Clozapine is the most effective antipsychotic for the treatment of schizophrenia however it is underused particularly in the African American population. Low Absolute Neutrophil Counts (ANC), either baseline or during treatment (a drop in ANC below the threshold of 1500 mm3 currently mandates clozapine discontinuation) is a significant barrier to clozapine use in AA patients. Our pilot work finds that discontinuation of clozapine (particularly for neutropenia) in AA patients is over twice that in Caucasians. Recently the phenomenon of Benign Ethnic Neutropenia (BEN) in AAs has gained attention. BEN is frequent in AA with low ANCs, but is NOT associated with an increased risk for agranulocytosis or infection. Normative ranges for white blood cell (WBC) and ANC counts were established with Caucasian samples and clozapine guidelines in the US do not permit lower fluctuations of ANC. Unfortunately, lower fluctuations are often seen in persons with BEN, requiring clozapine discontinuation. Our pilot work has shown that AA BEN patients may be successfully treated with clozapine despite low ANC (outside current guidelines) with no greater risk of agranulocytosis. Our work to date, if supported by a larger study, suggests that clozapine could be safely used in people with BEN, improving access to clozapine treatment for AA patients with schizophrenia as well as evaluation for the first time the Duffy Antigen Receptor Chemokine (DARC) gene in relation to BEN and ANC levels.
We aim to safely use clozapine in 250 black patients (100-120 in US and 130-150 in a SubSaharan Nigerian population) to examine the safety of use and the risk of agranulocytosis. Our study will evaluate ANC twice weekly for 3 months prior and weekly 6 months after clozapine initiation. We also plan to evaluate the fluctuating patterns of WBC and ANC (mean levels, within subject s.d., frequency and duration of mild, moderate or severe neutropenia, and requirement for initiation of extra monitoring for very low ANC) in psychotic patients with BEN.

Public Health Relevance

Clozapine is underused and detrimentally often discontinued in the US, particularly in African Americans, in part due to Benign Ethnic Neutropenia (BEN) and fluctuating low Absolute Neutrophil Counts (ANC) in this population. We will test the safety of clozapine in BEN patients and will establish the fluctuating patterns of ANC (mean levels, within subject standard deviations, frequency and duration of mild, moderate or severe neutropenia, and requirement for initiation of extra monitoring for very low ANC) as well as study the impact of a potential biomarker, the Duffy Antigen Receptor Chemokine (DARC) null genotype (a genetic polymorphism in AA patients).

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Interventions Committee for Adult Disorders (ITVA)
Program Officer
Rudorfer, Matthew V
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
Schools of Medicine
United States
Zip Code
Patchan, Kathleen; Vyas, Gopal; Hackman, Ann L et al. (2018) Clozapine in Reducing Aggression and Violence in Forensic Populations. Psychiatr Q 89:157-168
Kelly, Deanna L; Freudenreich, Oliver; Sayer, MacKenzie A et al. (2018) Addressing Barriers to Clozapine Underutilization: A National Effort. Psychiatr Serv 69:224-227
Norman, Sarah M; Sullivan, Kelli M; Liu, Fang et al. (2017) Blood Pressure and Heart Rate Changes During Clozapine Treatment. Psychiatr Q 88:545-552
Richardson, Charles M; Davis, Erica A; Vyas, Gopal R et al. (2016) Evaluation of the Safety of Clozapine Use in Patients With Benign Neutropenia. J Clin Psychiatry 77:e1454-e1459
Patchan, Kathleen M; Richardson, Charles; Vyas, Gopal et al. (2015) The risk of suicide after clozapine discontinuation: Cause for concern. Ann Clin Psychiatry 27:253-6