No Increased Risk for Death With Antipsychotics in Alzheimer's?

Katharine Gammon

April 05, 2013

LOS ANGELES — For years, clinicians have been warned that off-label use of antipsychotic medications to treat behavioral disturbances in patients with dementia could increase mortality. However, preliminary evidence from a new Japanese study appears to refute this tenet.

A large, prospective cohort study conducted by investigators at Juntendo University Graduate School of Medicine in Tokyo, Japan, showed no significant differences in mortality risk between patients with dementia who received antipsychotics and those who did not.

In addition, the mortality rate of 1.3% found in the study was much lower than a rate of 3.5% found in a previous meta-analysis (JAMA 2005;294:3005-3007).

According to study investigator Heii Arai, MD, PhD, whereas other studies have been retrospective, this new work is prospective, offering a different point of view on the issue.

"The mortality rate in real clinical medicine is relatively low compared to that previously reported in clinical trials of antipsychotics for BPSD [behavioral and psychological symptoms of dementia] treatment," Dr. Arai told Medscape Medical News.

The findings were presented here at the American Association for Geriatric Psychiatry (AAGP) 2013 Annual Meeting.

"No Conclusive Evidence"

The investigators note that previous meta-analyses have suggested that off-label use of antipsychotics for treatment of behavioral disturbances in dementia is associated with a high risk for mortality. In 2005, the US Food and Drug Administration issued a black box warning about the use of these agents in this patient population.

However, Dr. Arai and colleagues note that "there has been no conclusive evidence based on prospective studies about the mortality risk associated with the use of antipsychotics."

To examine mortality risk and the use of antipsychotics prospectively, the investigators conducted a multicenter,10-week study in which they examined the potential link between antipsychotic use and mortality risk in 5148 patients aged 65 years and older (mean age, 81.8 years) who had been treated for Alzheimer's disease (AD). They compared mortality risk in those who did and in those who did not receive antipsychotics.

Of the total cohort, 1573 were inpatients (30.6%), and 2532 (49.2%) received antipsychotic medications.

After 10 weeks, the mortality rate in the total sample was 62 (1.2%). Dr. Arai and his colleagues report that there were no significant differences in the mortality between those who received the antipsychotics and those who did not (P = .38).

The most common cause of death overall was pneumonia, followed by cardiovascular events and cancer.

Previous meta-analyses had put the mortality risk associated with antipsychotic use in this patient population at about 3.5%. However, Dr. Arai said that in the real world of the clinic, this number may be much lower. He plans to expand the work going forward.

"We will increase the number of patients to 10,000 and analyze the data related to mortality rate," he said.

Findings Not Generalizable?

Commenting on the findings for Medscape Medical News, George T. Grossberg, MD, professor and director of geriatric psychiatry at St Louis University School of Medicine in Missouri, who was not involved in the study, described the research as a "good study that contributes to the literature," but he cautioned against generalizing about its conclusions.

According to Dr. Grossberg, the length of the study is a concern, and he noted that the study period may not be long enough to determine the true impact of these agents in elderly patients with dementia.

"We don't know over 6 months, or 12 months, if we'd begin to see a growing risk of mortality in patients who continue to be maintained with antipsychotics," he said.

In addition, older adults in Japan are different from American patients of the same age. Their body mass index scores (BMIs) are about 5 points lower than those of Americans, they have a longer lifespan, and they tend to eat better, he added.

"The typical 82-year-old in Japan is healthier than their 82-year-old counterparts in the US," said Dr. Grossberg. "And if we accept that, then the Japanese patients could be less likely to have consequences, side effects, and mortality than the US patients."

Those differences make it hard to generalize about mortality risk, he added.

"This is a story that's still evolving," said Dr. Grossberg. "Studies like this one give us have a better view and take away the hoopla from an issue that is fraught with emotion."

Dr. Arai and Dr. Greenberg report no relevant financial relationships.

American Association for Geriatric Psychiatry (AAGP) 2013 Annual Meeting. Abstract NR 42. Presented March 15, 2013.

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