Use of Atypicals for Dementia Takes Sharp Downturn After FDA Warning

Deborah Brauser

February 10, 2011

February 10, 2011 — Although overall use of atypical antipsychotics to treat behavioral symptoms in patients with dementia was declining by 2003, there was a sharp downturn after a 2005 Food and Drug Administration (FDA) black box warning about a link between these agents and increased mortality risk in this population.

When focusing on specific antipsychotics, investigators found that use of olanzapine and risperidone were on the decline. However, quetiapine use increased during the period right until the warning was issued and then declined.

"We found that the black box warning had a significant effect in lowering the rate of use. But what was surprising was that the decline started to happen well before the warning," lead author Helen C. Kales, MD, associate professor of psychiatry at the University of Michigan in Ann Arbor and research scientist at the Veterans Affairs Center for Clinical Management Research, told Medscape Medical News.

Dr. Helen C. Kales

"At the beginning of the study in 1999, about 18% of the patients with dementia were prescribed these agents and by the end of the study it was 12%. I think the take-away is that physicians did a good job in responding to concerns about side effects of these agents. However, there are still a small, but significant, proportion of patients using them," said Dr. Kales.

She added that this finding may reflect the fact that these agents are extremely common and that behavioral symptoms associated with dementia can pose major difficulties for patients and their families. Furthermore, she noted, there are currently no good alternative agents.

The study is published in the February issue of the Archives of General Psychiatry.

National Impact?

According to the study, federal oversight regulations were established in 1987 because of the overuse of conventional antipsychotics for treating neuropsychiatric symptoms in patients in nursing homes. This led to increased use of atypical antipsychotics, particularly because they had lower rates of parkinsonism and tardive dyskinesia.

"In 2001, more than 70% of US atypical antipsychotic prescriptions were written for off-label indications such as dementia, and atypical antipsychotics accounted for 82% of antipsychotic prescriptions written for older patients in Canada in 2002," the investigators write.

In 2002, however, growing safety concerns, including reported increases in diabetes and stroke risk, began to emerge. These concerns eventually culminated in an FDA black box warning in 2005.

Although this is the strictest warning the FDA issues, it was not clear whether it had an effect on reducing the use of these medications in this patient population.

"As a practicing geriatric psychiatrist, I know that the black box warning was a significant event for those of us in the field because it's the strongest warning the FDA can give about drugs other than pulling them off the market. It had an impact on my practice and we started wondering if the warning had an impact nationally," Dr. Kales added.

I know that the black box warning was a significant event for those of us in the field because it's the strongest warning the FDA can give about drugs other than pulling them off the market.

The investigators evaluated data from national Veterans Affairs registries on 254,564 patients (97% male) over age 65 years who were diagnosed with dementia.

Time-series analyses estimated the effect of the various warnings on atypical and conventional antipsychotic usage across 3 periods: no warning (1999-2003), early warning (2003-2005), and black box warning (2005-2007), the researchers report.

Risk/Benefit Approach Warranted

Results showed that 17.7% of the patients were using atypical or conventional antipsychotics at the beginning of the study.

This overall use rate began to decline during the no-warning period (rate per quarter, -0.12%; P < .001), continued to decline after the FDA's warning (rate, -0.26%; P < .001), and significantly decreased between the early and black box warning periods (P = .006).

On the other hand, use of only atypical antipsychotics increased during the no-warning period (rate, 0.23; P < .001) before starting to decline during the early-warning period (rate, -0.012; P = .85) and then decreasing sharply during the black box warning period (rate, -0.27; P < .001).

"While the rates of use of nonantipsychotic psychotropics as a group increased significantly after the black box warning (from 20% to 25%), there appeared to be no major compensatory increases in any individual nonantipsychotic psychotropic drug classes," the researchers add.

However, a "small but significant" increase was found during the warning period in anticonvulsant prescriptions (rate, 0.117; P < .001).

Dr. Kales said that because an efficacious substitute for atypical antipsychotics has not yet been found, clinicians should use a risk/benefit approach when talking with patients and their families.

"We should really target these agents for where we think they'd be most effective. If someone is really aggressive or even psychotic, that might be better than for somebody who is wandering. There, an antipsychotic isn't really going to help except to sedate them."

Dr. Kales noted that an earlier paper published by her team "confirmed the mortality risks" for both conventional and atypical antipsychotics.

"We are now looking at individual agents to see whether there's more risk in some versus others. Right now we just know that it is a class effect but we don't really know if there's any differential risk amongst the agents."

"We'd also like to know if there are certain profiles that make patients more or less susceptible to these side effects. We don't know what the mechanism of mortality for this is. Is it sedation and development of infection? Or is it a cardiac side effect? I think pinpointing that risk will be helpful," said Dr. Kales.

Prescribing Rates Still "Substantial"

"There has been a lot of work done related to the use of antipsychotic therapy for the management of behavioral problems in the setting of dementia; and it's always interesting to see another study come out in this area," Paula A. Rochon, MD, senior scientist at the Women's College Research Institute, Women's College Hospital at the University of Toronto, Ontario, Canada, told Medscape Medical News.

Dr. Paula A. Rochon

"I think the message that comes through in this study, as well as studies done in other countries, including Canada, is that while the warnings had some effect in decreasing the rates of prescribing these medications, the prescribing rate still remains fairly substantial," said Dr. Rochon.

"When you tell somebody not to prescribe something, they want to know what they should do instead. And we currently don't have a single drug therapy that is beneficial and has no side effects."

When you tell somebody not to prescribe something, they want to know what they should do instead. And we currently don't have a single drug therapy that is beneficial and has no side effects.

Instead, Dr. Rochon said that "the solution is much bigger and complex," including thinking about such issues as how to provide a less stressful environment for these patients.

"How can we use staffing and families and caregivers to help manage these people in an approach that doesn't involve drug therapy? In addition to having warnings come out, it's important to think about what people should be doing and providing different types of guidance," she concluded.

The study was supported by a grant from the National Institute of Mental Health and by the Serious Mental Illness Treatment, Research, and Evaluation Center. The study authors report several financial relationships, which are listed in the original article. Dr. Rochon has disclosed no relevant financial relationships.

Arch Gen Psychiatry. 2011;68:190-197. Abstract


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