Clozapine Underutilization and Discontinuation in African Americans Due to Leucopenia

The Maryland Psychiatric Research Center, Box 21247, Baltimore, MD 21228, USA.
Schizophrenia Bulletin (Impact Factor: 8.45). 10/2007; 33(5):1221-4. DOI: 10.1093/schbul/sbl068
Source: PubMed


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.

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Available from: Robert R Conley, Aug 19, 2014
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    • "The reasons for the discrepancy are not entirely clear, but non-modifiable genetic factors appear to be important (Athanasiou et al. 2011; Mcknight et al., 2011). For example, in a large U.S. study, neutropenia leading to discontinuation of clozapine was significantly more prevalent in African-American than in Caucasian patients (5.3% vs 2.4%), but agranulocytosis developed only in Caucasians (Kelly et al., 2007). The genetic control of proteins related to reactive oxygen clearance systems correlates with the susceptibility for clozapine-induced agranulocytosis (Yang et al., 2011) and may influence the increased rate of cell death described after exposure to clozapine plus peroxidase-peroxide preparations (Tschen et al., 1999). "
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    ABSTRACT: Clozapine is widely prescribed for treatment refractory patients with schizophrenia, but its use is limited by potentially life threatening adverse effects. Rechallenge after these complications has been occasionally attempted in patients with severe psychotic symptoms. To review the outcome of clozapine rechallenge after potentially life threatening adverse effects. Electronic, all-language, literature search (1972-2011) followed by demographic and clinical data extraction. The outcome of rechallenge was considered favorable when the lower bound of the 95% confidence interval (CI) of the proportion of patients who could continue clozapine was >50%. Altogether, 138 patients (mean age: 36.3years, 65.7% male, 57.6% Caucasian, virtually all with schizophrenia spectrum diagnosis) underwent clozapine rechallenge after developing neutropenia (n=112), agranulocytosis (n=15), neuroleptic malignant syndrome (NMS) (n=5), myocarditis (n=4), pericarditis (n=1) and lupus erythematosus (n=1). Rechallenge strategies were heterogeneous and not systematically evaluated. Clozapine rechallenge was successful in 78/112 patients (69.6%, CI: 60.6-77.4) after neutropenia, 3/15 (20%, CI: 7.1-45.2) after agranulocytosis, 5/5 (100%, CI: 56-100) after NMS, 3/4 (75%, CI: 30-95) after myocarditis, 1/1 after pericarditis, and 0/1 after clozapine-induced lupus. Successfully rechallenged patients were followed for 16-96weeks. None of the rechallenged patients died. Although controlled studies are clearly needed, using a priori, confidence interval-based criteria, case reports/series suggest that in refractory patients who benefited from clozapine, careful rechallenge can be considered after neutropenia and NMS, but not after agranulocytosis and myocarditis.
    Schizophrenia Research 11/2011; 134(2-3):180-6. DOI:10.1016/j.schres.2011.10.014 · 3.92 Impact Factor
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    • "It is possible that the poorer survival of black women with breast cancer may be partly due to this fact [5,6]. The anti-schizophrenia drug clozapine, which often causes neutropenia, is more likely to be discontinued in Blacks than Whites [7]. Similarly, the drug is less often initiated in Blacks due to a fear of the dreaded agranulocytosis [8]. "
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    ABSTRACT: Benign neutropenia, i.e., neutropenia not associated with an increased risk of infection, may result in serious medical consequences when a 'standard' definition of neutropenia (absolute neutrophil count (ANC) < 1.5 x 10(9)cells/L) is universally applied to all races. The aims of this study were to determine the prevalence of benign neutropenia among healthy Arabs and evaluate its mode of inheritance. ANCs were studied prospectively amongst a healthy indigenous population (n = 1032) from the United Arab Emirates undergoing a nation-wide sickle-cell and thalassemia screening program. The mean neutrophil count and the prevalence of benign neutropenia were compared by age, sex and amongst various tribes. The mean neutrophil count (x 10(9)cells/L) was 3.3 (range 0.95-7.6). Benign neutropenia was present in 110 (10.7%) subjects of whom 24 (2.3%) individuals had moderate neutropenia (ANC 0.5 - 1.0 x 10(9) cells/L). In the 22 tribe-family groups, the prevalence of benign neutropenia varied between 0% and 38%. Benign neutropenia showed no difference in the frequency amongst the sexes (p = 0.23) and it was independent of age (Spearman's rho = 0.05, p = 0.13). The age-related mean neutrophil count was the lowest in Arabs when compared with other ethnic groups (Blacks, Europeans and Mexicans). The inheritance of benign neutropenia was consistent with an autosomal dominant pattern; however, the diversity of observed phenotypes suggested the presence of more than one genetic variant for this trait. Arabs have a high prevalence of benign neutropenia that may be inherited as an autosomal dominant trait.
    BMC Blood Disorders 04/2009; 9(1):3. DOI:10.1186/1471-2326-9-3
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    • "Clozapine is used much less among African-Caribbean patients than other ethnicities (Mallinger and Lamberti, 2006). It has been suggested that lower normal ranges for white blood cell (WBC) counts in these patients, known as benign ethnic neutropenia, may account partially for the disparity (Kelly et al., 2006). Increasing age and female gender have been reported to increase the risk of agranulocytosis, while low-baseline WBC counts and ethnicity increase the risk of clozapine-induced neutropenia. "
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    ABSTRACT: In clinical studies and cross-national surveys, cultural or ethnic factors have been found to be significant determinants in patients' responses to psychotropic medication. Dosage requirements and the potential for toxic reactions might differ amongst racial and ethnic groups. In this paper, the authors review the relevant literature and examine pharmacodynamic, pharmacokinetic and cultural-psychological factors, all of which could be responsible for such ethnic variations.
    Culture Medicine and Psychiatry 05/1986; 10(2):151-165. DOI:10.1007/BF00156581 · 1.29 Impact Factor
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