The use of atypical antipsychotic medications for treating behavioral disorders in elderly patients with dementia is associated with increased mortality, the FDA has determined. The deaths were primarily due either to heart-related events, such as heart failure and sudden death, or to infections such as pneumonia. Atypical antipsychotics are approved for treating patients with schizophrenia and mania, but none is approved for treating behavioral disorders in patients with dementia. Thus, the agency has requested that manufacturers of these drugs revise the package insert to include a black box warning describing this risk and noting that these drugs are not approved for this off-label indication.

The FDA reached its conclusion after analyzing the data from 17 placebo-controlled trials with olanzapine, aripiprazole, risperidone, or quetiapine in elderly demented patients with behavioral disorders. Fifteen studies showed increases in mortality in the drug-treated group compared with the placebo-treated patients. Several analyses of these trials, which enrolled a total of 5,106 patients, “demonstrated an approximately 1.6- to 1.7-fold increase in mortality,” the FDA reported on its Web site. During the course of the trials, which averaged about 10 weeks, the rate of death in drug-treated patients was about 4.5%, compared with a rate of about 2.6% in the placebo group.

The FDA also issued a public health advisory to alert health care providers, patients, and caregivers to the new safety information concerning the unapproved use of atypical antipsychotic drugs. The agency recommended that patients receiving these drugs for the treatment of behavioral disorders associated with dementia have their therapy reviewed by their health care providers. The FDA is also considering adding a similar warning label for older antipsychotic medications, because the limited data that are available suggest that similar increases in mortality in elderly patients may exist with these drugs as well. However, the review of data regarding these older drugs is ongoing.

ATYPICAL ANTIPSYCHOTICS—UNDER THE MICROSCOPE

Atypical antipsychotics are categorized into three drug classes based on their chemical structure. Because the increase in mortality was observed with atypical antipsychotic medications in all three chemical classes, the FDA concluded that the effect was probably related to the common pharmacologic effects of all atypical antipsychotic medications, including those that have not been systematically studied in the dementia population. Therefore, clozapine and ziprasidone, which were not included in the trials, will also carry the warning. A combination product containing olanzapine and fluoxetine, which is approved for the treatment of depressive episodes associated with bipolar disorder, will also be included in the FDA’s request.

The new warnings on antipsychotics are the latest chapter in what has been a year of controversy for the FDA. Last fall, the agency issued a black box warning regarding potential suicide risks associated with the use of antidepressants and then subsequently modified its original wording in February. It has also been criticized for not reacting quickly enough to reported findings of cardiac risks stemming from the use of COX-2 selective and nonselective nonsteroidal anti-inflammatory drugs.

TREATMENT IMPLICATIONS FOR PATIENTS AND PHYSICIANS

Neuropsychiatry Reviews contacted a number of clinicians in the United States for this story, all of whom declined to comment. However, one European researcher who has published on the topic offered his viewpoints on the FDA’s decision.

“It seems fairly clear as the studies come in that atypical antipsychotics do have an increase in mortality that is close to statistical significance over no treatment in clinical trials,” Roger Bullock, MA, MRCPsych, told Neuropsychiatry Reviews. “I am sure that this would be worse in studies of typical antipsychotics. I expect that this is an effect on the cerebral vasculature that happens with all of the compounds—more so in the more anticholinergic drugs, but this needs [to be confirmed]. The worry is that when this difference becomes significant, the headlines will say these drugs kill people, [which will] lead to the loss of an effective intervention—the safety of which depends on the skill of the user. Proper patient selection reduces these adverse events hugely.” Dr. Bullock is Director and Principal Investigator at the Kingshill Research Centre, Victoria Hospital, in Swindon, United Kingdom.

Dr. Bullock said that research has shown that antipsychotics are effective for treating patients for aggression and psychosis, but not as effective for agitation, in which “memantine is probably the better choice. The former are common symptoms that must be treated, as the patient not only is suffering, but they correlate to rapid disease progression. The evidence suggests that typicals are really too toxic to consider—with two thirds of patients getting dyskinesias, gait disturbances, and swallowing problems. So atypicals should be used, and I believe risperidone still has the best evidence to date.

“I think the FDA action will scare physicians back to using the older typical drugs, which are not safer but have no studies to prove that,” said Dr. Bullock. “This will expose people to much greater morbidity and some unpleasant side effects. There is also little evidence that low-dose typicals are actually effective. What is needed is a commonsense approach [in which] patients without significant cerebrovascular disease are selected for atypical drugs once a behavioral program has failed and the risks and benefits are clearly explained to relatives. I suspect in Europe this will work, but with the lawyers hanging around in the US, people may go more cautiously.

“The bottom line is that with this patient group there are times when these drugs have to be used, and there are currently no alternatives,” Dr. Bullock continued. “In some areas, that point may have been reached too readily, so this needs [to be limited]. However, this is a difficult disease, and like with other difficult diseases (eg, cancer), there are times when the benefit–safety ratios are very tight.”

—Colby Stong

Suggested Reading
Bullock R. Treatment of behavioural and psychiatric symptoms in dementia: implications of recent safety warnings. Curr Med Res Opin. 2005;21:1-10.
Herrmann N, Lanctot KL. Do atypical antipsychotics cause stroke? CNS Drugs. 2005;19:91-103.
Liperoti R, Mor V, Lapane KL, et al. The use of atypical antipsychotics in nursing homes. J Clin Psychiatry. 2003;64:1106-1112.
USFDA Web site: www.fda.gov/cder/drug/advisory/antipsychotics.htm.

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