Benign Ethnic Neutropenia and Clozapine Monitoring

Abstract

Early-onset schizophrenia is associated with greater impairment at follow-up, poorer treatment response, and higher risk for rehospitalization than the adult-onset disorder. Although clozapine has been found superior to first-generation and other second-generation antipsychotics in children and adolescents, its use is limited by significant side effects. Metabolic changes, seizures, and agranulocytosis are thought to occur at similar rates in youths and adults. 1 Kranzler HN Kester HM Gerbino-Rosen G et al. Treatment-refractory schizophrenia in children and adolescents: an update on clozapine and other pharmacologic interventions. Child Adolesc Psychiatr Clin N Am. 2006; 15: 135-159 Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar In a recent study of urban youths, the cumulative 1-year incidence of agranulocytosis (absolute neutrophil count [ANC] <500/mm3) was similar between adults and youths (0.7%-0.8% and 0.99%, respectively). 2 Gerbino-Rosen G Roofeh D Tompkins DA et al. Hematological adverse events in clozapine-treated children and adolescents. J Am Acad Child Adolesc Psychiatry. 2005; 44: 1024-1031 Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar However, in the same study, neutropenia (ANC <1,500/mm3) occurred in youths at a greater rate (1-year cumulative incidence of 16%) than in adults (2.3%). Due to agranulocytosis risk, treatment with clozapine in the United States requires enrollment in a central national database, the Teva Clozapine Patient Registry () or Novartis Clozaril National Registry (), which monitor the white blood cell (WBC) count and ANC, weekly for the first 6 months, then less frequently. Dispensing of clozapine prescriptions is tied to laboratory results (Table 1). Table 1U.S. and U.K. WBC/ANC Clozapine Monitoring Guidelines and Ethnicity-Specific Reference Ranges Registry Stop Treatment Increase Monitoring Normal Monitoring Teva/Novartis Agranulocytosis: <0.5 Severe: <1 (<2) Moderate: 1-1.4 (2-2.9) Mild: 1.5-1.9 (3-3.4) Normal: =2 (=3.5) CPMS non-BEN 5 Rajagopal S Clozapine, agranulocytosis, and benign ethnic neutropenia. Postgrad Med J. 2005; 81: 545-546 Crossref PubMed Scopus (70) Google Scholar Red: <1.5 (<3) Amber: 1.5-2 (3-3.5) Green: ≥2 (≥3.5) CPMS BEN 5 Rajagopal S Clozapine, agranulocytosis, and benign ethnic neutropenia. Postgrad Med J. 2005; 81: 545-546 Crossref PubMed Scopus (70) Google Scholar <1.0 (<2.5) 1-1.5 (2.5-3) >1.5 (>3) Reference range 3 Bain BJ Ethnic and sex differences in the total and differential white cell count and platelet count. J Clin Pathol. 1996; 49: 664-666 Crossref PubMed Scopus (285) Google Scholar White 1.7-6.1 (3.6-9.2) Afro-Caribbean 1.0-5.8 (2.8-9.5) African 0.9-4.2 (2.8-7.2) Note: Shown is absolute neutrophil count range (white blood cell count range) X 1,000/mm3. Teva = Teva Clozapine Patient Registry (http://www.clozapineregistry.com); Novartis = Novartis Clozaril National Registry data from Novartis (Clozaril) package insert: http://www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf; BEN = benign ethnic neutropenia; CPMS = Clozaril Patient Monitoring Service; red, amber, and green = alert ranges designated by CPMS. 5 Rajagopal S Clozapine, agranulocytosis, and benign ethnic neutropenia. Postgrad Med J. 2005; 81: 545-546 Crossref PubMed Scopus (70) Google Scholar Open table in a new tab Note: Shown is absolute neutrophil count range (white blood cell count range) X 1,000/mm3. Teva = Teva Clozapine Patient Registry (http://www.clozapineregistry.com); Novartis = Novartis Clozaril National Registry data from Novartis (Clozaril) package insert: http://www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf; BEN = benign ethnic neutropenia; CPMS = Clozaril Patient Monitoring Service; red, amber, and green = alert ranges designated by CPMS. 5 Rajagopal S Clozapine, agranulocytosis, and benign ethnic neutropenia. Postgrad Med J. 2005; 81: 545-546 Crossref PubMed Scopus (70) Google Scholar