsychotic medication approved for treatment-resistant schizophrenia. The superiority of this second-line antipsychotic compared with conventional antipsychotics in treatment-resistant schizophrenia is well established.1 Additionally, recent findings from the clinical antipsychotic trials of intervention effectiveness II trial demonstrate the superiority of clozapine over other second-generation antipsychotics2 in a population of patients who prospectively failed an optimized antipsychotic trial.
Given the high costs of medication discontinuation, rehospitalization and inadequate treatments for schizophrenia, the underutilization of clozapine in the United States in particular is noteworthy.3,4 It is likely that clozapine's underutilization is related in part to its frequent monitoring and serious side effects including agranulocytosis, myocarditis, other inflammatory reactions, seizures, obesity, diabetes mellitus, and other metabolic abnormalities. Moreover, racial disparities in the use of clozapine have been consistently observed, with African Americans less likely to receive this medication than Caucasians.5–7 Possible explanations for this prescribing pattern include prescriber bias, the anticipation of nonadherence, and the notion of lower effectiveness in African Americans. The superior effectiveness of clozapine relative to other antipsychotics merits increased efforts to encourage greater use in appropriate patients and to more efficiently monitor for side effects.2 Earlier work by our group had also found lower rates of clozapine prescribing among inpatients with schizophrenia who are African American as compared with Caucasians. We have also attempted to examine reasons for the continued racial disparity and found that differences in presenting symptoms and response potential do not explain the apparent underutilization of clozapine in African Americans relative to Caucasians.7
A hypothesized explanation for the disparity in clozapine prescribing may be related to the requirements for white blood cell (WBC) monitoring. Current guidelines require WBCs to be >3500/mm3 before clozapine is initiated, and the drug must be discontinued if WBCs fall below 3000/mm3 or if the absolute neutrophil count (ANC) goes below 1500/mm3 (red alert zone). However, normal WBC levels in African American males generally range from 2800 to 9500/mm3, which is significantly lower than the normal range for Caucasians (3600–9500/mm3) and also overlaps with the red alert zone, a range of WBC that requires stopping clozapine.8 Due to this phenomenon, known as benign ethnic neutropenia, it has been estimated that approximately 20% of African Americans may be deemed ineligible for clozapine. Further, up to one quarter of African American patients may have clozapine discontinued for this reason.9,10 In fact, in a few publications, the prescribing guidelines of clozapine in African Americans have been challenged.9,11 Thus, the aim of the current study was to compare the rates of clozapine discontinuation and reasons for discontinuation including leucopenia or agranulocytosis in a large population of African American and Caucasian patients.
All data in this study were derived from the Clozapine Authorization and Monitoring Program (CAMP) database from the State of Maryland. Between January 1, 1989, and December 31, 1999, 2136 patients began clozapine therapy. Clozapine patients had a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia/schizoaffective disorder, had a trial of at least 2 different chemical classes of antipsychotic medications, were considered treatment-resistant by the treating clinician, and had a total score of ≥35 or a score of ≥4 on selected individual items of the Brief Psychiatric Rating Scale. Clozapine use was contraindicated in patients with a history of a drug-induced blood dyscrasia, an uncontrolled seizure disorder, a WBC <3500/mm3, a history of myeloproliferative disorder, or pregnancy. All patients contained in the CAMP data were those who were treated with medical or pharmacy assistance.
Of the 2136 patients, 1875 patients with race data (African American or Caucasian) were included in this study. A small sample of Hispanic, Asian, and Pacific Islanders were excluded and not included in the analysis. Reasons for clozapine discontinuation were categorized as lack of efficacy, nonadherence, agranulocytosis, leucopenia, other hematologic adverse effect, other nonhematologic adverse effect, death, and unknown. All sites utilizing clozapine were required to report reasons for discontinuation and a clinical pharmacist followed up to ensure consistent reporting. According to manufacturer labeling and CAMP guidelines for clozapine discontinuation due to the WBC profile, leucopenia was a WBC <3000/mm3 or ANC of <1500/mm3. Agranulocytosis was defined as an ANC <500/mm3. Patients who discontinued clozapine for <7 days were not considered as discontinued from clozapine. This study was approved by the State of Maryland and the University of Maryland Institutional Reviews Boards, and a waiver of informed consent was granted due to the nature of the data.
We examined differences by race in rates of clozapine discontinuation using chi squares. Student t tests were used for analyzing differences in continuous variables. All analyses were 2-tailed, and significance was defined as alpha < 0.05.
During the study, 1287 Caucasian and 588 African American patients initiated treatment with clozapine. Overall, 864/1875 (46.1%) discontinued clozapine at some point during their first clozapine trial. Similar proportions of African American (48.6%) and Caucasian patients (44.9%) discontinued clozapine for any reason. As shown in table 1, discontinuation for leucopenia and for unknown reasons were significantly higher in African Americans compared with Caucasians.
A significantly higher percentage of males in the African American group were noted to discontinue clozapine due to leucopenia as compared with the Caucasian cohort. (80.6% vs 45.2%; chi square = 8.36, df = 1, P = 0.0038). No differences in age were noted (38.1 ± 12.9 and 40.1 ± 12.1 years; t = 0.63, df = 60, P = 0.53). The percent of African Americans and Caucasians who discontinued in the first 18 weeks was 58.1% (18/31) and 38.7% (12/31), respectively. Between 18 and 52 weeks 29.0% (9/31) of African Americans and 32.3% (10/31) of Caucasians discontinued. After >52 weeks, 29.0% (9/31) and 32.3% (8/31) of the groups discontinued clozapine (chi square = 3.18, df = 2, P = 0.20).
No African American patients developed agranulocytosis while 8 Caucasian patients (0.62%) developed this blood dyscrasia. The total rate of agranulocytosis for both races was 8/1875 (0.43%). Of the 8 Caucasians who discontinued due to agranulocytosis, 5/8 (62.5%) were males, and the mean age was 48.1 ± 10.1 years. Seven of 8 (87.5%) Caucasians who developed agranulocytosis did so in the first 18 weeks of treatment (mean: 68.3 ± 30.2 days).
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.
This project was supported by pilot funding from the Health Disparities Research Grant (NIH P60, Wilson D, Principal Investigator (PI)) and an Advanced Center for Intervention and Services Research (P50 MH40279, Carpenter WT Jr, PI). The authors would like to thank Yang Yu, MS for data analysis and the members of the Mental Health Disparities Steering Committee.