Race-Based Medicine, Clozapine, and Benign (Ethnic) Neutropenia: A Call for Nuance

TO THE EDITOR: Race-based medicine—the use of race as a proxy for shared biology in medical diagnosis and treatment—has come under increased scrutiny as physicians confront the pervasive and insidious role that structural racism plays in the U.S. health care system (1). Recognizing that racial categories are imprecise social constructs with limited correlation to genetic ancestry, many institutions are now critically reexamining the use of treatment algorithms and laboratory values that account for a patient’s race (1). Given this context, it is time for psychiatry to reflect on the historical origin and current application of these practices in our own field. The influence of benign ethnic neutropenia (BEN) on clozapine prescribing serves as a particularly illustrative case study on institutional bias and the nuanced complexities advocates face in attempting to eliminate health disparities.

Clozapine is an essential, potentially life-saving antipsychotic with a rare but serious side effect of agranulocytosis. This necessitates regular monitoring of the absolute neutrophil count (ANC) to reduce mortality. The ANC lower limit of normal (1,500 neutrophils/µL) was derived in the early 1900s with research that enrolled primarily White populations with European ancestries (2). Later studies using more diverse populations identified many individuals with lower counts who had no increased predisposition toward infection (3). This finding was labeled “benign ethnic neutropenia” because its prevalence shows considerable variation in populations around the world.

Early clozapine prescribing guidelines did not take BEN into account, thereby systematically creating disparities in the initiation and discontinuation of clozapine for patients from racial-ethnic minority groups (4). Advocates subsequently lobbied the U.S. Food and Drug Administration (FDA) to alter the clozapine monitoring program to include an exception for patients of color in the hope that prescribing would become more equitable. When the FDA created the consolidated Risk Evaluation and Mitigation Strategy database in 2015, it established distinct guidelines for BEN, allowing individuals with this condition to continue treatment despite lower ANCs. Emerging evidence now suggests that BEN is associated with a null polymorphism in the Duffy antigen receptor for chemokines (DARC) gene, which likely provides some protection against malaria, resulting in the uneven geographic distribution of this mutation (2). This line of research may eventually allow more accurate personalized medicine approaches based on an individual’s genetic profile.

This historical context of BEN shows that some attempts to eliminate race-based laboratory adjustments could perpetuate the very disparities that we are attempting to address. Although BEN falls under the race-based medicine umbrella, it is also a thoughtful, well-researched, and justice-oriented approach. Nonetheless, the use of the word “ethnic” is problematic because it reinforces a Eurocentric worldview. Although the BEN variant is more common among individuals of African and Middle Eastern ancestry, it can be diagnosed in any patient. We therefore propose renaming this label (for instance, simply “benign familial neutropenia” or “constitutional neutropenia,” as it is sometimes called). Such an approach may be a preferable compromise between alternative proposals, such as race-specific normal values (a race-based medicine approach that could lend undue biological credence to social categories) (5) or expansion of the “normal” ANC range (a “color-blind” approach that could overlook meaningful genetic diversity in the population) (3).