How the FDA approved an antipsychotic that failed to show a meaningful benefit but raised the risk of death

In trials, brexpiprazole failed to provide a clinically meaningful benefit and it increased mortality, but the FDA fast tracked its approval and the sponsor predicts $1bn in annual sales. Robert Whitaker investigates the first licensed antipsychotic for treating agitation in elderly patients with dementia

For years, health officials have tried to rein in the prescribing of atypical antipsychotics to elderly patients with dementia. The practice has been entirely “off label” yet widespread. The US Food and Drug Administration reports that around 60% of patients with Alzheimer’s dementia in residential care have received an off-label prescription for an antipsychotic, benzodiazepine, antidepressant, or anti-epileptic drug. After a 2005 FDA warning that cited a 60-70% increased risk of death associated with antipsychotic drug use, the US Centers for Medicare and Medicaid Services established the National Partnership to Improve Dementia Care in Nursing Homes, a public-private collaboration that sought to “reduce the use of antipsychotics” and “enhance the use of non-pharmacological approaches.”1

But a May 2023 FDA approval of the antipsychotic brexpiprazole for agitation in patients with Alzheimer’s dementia may reverse all of this. At a cost of around $1400 (£1102; €1280) a month, the manufacturers Otsuka and Lundbeck, which jointly brought the “first in class” approval to market, are forecasting an additional $1bn in annual sales of Rexulti.2

Serious questions remain, however, about the harm-benefit balance of Otsuka and Lundbeck’s drug. The drug carries a “boxed warning”—the FDA’s most serious type of warning, informing prescribers of increased mortality. And among four efficacy evaluations across the three prelicensure clinical trials, the highest efficacy observed was a 5.3 point improvement over placebo on a 174 point scale. In the two trials that assessed quality of life, no benefit for either the patient or the caregiver was demonstrated.

“The small benefits do not outweigh serious safety concerns,” said Nina Zeldes, health researcher at the consumer advocacy organisation Public Citizen, addressing the FDA’s advisory committee at its 14 April meeting before the approval.3 “Like other antipsychotics, this is a drug that can kill patients without providing a meaningful benefit.”4

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