Inappropriate Use of Antipsychotics in the Elderly Continues Despite FDA Warnings

Caroline Cassels

January 15, 2010

January 15, 2010 — The off-label use of atypical antipsychotics to control behavioral symptoms in elderly patients with dementia appears to have decreased after a 2005 US Food and Drug Administration (FDA) advisory and subsequent black box warning regarding the risks — that include increased diabetes risk, cerebrovascular events, and sudden death — in this patient population.

Although on the surface the study is positive, researchers say it brings into question whether FDA warnings in fact improve public health because the findings also suggest such warnings may have a potentially negative "spillover" effect in populations that are not their intended target.

"We found that the FDA advisory was associated with a substantial reduction in the use of atypical antipsychotics among the elderly with dementia. However, the advisory was also associated with unintended reductions of antipsychotic use in other patient populations," study investigator Caleb Alexander, MD, MS, University of Rochester Medical Center, New York, told Medscape Psychiatry.

The study is published in the January 11 issue of Archives of Internal Medicine.

Little Evidence to Support Off-Label Use

Behavioral disturbances are common in dementia, affecting more than 50% of patients, and represent a major challenge for clinicians ad patients' families, who are faced with managing agitated and sometimes aggressive behavior.

In the absence of approved agents, many physicians have turned to off-label use of both conventional antipsychotics and atypical agents, also known as second-generation antipsychotics.

However, said Dr. Alexander, the evidence to support off-label use is poor. "Not all off-label use is bad; there are many instances where it is supported by substantial evidence, but with antipsychotic use [in the elderly] this is not the case. Not only that, but there is good epidemiologic evidence that shows that there are significant safety concerns, which include a doubling of mortality risk in this patient population," said Dr. Alexander.

The purpose of the study, he said, was to assess the impact of these warnings on antipsychotic drug use, which, to date, is unknown.

Using nationally representative data from the National Drug and Therapeutic Index, the investigators derived monthly data regarding second-generation and conventional antipsychotic use from January 2003 to December 2008.

The primary outcome from the audit of office-based physicians was the use of an atypical antipsychotic agent. Investigators also quantified the impact of the advisory on atypical antipsychotic use among all individuals and those 65 years or older with dementia.

Residual Use

From January 2003 to March 2005, mentions of total atypical antipsychotic drugs increased at an overall annual rate of 34% and 16% in patients with dementia. The investigators report that in the year before the FDA advisory, there were approximately 13.6 million atypical drug mentions, including 0.8 million among those with dementia.

An overall decrease in the use of atypical medication began within 1 month of the FDA advisory. Mentions of atypical antipsychotics decreased 2% overall and 19% among those with dementia in the year after the warning. By 2008 monthly drug use among elderly patients with dementia decreased more than 50%.

The use of these medications for both FDA-approved and off-label indications continued to decrease for all populations through the end of the study period in December 2008.

However, despite the uncertain benefits and the decrease in use among elderly patients with dementia, atypical antipsychotics still comprised 9% of prescription drug uses for dementia among older adults by the end of 2008.

"The residual use in the population at risk and the decrease in the use of atypical antipsychotics in the general population, who were not targeted by the warning, raise the question as to whether the effect and specificity of FDA regulatory actions could be enhanced," the study authors write.

Dr. Alexander said 1 potential solution is for the FDA and possibly other professional organizations to target specific segments of patients and high-prescribing physicians to improve the specificity of such warnings and minimize the risk for antipsychotic use.

High Rate of Inappropriate Use in Nursing Homes

A separate study led by Yong Chen, MD, MHS, at the University of Massachusetts Medical School, Worchester, and also published in the January 11 issue of Archives of Internal Medicine found more than one-third of nursing home residents who were prescribed an antipsychotic had no clinical indication for the drug.

"Residents newly admitted to nursing homes with the highest prescribing rates were 1.37 times more likely to receive an antipsychotic medication relative to those in nursing homes with the lowest prescribing rates," the study authors write. "The influence of the facility-level prescribing rate was most apparent in residents without psychosis, who have the weakest indication for antipsychotic medication use," the investigators add.

Sending the Right Message

In an accompanying editorial, Paula Rochon, MD, MPH, Women's College Research Institute in Toronto, Ontario, Canada, and Geoffrey M. Anderson, MD, PhD, Faculty of Medicine, University of Toronto, Ontario, Canada, said that these studies indicate a need for changes in regulatory agency warnings to improve their impact.

"Strategies need to be in place to get information about the warning down to the level of the prescriber. With the increased availability of electronic health records, computerized physician order entry and clinical decision support could facilitate getting information from the warnings to the prescriber at the time of prescribing. Specifically, when a prescriber selects an antipsychotic therapy, they could be alerted to the black box warnings and provided alternatives," they write.

The editorialists add that ensuring the safety of elderly patients will require collaboration among "researchers, regulators, manufacturers, professional organizations, and healthcare provider organizations to send the right message to prescribers."

Dr. Alexander serves as a consultant to IMS Health and has received grants from Pfizer and the Merck Foundation and has previously served as a consultant to AstraZeneca. Dr. Dorsey receives research support from Medivation Inc and Pfizer Inc and has previously received support from Amarin, Avid Radiopharmaceuticals, and Merck. He holds stock options in Avid Radiopharmaceuticals and consults for Lundbeck. None of the authors or editorialists have disclosed any relevant financial relationships.

Arch Intern Med. 2010;170:96-103, 89-95,103-106.