The first drug specifically approved to treat agitation in Alzheimer's patients appears to be safer than feared, according to a major analysis of Medicare data tracking over 40,000 dementia patients. The findings could ease concerns about brexpiprazole, which carries a stark FDA warning about increased death risk in elderly dementia patients.
Agitation affects up to 90% of people with Alzheimer's disease during their illness, causing distress for both patients and caregivers. Until 2023, doctors had no FDA-approved options and relied on off-label use of antipsychotic medications all of which carry "black box" warnings about potentially fatal risks in dementia patients.
"We're seeing real-world evidence that contradicts some of our worst fears about this medication," Says the research team from the University of Southern California.
Who analyzed nine years of Medicare claims data. Their study found that dementia patients starting brexpiprazole had roughly half the mortality risk compared to those starting aripiprazole, a similar antipsychotic commonly prescribed off-label.
The stakes couldn't be higher. Approximately 250,000 people die annually from severe dementia-related agitation, and behavioral symptoms are a leading cause of nursing home placement. Yet the very drugs used to manage these symptoms have been linked to increased mortality, creating an agonizing treatment dilemma for physicians and families.
Brexpiprazole works as a dopamine modulator in the brain, with a mechanism similar to other atypical antipsychotics but with potentially milder side effects. In clinical trials leading to its approval, the drug showed modest improvements in agitation scores. However, those trials included only 345 patients followed for 12 weeks too small and brief to assess real mortality risks.
The new study examined 1,337 dementia patients who started brexpiprazole between 2015 and 2023, comparing them to 40,534 similar patients starting aripiprazole. After six months, only 4% of brexpiprazole users had died, compared to 11% of aripiprazole users.
"What's particularly interesting is that when we dug deeper with sophisticated statistical methods to account for hidden differences between patient groups, the mortality advantage disappeared,"
Explains the research team. This suggests that brexpiprazole users might have been healthier to begin with, but crucially, the drug doesn't appear to increase death risk compared to existing treatments.
The study also found no differences in hospitalization rates or emergency department visits between the two drugs, further supporting brexpiprazole's safety profile in real-world use.
Dr. Julie Zissimopoulos, lead author of the study, emphasizes the importance of having options:
"Even if brexpiprazole proves merely equivalent to existing drugs, that's valuable. We know there's tremendous variability in how individual patients respond to these medications."
While these findings are reassuring, researchers caution that the study has limitations. The Medicare data doesn't capture dementia severity or the intensity of behavioral symptoms, factors that could influence both drug choice and outcomes. Additionally, the relatively small number of brexpiprazole users reflects its recent approval and higher cost as a brand-name medication.
The research arrives at a critical moment. As the population ages and dementia cases rise, the need for safe, effective treatments for behavioral symptoms becomes increasingly urgent. The International Psychogeriatric Association recently published guidelines emphasizing integrated approaches combining psychosocial interventions with medications when necessary.
"This isn't about medicating away behavioral symptoms," notes the research team. "It's about having tools that can help when non-drug approaches aren't enough, without adding unacceptable risks."
For the millions of families grappling with dementia's behavioral challenges, this real-world evidence offers a measure of hope. While brexpiprazole isn't a miracle cure and still requires careful monitoring it appears to provide another option in the limited arsenal against one of dementia's most distressing aspects.
The findings underscore a broader principle in medicine: real-world evidence from diverse patient populations often tells a different story than controlled clinical trials. As more patients use brexpiprazole and data accumulates, the true risk-benefit profile will become clearer. For now, families and physicians have reason for cautious optimism about this new tool in dementia care.