Unintended Consequences of FDA Antipsychotic Warning?

Pauline Anderson

April 30, 2020

The 2005 US Food and Drug Administration (FDA) black-box warning about increased mortality being linked to atypical antipsychotic (AAP) use in elderly patients with dementia may have had unintended consequences. However, at this point, the findings are "hypothesis generating," and more research is required to definitively confirm or refute this.

Following the warning, there was a steady reduction in the use of AAPs in this patient population, and there were fewer associated cerebrovascular events. However, there was also an associated increase in antiepileptic and opioid use and an increase in cardiovascular events.

Dr Howard Fillit

These unanticipated negative consequences linked to the warning "puts physicians in a difficult position," study coinvestigator Howard Fillit, MD, clinical professor of geriatric medicine, palliative care, and neuroscience at the Icahn School of Medicine at Mount Sinai, New York City, told Medscape Medical News.

"Very frequently in medicine, we have competing risks, and we have to make difficult treatment decisions for patents, balancing safety and efficacy," said Fillit, who is also founding executive director and chief science officer at the Alzheimer's Drug Discovery Foundation.

This is especially true for older patients with agitation, a major risk factor for institutionalization and decreased quality of life, he noted.

The bottom line is that "we need better and safer drugs for the treatment of agitation and psychosis in patients with Alzheimer's disease and related dementias. That's how the problem is going to be solved," he said.

The findings were published online April 28 in JAMA Network Open.

Neuropsychiatric Symptoms Common

Up to 90% of patients with dementia experience neuropsychiatric symptoms, which include agitation, mood disorders, sleep disorders, psychotic symptoms, and excessive verbal or physical motor activity.

Previous research shows that these symptoms contribute to poor patient and caregiver health-related quality of life (QoL), caregiver burden and burnout, and patient institutionalization.

Currently, there are no FDA-approved medications for the treatment of dementia-related neuropsychiatric symptoms.

Although AAPs have been used off label to manage dementia-associated neuropsychiatric symptoms, concerns emerged in the early 2000s about a potential increase in risk for cerebrovascular events and death.

As a result, in 2005, the FDA issued a black-box warning about risks regarding specific AAPs in elderly patients with dementia-related psychosis. In 2008, it extended the warning to all antipsychotics.

However, to date, the long-term impact of the warning on outcomes in dementia patients has not been examined, so the investigators set out to address this knowledge gap.

The study included data from three nationally representative healthcare surveys of the noninstitutionalized US population: 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).

The researchers used the MEPS as their primary data source. They pooled data from the NAMCS and the NHAMCS to confirm findings for measures common across all surveys.

Factors assessed included use of AAPs, other psychiatric medications, and opioids; health events, such as cerebrovascular events, cardiovascular events, falls, fractures, and mortality; and health-related QoL between a period prior to the FDA warning (1996 to 2004) and a period following the warning (2005 to 2014).

The investigators identified 2430 noninstitutionalized elderly respondents with dementia or Alzheimer disease from the MEPS and 5490 from the NAMCS and NHAMCS data, which corresponded to weighted populations of 22,996,526 and 65,502,344, respectively.

The mean age of the total study population was 81 years, and 63.1% were women. Participants were predominantly white non-Hispanic persons and persons living in urban areas.

Increase in Antiepileptic, Opioid Use

Results showed that the prevalence of AAP use decreased −0.15 percentage points in 2005 and continued to decrease −0.18 percentage points annually after 2005.

Findings based on the NAMCS and NHAMCS data were more pronounced, with a change of −0.54 percentage points in 2005; there was a post-warning slope of −0.83 percentage points.

The decrease in AAP use after 2005 was accompanied by an uptick in the use of other psychiatric medications, including antiepileptics and opioids.

The prevalence of antiepileptic use increased by 2.23 percentage points in 2005 and continued to increase at a rate of 1.21 percentage points per year.

The mood-stabilizing effects of antiepileptics may ameliorate some symptoms of agitation and aggression in patients with dementia, but evidence for their use is mixed.

"We don't really know the efficacy of antiepileptics in the treatment of agitation" in these patients, Fillit noted.

Although opioid use in this patient population was stable before 2005, the prevalence of use in the main survey decreased by −1.14 percentage points in 2005 and then increased by 1.29 percentage points annually.

The steady increase in opioid use in dementia patients after 2005 in the MEPS sample "is an important finding, especially in the context of the ongoing opioid epidemic," the investigators write.

Although there was no significant increase in opioid use after 2005 in the NAMCS and NHAMCS samples, the direction of the opioid use trend was in line with the MEPS data, they add.

No Proof of a Direct Relationship

Fillit said he's unsure why opioid use increased. He pointed out that evidence for their use in treating dementia-related agitation is limited.

It is possible that in some cases, opioids were used to treat pain, which is increasingly recognized as a contributor to agitation. The investigators emphasize that in patients with agitation, practitioners should assess and manage pain as clinically indicated and that treatment could include the use of nonopioid analgesics.

In the main analysis, prevalence of cerebrovascular events increased by 0.75 percentage points per year before 2005, decreased by −0.74 percentage points in 2005, and decreased by −0.50 percentage points annually thereafter.

The decrease in cerebrovascular events after 2005 is consistent with the hypothesized association between the use of antipsychotics and stroke.

However, the prevalence of cardiovascular adverse events increased by 1.30 percentage points annually after the 2005 FDA warning. Although the reason for this is unclear, it "may signal a negative unintended consequence" of the 2005 warning, the investigators note.

The 2-year mortality risk also increased from −0.68 percentage points before the warning to 0.18 percentage points after.

"We can't say there's a direct relationship between the FDA black-box warning and the increased cardiovascular events and 2-year mortality, but there is something there," Fillit said.

In the MEPS sample, the prevalence of falls or fractures decreased before the 2005 warning and continued to decrease by −0.40 percentage points per year despite an immediate increase of 1.88 percentage points in 2005. Health-related QoL remained relatively unchanged.

The overall findings should be considered as hypothesis generating and do not suggest that the 2005 FDA warning was the only factor responsible for the changes found in the study, the researchers write.

Only a First Step

Commenting on the study for Medscape Medical News, David Knopman, MD, professor of neurology, Mayo Clinic, Rochester, Minnesota, said he was "very impressed" with the data showing a reduction in prescriptions for AAPs after 2005.

However, he was less impressed with information on the rise in prescriptions for other "psychoactives."

"In particular, the curve for opiates looks relatively linear" during the period 1997 to 2013, said Knopman, who was not involved in the research.

"It's too speculative to make any claims of causal linkage" between the black-box warning for AAPs and a rise in use of opioids and antiepileptic medications in elderly patients with dementia, he added.

"It's certainly a possibility, but the evidence here is merely a first step in establishing, or failing to establish, a causal link."

Even the investigators were quite cautious about this link, Knopman noted.

"But I can see how others might be drawn to a stronger claim than the authors were comfortable making," he said.

Fillit received research consultancy funding from Otsuka Pharmaceutical Development and Commercialization Inc during the study. Knopman has reported no relevant financial relationships.

JAMA Netw Open. Published online April 28, 2020. Full text

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