What is the recommended treatment approach for dementia agitation using Rexulti (brexpiprazole)?

Rexulti (Brexpiprazole) for Dementia Agitation

Brexpiprazole is the first and only FDA-approved medication specifically for treating agitation in Alzheimer's disease dementia, dosed at 2-3 mg daily, but should only be used after nonpharmacological interventions have failed and when symptoms are severe, dangerous, or causing significant distress. 1, 2

Critical Black Box Warning

Brexpiprazole carries an FDA black box warning for increased mortality risk when used in elderly patients with dementia-related psychosis—this must be discussed with patients and surrogate decision-makers before initiating treatment. 1, 2

Treatment Algorithm

Step 1: Nonpharmacological Interventions (Mandatory First-Line)

Before considering brexpiprazole, you must implement person-centered nonpharmacological strategies: 3

• Assess and treat underlying medical causes: pain (often undertreated and manifests as agitation), urinary tract infections, dehydration, constipation, and electrolyte abnormalities 3, 4
• Environmental modifications: reduce noise, optimize lighting, create predictable routines with scheduled meals and toileting 4
• Individualized activities: structured activities tailored to the patient's interests, abilities, and previous roles 5, 3
• Use quantitative measures to assess agitation severity at baseline (e.g., Cohen-Mansfield Agitation Inventory) 3

Step 2: When to Initiate Brexpiprazole

Consider brexpiprazole only when: 3, 4

• Nonpharmacological interventions have been adequately tried and failed
• Symptoms are severe, dangerous, or causing significant distress
• The potential benefits outweigh the mortality risk in this specific patient

Step 3: Dosing and Administration

Brexpiprazole is a maintenance medication—never use it "as needed" or PRN for breakthrough agitation. 2

Dosing regimen: 1, 2

• Start at 0.5-1 mg daily
• Titrate gradually to target dose of 2-3 mg daily
• Clinical trials demonstrated efficacy at 2-3 mg/day with approximately 5-point greater reduction on Cohen-Mansfield Agitation Inventory compared to placebo at 12 weeks 2

Important drug interactions: 2

• Brexpiprazole is metabolized by CYP2D6 and CYP3A4
• Dose adjustments required for strong CYP2D6 or CYP3A4 inhibitors/inducers
• Adjust dose for impaired renal or hepatic function

Step 4: Monitoring and Reassessment

Monitor closely for: 3, 2

• Common adverse effects: dizziness, headaches, insomnia, nasopharyngitis, somnolence, urinary tract infections
• Extrapyramidal symptoms (though less common than with typical antipsychotics)
• Falls and sedation
• Use quantitative measures to assess treatment response

Reassessment timeline: 3

• If no clinically significant response after 4 weeks at adequate dose, taper and discontinue
• For responders, periodically reassess need for continued medication
• If significant side effects develop, review risk/benefit balance and consider tapering

Mechanism and Evidence Base

Brexpiprazole works through partial agonism at serotonin 5-HT1A and dopamine D2 receptors, plus antagonism at serotonin 5-HT2A receptors. 2, 6 Phase 2/3 and Phase 3 trials demonstrated statistically significant efficacy for agitation reduction, though the clinical meaningfulness of the effect size (approximately SMD -0.21, similar to other atypical antipsychotics) remains debated among experts. 1, 2, 6

Key Clinical Considerations

Advantages over off-label antipsychotics: 1

• Only FDA-approved agent for this specific indication
• May be prioritized over off-label use of other antipsychotics given regulatory approval
• Generally well-tolerated safety profile in clinical trials

Critical pitfall to avoid: Do not use brexpiprazole as a first-line treatment or without attempting nonpharmacological interventions—guidelines universally emphasize that behavioral management strategies must be tried first. 5, 3, 4 The Canadian guidelines specifically note that pharmacological treatment should only occur after non-pharmacological strategies have been exhausted. 5

Documentation requirement: Always document the discussion of risks (including increased mortality) and benefits with surrogate decision-makers in the patient's chart. 3, 7