FDA Fast-Tracks Brexpiprazole for Agitation in Dementia: Questions Arise

In a surprising move, the FDA fast-tracked approval of brexpiprazole (Rexulti) in May 2023 for the treatment of agitation in older adults with dementia due to Alzheimer’s disease. The approval was based on initial clinical trials showing marginal improvements on the Cohen-Mansfield Agitation Inventory (CMAI), although they fell far short of clinical significance. The FDA defended its decision, citing advisory committee support and an unmet medical need in the treatment of dementia-related agitation. 

Beyond worries about brexpiprazole’s effectiveness, safety issues included somnolence, urinary tract infections, insomnia, and cardiovascular events. More alarmingly, patients taking brexpiprazole faced a fourfold higher risk of death compared to those on placebo over the trial’s 16-week period. What makes the situation even trickier is that the FDA couldn’t identify a specific group where the benefits outweighed the risks. 

We don’t have enough data to determine which patients, whether those with mild or severe symptoms, would benefit the most. However, the small difference on the CMAI aligns with outcomes from previous trials involving other atypical antipsychotics (Whitaker R, BMJ 2023;382:1801). We therefore recommend cautious consideration of brexpiprazole for agitation in dementia only after a careful risk-benefit evaluation and exploration of alternative interventions.