Can Rexulti (brexpiprazole) be used to treat sundowning (evening agitation, confusion, and sleep disturbance) in an older adult with dementia?

Rexulti (Brexpiprazole) for Sundowning in Dementia

Brexpiprazole is FDA-approved specifically for agitation associated with Alzheimer's dementia and can be used for sundowning symptoms, but only after systematic evaluation of reversible medical causes and documented failure of non-pharmacological interventions, and only when the patient exhibits severe, dangerous agitation. 1, 2

Critical Prerequisites Before Prescribing Brexpiprazole

Before initiating brexpiprazole, you must systematically rule out and treat reversible medical contributors that commonly drive evening agitation in dementia patients who cannot verbally communicate discomfort 3:

• Pain assessment and management – a major contributor to behavioral disturbances 3
• Infections – urinary tract infections and pneumonia disproportionately trigger sundowning 3
• Metabolic disturbances – hypoxia, dehydration, electrolyte abnormalities, constipation, urinary retention 3
• Medication review – identify and discontinue anticholinergic agents (diphenhydramine, hydroxyzine, oxybutynin) that worsen confusion and agitation 3, 4

First-Line: Non-Pharmacological Interventions (Mandatory Before Medication)

Morning bright-light therapy is the primary evidence-based intervention for sundowning, with the strongest safety profile and efficacy data 5:

• 2 hours of bright light exposure at 3,000–5,000 lux positioned ~1 meter from the patient between 9:00–11:00 AM for 4 weeks consolidates nighttime sleep, decreases daytime napping, reduces agitated behavior, and increases circadian rhythm amplitude 5
• At least 30 minutes of daily sunlight exposure combined with physical and social activities provides temporal cues 5
• Adequate lighting during late afternoon (when sundowning peaks) reduces visual misinterpretations and confusion 5
• Avoid bright light in the evening to help consolidate the sleep-wake cycle 5

Additional environmental modifications 5:

• Establish consistent daily schedules for exercise, meals, and bedtime
• Reduce nighttime light and noise while maintaining sufficient illumination to prevent confusion
• Use calm tones, simple one-step commands, and gentle touch for reassurance
• Implement the "three R's" approach (repeat, reassure, redirect) when agitation begins 5

When Brexpiprazole Is Appropriate

Brexpiprazole should be reserved for patients who 1, 2:

• Exhibit severe agitation, distress, or pose substantial risk of harm to themselves or others
• Have documented failure of non-pharmacological interventions after adequate trial (generally ≥30 days)
• Continue to have dangerous evening/nighttime agitation despite treatment of reversible medical causes

Brexpiprazole Dosing and Administration

Brexpiprazole is a maintenance medication and should NOT be used "as needed" or PRN for breakthrough agitation 2:

• Starting dose: 0.5 mg once daily for 1 week
• Week 2: Increase to 1 mg once daily
• Week 3: Increase to 2 mg once daily (target dose for most patients)
• Maximum dose: 3 mg once daily if needed 2

Dose adjustments required for 2:

• CYP2D6 poor metabolizers or strong CYP2D6 inhibitors: Reduce dose by 50%
• Strong CYP3A4 inhibitors: Reduce dose by 50%
• Moderate to severe renal or hepatic impairment: Maximum 2 mg/day

Clinical Efficacy Data

In clinical trials, brexpiprazole 2–3 mg/day demonstrated approximately 5-point greater reduction on the Cohen-Mansfield Agitation Inventory total score at week 12 compared with placebo 2. Common adverse reactions include dizziness, headaches, insomnia, nasopharyngitis, somnolence, and urinary tract infections 2, 6.

Critical Safety Warnings (Mandatory Discussion with Surrogate)

Black-Box Warning: Increased mortality risk in elderly dementia patients 1:

• All antipsychotics, including brexpiprazole, increase mortality risk 1.6–1.7 times higher than placebo in elderly patients with dementia 3
• This risk must be discussed with the patient's surrogate decision maker before initiation 3

Additional risks 1, 6:

• Cerebrovascular adverse events (stroke risk)
• Cardiovascular effects including QT prolongation and sudden death
• Falls and orthostatic hypotension
• Metabolic changes (weight gain, diabetes risk)
• Extrapyramidal symptoms (though lower than typical antipsychotics)

Monitoring Requirements

• Daily in-person assessment during initial weeks to evaluate ongoing need and detect adverse effects 3
• Monitor for extrapyramidal symptoms, falls, sedation, metabolic changes, and cognitive worsening 3
• Evaluate response within 4 weeks using quantitative measures (Cohen-Mansfield Agitation Inventory or NPI-Q) 3
• Attempt taper within 3–6 months to determine if still needed, as approximately 47% of patients continue receiving antipsychotics without clear indication 3

Alternative Pharmacological Options (If Brexpiprazole Unavailable or Not Tolerated)

For chronic agitation without psychotic features, SSRIs are preferred first-line 3, 5:

• Citalopram 10 mg/day (maximum 40 mg/day) or Sertraline 25–50 mg/day (maximum 200 mg/day)
• SSRIs significantly reduce overall neuropsychiatric symptoms, agitation, and depression in dementia patients 3
• Require 4 weeks at adequate dosing to assess response 3

For severe acute agitation with imminent risk of harm 3:

• Risperidone 0.25–0.5 mg at bedtime (maximum 1–2 mg/day)
• Quetiapine 12.5–25 mg twice daily (maximum 200 mg twice daily) – note increased sedation and orthostatic hypotension risk

What NOT to Use for Sundowning

• Benzodiazepines (except for alcohol/benzodiazepine withdrawal) – increase delirium incidence and duration, cause paradoxical agitation in ~10% of elderly patients 3, 5
• Melatonin – American Academy of Sleep Medicine provides WEAK AGAINST recommendation; high-quality trials show no improvement in total sleep time 5
• Sleep-promoting medications – American Academy of Sleep Medicine provides STRONG AGAINST recommendation due to significantly increased risks of falls, cognitive decline, and mortality 5
• Anticholinergic antihistamines (hydroxyzine, diphenhydramine) – worsen confusion and agitation in dementia patients 4
• Typical antipsychotics (haloperidol, chlorpromazine) as first-line – 50% risk of tardive dyskinesia after 2 years of continuous use 3

Common Pitfalls to Avoid

• Do not prescribe brexpiprazole without first addressing reversible medical causes (pain, infection, metabolic disturbances) 3
• Do not use brexpiprazole PRN – it is a maintenance medication requiring daily dosing 2
• Do not continue indefinitely – review need at every visit and attempt taper within 3–6 months 3
• Do not use for mild agitation or behaviors like unfriendliness, poor self-care, repetitive questioning, or wandering – these are unlikely to respond to antipsychotics 3
• Do not skip non-pharmacological interventions – bright light therapy and environmental modifications must be attempted first 5