Dr. Deanna Kelly will present a session on hematologic issues with antipsychotics with a portion of her talk focused on the BEN population at CPNP 2016 in Colorado Springs, April 17-20.
Clozapine is the most effective antipsychotic for treatment-refractory schizophrenia [1-3]. Despite the overwhelming evidence of superior efficacy, clozapine is infrequently prescribed in the US, at a considerably lower rate than the estimated prevalence of treatment-resistant schizophrenia [4-8], especially for African-Americans (AA) [9-12]. Recent evidence suggests that low Absolute Neutrophil Counts (ANC), either at baseline or during treatment have been a significant barrier to clozapine use in AA patients [13, 14]. Drs. Deanna Kelly and Raymond Love have shown that discontinuation of clozapine in AA patients is over twice that in Caucasian patients (N~400; 42% vs.19%, P=0.041)  and initiation rates are 50% lower . In a Statewide study in Maryland (N=1875), they reported that discontinuation is more frequently due to neutropenia in the AA sample, though no AA has developed agranulocytosis (8 cases in Caucasians identified).
Benign Ethnic Neutropenia (BEN) occurs in people of African or Middle Eastern ancestry, and identifies a group with low ANCs but no increased risk of severe neutropenia or infection [15-17]. Low baseline or in-treatment fluctuations requiring clozapine discontinuation under current prescribing guidelines are common in clozapine-treated persons with BEN . Recent evidence possibly implicates a polymorphism in the Duffy Antigen Receptor Chemokine (DARC) gene in the pathophysiology of BEN [19-23]. This is currently under study.
There is no definitive definition of BEN patients; however, they are usually of African or Middle Eastern descent. BEN has been defined as “the occurrence of neutropenia, defined by normative data in European Ancestry (EA) populations, in individuals of other ethnic groups who are otherwise healthy and do not have repeated or severe infections” . BEN is diagnosed by repeated low measurements of ANC (usually < 1500 cells/mm³ without identifiable causes of Neutropenia)  BEN occurs in about 50% of Africans [25-27], in some ethnic groups in the Middle East, and up to 38% of certain Arab populations .
In a large US population based cross sectional study of data from the National Health and Nutrition Examination Survey (NHANES) from 1999-2004, rates of neutropenia by ancestry were examined. Relative to Caucasians, AAs had lower mean WBC counts and lower neutrophil counts while having similar lymphocyte counts . Neutrophil counts below 1500 cells/mm3 were almost 6 times more prevalent in AA compared to EAs (4.5% AAs vs. 0.79% EAs).
It should be noted that BEN is clinically different from other neutropenias: congenital neutropenia (also known as Kostmann syndrome), cyclic neutropenia, and chronic idiopathic neutropenia. These disorders are diagnosed mostly in EAs, are characterized by very low neutrophil counts, and lead to frequent and potentially life-threatening oral, cutaneous or systemic infections. BEN should not be confused with these disorders or with neutropenia secondary to other conditions, such as pharmacologically induced bone marrow suppression, comorbid infections, neoplastic disease, autoimmune diseases, metabolic disturbances, or hematologic disorders .
The new clozapine monitoring guidelines that went into effect October 12, 2015 take into account ANC differences in BEN patients. The guidelines provide separate algorithms for non-BEN and BEN patients establishing a lower threshold for discontinuation for those with BEN. The patient enrollment form for patients in the new REMS system allows the prescriber to indicate that the patient enrolling is considered a BEN patient. Unlike similar guidelines in the UK, it is not mandatory to get a hematology consult for BEN patients. Furthermore, the Clozapine REMS Program offers no strict definition for BEN. The new guidelines are meant to facilitate access to clozapine and reduce unnecessary interruptions in treatment.
The Maryland Clozapine Authorization and Monitoring Program and the Maryland Psychiatric Research Center have successfully used modified clozapine prescribing guidelines that permitted lower ANC levels in over 25 BEN patients without the occurrence of severe neutropenia. This group is also conducting the first prospective study to examine the safety of clozapine in BEN patients, establish confidence intervals for risk categories and look at a possible genetic biomarker for BEN in a large ongoing NIMH funded grant with full FDA support.
Available Online Resources:
- New Clozapine Program: FAQs
- Clozapine REMS Update
- Conley RR, Tamminga CA, Kelly DL, Richardson CM. Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response. Biol Psychiatry. 1999;46(1):73-7. PubMed PMID: 10394475.
- Volavka J, Citrome L. Pathways to aggression in schizophrenia affect results of treatment. Schizophr Bull. 2011;37(5):921-9. DOI: 10.1093/schbul/sbr041. PubMed PMID: 21562140.
- Lieberman JA, Saltz BL, Johns CA, Pollack S, Borenstein M, Kane J. The effects of clozapine on tardive dyskinesia. Br J Psychiatry. 1991;158:503-10. PubMed PMID: 1675900.
- Fayek, M, Flowers, C, Signorelli, D, et al. Psychopharmacology: underuse of evidence-based treatments in psychiatry. Psychiatr Serv 2003;54:1453-1454, 1456.
- Conley RR, Kelly DL, Lambert TJ, Love RC. Comparison of clozapine use in Maryland and in Victoria, Australia. Psychiatr Serv. 2005;56(3):320-3. DOI: 10.1176/appi.ps.56.3.320. PubMed PMID: 15746507.
- Lieberman JA. Maximizing clozapine therapy: managing side effects. J Clin Psychiatry. 1998;59 Suppl 3:38-43. PubMed PMID: 9541337.
- Taylor, DM, Young, C, and Paton, C. Prior antipsychotic prescribing in patients currently receiving clozapine: a case note review. J Clin Psychiatry 2003;64:30-34.
- Weissman EM. Antipsychotic prescribing practices in the Veterans Healthcare Administration--New York metropolitan region. Schizophr Bull. 2002;28(1):31-42. PubMed PMID: 12047020.
- Mallinger JB, Fisher SG, Brown T, Lamberti JS. Racial disparities in the use of second-generation antipsychotics for the treatment of schizophrenia. Psychiatr Serv. 2006;57(1):133-6. DOI: 10.1176/appi.ps.57.1.133. PubMed PMID: 16399976.
- Copeland LA, Zeber JE, Valenstein M, Blow FC. Racial disparity in the use of atypical antipsychotic medications among veterans. Am J Psychiatry. 2003;160(10):1817-22. PubMed PMID: 14514496.
- Kelly DL, Dixon LB, Kreyenbuhl JA, Medoff D, Lehman AF, Love RC, et al. Clozapine utilization and outcomes by race in a public mental health system: 1994-2000. J Clin Psychiatry. 2006;67(9):1404-11. PubMed PMID: 17017827.
- Kelly DL, Kreyenbuhl J, Dixon L, Love RC, Medoff D, Conley RR. Clozapine underutilization and discontinuation in African Americans due to leucopenia. Schizophr Bull. 2007;33(5):1221-4. DOI: 10.1093/schbul/sbl068. PubMed PMID: 17170061.
- Pai NB, Vella SC. Reason for clozapine cessation. Acta Psychiatr Scand. 2012;125(1):39-44. DOI: 10.1111/j.1600-0447.2011.01776.x. PubMed PMID: 22017729.
- Derogatis LR, Rosen R, Leiblum S, Burnett A, Heiman J. The Female Sexual Distress Scale (FSDS): initial validation of a standardized scale for assessment of sexually related personal distress in women. J Sex Marital Ther. 2002;28(4):317-30. PubMed PMID: 12082670.
- Haddy TB, Rana SR, Castro O. Benign ethnic neutropenia: what is a normal absolute neutrophil count?. J Laboratory Clin Medicine. 1999;133(1):15-22. DOI: 10.1053/lc.1999.v133.a94931. PubMed PMID: 10385477.
- Shoenfeld Y, Alkan ML, Asaly A, Carmeli Y, Katz M. Benign familial leukopenia and neutropenia in different ethnic groups. Eur J Haematol. 1988;41(3):273-7. PubMed PMID: 3181399.
- Denic S, Showqi S, Klein C, Takala M, Nagelkerke N, Agarwal MM. Prevalence, phenotype and inheritance of benign neutropenia in Arabs. Bmc Blood Disord. 2009;9:3. DOI: 10.1186/1471-2326-9-3. PubMed PMID: 19323844.
- Hsieh MM, Everhart JE, Byrd-Holt DD, Tisdale JF, Rodgers GP. Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences. Ann Intern Med. 2007;146(7):486-92. PubMed PMID: 17404350.
- Paz Z, Nails M, Ziv E. The genetics of benign neutropenia. Isr Med Assoc J. 2011;13(10):625-9. PubMed PMID: 22097233.
- Crosslin DR, McDavid A, Weston N, Nelson SC, Zheng X, Hart E, et al. Genetic variants associated with the white blood cell count in 13,923 subjects in the eMERGE Network. Hum Genet. 2012;131(4):639-52. DOI: 10.1007/s00439-011-1103-9. PubMed PMID: 22037903.
- Nalls MA, Wilson JG, Patterson NJ, Tandon A, Zmuda JM, Huntsman S, et al. Admixture mapping of white cell count: genetic locus responsible for lower white blood cell count in the Health ABC and Jackson Heart studies. Am J Hum Genet. 2008;82(1):81-7. DOI: 10.1016/j.ajhg.2007.09.003. PubMed PMID: 18179887.
- Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467(7319):1061-73. DOI: 10.1038/nature09534. PubMed PMID: 20981092.
- Reich D, Nalls MA, Kao WHL, Akylbekova EL, Tandon A, Patterson N, et al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. Plos Genet. 2009;5(1):e1000360. DOI: 10.1371/journal.pgen.1000360. PubMed PMID: 19180233.
- Thobakgale CF, Ndung'u T. Neutrophil counts in persons of African origin. Curr Opin Hematol. 2014;21(1):50-7. DOI: 10.1097/MOH.0000000000000007. PubMed PMID: 24257098.
- Combs DR, Advokat C. Antipsychotic medication and smoking prevalence in acutely hospitalized patients with chronic schizophrenia. Schizophr Res. 2000;46(2-3):129-37. PubMed PMID: 11120425.
- George TP, Sernyak MJ, Ziedonis DM, Woods SW. Effects of clozapine on smoking in chronic schizophrenic outpatients. J Clin Psychiatry. 1995;56(8):344-6. PubMed PMID: 7635849.
- McEvoy J, Freudenreich O, McGee M, VanderZwaag C, Levin E, Rose J. Clozapine decreases smoking in patients with chronic schizophrenia. Biol Psychiatry. 1995;37(8):550-2. DOI: 10.1016/0006-3223(94)00365-A. PubMed PMID: 7619979.
- Hsieh MM, Tisdale JF, Rodgers GP, Young NS, Trimble EL, Little RF. Neutrophil count in African Americans: lowering the target cutoff to initiate or resume chemotherapy?. J Clin Oncol. 2010;28(10):1633-7. DOI: 10.1200/JCO.2009.24.3881. PubMed PMID: 20194862.