Atypical Antipsychotic Use Decreasing for Older Patients After FDA Warning

Annalisa Rubino, PhD

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Atypical antipsychotics are generally used off-label to manage dementia-associated neuropsychiatric symptoms. However, in 2005 the US Food and Drug Administration (FDA) issued a boxed warning for their use in elderly patients.

A team, led by Annalisa Rubino, PhD, Evidera, examined the long-term association of boxed warnings with medication use, health outcomes, and quality of life for elderly patients with dementia.

The cross-sectional study of nationally representative 1996-2014 survey data from 3 different survey data sources of individuals at least 65 years old.

The study population included 2430 individuals from the Medical Expenditure Panel Survey (MEPS) and 5490 respondents from the National Ambulatory Medical Care Survey (NAMCS), and the National Hospital Ambulatory Medical Care Survey (NHAMCS).

The mean age of the respondents was 81 years old.

The investigators applied the interrupted time-series analysis to 3-year moving means derived from the surveys.

The team sought main outcomes of psychiatric medication and opioid use, the prevalence of cerebrovascular and cardiovascular events, the prevalence of falls or fractures, the two-year mortality rate, and health-related quality of life, which was assessed by the Medical Outcomes Study 12-Item Short-Form Health Survey scores.

The investigators found the 2005 FDA boxed warning was linked to a decrease in atypical antipsychotic use and cerebrovascular events, as well as an increase in opioid and antiepileptic use and cardiovascular events.

In the MEPS sample, compared with before 2005, atypical antipsychotic 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, while opioid use (0.04-1.29 percentage points), antiepileptic use (−0.42-1.21 percentage points), cardiovascular events (−0.13-1.30 percentage points), and two-year mortality risk (−0.68-0.18 percentage points) increased.

“The prevalence of [atypical antipsychotics] use and cerebrovascular events continuously decreased during the decade after the 2005 FDA boxed warning on [atypical antipsychotics],” the authors wrote. “The reduction in use of antipsychotics was associated with increases in the use of antiepileptics and opioids and with increased rates of cardiovascular events.”

Currently, Alzheimer disease accounts for 60-80% of dementia cares, with up to 90% of patients with dementia experiencing neuropsychiatric symptoms, including mood disorders, sleep disorders, psychotic symptoms, agitation, and excessive verbal or physical motor activity.

Neuropsychiatric symptoms are substantially prevalent in all stages of Alzheimer disease, contributing to poor patients and caregiver health-related quality of life, caregiver burden and burnout, institutionalization, and increased medical costs.

According to the 2016 American Psychiatric Association practice guideline, the treatment of agitation or psychosis in patients with dementia recommends a patient-centered comprehensive treatment plan that incorporates both nonpharmacologic and pharmacologic approaches.

As part of this approach, antipsychotics are recommended when symptoms are serious, dangerous, or cause significant patient distress. There is currently no FDA approved medication of dementia-associated neuropsychiatric symptoms, including agitation.

The FDA’s boxed warning decision was due to concerns over cerebrovascular events in elderly patients with dementia association with certain atypical antipsychotics.

The FDA issued warnings for risperidone in 2003, olanzapine in 2004, and aripiprazole in 2005, while clinical trials confirmed the use of those treatments is tied to increased mortality (OR, 1.54; risk difference, 1%).

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.

The investigators suggest additional longitudinal studies to support or refute the findings.

The study, “Association of the US Food and Drug Administration Antipsychotic Drug Boxed Warning With Medication Use and Health Outcomes in Elderly Patients With Dementia,” was published online in JAMA Network Open.