No Increased Mortality Risk With Brexpiprazole vs Aripiprazole for Dementia Patients, Data Suggest

An observational study of Medicare patients with dementia found that brexpiprazole did not increase 6-month mortality versus aripiprazole.

"This study provides Class III evidence that brexpiprazole does not increase the risk of mortality at 6 months compared with aripiprazole in people living with dementia," wrote Julie Zissimopoulos, PhD, of the University of Southern California in Los Angeles, and co-authors in Neurology.

"Using matching and logistic regression, we found reduced risk of death associated with brexpiprazole compared with aripiprazole use and no difference in hospitalization or ED [emergency department] use," they continued. "We also used instrumental variables estimation to adjust for any potential unobserved confounders and found no statistically different mortality risk between the users of the 2 drugs. Together, the findings suggest that brexpiprazole is not associated with higher mortality risk compared with aripiprazole."

The group reported:

• Six-month mortality was statistically lower among new users of brexpiprazole versus aripiprazole in propensity-matched results (OR 0.49, 95% CI 0.37–0.65).
• There was no statistical difference between the incident use of brexpiprazole and aripiprazole use for ED visits or hospitalization within 6 months of initiation.
• Results were similar after adjustment for potential unobserved confounding.

"In 2023, brexpiprazole became the first antipsychotic approved by the U.S. Food and Drug Administration to treat agitation in persons with Alzheimer disease, but, like all atypical antipsychotics, it includes a black box warning of an increased risk of mortality among persons with dementia," Zissimopoulos and co-authors explained.

The researchers used Medicare claims data Parts A, B, and D from 2014 to 2023 for 41,871 patients with dementia to study the relationship between incident use of brexpiprazole (n=1,337, mean age 76) versus aripiprazole (n=40,534, mean age 78)for mortality, ED visits, and hospitalizations within 6 months.

About 85% of the overall cohort was White and about 70% were women.

Beneficiaries had diagnosed dementia with 2 continuously enrolled years in Medicare. All were new users of the atypical antipsychotics brexpiprazole or aripiprazole in a given year.

Propensity score matching was used to match each brexpiprazole user to 10 aripiprazole users to balance covariates across the two groups. The variables used for matching included sex, age, race, comorbidities, Medicare and Medicaid dual eligibility, time since dementia diagnosis, and use of opioids, anxiolytics, antidepressants, and/or anticonvulsants.

Incident use of either drug was defined as having at least a 30-day supply fill in a given year along with no use of that specific drug or any other atypical antipsychotic in the previous 365 days.

In addition to the imbalance between numbers of participants with brexpiprazole versus aripiprazole, several other imbalances were seen between the two groups, including presence of atrial fibrillation (11.4% versus 17.1%, respectively; P<0.001), Medicare/Medicaid dual eligibility (40.6% versus 32.7%; P< 0001, and use of anxiolytics (65.1% versus 52.4%), antidepressants (96.0% and 88.1%), and anticonvulsants (52.7% and 42.1%; P<0.001 for all).

"Brexpiprazole offers a treatment option which is important given the heterogeneity of effects of antipsychotics on persons," Zissimopoulos and co-authors wrote.

Both aripiprazole and brexpiprazole affect dopamine metabolism through similar mechanisms and are used for the same indications. "Although they are chemically and structurally similar, they are distinct and thus safety and efficacy may differ across users," the authors pointed out.

Aripiprazole is also one of the more commonly prescribed atypical antipsychotics among people with dementia despite it, like other atypical antipsychotics (except brexpiprazole) not being FDA-approved for treatment in people with dementia.

Three 12-week trials — two published together in 2020 and a separate trial in 2023 demonstrated improvement in agitation over a 12- week period for brexpiprazole versus placebo. In the three trials overall, seven patients died: six participants treated with brexpiprazole and one in the control group.

"Study investigators reported that the deaths were unrelated to treatment but acknowledged that with limited duration of treatment, longer-term safety data were needed," Zissimopoulos and colleagues noted.

The present study included only Medicare fee-for-service beneficiaries ages 65 years and older and thus may not be generalizable to younger people with dementia, the researchers noted.

Other limitations included the combination of information about all dementia subtypes, based on diagnostic codes, into a single "dementia" category. No information on severity of dementia or behavioral symptoms was available; the authors noted that it is possible severity differs for users of the two agents. The large difference in sample size across users of the two drugs in this study may indicate unobserved confounders, they added.

"Treatment of agitation is important for supporting the quality of life and safety of people living with dementia and their care partners," Zissimopoulos and colleagues wrote.

"Brexpiprazole may not offer additional advantages over aripiprazole for mortality risk but even if equitable, options are important given the heterogeneity of effects of antipsychotics on persons. This study adds real-world evidence to the limited information on treatment effects of brexpiprazole in a population of people living with dementia."

The study was funded by the National Institute on Aging.

Zissimopoulos had no disclosures.

Zissimopoulos J, et al "Real-world evidence of brexpiprazole use and 6-month mortality, hospitalization, and emergency department visits among persons with dementia" Neurology 2025; DOI: 10.1212/WNL.0000000000213717.