Antipsychotics in Dementia: Evidence of Risk Mounts

The use of antipsychotics to quiet agitated older adults with dementia has come under increasing fire. After a Canadian study demonstrated an increased risk of adverse events or death with these agents,¹ the FDA expanded its earlier warning to physicians.

“This adds to the mounting evidence about potential safety issues surrounding all antipsychotics,” said Kevin Foley, MD, FACP, medical director of the Hauenstein Alzheimer’s Disease and Memory Disorders Program in Grand Rapids, Mich. “It’s like the situation with Vioxx: postmarketing safety data show that there were concerns we weren’t aware of. The data are compelling.

“Those in my field are completely aware of these limitations and are not ignoring the warnings. I’m not sure of the balance of the various specialties of medicine. We need to know how many of these prescriptions are being written by primary care physicians and others. I suspect that most are being prescribed by primary care physicians, certainly for patients in long-term–care facilities.”

In the latest in a series of studies of the risks associated with antipsychotics in patients with dementia, researchers at the University of Toronto and other institutions found that antipsychotic use appears to be widespread.¹ “Of residents newly admitted to a nursing home, 17% are started on an antipsychotic drug within 100 days of their admission, and 10% receive only a single antipsychotic prescription,” they wrote.^1,2

“In some guidelines, antipsychotic drugs are recommended for short-term use as part of the pharmacologic treatment of delirium,”^1,3 they added, “although there is no randomized controlled trial evidence to support this practice.”^1,4

Paula Rochon, MD, MPH, FRCPC, lead author of the Canadian study, told Psychiatric Times, “In another study, we found that one-third of nursing-home residents have a prescription for one of these antipsychotics.”

In a population-based, retrospective cohort study, Rochon and colleagues identified 20,682 matched older adults with dementia living in the community and 20,559 matched individuals living in nursing homes between April 1, 1997, and March 31, 2004. They divided patient groups by living arrangements (community or nursing home residents) as well as by the type of antipsychotic exposure (atypical or conventional) they received. In each residential setting, the patients who received an antipsychotic agent were matched against a group of patients who were not given prescriptions for antipsychotic drugs but who had received at least 1 other medication.

At 30 days, 13.9% of the community-dwelling older adults who received an atypical antipsychotic had experienced a “serious” adverse event, and 2.7% of them had died. “The pattern of serious adverse events was similar among drug exposure groups,” the researchers noted, “but events were more frequent among individuals who received a conventional antipsychotic drug.

“Individuals in the conventional antipsychotic therapy group were 3.8 times more likely to have experienced any serious event at 30 days’ follow-up than those in the control group. Those in the atypical antipsychotic therapy group were 3.2 times more likely to have experienced any serious event leading to a hospital visit or death during the 30 days of follow-up.”

In the nursing home group, 9.4% of the patients who received an atypical antipsychotic drug had experienced a serious event by the 30-day evaluation, and 5.2% had died within 30 days of receiving a prescription for an atypical antipsychotic drug. As with the community group, serious adverse events were common among patients who received conventional antipsychotic medications.

“Relative to nursing home residents in the control group, individuals in the conventional antipsychotic therapy group were 2.4 times more likely to experience a serious adverse event leading to an acute care hospital admission or death. Those in the atypical antipsychotic group were 1.9 times more likely to experience a serious adverse event during 30 days of follow-up.”

“We have done quite a number of studies in this area,” Rochon said in an interview. “We’ve looked at parkinsonism, stroke issues, and death. We did one of the first studies to look at the evidence for these drugs. What was important about the current study was that it tried to put together things that are often somewhat compartmentalized. We felt it was important to know about the whole spectrum of side effects so clinicians can weigh the risks and the benefits. By using observational data for a large group of people who are old and frail, we are able to see the real-world impact of these therapies, which is somewhat different from a clinical trials situation.”

After publication of the latest study, the FDA announced that it is requesting manufacturers of conventional antipsychotics to add a “black box” warning to their labels similar to the one imposed on atypical antipsychotics in 2005. In an alert for health care professionals, the agency said, the “FDA is notifying health care professionals that both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis.” It added, “antipsychotics are not indicated for the treatment of dementia-related psychosis.”

In a conference call for reporters, Tom Laughren, MD, director of the FDA’s Division of Psychiatry Products in the Center for Drug Evaluation and Research, said, “For the conventional antipsychotic drugs, this will involve entirely new language. For the atypical drug, this will involve a slight revision of a boxed warning that was already implemented in 2005. Now the boxed warning will say that elderly patients with dementia-related psychosis who are treated with antipsychotic drugs have an increased risk of death.” He added, “It’s important to emphasize that this is not a contraindication. Clinicians still have the option of using these drugs to treat this aspect of dementia at their discretion. However, [these drugs] are not approved for this indication. And we do want clinicians to be aware of the risks in using drugs in this population if they choose to use them.”

Howard Fillit, MD, executive director of the Alzheimer’s Drug Discovery Foundation, said he believes that antipsychotics are an important tool in the clinician’s arsenal but primarily as a last resort.

“I do think antipsychotics can be overused in patients with dementia,” he said in an interview. “The first approach to treatment should be a very informed and disciplined effort at behavioral management, including understanding the triggers for aberrant behaviors, the environment, and any drugs that the patient might be taking that might be increasing his or her confusion. I think there’s a clear approach to the evaluation and management of behavioral disorders. Once all the potentially manageable or treatable causes have been ruled in or out or addressed, we sometimes are left, as physicians treating patients and their families, between a rock and a hard place.”

Rochon concurs. “Our take-away message is the idea that when you’re prescribing a drug therapy, it’s important to know about the spectrum of adverse effects. We’re hoping to give you the information you need when weighing the risks and benefits,” she said.