Patients who receive a prescription for the antipsychotic medication clozapine must have their blood monitored for signs the drug is impairing their immune system’s ability to fight infection. A recent study by Johns Hopkins researchers suggests the true risk for this side effect is much lower than previously thought and calls this onerous monitoring system into question.

Published in Schizophrenia Research, the study tracked 974 Johns Hopkins Medicine patients who were prescribed clozapine to treat schizophrenia between 2013 and 2023. None developed severe neutropenia, in which immune cells known as neutrophils become so scarce that they can no longer defend the body against bacterial and fungal pathogens. 

“Those of us who prescribe clozapine know it can be life-changing for the patients who respond to it,” says the study’s first author, Allison Brandt, a Johns Hopkins psychiatrist. She adds that the most common side effects of the medication don’t include neutropenia and that severely low neutrophil levels — which lead to life-threatening infections — are exceedingly rare.

“Clozapine is not as dangerous as it's made out to be,” she says. 

Clinicians may prescribe clozapine after first-line antipsychotic medications have proven ineffective at treating delusional thoughts and other symptoms of schizophrenia. However, many patients who qualify do not receive the drug, at least in part because of concerns over clozapine-related severe neutropenia. The first such cases, including eight deaths, were first reported in 1975. 

The FDA monitoring program, the Clozapine Risk Evaluation and Mitigation Strategy (REMS) program, requires patients to obtain neutrophil tests as frequently as once a week to receive their prescriptions. While well-intentioned, this system can put patients at risk of missing medication due to delays in getting blood tests and other issues, according to Brandt.

To see if the risk of severe neutropenia warranted this restrictive monitoring, Brandt and her colleagues analyzed electronic medical records stripped of any identifying information. While none of the 974 patients whose data they studied developed severe neutropenia, the researchers documented 59 cases of mild or moderate neutropenia. Unlike the severe version, moderate neutropenia does not increase risk of infection, Brandt says.

This research may help make it easier for patients to receive their prescriptions. At a meeting in November, the FDA’s Drug Safety and Risk Management and Psychopharmacologic Drug advisory committees heard testimony that cited this study. The committees voted overwhelmingly to dissolve the monitoring system.

The FDA has yet to respond to its committees’ recommendations. Should it choose to end REMS, “it becomes a chance for patients to access their care based solely on conversations they have with their physicians,” Brandt says.