More Minority Patients May Be Able to Safely Use Clozapine

More African Americans and people of Middle-Eastern descent with schizophrenia who are not prescribed the antipsychotic clozapine because of low white blood cell counts could potentially use the drug safely, said Deanna Kelly, Pharm.D., and Gopal Vyas, D.O., last month at APA’s IPS: The Mental Health Services Conference.

That’s because they may have a naturally occurring condition known as benign ethnic neutropenia (BEN), in which they have absolute neutrophil counts that fall below the standards established for clozapine use, but which do not put them at greater risk for agranulocytosis (a condition of extremely low white blood cell counts that can be life threatening). BEN may be linked to a genetic anomaly peculiar to people of Middle Eastern and African descent.

Kelly is the director of the Treatment Research Program (TRP) at the Maryland Psychiatric Research Center, and Vyas is a psychiatrist with TRP at Spring Grove Hospital Center, in Catonsville, M.D.

Clozapine has been shown repeatedly to be the best medication for treatment-resistant schizophrenia but is associated with neutropenia (lowered white blood cell counts) in some patients. Since 1989, when clozapine was introduced in the United States, the Food and Drug Administration (FDA) has required that patients prescribed the medication be regularly monitored for agranulocytosis.

Kelly and Vyas explained that African Americans with schizophrenia are much less likely to receive clozapine and more likely to have the medication discontinued because of neutropenia.

In a 2006 report in the Journal of Clinical Psychiatry, Kelly and colleagues reported that of 2,911 inpatients in the state of Maryland, 10.3 percent of African Americans versus 15.3 percent of Caucasians were prescribed clozapine. African Americans were also significantly more likely to be discontinued from the medication (42 percent versus 23 percent after two years) and significantly more likely to be discontinued specifically because of neutropenia (5.3 percent versus 2.4 percent).

But Kelly and Vyas said that in patients with BEN, lower neutrophil counts do not necessarily put them at a greater risk for agranulocytosis. BEN is believed to occur in about 25 percent to 50 percent of people of African ancestry and up to 38 percent of people of Middle-Eastern descent.

Kelly and Vyas said that the standards for determining when a patient has neutropenia have largely been drawn from European Caucasian populations. For instance, up until 2015, the FDA required clozapine to be discontinued when neutrophil counts fell below 1,500/uL. Many African-American patients with BEN are likely to have neutrophil counts between 1,000/uL and 1,500/uL or lower.

“Fear of neutropenia is one of the most frequently cited reasons for discontinuing clozapine treatment in people of African descent,” Kelly told attendees at the IPS. “BEN may explain these sporadic fluctuations and discontinuations in this racial group. The condition identifies a group with low absolute neutrophil counts that does not have an increased risk of severe neutropenia or infection.”

Vyas explained that much of the hematologic concern about the drug stemmed from a single epidemic in Finland in 1975 when 16 patients developed agranulocytosis shortly after exposure to the drug, eight of whom later died.

Yet he noted that subsequent research found that the incidence of clozapine-related agranulocytosis in Finland was 20 times that of any other country. All of these cases were localized to a specific region of Finland despite the drug being used evenly throughout the country. Furthermore, most of the patients were taking additional medications that are known to increase the risk of neutropenia, he said.

In 2016, Kelly and Vyas and colleagues published pilot data in the Journal of Clinical Psychiatry demonstrating the safety of using clozapine in 26 patients with BEN. New guidelines have been issued for patients believed to have BEN, which are intended to make it easier to prescribe and continue clozapine use for these patients.

Kelly is conducting an ongoing study funded by the National Institute of Mental Health to look at the safety and genetics associated with clozapine in people with BEN.

“Clozapine is underutilized due to many reasons, and its use in African-descent patients is very low,” Kelly said. “The underuse most likely is attributed to BEN, but clozapine use in BEN does not increase the risk for agranulocytosis or infection related to using clozapine.” ■