What is the role of Rexulti (brexpiprazole) in treating Alzheimer's disease?

Brexpiprazole (Rexulti) in Alzheimer's Disease

Brexpiprazole is FDA-approved only for treating agitation associated with dementia due to Alzheimer's disease, but carries a black box warning about increased mortality in elderly patients with dementia-related psychosis. 1

FDA Approval Status and Warning

Brexpiprazole (Rexulti) has received FDA approval specifically for the treatment of agitation associated with dementia due to Alzheimer's disease. However, it carries a significant black box warning that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death 1. The FDA label explicitly states: "Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Brexpiprazole is not approved for the treatment of patients with dementia-related psychosis." 1

This creates an important distinction - brexpiprazole is approved for agitation in Alzheimer's dementia but not for psychosis in these patients.

Efficacy for Agitation in Alzheimer's Disease

Brexpiprazole has demonstrated efficacy in treating agitation in Alzheimer's disease:

• It is the first FDA-approved pharmacologic agent specifically for agitation associated with dementia due to Alzheimer's disease 2
• Clinical trials showed brexpiprazole 2-3 mg/day produced significant improvements in agitation, with approximately a 5-point greater reduction on the Cohen-Mansfield Agitation Inventory (CMAI) total score compared to placebo at 12 weeks 2
• Its mechanism of action involves partial serotonin 5-HT1A and dopamine D2 receptor agonist activity along with serotonin 5-HT2A receptor antagonism 2

Safety Profile and Considerations

Despite its efficacy, several important safety considerations exist:

• Common adverse reactions include dizziness, headaches, insomnia, nasopharyngitis, somnolence, and urinary tract infections 2
• Like other antipsychotics, brexpiprazole is associated with higher mortality rates in elderly patients with dementia compared to placebo 2
• In pooled safety data from clinical trials, 51.1% of participants on brexpiprazole reported at least one treatment-emergent adverse event compared to 45.9% on placebo 3
• The incidence of cerebrovascular events (0.5% vs 0.3%), cardiovascular events (3.7% vs 2.3%), and extrapyramidal symptoms (5.3% vs 3.1%) were generally similar between brexpiprazole and placebo 3

Dosing and Administration

Brexpiprazole should be used as a maintenance medication, not as an "as needed" or "PRN" treatment for breakthrough agitation 2. Important dosing considerations include:

• It is a major substrate of CYP2D6 and CYP3A4, requiring dose adjustments for drug interactions or impaired renal/hepatic function 2
• The effective dose range in clinical trials was 2-3 mg/day 4
• The maximum recommended dosage in patients with moderate to severe hepatic impairment or creatinine clearance <60 mL/minute is 3 mg once daily 1

Alternative Treatments for Alzheimer's Disease

For cognitive symptoms of Alzheimer's disease (not agitation), other FDA-approved medications include:

• Cholinesterase inhibitors: donepezil, rivastigmine, and galantamine 5
• NMDA receptor antagonist: memantine 5
• Disease-modifying drugs: aducanumab and lecanemab (targeting amyloid-beta plaques) 5

Clinical Decision Algorithm for Brexpiprazole Use in Alzheimer's Disease

1. Confirm diagnosis: Ensure patient has Alzheimer's disease with clinically significant agitation
2. Try non-pharmacological interventions first: These should be the initial approach for behavioral symptoms 6
3. Consider brexpiprazole when:
   • Non-pharmacological interventions have failed
   • Agitation is severe enough to cause distress or danger
   • Patient has no contraindications
4. Start at low dose: Begin with lowest effective dose and titrate slowly
5. Monitor closely for:
   • Cardiovascular events
   • Cerebrovascular events
   • Extrapyramidal symptoms
   • Cognitive decline
6. Reassess regularly: Evaluate continued need for medication and consider discontinuation if possible

Important Caveats

• Brexpiprazole has not been studied in head-to-head clinical trials against other antipsychotics 2
• There are differing opinions on whether the agitation score reductions translate to clinically meaningful differences 2
• The black box warning regarding increased mortality must be carefully considered when prescribing 1
• Post-marketing surveillance will be crucial to better understand the long-term safety profile 4