Rexulti Approved for Agitation Associated With Dementia Due to Alzheimer Disease

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Brexpiprazole is an atypical antipsychotic.

The Food and Drug Administration (FDA) has approved Rexulti® (brexpiprazole) for the treatment of agitation associated with dementia due to Alzheimer disease (AAD). This marks the first approval of a pharmacological therapy for this indication.

Brexpiprazole is an atypical antipsychotic. While its mechanism of action in the treatment of AAD is unknown, it is believed to be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.

The approval was based on data from two 12-week, double-blind, placebo-controlled phase 3 studies (Study 331-12-283 [ Identifier: NCT01862640] and Study 331-14-213 [ Identifier: NCT03548584]) in which patients with AAD were randomly assigned to receive either brexpiprazole or placebo.

Study participants were required to have a diagnosis of probable Alzheimer disease (according to NINCDS-ADRDA criteria), have a Mini-Mental State Examination score of at least 5 and less than or equal to 22 and have a total score of at least 4 by the agitation/aggression item of the NPI/NPI-NH, and exhibit sufficient agitation behaviors at time of entry to warrant use of pharmacotherapy, after excluding other factors.

The primary endpoint for both studies was the change from baseline in the Cohen-Mansfield Agitation Inventory (CMAI) total score at week 12. The CMAI consists of 29 items that assess the frequency and manifestations of agitated behaviors in elderly patients, based on caregiver input. Total scores range from 29 (best) to 203 (worst).

In Study 331-12-283, results showed that treatment with brexpiprazole 2mg/day significantly improved symptoms of agitation compared with placebo based on the mean change in CMAI total score from baseline to week 12 (placebo-subtracted difference: -3.8 [95% CI, -7.4, -0.2]; P <.05). A statistically significant improvement was also observed with brexpiprazole 2mg/day and 3mg/day compared with placebo in Study 331-14-213 (placebo-subtracted difference: -5.3 [95% CI, -8.8, -1.9]; P <.05).

The most common adverse reactions reported in AAD trials included nasopharyngitis and dizziness. The prescribing information for Rexulti includes a Boxed Warning regarding an increased risk of mortality in elderly patients with dementia-related psychosis; the drug is not approved for use in patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer disease. It is also not indicated for use on an as-needed basis for AAD patients.

Rexulti is supplied as tablets in 0.25mg, 0.5mg, 1mg, 2mg, 3mg, and 4mg dosage strengths. It is also indicated for use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder in adults and for the treatment of schizophrenia in adults and pediatric patients ages 13 years and older.


  1. Otsuka and Lundbeck announce US Food and Drug Administration (FDA) approval of supplemental New Drug Application (sNDA) for Rexulti® (brexpiprazole) for the treatment of agitation associated with dementia due to Alzheimer’s disease. News release. Otsuka ad Lundbeck. May 10, 2023.
  2. Package insert. Otsuka and Lundbeck; 2023. Accessed May 11, 2023.