Clozapine Risks Drop Sharply Within Months, May Warrant Less Monitoring

Rubio and colleagues found that antipsychotics as a class appear to be associated with an elevated risk of agranulocytosis during the initial six months of treatment.

However, the risk appears to abate after six months among those taking other antipsychotics. With clozapine, the risk of agranulocytosis drops sharply over time, but remains persistently greater (4-fold higher after 54 months or more of treatment) than with other antipsychotics.

Other results include the following:

Rubio and colleagues note that this relative risk should be put into perspective, “the low rates of absolute cumulative incidence, recurrence, and fatality of clozapine-induced agranulocytosis should be weighed against its clear superiority in symptom, function, and mortality-related outcomes.”

Rubio pointed out that while the FDA has generated a lot of patient safety data through its clozapine monitoring program over the past decade, most researchers cannot access it. “My call to the FDA is to make that data accessible to researchers so we can better examine the risks in the U.S. population,” he said.

The Finnish study comes on the heels of an epidemiologic study in November 2023 that reported similar results among individuals with schizophrenia in New Zealand and Australia: most serious neutropenia leading to clozapine cessation in occurred within the first 18 weeks of treatment. Furthermore, the risk was negligible after two years, according to that report from Korinne Northwood, MBBS, Ph.D., and colleagues, also in Lancet Psychiatry. They found only 1.2% had serious neutropenia leading to cessation (313 people among 26,300 taking clozapine). Furthermore, previous exposure to clozapine reduced the risk.

“Weekly hematological monitoring after the first 18 weeks could be safely reduced to once every four weeks and ceased after two years unless clinically indicated,” Northwood and colleagues concluded.

Prescribers have long called for more discretion on obtaining blood draws based on a patient’s circumstances, Frederick C. Nucifora Jr. Ph.D., D.O., M.H.S., program director of the Clozapine Clinic at Johns Hopkins Bayview Medical Center, told Psychiatric News. “As it stands now, patients who are unable to get regular blood draws are not permitted to take clozapine. Often it is the only medication that will help them.

“If a patient misses one blood draw, the patient cannot obtain a refill, and that interruption in clozapine often leads to worsening of symptoms and the possibility of hospitalization. There should be provisions for these situations,” added Nucifora, who is also an associate professor of Psychiatry and Behavioral Sciences at the Johns Hopkins School of Medicine.

The FDA’s REMS is just one of several obstacles to wider clozapine utilization. Nucifora said psychiatrists also need to become more comfortable prescribing clozapine and recognizing and managing its potential side effects, which can also include cardiac problems, paralytic ileus, and excess salivation. “Psychiatrists often overestimate the frequency of these side effects, especially severe neutropenia, and think that patients will not tolerate clozapine or be willing to get blood draws. However, there is evidence to suggest that patients do better and prefer to be on clozapine.”

Rubio said that aside from the REMS, other challenges include a lack of training in psychiatry resident programs on initiating and managing patients on clozapine. Other roadblocks include practices’ lack of ability to do onsite bloodwork and lack of access to a medical consultant.

Still, Rubio remains hopeful that the push to decrease regulations and remove administrative burdens will result in real change. “I see that there’s a growing interest in addressing the underutilization of clozapine. I think this is an area in which we can improve the lives of people living with treatment-resistant schizophrenia tremendously, if we to help patients obtain this drug whenever it is indicated.” ■