Greater Monitoring of Clozapine for Serious AEs Needed

Agranulocytosis Not the Only Serious Side Effect

Deborah Brauser

November 30, 2012

Guideline modifications are needed for monitoring for treatment-related adverse effects during the initial phase of clozapine therapy for schizophrenia, new research suggests.

Although current guidelines call for weekly screening of white blood count during the first phase, and monthly screenings thereafter, to monitor for agranulocytosis, a review of 16 studies examining use of clozapine calculated overall incidence rates of only 4% to 8%, mortality rates of 0.1% to 0.3%, and case-fatality rates of 2% to 4% for this adverse event.

In contrast, the incidence rates for diabetic ketoacidosis in this patient population were just 1% to 3%, but the case-fatality rates were 20% to 31%. And for gastrointestinal hypomotility, rates were 4% to 8% and 15% to 27.5%, respectively.

Dr. Dan Cohen

"The obligation of lifelong, mandatory monitoring was issued a long time ago. Since then, new studies have been published that support some but not all of the obligations," lead author Dan Cohen, MD, PhD, from the Department of Severe Mental Illness at Mental Health Care Organization North-Holland, in Heerhugowaard, the Netherlands, told Medscape Medical News.

"In short, this is an update in light of data published in the past 10 to 15 years," he said.

Recommended guideline modifications, which Dr. Cohen said are applicable worldwide, include baseline and periodic monitoring for constipation and diabetes, and less frequent assessments of white blood cell control after the first year of treatment.

He noted that the study has 2 important takeaway messages. First, clinicians should "look beyond" just monitoring for agranulocytosis.

"And second, be sure to keep your knowledge on clozapine up to date. Although it is an old drug, it remains a complex drug. In the hand of an experienced physician who doesn't only focus on the danger of agranulocytosis, it is a safe drug with great potential benefits to the patient."

The study is published in the Journal of Clinical Psychiatry.

Modify Current Recommendations

Although clozapine is commonly used for treatment-resistant schizophrenia, clinicians have known since 1975 that it is also associated with agranulocytosis, especially during the first months of treatment, so white blood cell screening is mandatory.

"In the past 20 years, after its reintroduction, 3 other serious side effects, namely diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis, have been documented but have so far failed to be incorporated in the screening guidelines," write the investigators.

Therefore, they sought to determine whether updating current screening guidelines would be evidence-based.

They examined 16 English-language studies and compared 1-year incidence rates and mortality rates for clozapine-associated agranulocytosis, diabetic ketoacidosis, gastrohypomotility, and myocarditis.

The following table shows the results.

Adverse Event Incidence Rates* Case-Fatality Rates*
Agranulocytosis 3.8% - 8.0% 2.2% - 4.2%
Diabetic ketoacidosis 1.2% - 3.1% 20% - 31%
Gastrohypomotility 4.0% - 8.0% 15% - 27.5%

*All rates represent ranges.

For myocarditis, the incidence rates differed widely in Australia (7% - 34%) compared with the rest of the world (0.07% - 0.6%).

Dr. Cohen called this finding "unexpected," and noted that he cannot provide an explanation. For now, he recommends routine monitoring for new-onset myocarditis in Australia and New Zealand only.

"In 2 of the 3 studied side effects, diabetic ketoacidosis and gastrointestinal hypomotility, reduction of mortality to the level of agranulocytosis is both necessary and feasible. In order to obtain this outcome, the screening guidelines need to be modified," write the investigators.

They add that because treatment-emergent hyperglycemia can develop into diabetic ketoacidosis, "obligatory monthly measurement of fasting plasma glucose" is needed.

"To prevent gastrohypomotility, and complications therefrom, the clinician should be required to choose between either weekly monitoring or standard coprescription of laxatives for prevention," they write.

Dr. Cohen added that the results also support a call for less frequent monitoring of white blood cell count after 1 year.

"In practice, this would mean measurement every quarter (instead of every month). It could be argued to abolish white blood cell control after the first year altogether, but we expect that this measure will psychologically, not scientifically, be considered as too drastic."

Vigilant Follow-up

"Clozapine has clearly been shown to be the most effective pharmacologic treatment currently available for positive symptoms in psychotic patients," writes M. Bak, MD, PhD, from the Department of Psychiatry and Psychology at Maastricht University in the Netherlands, in an accompanying editorial.

However, because of the medication's adverse side effects profile, clinicians are often reluctant to prescribe it, he adds. Therefore, a good monitoring system is essential.

Dr. Bak, who was not involved with this research, recommends that screening for myocarditis, especially within the first weeks of starting treatment, "seems to be a good strategy."

Although monitoring for metabolic side effects is required when treating with all types of antipsychotics, monitoring alone for diabetic ketoacidosis "is insufficient" because the disorder can develop quickly.

For gastrointestinal hypomotility, Dr. Bak writes that monitoring "might help bring the problem to the attention of the clinician and patient and identify whether an intervention is necessary."

"But is a monitoring system really necessary?" he asks. "Should a good patient-doctor contact not be more appropriate?"

Overall, Dr. Bak said that for patients who use clozapine, clinicians should focus on hard-to-detect adverse effects, follow up on questionable signs or test results, and provide specific intervention or prevention strategies.

Effective Medication

Dr. Jacob Ballon

"I think what these authors have done is very helpful," Jacob S. Ballon, MD, assistant professor of clinical psychiatry at Columbia University in New York City and from the New York State Psychiatric Institute, told Medscape Medical News.

"I'm not quite sure that I'm ready, based on this data, to want to add mandatory screening measures. But I do think it is very important that they have highlighted the risks, especially of gastrointestinal hypomotility."

Dr. Ballon, who was not involved with this research, noted that general constipation is common with this treatment, yet it is something many people do not really complain about.

"But the much more severe hypomotility can potentially be fatal. My concern in making it a mandatory screening requirement is that adding that might make providers more reticent to prescribe clozapine. And we already have a lot of barriers in the way of prescribing it," he said.

"This is such an effective medication. And all of this is something that should be in people's minds. They should be thinking about the possibility of these side effects but not feeling especially hindered in their prescription patterns," said Dr. Ballon.

He added that when adding a screening regimen, clinicians need to be aware of the possibility of false-positive test results and increased costs. He also noted that Dr. Cohen's recommendation to decrease screenings for agranulocytosis after a year of treatment from monthly to quarterly makes sense.

"Without doing a financial analysis, I can't say that would decrease costs enough to pay for adding constipation screenings. But I do think the risk drops off substantially after a year," said Dr. Ballon.

"The upside to close screening for agranulocytosis is it really does force patients and doctors to pay attention to a medication that has potentially threatening side effects. Still, going to quarterly screenings is a reasonable thing to consider."

Dr. Cohen reports having served on speakers or advisory boards of AstraZeneca and Bristol-Myers Squibb. He and one other study author also report having received honoraria from AstraZeneca, Bristol-Myers Squibb, and Eli Lilly. The other 3 authors and Dr. Ballon have disclosed no relevant financial relationships. Dr. Bak reports having been a speaker for Janssen and AstraZeneca.

J Clin Psychiatry. 2012;73:1307-1312;1313-1314. Abstract, Editorial