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The FDA has approved brexpiprazole for treating agitation in dementia, but some experts have expressed concern. josemoraes/Getty Images
  • The FDA fast-tracked approval for an antipsychotic drug, brexpiprazole, to treat agitation in elderly patients with dementia.
  • The medication produced clinically insignificant improvements in clinical trials and increased the risk of death by four times compared to a placebo.
  • However, a recent investigative report questioned the FDA’s approval of the drug.
  • Medical News Today spoke with experts in the field to learn more about the drug and the FDA’s decision.

In May 2023, the FDA fast-tracked approval for the antipsychotic drug brexpiprazole, sold under the brand name Rexulti, for treating agitation in older adults with dementia.

While advocacy groups like the Alzheimer’s Association have supported the news, others have been more skeptical. On August 17, investigative journalist Robert Whitiker published a feature in the BMJhighlighting some key issues with the FDA’s decision to fast-track the drug.

He wrote that the first two placebo-controlled clinical trials involving Rexulti produced unconvincing results.

While a third trial provided a 5.3-point reduction in symptoms according to a 203-point agitation questionnaire known as the CMAI, it fell short of the 17-point minimum needed for clinical significance.

Whitiker also noted that the risk of death among those taking brexpiprazole was four times higher than those taking a placebo over 16 weeks and that other safety concerns included sleepiness, urinary tract infections, insomnia, and cardiovascular events.

Medical News Today talked with various medical doctors, an FDA spokesperson, and the Alzheimer’s Association to understand more about brexpiprazole’s potential for treating those with dementia.

MNT began by asking a spokesperson from the FDA why they fast-tracked the drug’s approval. He said that brexpiprazole was fast-tracked to meet an unmet medical need and that it is the first FDA-approved drug to treat dementia-related agitation.

“[Fast-track programs intend] to help ensure that therapies for serious conditions are approved and available to patients as soon as it can be concluded that the therapies’ benefits justify their risks,” the spokesperson said.

The spokesperson added that the submission for approval was discussed by an advisory committee meeting, which includes outside experts, and that ‘an overwhelming majority’ of members agreed with the FDA’s conclusion that the drug is effective and could benefit patients with agitation due to Alzheimer’s disease (AD).

MNT next spoke with Dr. J. Wes Ulm, a bioinformatic scientific resource analyst, and biomedical data specialist at the National Institutes of Health, about the FDA approval.

Dr. Ulm noted that there is currently a shortage of good options for managing dementia, and that some forms of dementia-related agitation persist despite receiving physical, emotional, and activity support and treatments to relieve potential underlying causes, including:

  • infections
  • drug interaction
  • insomnia

“As a result, there’s been profound interest in drugs that might curb such [presistent] agitation, particularly with so many [older adults] entering ages when [Alzheimer’s] and other forms of dementia become more prevalent,” he said.

MNT also spoke with Dr. Ulm about when it may be safe to prescribe brexpiprazole for patients with dementia in light of the clinical trial results.

He said that the decision presents a complicated risk-benefit calculation for clinicians and caregivers and that studies show that benefits depend on factors such as:

  • the nature of the dementia
  • patients’ general health
  • quality and availability of care
  • setting in which the patient receives care

When agitation becomes [persitent-enough] to sharply limit quality of life and interfere with care—and when other options offer little to improve conditions for both patients and caregivers—then antipsychotics may become a viable modality to consider.”
— Dr. J. Wes Ulm

In a public statement, the Alzheimer’s Association noted that while they remain a strong proponent of non-drug approaches to manage behavioral symptoms of Alzheimer’s, medications may be considered in cases when patients don’t respond to non-drug approaches, especially when they have the potential to harm themselves or others.

Dr. Nicole Purcell, the Alzheimer’s Association senior director of clinical practice, said in a press release:

“People living with moderate and severe Alzheimer’s and other dementia need and deserve treatment that improves the quality of their life, including effective treatments for behavioral and psychiatric symptoms associated with dementia.”

MNT asked Dr. James Giordano, Pellegrino Center professor of neurology, biochemistry, and clinical ethics at Georgetown University Medical Center, how to minimize the drug’s risks.

“For brexpiprazole, the apparently most favorable utility—other than as antipsychotic medication—is for patients with mild dementia that exhibit agitative features and who thus are less at risk for the adverse side effects of this agent,” he said.

“Despite apparent ambiguities—if not shortcomings—in phase trials, the addition of another pharmacologic agent in the therapeutic armamentarium could provide particular benefit to select patients for whom other drugs and treatment approaches have not proven to be effective or viable,” he said.

MNT also spoke with Dr. David Merrill, PhD, a geriatric psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center in Santa Monica, California, about potential use cases for brexpiprazole and how to reduce its associated risk.

“Some aggressive behaviors in patients with dementia may result in a patient needing to be placed into a locked memory care unit rather than being able to remain at home. Use of these medications may bring enough of a calming effect to prevent placement. Potentially dangerous behaviors may also be lessened by use of these medications,” said Dr. Merrill.

He noted, however, that using the lowest effective dose for the shortest duration possible may be a way to lessen the risks related to the medication.

Dr. Girodano noted that when seeking to develop a “personalized precision medicine” regimen, not all therapeutic interventions have the same profile of effectiveness and effects.

“Thus, the goal is to evaluate each particular patient’s unique presentation and characteristics and match the therapeutic intervention to these features so as to maximize therapeutic benefit and minimize potential side and adverse effects,” said Dr. Girodano.

He added that while antipsychotics — especially at low doses — can effectively reduce ‘vegetative features’ in some patients with dementia, it is vital to consider other interventions, too.

“[These might include other] classes of pharmacological agents, as well as some emerging neurotechnologies such as transcranial electrical and or magnetic modulation,” he said.

Considering a wide range of treatment options, he concluded, could help clinicians distinguish between interventions ‘should’ be used from those that ‘can’ be used.