Can Brexiprazole (brexiprazole) be used as a single medication for agitation in patients with dementia?

Brexiprazole as Monotherapy for Agitation in Dementia

Brexiprazole can be used as a single medication for agitation in patients with dementia due to Alzheimer's disease, but only after non-pharmacological interventions have been exhausted, and it is FDA-approved specifically at doses of 2 mg/day or 3 mg/day for this indication. 1

Non-Pharmacological Interventions Must Come First

Before considering brexiprazole or any antipsychotic medication, you must implement non-pharmacological strategies 2, 3:

• Assess and treat reversible causes of agitation including pain (often undertreated in dementia), infections, constipation, and environmental stressors 2, 3
• Implement structured routines with predictable schedules for meals, exercise, and bedtime 4
• Modify the environment by reducing noise, optimizing lighting, removing clutter, and ensuring safety features like grab bars 4
• Use behavioral techniques including the "three R's" (repeat, reassure, redirect) and distraction strategies 4

When to Consider Brexiprazole

Brexiprazole should only be initiated when 2, 3:

• Symptoms are severe, dangerous, or cause significant distress to the patient 2, 3
• Non-pharmacological interventions have failed to adequately control agitation 2, 3
• The potential benefits outweigh the substantial risks, including increased mortality 2, 3

FDA-Approved Dosing and Administration

The only FDA-approved doses for agitation in Alzheimer's dementia are 2 mg/day and 3 mg/day 1:

• Start at 0.5 mg once daily for Days 1-7 1
• Increase to 1 mg once daily on Day 8 1
• Increase to 2 mg once daily on Day 15 (target dose) 1
• May increase to 3 mg once daily after 2 weeks at 2 mg if needed 1
• The 1 mg dose is NOT approved and NOT recommended for this indication, as it failed to demonstrate efficacy in clinical trials 1

Critical point: Brexiprazole is a maintenance medication and should NOT be used "as needed" or PRN for breakthrough agitation 5

Evidence of Efficacy

In two Phase 3 trials involving 778 patients with agitation in Alzheimer's dementia 1, 6:

• Brexiprazole 2 mg/day showed statistically significant improvement on the Cohen-Mansfield Agitation Inventory (CMAI) compared to placebo, with a placebo-subtracted difference of approximately -3.8 to -5.3 points at Week 12 1, 6
• The effect size is modest (SMD approximately -0.21), and there is debate about whether this represents a clinically meaningful difference 3, 5
• Brexiprazole is the first and only FDA-approved medication specifically for agitation in Alzheimer's dementia 7, 5

Critical Safety Warnings

Black Box Warning: Increased Mortality

Brexiprazole carries a black box warning for increased mortality in elderly patients with dementia-related psychosis 1, 7:

• This risk applies to the entire class of antipsychotic medications 1
• Six deaths (0.9%) occurred in brexiprazole-treated patients versus 1 death (0.3%) in placebo groups during 12-week trials 8
• You must discuss this mortality risk with the patient (if feasible) and surrogate decision-makers before initiating treatment 2, 3

Other Important Safety Considerations

Monitor closely for 1, 8:

• Cerebrovascular events (stroke risk) - occurred in 0.5% of brexiprazole patients versus 0.3% of placebo 8
• Extrapyramidal symptoms - occurred in 5.3% versus 3.1% with placebo 8
• Somnolence/sedation - occurred in 3.7% versus 1.8% with placebo 8
• Falls and orthostatic hypotension 2, 1
• Worsening cognition (though minimal changes were observed in trials) 8

Common adverse events (≥5% incidence) include headache, dizziness, insomnia, nasopharyngitis, somnolence, and urinary tract infections 5, 8

Monitoring and Duration of Treatment

Implement a structured monitoring protocol 2, 3:

• Use quantitative measures (like CMAI) to assess treatment response 2, 3
• If no clinically significant response after 4 weeks at adequate dosing, taper and discontinue the medication 2, 3
• For responders, regularly reassess the need for continued treatment - antipsychotics should be used for the shortest duration necessary 2, 3
• Monitor for extrapyramidal symptoms, orthostatic hypotension, and cognitive changes at each visit 2

Drug Interactions

Brexiprazole is a major substrate of CYP2D6 and CYP3A4 5:

• Reduce dose by 50% when used with strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine) 5
• Reduce dose by 50% when used with strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole) 5
• Reduce dose by 75% when used with both strong CYP2D6 AND CYP3A4 inhibitors 5
• Double the dose when used with strong CYP3A4 inducers (e.g., rifampin, carbamazepine) 5

Comparison to Other Options

While brexiprazole is the only FDA-approved option for this specific indication 7, 5:

• No head-to-head trials exist comparing brexiprazole to other antipsychotics like quetiapine or risperidone 5
• Guidelines previously suggested quetiapine (starting at 12.5 mg twice daily) or low-dose risperidone for agitation in dementia 2
• The FDA approval of brexiprazole may lead to its prioritization over off-label use of other antipsychotics 7
• Emerging alternatives include escitalopram and dextromethorphan-bupropion, currently in clinical trials 5

Common Pitfalls to Avoid

• Do not use the 1 mg dose - it is not approved and showed no efficacy 1
• Do not use brexiprazole PRN - it requires daily dosing as maintenance therapy 5
• Do not skip non-pharmacological interventions - they must be attempted first 4, 2, 3
• Do not continue indefinitely without reassessment - regularly evaluate whether continued treatment is necessary 2, 3
• Do not forget to discuss mortality risk with decision-makers before starting 2, 3