By Caitlin Heaney West

May 16, 2023

The US Food and Drug Administration (FDA) granted supplemental approval on May 11 to brexpiprazole, the first approved drug to treat agitation in people with dementia due to Alzheimer's disease (AD).

The agency granted approval of the oral tablets via Fast Track designation, which aims to speed up the process of getting new drugs to patients to fulfill unmet medical needs.

The approval was based on two 12-week, randomized, double-blind, placebo-controlled, fixed-dose studies published in 2020 in the American Journal of Geriatric Psychiatry. The trials included patients ages 55 to 90 who had a probable Alzheimer's dementia diagnosis; a score of 5 to 22 on the Mini-Mental State Examination; and the type, frequency, and severity of agitation behaviors requiring medication.

Patients received 1 mg or 2 mg of brexpiprazole in the first study and 2 mg or 3 mg in the second study. At week 12, patients who received 2 mg or 3 mg in both studies experienced statistically significant and clinically meaningful improvements in their total Cohen-Mansfield Agitation Inventory (CMAI) scores versus patients taking a placebo. 

Eric McDade, DO, said the drug's approval seems appropriate based on the differences in CMAI and the data from the phase 3 trials he has seen in public presentations. Still, he said, how brexpiprazole fills the “tremendous" need for effective treatment of agitation is unclear.

“Although the drug had a statistically significant benefit, the placebo group also had significant improvements suggesting the importance of just having appropriate attention and regular monitoring of behavioral symptoms in those with dementia," said Dr. McDade, professor of neurology in the division of cognitive neurology at Washington University School of Medicine in St. Louis and associate director of the Dominantly Inherited Alzheimer Network Trials Unit. “Additionally, six deaths were reported in the treatment group (one in the placebo), raising concern. However, over the 12-week treatment period, the drug appeared to be relatively safe."

The FDA noted in a statement announcing the decision that “agitation is among the most persistent, complex, stressful, and costly aspects of care among patients with behavioral and psychological symptoms of dementia."

“'Agitation' can include symptoms ranging from pacing or restlessness to verbal and physical aggression," Tiffany Farchione, MD, director of the division of psychiatry in the FDA's Center for Drug Evaluation and Research, noted in the statement. “These symptoms are leading causes of assisted living or nursing home placement and have been associated with accelerated disease progression."

Agitation is one of the behavioral and psychotic disorders associated with AD and related dementias, Dr. McDade said, and “these behavioral changes, along with sleep disorders, represent the most challenging aspects of caring for individuals with dementia." 

“Why patients experience agitation is not completely known and likely represents both contributions of the underlying neurodegenerative process and the effect these changes have on the perceptual experience of external and internal stimuli," he said.

How brexpiprazole could help these patients remains to be seen, Dr. McDade noted, “but based on the reported trial results, this drug would be expected to offer some benefit for treating agitation and related symptoms."

“However, it is unlikely to completely eliminate the symptoms, indicating the need for continued therapeutic research and education on environmental and behavioral management approaches to agitation as well," he added.

The FDA recommends that patients start brexpiprazole treatment with 0.5 mg taken once daily for seven days; dosage then will increase to 1 mg once daily for days eight through 14 and to 2 mg once daily after that. Prescribers can increase treatment to 3 mg once daily, the maximum recommended dosage, after at least 14 days of treatment.

Common side effects include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances (somnolence and insomnia), according to the FDA. Brexpiprazole also can increase the risk of death in elderly patients with dementia-related psychosis being treated with antipsychotic drugs.


Dr. McDade has received research funding from NIA (K23AG046363; U01AG059798), Anonymous Foundation, GHR, and the Alzheimer Association; institutional support from, Eli Lilly, Eisai, Hoffmann La-Roche, and DIAN-TU Pharma Consortium; has done speakers engagements for Eli Lilly, Esai, Neurology Live, and Projects in Knowledge-Kaplan; has served on the advisory, consulting, or Data and Safety Monitoring boards for Eli Lilly, Alector, Alzamend, Sanofi, AstraZeneca, Hoffmann La-Roche, and Grifols. He also is co-inventor of the “Methods of diagnosing AD with phosphorylation changes" technology licensed by Washington University (WU) to C2N Diagnostics; WU holds equity in C2N, and WU and Dr. McDade are entitled to receive royalties from the license agreement with C2N.