Can Rexulti (brexpiprazole) be used to treat sundowning (evening agitation and confusion) in a patient with dementia?

Rexulti (Brexpiprazole) for Sundown Syndrome in Dementia

Brexpiprazole is FDA-approved specifically for agitation in Alzheimer's dementia and can be used for sundowning (evening agitation), but only after systematic evaluation of reversible causes and failure of non-pharmacological interventions, with mandatory discussion of increased mortality risk with the patient's surrogate decision-maker. 1, 2

Prerequisites Before Prescribing Brexpiprazole

Before initiating brexpiprazole for sundowning, you must systematically rule out and treat reversible medical contributors:

• Pain assessment and management – a major driver of behavioral disturbances in patients who cannot verbally communicate discomfort 3, 1
• Infections – check for urinary tract infections and pneumonia, which frequently precipitate agitation 3, 1
• Metabolic disturbances – evaluate for hypoxia, dehydration, electrolyte abnormalities, constipation, and urinary retention 3, 1
• Medication review – identify and discontinue anticholinergic agents that worsen confusion and agitation 3, 1

Non-Pharmacological Interventions (Mandatory First-Line)

Implement these evidence-based strategies before considering brexpiprazole:

Circadian Rhythm Regulation for Sundowning

• Morning bright-light therapy – 2 hours at 3,000–5,000 lux over 4 weeks decreases daytime napping, increases nighttime sleep, and reduces agitated behavior 3
• Adequate late-afternoon lighting – ensures proper illumination during peak sundowning hours to reduce visual misinterpretations 3
• Daily sunlight exposure – at least 30 minutes combined with physical and social activities provides temporal cues 3
• Limit daytime bed rest – reduces time in bed during the day to consolidate nighttime sleep 3

Environmental and Behavioral Modifications

• Structured daily routines – predictable schedules for meals, exercise, and bedtime 3, 1
• Environmental simplification – reduce noise, optimize lighting, remove clutter, install safety features 3, 1
• Communication strategies – calm tones, simple one-step commands, gentle touch, adequate processing time 3, 1

When to Consider Brexpiprazole

Brexpiprazole should only be initiated when:

• Symptoms are severe, dangerous, or cause significant distress to the patient 1, 2
• Non-pharmacological interventions have been exhausted and documented as failed 1, 2
• The patient is severely agitated, threatening substantial harm to self or others 3, 1
• Potential benefits outweigh the substantial mortality risk 1, 2

Dosing and Administration

• Starting dose: Brexpiprazole 0.5–1 mg/day orally 1, 2
• Target dose: 2–3 mg/day (FDA-approved doses for agitation in Alzheimer's dementia) 2, 4, 5
• Titration: Gradual upward adjustment to minimize adverse effects 1, 2
• Timing consideration: For sundowning specifically, consider dosing in late-afternoon/early-evening to align drug exposure with symptom onset 3
• Important: Brexpiprazole is a maintenance medication and should NOT be used "as needed" or PRN for breakthrough agitation 4

Critical Safety Discussion Required

Before initiating brexpiprazole, you MUST discuss with the patient (if feasible) and surrogate decision-maker:

• Increased mortality risk – 1.6–1.7 times higher than placebo in elderly patients with dementia-related psychosis 2, 6
• Cardiovascular effects – including heart failure, sudden death 2
• Cerebrovascular adverse events – stroke risk 2
• Other risks – falls, pneumonia, extrapyramidal symptoms 2, 6

Monitoring Requirements

• Quantitative assessment – use Cohen-Mansfield Agitation Inventory (CMAI) to establish baseline and monitor response 1, 4
• Response evaluation – assess after 4 weeks of adequate dosing; if no clinically significant response, taper and discontinue 1
• Ongoing reassessment – regularly evaluate need for continued treatment; use lowest effective dose for shortest duration 1, 2
• Adverse effect monitoring – watch for extrapyramidal symptoms, orthostatic hypotension, cognitive changes, weight gain 1, 6

Efficacy Data

• Clinical trials demonstrated approximately 5-point greater reduction on CMAI total score at week 12 compared with placebo 4
• Headache was the only adverse event with incidence ≥5% (7.6% brexpiprazole vs 9.3% placebo) 6
• Generally well tolerated with minimal weight change, suicidality, and extrapyramidal symptoms over 12–24 weeks 6

Common Pitfalls to Avoid

• Do NOT initiate brexpiprazole without first addressing reversible medical causes (pain, infection, metabolic issues) 3, 1
• Do NOT use brexpiprazole as a PRN medication – it is a maintenance treatment requiring daily dosing 4
• Do NOT continue indefinitely – attempt taper within 3–6 months to determine lowest effective maintenance dose 3
• Do NOT skip the mandatory mortality risk discussion with surrogate decision-makers 1, 2

Drug Interactions

• Brexpiprazole is a major substrate of CYP2D6 and CYP3A4 4
• Dose adjustments required for drug interactions or impaired renal/hepatic function 4

Real-World Evidence

• A 2025 Medicare claims study of 41,871 beneficiaries with dementia found 6-month mortality was statistically lower among brexpiprazole users compared to aripiprazole users (OR 0.49,95% CI 0.37–0.65) 7
• No statistical difference in emergency department visits or hospitalizations within 6 months 7

Alternative Considerations

If brexpiprazole is not appropriate or fails:

• SSRIs (citalopram or sertraline) – first-line for chronic agitation without psychotic features 3
• Low-dose risperidone (0.25–0.5 mg) – for severe agitation with psychotic features 3, 8
• Quetiapine (12.5 mg twice daily) – alternative atypical antipsychotic, though more sedating 3, 9

Note: Brexpiprazole represents the first and only FDA-approved pharmacologic agent for agitation in Alzheimer's dementia, making it a regulatory precedent for this indication 5.