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PsychopharmacologyFull Access

Why Won’t Clinicians Use Clozapine Despite Proven Superiority?

Published Online:

Abstract

Blood monitoring requirements and concerns over agranulocytosis may be what’s to blame for the underuse of a medication that has been shown to be effective for treating patients with treatment-resistant schizophrenia.

Clozapine, approved by the Food and Drug Administration (FDA) in 1989, has been repeatedly shown to be superior to other medications for treatment-resistant schizophrenia. In 2002, it became the first and only drug approved for suicidality; however, the clinical reality that has persisted since its approval is that clozapine is underutilized in the United States. In certain subgroups—especially African Americans—it is severely under-used.

Photo: Kelly headshot

Deanna Kelly, Pharm.D. believes that more efforts must be put in place to increase the use of clozapine in psychiatric practices throughout the United States.

Deanna Kelly

“All the data suggest this is a superior medication, particularly for treatment-resistant schizophrenia,” said Deanna Kelly, Pharm.D., of the Maryland Psychiatric Research Center (MPRC), in an interview with Psychiatric News. “For people who have suicidal ideation, it is very effective in calming their suicidal thoughts. Clozapine is also effective for aggressive and violent patients and for patients who experience tardive dyskinesia related to other medications.”

“Clozapine remains the only antipsychotic that has been FDA-approved for treatment-resistant schizophrenia,” she added, “and it provides effective treatment even when patients do not respond to other second-generation antipsychotics. No existing first- or second-generation antipsychotic is as effective as clozapine monotherapy in treatment-resistant patients.”

“There really is no doubt that it is a superior medication,” said Kelly.

Effect Size Greater Than Comparison Drugs

The evidence for the effectiveness of clozapine is not new. As early as 2003, a meta-analysis by John Davis, M.D., a professor of psychiatry at the University of Illinois, Chicago, College of Medicine, and colleagues comparing clozapine with five other antipsychotics (amisulpiride, risperidone, olanzapine, zotepine, and aripiprazole) found that the effect size for clozapine was substantially stronger than the closest competitor (amisulpiride) and twice that, or greater, of the other four drugs.

In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study (phase 2), those treated with clozapine (open label) averaged significantly greater time to treatment discontinuation (10.5 months) compared with patients treated with other antipsychotic medications (2.7-3.3 months). In the randomized Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS) trial, clozapine treatment was associated with significantly greater improvement in Positive and Negative Symptom Scale (PANSS) total scores and higher patient subjective ratings compared with risperidone, olanzapine, quetiapine, and amisulpiride.

But according to Kelly, only about 5 percent of patients received clozapine last year in the United States. “It is underutilized in other countries, but in the U.S. it is far more underutilized than in Europe and Asia. In Australia, China, and Japan, it is used in upward of 30 percent of patients.”

This problem occurs despite the fact that the drug is available in a generic form—so price is not the problem. Moreover, a 2013 report in Psychiatric Services by Jessica Goren, Pharm.D., an assistant professor at the University of Rhode Island College of Pharmacy and colleagues, found that polypharmacy was used more consistently than clozapine.

Blood Monitoring Requirements Called Biggest Obstacle

What is holding clinicians back?

Undoubtedly the most significant barrier to use of clozapine is the stringent restrictions around blood monitoring. Clozapine was first introduced in the 1970s in Europe, but was withdrawn after the drug was shown to be associated with agranulocytosis—an acute condition involving severe leukopenia. When the FDA approved clozapine, it mandated stringent blood monitoring requiring regular white blood cell and absolute neutrophil counts (ANC).

“For clinicians and systems of care, the logistics of blood monitoring are clearly a disincentive,” Kelly explained. There are currently five companies offering generic clozapine, and each has a separate system requiring clinician (or health system) and pharmacy registration. Clinicians must draw patients’ blood on a weekly basis, and the white blood cell count and ANC must be reviewed by the pharmacy, as well as the clinician, before the drug can be continued.

At a presentation at the meeting of the American College of Neuropyschopharmacology in 2013, Kelly presented survey data indicating the top reasons why prescribers may not prescribe clozapine to patients who might have benefited. The leading reasons were the need for monitoring and regular blood work; the lack of a centralized system for registering patients was also cited, as was the amount of administrative time associated with registry and blood work.

Clinicians also indicated concerns about side effects such as agranulocytosis, myocarditis, and weight gain. Kelly says that she believes many clinicians overestimate the risk of agranulocytosis. “A lot of physicians are more leery than they should be and think it occurs more frequently than it does,” Kelly said. “It’s actually quite rare, occurring in less than one percent of patients (approximately 0.86%).”

Agranulocytosis is defined as an ANC of less than 500/mm. Before a patient can start taking clozapine, ANC must be greater than or equal to 2,000/mm and the white blood cell count must be greater than or equal to 3,500/mm; the drug must be discontinued when the ANC is less than 1,000/mm3 or the white blood cell count is less than 2,000/mm.

There is a further wrinkle, complicating access to the drug for a segment of the population: Africans and African-Americans typically have a lower WBC, a phenomenon that has been termed “benign ethnic neutropenia” (BEN).

“Our norms have been developed for people of European descent,” Kelly explained. “So this is problematic and leads to an underprescribing in African-American populations and to early termination of the drug when it is prescribed.”

Kelly says European countries have used a modified blood count for patients of African descent, enabling them to successfully treat patients using clozapine with no increased risk of agranulocytosis.

Kelly currently has an NIMH grant to study the use of clozapine in 250 African and African-American patients whose blood counts do not meet the cutoff under current guidelines. The success of the study could lend support to a push for modified standards for this subgroup.

Culture Change Occurring

Kelly described changes on a number of fronts that she thinks may begin to lift the barriers to prescribing clozapine.

Researchers are closing in on a possible genetic marker for agranulocytosis, a development in “personalized medicine” that could help clinicians identify those patients most at risk—and reassure clinicians about prescribing to others. Residency programs are also increasingly adopting the medication and training their residents in how to use it, so that a new cadre of young psychiatrists will enter the field aware of the effectiveness of clozapine.

In an effort to reduce the administrative burden associated with clozapine registration and monitoring, several researchers have petitioned the FDA to develop a centralized registry system. Kelly also said that MPRC is working with the University of Maryland engineering department to develop a “point of care” finger-prick mechanism that would allow for nearly instantaneous, in-office blood monitoring.

Finally, policymakers and health care systems operating in today’s environment are ever more interested in delivering value—high quality and lower costs—so clozapine for treatment-resistant patients and other potentially costly patients will necessarily be more attractive.

“Clozapine can save thousands of dollars for health care systems, so there is a benefit for the patient and for the health care system generally,” Kelly said. “In all of these ways, things are happening that can slowly change the culture so that this medication can be more available.” ■

“A Meta-Analysis of the Efficacy of Second-Generation Antipsychotics” can be accessed here. “Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia” is available here.

“Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia” can be accessed here.

“Antipsychotic prescribing pathways, polypharmacy, and clozapine use in treatment of schizophrenia” is available here.

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