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The risk for moderate neutropenia associated with clozapine therapy is low in patients with treatment-resistant schizophrenia, and the risk for severe neutropenia is minimal, new research showed.

None of the nearly 1000 patients in the study developed severe neutropenia. Rates of moderate and mild neutropenia were also low, at less than 1% and less than 6%, respectively.

Investigators noted the findings suggest that current hematologic monitoring requirements should be reconsidered.

"Clozapine is the best treatment for treatment-resistant schizophrenia but is hugely underutilized in the United States, and one of the barriers is the requirements around hematologic monitoring for patients who are receiving the drug," investigator Allison Brandt, MD, MPhil, with the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, told Medscape Medical News. "These findings suggest a need for careful reconsideration of current clozapine hematologic monitoring requirements."

The findings were presented on May 6 at the American Psychiatric Association (APA) 2024 Annual Meeting.

Reassuring Data

The researchers evaluated rates of neutropenia in 974 patients (64% male; 51% White, 39% Black) treated with clozapine at their center.

Participants were divided into groups on the basis of no neutropenia, mild neutropenia (absolute neutrophil count [ANC], 1000-1499 cells/µL), moderate neutropenia (ANC, 500-999 cells/µL), and severe neutropenia (ANC < 500) during clozapine use.

No patient developed clinically significant neutropenia while taking clozapine, and rates of mild and moderate neutropenia were low (5.9% and 0.92%, respectively).

Patients who developed nonclinically significant neutropenia did so within 8 months of starting the antipsychotic.

There was no significant difference in age, gender, or ethnicity among neutropenia groups. However, Black patients were more likely than patients of other races to develop moderate neutropenia (P < .001).

Several factors are behind low clozapine prescribing rates, including "clinicians lack of familiarity with its use, legitimate concerns about side effects and the rather onerous FDA requirements that mandate that patients receive frequent blood draws, and that physicians, patients, and pharmacies are appropriately registered," study investigator Russell Margolis, MD, clinical director, Johns Hopkins Schizophrenia Center, Baltimore, told Medscape Medical News.

"It's both a burden and a fear that unfortunately overlooks the very strong evidence of how valuable it is for patients' long-term outcome," said Margolis.

But is it time to ease federal restrictions on clozapine?

"Yes," Margolis said. "The data are quite convincing from many different sources that the restrictions are too stringent, and, in fact, my understanding is that the FDA is going to be reviewing their policy."

Stop Mandatory Blood Testing

Commenting on the findings for Medscape Medical News, Robert S. Laitman, MD, with Bronx Westchester Medical Group in New York, noted that severe neutropenia (ANC < 500) is quite rare.

"The FDA can fix the irrational REMS [Risk Evaluation and Mitigation Strategies] requirement for clozapine with a strike of a pen," said Laitman, who wasn't involved in the study.

"Clozapine is the most effective and safest antipsychotic," he said. "It is the only rational choice once two antipsychotics have failed or in someone with psychosis and persistent suicidal symptoms."

Yet, in the United States, less than 2% of these patients received clozapine, Laitman noted.

In his experience, the number-one reason psychiatrists give for not prescribing this evidence-based treatment is the REMS system, and the fear that patients will not do the required bloodwork and therefore be faced with the "no blood, no drug" scenario, he said.

"Because of clozapine REMS, unfortunately, we have seen dozens of tragedies when patients cannot access their clozapine," Laitman said.

"What needs to happen is stopping mandatory blood tests and changing REMS to an educational site teaching EASE," which involves early use of clozapine, assertive management of side effects and wraparound services and monitoring, slow titration and realizing that response may be slow, and full engagement of the patient and the family, he said.

The study was supported by the Abramson Fund, Johns Hopkins inHealth, and the ABCD Charitable Trust. Brandt and Margolis had no relevant disclosures. Laitman is on the Board of Directors for the Schizophrenia and Related Disorders Alliance of America and is co-author of the book, Clozapine: Meaningful Recovery from Schizophrenia.