A Review of using Brexpiprazole (Rexulti®) in treating Agitation in Alzheimer's Patients

 

 

Rexulti (brexpiprazole) was  approved by the FDA in 2023 for treating agitation associated with Alzheimer’s dementia, but because of its increased risk of death, guidelines recommend Rexulti only when agitation is severe, distressing, and non-drug approaches have not worked. Here’s a clear overview of the non-drug (behavioral and environmental) strategies that are recommended before starting medications like Rexulti:

 

 

Care Pathway for Agitation with Dementia

 

Step 1: Identify Triggers (Always Start Here)

 

  • Look for causes of agitation: pain, hunger, constipation, infection, noise, overstimulation, or boredom.

  • Treat or remove the trigger whenever possible.

 

Step 2: Try Non-Drug Strategies First

 

Environmental Adjustments

  • Calm, consistent surroundings

  • Reduce noise and clutter

  • Good lighting, especially in the evening

 

Communication Approaches

  • Speak calmly and simply

  • Validate feelings, avoid arguing

  • Redirect with reassurance

 

Daily Activities & Engagement

  • Gentle exercise (walking, stretching)

  • Music, art, or simple household tasks

  • Safe sensory stimulation (aromatherapy, pet therapy, tactile items)

 

Comfort & Routine

  • Predictable schedule for meals, rest, and toileting

  • Massage, touch therapy, or calming rituals

  • Provide snacks and hydration regularly

 

Step 3: Evaluate Response

 

  • If agitation improves → continue non-drug strategies.

  • If agitation is mild but manageable → keep monitoring and adjusting environment.

  • If agitation is severe, dangerous, or causes major distress despite trying non-drug approaches → consider medication.

 

Step 4: Consider Medication (Last Resort)

 

  • Used only when non-drug methods fail and agitation poses a risk to patient or caregivers.

  • Options include antipsychotics such as Rexulti.

  • Always weigh benefit vs. risk

 

 

Step 5: Monitor & Reassess

 

  • If a medication is started, use the lowest effective dose.

  • Reassess regularly — can the drug be reduced or stopped later?

  • Continue non-drug supports even while on medication.

Weighing Pros and Cons 

 

 

NUMBER NEEDED TO TREAT (NNT)

 

Clinical trials shows patients receiving Rexulti has significantly greater reduction in agitation scores measured by Cohen-Mansfield Agitation Inventory.

 

For a clinically meaningful CMAI improvement (≥20 points) the NNT ≈ 9 (i.e., ~1 in 9 additional patients will respond compared with placebo in trials). (5)

 

The effect is modest and variable — the 5-point CMAI improvement may not translate into dramatic clinical benefit for everyone.

 

Though effects are considered modest, agitation can be very distressing for both patients and caregivers, so even small improvements are meaningful.

 

 

 

HOW SOON CAN BREXPIPRAZOLE'S EFFECTS START? 

 

Though it may be plausible that some patients show early calming effects in the first 1–2 weeks, the primary trials confirmed benefit is at or by 12 weeks.

NUMBER NEEDED TO HARM (NNH)

 

Common side effects of Rexulti are weight gain, sleepiness, and restlessness. (4) Overall discontinuation rates due to adverse events were similar between brexpiprazole and placebo in the pivotal trial.

 

Rexulti carries a boxed warning:

Increased risk of death in elderly patients with dementia-related psychosis. Most deaths are due to cardiovascular events (e.g., stroke, heart attack) or infections (e.g., pneumonia).

This risk is present across all atypical antipsychotics (like risperidone, olanzapine, quetiapine, aripiprazole) for psychosis or behavioral symptoms in dementia. 

 

The NNH, which estimates how many patients need to be treated before one experiences a significant adverse effect. The number needed to harm (NNH) for death with atypical antipsychotics in patients with dementia varies by agent and comparison group, ranging from approximately 27 to 100 patients over 6 months.

 

NNH Compared to No Treatment

A large Veterans Health Administration study of 90,786 patients with dementia calculated NNH values over 180 days comparing antipsychotic users to matched nonusers: (9)

  • Risperidone: NNH = 27 
  • Olanzapine: NNH = 40  
  • Quetiapine: NNH = 50 
  • Haloperidol: NNH = 26

 

NNH Compared to Antidepressants

When comparing antipsychotic users directly to antidepressant users (rather than nonusers), the mortality risk and corresponding NNH values were even more concerning: (9)

  • Haloperidol: NNH = 8 
  • Risperidone: NNH = 21 
  • Olanzapine: NNH = 24
  • Quetiapine: NNH = 31 

 

These NNH values are substantially lower (indicating greater harm) than previously reported from randomized controlled trials.[1] The original meta-analysis by Schneider et al. in 2005 reported an NNH of 100 for atypical antipsychotics over 8-12 weeks, and a subsequent Agency for Healthcare Research and Quality review found an NNH of 87.

 

The discrepancy between RCT-based estimates (NNH ~87-100) and observational study estimates (NNH ~27-50) likely reflects differences in patient populations, treatment duration, and confounding by indication. The absolute effect of antipsychotics on mortality in elderly patients with dementia may be higher than previously reported from clinical trials.

 

 

Antipsychotics in Dementia: What Caregivers Should Know

 

Used for: Severe agitation or behavioral issues in dementia.

 

Risks:

Starting treatment: People are most vulnerable in the first 4–6 months after beginning an antipsychotic, so close monitoring is important. Higher doses increase risk.

 

Age: Older adults have a higher risk, which increases with each year of age.

 

Other medications: Using benzodiazepines (like some sleep or anxiety medicines) along with antipsychotics greatly increases risk. Other psychotropic medications can also add risk.

 

Medication choice: Haloperidol and risperidone carry higher risk than olanzapine or quetiapine.

 

Benefits: Often modest; may help reduce dangerous behaviors and improve comfort.

 

Safety tips:

Start with the lowest effective dose

Monitor closely during the first months

Discuss risks and alternatives with the doctor

 

Bottom line:

Antipsychotics can help in specific situations, but careful use and close monitoring are essential.

 

 

 

IN Summary of Rexulti (Brexpiprazole) for Agitation in Dementia

 

What it does: Rexulti is not for memory or thinking problems. It is used specifically to help manage agitation in people with dementia.

 

Effectiveness: In studies, doses of 2–3 mg per day helped reduce agitation more than a placebo over 12 weeks. The benefit is modest but meaningful. About 1 in 9 people may experience a noticeable improvement.

 

Side effects: Common effects include sleepiness, restlessness, and weight gain. Most people tolerate the medication, and rates of stopping it due to side effects were similar to placebo.

 

Important safety note: Like other similar antipsychotic medicines, Rexulti carries a small increased risk of death in older adults with dementia-related psychosis. The exact risk for Rexulti alone isn’t known, so it’s important to talk with your doctor about your loved one’s individual risks before starting treatment.

References:

1. Porsteinsson, A. P., Mintzer, J., Schneider, L. S., et al. (2023). Brexpiprazole for the treatment of agitation in Alzheimer dementia: A randomized clinical trial. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2023.XXXX 

2. Shah, A., et al. (2025). Safety and tolerability of brexpiprazole in participants with agitation associated with dementia due to Alzheimer’s disease: pooled analysis of randomized trials and an extension. CNS Drugs. 

3. Schneider, L. S., Dagerman, K., & Insel, P. (2005). Risk of death with atypical antipsychotic drug treatment for dementia: Meta-analysis of randomized placebo-controlled trials. JAMA, 294(15), 1934–1943. https://doi.org/10.1001/jama.294.15.1934.

4. U.S. Food and Drug Administration. (2023 / 2025). REXULTI® (brexpiprazole) prescribing information

5. NeurologyLive / post-hoc reports and pooled analyses summarizing NNT/NNH and likelihood-to-be-helped-or-harmed (LHH) for brexpiprazole (2024–2025). 

6. Lee, D., Slomkowski, M., Hefting, N., et al. (2023). Brexpiprazole for the treatment of agitation in Alzheimer dementia: A randomized clinical trial. JAMA Neurology, 80(12), 1307–1316. https://doi.org/10.1001/jamaneurol.2023.3810

7. da Silva, A. M. P., Falcão, L., Ribeiro Gonçalves, O., et al. (2025). Brexpiprazole for the treatment of agitation in older adults with Alzheimer’s disease: A systematic review, Bayesian meta-analysis, and meta-regression. CNS Drugs. Advance online publication. https://doi.org/10.1007/s40263-025-01219-y

8. U.S. Food and Drug Administration. (n.d.). Orange Book: Approved drug products with therapeutic equivalence evaluations. U.S. Food and Drug Administration.

9. Maust, D. T., Kim, H. M., Seyfried, L. S., et al. (2015). Antipsychotics, other psychotropics, and the risk of death in patients with dementia: Number needed to harm. JAMA Psychiatry, 72(5), 438–445. https://doi.org/10.1001/jamapsychiatry.2014.3018

10. American Psychiatric Association. (n.d.). The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. American Psychiatric Association.

11. Reus, V. I., Fochtmann, L. J., Eyler, A. E., et al. (2016). The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. The American Journal of Psychiatry, 173(5), 543–546. https://doi.org/10.1176/appi.ajp.2015.173501