Can Rexulti (brexpiprazole) help with sundowning in patients with dementia?

Rexulti for Sundowning in Dementia

Rexulti (brexpiprazole) is FDA-approved specifically for agitation associated with Alzheimer's dementia and has demonstrated efficacy in reducing late-day hyperactivity in animal models that correlate with sundowning, making it a reasonable treatment option for this symptom when severe, dangerous, or causing significant distress. 1, 2

FDA Approval and Indication

Rexulti received FDA approval in May 2023 for treating agitation associated with dementia due to Alzheimer's disease 1. Importantly, it is approved as a maintenance medication, not for "as needed" or PRN use 1. This is critical for sundowning, which typically follows a predictable temporal pattern.

Evidence for Sundowning Specifically

While clinical trials primarily measured overall agitation, preclinical data directly addresses the sundowning phenomenon:

• In APPSL-Tg mice (an Alzheimer's model), brexpiprazole at 0.01-0.03 mg/kg significantly reduced hyperlocomotion during late dark period (ZT20-24), which corresponds to late afternoon/evening agitation seen clinically in sundowning 2
• This temporal pattern of efficacy aligns with the classic presentation of sundowning in Alzheimer's patients

Clinical Trial Evidence

Multiple high-quality trials demonstrate efficacy for agitation:

• Brexpiprazole 2-3 mg showed approximately 5-point greater reduction in Cohen-Mansfield Agitation Inventory (CMAI) scores versus placebo at 12 weeks (P = 0.003; effect size 0.35) 3
• The 2 mg dose appears optimal, balancing efficacy with tolerability 4
• Benefits extended to reducing caregiver distress, not just patient symptoms 5
• Long-term data (up to 24 weeks) shows continued improvement and acceptable tolerability 6

Critical Safety Considerations

Black Box Warning: Increased mortality risk in elderly patients with dementia-related psychosis 1. This must be discussed with patients and surrogate decision-makers before initiating treatment.

Additional safety concerns:

• Cerebrovascular events (stroke, TIA) in elderly dementia patients 1
• Metabolic changes (hyperglycemia, dyslipidemia, weight gain) 1
• Falls (reported in 2.3% during extension trials) 6
• Orthostatic hypotension, particularly early in treatment 1

Treatment Algorithm

When to Use:

1. Sundowning symptoms are severe, dangerous, or cause significant patient distress 7
2. After attempting nonpharmacological interventions first (unless emergency situation) 7, 8
3. After assessing for modifiable contributors (pain, infection, medication effects, environmental triggers) 7

Dosing Strategy:

• Start: 0.5 mg once daily 1
• Target: 2 mg once daily (optimal efficacy/tolerability balance) 1, 4
• Maximum: 3 mg once daily 1
• Administer in the morning or early afternoon (not evening) to avoid exacerbating sleep disturbances
• Titrate slowly over weeks, not days

Dose Adjustments:

• CrCl <60 mL/min: Maximum 2 mg daily 1
• Moderate-severe hepatic impairment: Maximum 2 mg daily 1
• CYP2D6 poor metabolizers or strong CYP2D6/3A4 inhibitors: Reduce dose by 50% 1

Monitoring Requirements

Before initiating:

• Baseline metabolic panel (glucose, lipids, weight, BMI)
• Blood pressure (orthostatic measurements)
• CBC if history of leukopenia 1
• Document baseline agitation severity with quantitative measure 7

During treatment:

• Assess response at 4 weeks; if no clinically significant improvement, taper and discontinue 7
• Monitor for falls, sedation, extrapyramidal symptoms
• Reassess metabolic parameters at 12 weeks, then periodically
• Attempt dose reduction or discontinuation after 3-4 months of stability to determine ongoing need 7

Common Pitfalls to Avoid

1. Using as PRN medication - This is explicitly contraindicated; brexpiprazole requires consistent daily dosing 1
2. Skipping nonpharmacological approaches - Guidelines strongly recommend these first unless emergency 7, 8
3. Continuing indefinitely without reassessment - Regular attempts at dose reduction are recommended 7
4. Ignoring the mortality warning - This must be part of informed consent discussions 7, 1
5. Rapid titration - Start low, go slow in this vulnerable population

Comparison to Alternatives

While no head-to-head trials exist, brexpiprazole offers advantages over traditional antipsychotics:

• First and only FDA-approved agent specifically for agitation in Alzheimer's dementia 1, 9
• Lower risk of extrapyramidal symptoms compared to typical antipsychotics
• Partial agonist activity at D2/5-HT1A receptors may provide better tolerability than full antagonists 10

The APA guidelines note that benefits of all antipsychotics in dementia are "at best small" with consistent evidence of significant adverse effects including mortality 7. This underscores the importance of careful patient selection and ongoing risk-benefit assessment.

Patient Subgroups

Post hoc analyses suggest particular benefit in patients with:

• Co-occurring psychosis 11
• Co-occurring sleep disturbance 11
• Concomitant antidepressant use 11

These characteristics often accompany sundowning, supporting brexpiprazole's use in this context.