Brexpiprazole For Alzheimer’s Agitation – Is The Juice Worth The Squeeze?

Earlier this month the FDA approved Rexulti (Brexpiprazole) for the treatment of agitation in patients with dementia due to Alzheimer’s. Originally approved as an atypical antipsychotic used for schizophrenia, or an adjunct therapy for major depressive disorder, Rexulti finds itself alone as the only medication for this indication. In the clinical trials, the Cohen-Mansfield Agitation Inventory (CMAI) tool was used as the primary endpoint. In study 1 the change in placebo was 17.8 and in the Brexpiprazole 2 mg group was 21.6. This is a difference of about 4 points between the groups. When considering using brexpiprazole for Alzheimer’s agitation, is this worth it?

Let’s break down the CMAI first for those that are not aware of this scoring system. The CMAI consists of 29 items that capture different agitated behaviors, such as physically aggressive actions, verbally aggressive actions, non-aggressive physical activities, and verbally non-aggressive activities. Each item is scored on a seven-point scale based on the frequency of occurrence, ranging from “Never” (1) to “Several times an hour” (7). The items cover a wide range of behaviors, including pacing, screaming, cursing, and repetitive motions. The score can range from 29 to 203 with a higher score indicating worse behaviors.

Getting back to the research. The reduction was statistically significant, but is this clinically significant and worth the cost of the medication and associated risks? The question I always ask myself is would I recommend this medication for my parent or grandparent? I don’t think a 4-point reduction compared to placebo is that exciting on a 203-point scoring system so I’m not likely thrilled to recommend this medication and will likely hold off for now.

Also of note, there was one “no” vote on the approval from the FDA panel. In addition, there were 6 deaths in the brexpiprazole group and 1 in the placebo group. The argument was made that there were alternative justifications for the deaths. The trials also only lasted 12 weeks so we are unable to know whether or not any long-term problems from the medication exist from use in this patient population.

If You Are Going To Recommend Brexpiprazole for Alzheimer’s Agitation…

Brexpiprazole does have a variety of doses from 0.5-3mg. The study used a titration schedule increasing every week until the target dose of 2-3 mg was reached at 2 weeks. The study also showed that those that only received 1 mg of Brexpiprazole did not show statistical significance compared to placebo. As is common in geriatrics, a large number of medications can complicate a patient’s state more than solve it. The addition of a new medication may help slightly help ease aggression symptoms however we have to be mindful of ADRs, interactions, or intolerances. Brexpiprazole does work on both CYP3A4 and CYP2D6 enzymes (definitely something that could show up on board exams!). With the use of numerous agents in geriatrics, we are more likely to run into interactions. Another issue potential users may face is the cost. Rexulti cash cost at community pharmacies hovers around $1,475 for a 30-day supply. The website does offer a discount card, however, a majority of the patients this will be utilized for will be Medicare patients. Unfortunately, Part D plans do not allow for the use of these discount cards if they are the primary biller.

With this approval, we have an FDA-backed medication for the treatment of agitation due to Alzheimer’s. Brexpiprazole has been statistically shown to decrease CMAI scores in both trials significantly compared to placebo. How clinically significant this is is debatable. With possible interactions, questions about higher deaths in the treatment group, a titration period necessary prior to receiving any clinical benefit (at least 2 weeks), and the cost of the medication, there is a propensity to look toward other off-label alternatives.

What do you think about brexpiprazole for Alheimer’s agitation?

Eric Christianson, PharmD, BCPS, BCGP

4 Comments

  1. Brian J. Isetts

    Another key consideration is the use of brexpiprazole in residents of long-term care facilities as it relates to how State and CMS Surveyors view anti-psychotic medication dosage reduction requirements and principles of minimal effective doses. Just because this is the first FDA-approved treatment for agitation in patients with dementia due to Alzheimer’s disease, doesn’t mean that we can cease target behavior monitoring in residents taking this drug. I concur with you Eric – I don’t think the 4-point improvement juice is worth the squeeze, and I certainly will refrain from recommending this drug at this time. Great Post – Thanks Eric!

    Reply
    • Eric Christianson

      Thanks for the comment!

      Reply
  2. Patty Still

    I posted a link to this article, along with my comment, to psychiatrist Awais Aftab’s substack “Psychiatry at the Margins” under an article he wrote expressing the same sentiment, “Brexpiprazole’s FDA Approval for Agitation in Dementia: Is it a Game Changer? Clinically, not really… but perhaps bureaucratically?” I hope that’s okay; I will be happy to remove it. https://awaisaftab.substack.com/p/brexpiprazoles-fda-approval-for-agitation My comment: As someone with bipolar II, I rely on my pharmacist as much as I do my psychiatrist; I’m fortunate that both are very, very good. As someone who helps care for a person with early-onset Alzheimer’s, I’m not sure this is a good idea… Here’s PharmD Eric Christianson’s take: “Brexpiprazole For Alzheimer’s Agitation – Is The Juice Worth The Squeeze?” https://www.meded101.com/brexpiprazole-for-alzheimers-agitation-is-the-juice-worth-the-squeeze

    Reply
  3. Ken Lancaster

    44 years a pharmacy consultant in multiple facilities my opion is that CMS requirement for GDR’s on even very low doses of atypical antipsychotics due to the Boxed Warning concerning Dementia is sadly missing the mark. In past years I feel many antipsychotics required reductions due to higher dosages. In most recent years with low dosages of Quetiapine 25mg daily or Risperidone 0.25mg q day which I find helpful in inhanclng cognition I really feel it serves no purpose to require GDR’s which leads to use of multiple other medication’s in attempting to treat behaviors of dementia & alzherimer’s – those other medications can be just as bad side effect wise and are no better for the resident just don’t have the boxed warning concerning dementia

    Reply

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Written By Eric Christianson

June 4, 2023

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