Princeton, NJ—Atypical antipsychotics (AAPs) are often used off-label to manage neuropsychiatric symptoms associated with dementia, despite a boxed warning issued 15 years ago concerning use of the medications in older patients.

Now, a study published in JAMA Network Open suggests that the boxed warning, issued in 2005 by the FDA, was associated with some unintended negative patient outcomes.

To reach those conclusions, industry researchers conducted a cross-sectional study, analyzing data from the household component of the Medical Expenditure Panel Survey (MEPS), the National Ambulatory Medical Care Survey (NAMCS), and the National Hospital Ambulatory Medical Care Survey (NHAMCS) fielded between January 1, 1996, and December 31, 2014.

Included in the analysis was survey information about patients aged 65 years and older who had dementia—2,430 from MEPS and 5,490 from NAMCS and NHAMCS. Researchers focused on use of psychiatric medications and opioids, prevalence of cerebrovascular and cardiovascular events, prevalence of falls and/or fractures, 2-year mortality, and health-related quality of life assessed by the Medical Outcomes Study 12-Item Short-Form Health Survey scores.

Results indicate that, in the MEPS sample, compared with before 2005, AAP use (from an annual slope of 0.99 to -0.18 percentage points), cerebrovascular events (0.75 to -0.50 percentage points), and falls and/or fractures (-1.72 to -0.40 percentage points) decreased and opioid use (0.04 to 1.29 percentage points), antiepileptic use (-0.42 to 1.21 percentage points), cardiovascular events (-0.13 to 1.30 percentage points), and 2-year mortality risk (-0.68 to 0.18 percentage points) increased, while health-related quality of life remained relatively unchanged. The NAMCS and NHAMCS sample yielded similar findings, according to the authors.

“The 2005 FDA boxed warning was associated with a reduced prevalence of atypical antipsychotic use in elderly patients with dementia and with long-term unintended outcomes that exposed patients to new health risks,” the researchers emphasize.

Background information in the article points out that up to 90% of patients with dementia experience neuropsychiatric symptoms (NPSs), a group of distressing and disruptive behavioral symptoms that include mood disorders, sleep disorders, psychotic symptoms, agitation, and excessive verbal or physical motor activity.

It adds that the 2016 American Psychiatric Association practice guideline on the treatment of agitation or psychosis in patients with dementia recommends a patient-centered comprehensive treatment plan incorporating nonpharmacologic and pharmacologic approaches. The guidance advises the use of antipsychotics as part of the approach when symptoms are serious, are dangerous, and/or cause significant patient distress, according to the report, which notes that no medication has been approved by the FDA for the treatment of dementia-associated NPSs, including agitation.

The authors explain that concerns regarding increased risk of cerebrovascular events in elderly patients with dementia associated with certain AAPs began in the 2000s, leading to FDA warnings for risperidone in 2003, olanzapine in 2004, and aripiprazole in 2005. In addition, other research suggested that use of AAPs in patients with dementia was associated with increased mortality, leading to the boxed warning in elderly patients with dementia. In 2008, the FDA extended the boxed warning to all antipsychotics based on reports of similar or higher mortality risk in elderly individuals with dementia taking conventional antipsychotics; as a result, some studies have reported a decreased prevalence of antipsychotic medication use by elderly patients with dementia.

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