Is it safe and appropriate to add Rexulti (brexpiprazole) to a patient with Alzheimer’s disease who is on an Exelon (rivastigmine) transdermal patch for severe agitation/aggression unresponsive to non‑pharmacologic measures?

Adding Rexulti (Brexpiprazole) to Exelon Patch for Severe Agitation in Alzheimer's Disease

Brexpiprazole can be added to rivastigmine (Exelon patch) for severe, dangerous agitation in Alzheimer's disease that has failed non-pharmacologic interventions, but only after systematic evaluation of reversible causes and with full disclosure of the FDA black-box warning regarding increased mortality risk in elderly dementia patients. 1

Mandatory Prerequisites Before Initiating Brexpiprazole

Medical Evaluation Required

• Systematically investigate and treat all reversible contributors including pain (a major driver of agitation in non-communicative patients), urinary tract infections, pneumonia, constipation, urinary retention, dehydration, electrolyte abnormalities, and medication side effects—particularly anticholinergic agents that worsen confusion. 2, 3
• Review all current medications to identify drugs that may be worsening agitation, as anticholinergic medications and other psychotropics can exacerbate behavioral symptoms. 3

Non-Pharmacologic Interventions (Must Be Attempted First)

• Implement environmental modifications including adequate lighting (especially late afternoon), reduced noise, predictable daily routines, simplified surroundings with clear labeling, and structured activities tailored to the patient's abilities. 2, 4
• Use behavioral communication strategies with calm tones, simple one-step commands, gentle reassuring touch, and allowing adequate processing time before expecting responses. 2, 3
• Provide morning bright-light exposure (2 hours at 3,000-5,000 lux) and at least 30 minutes of daily sunlight to help regulate circadian rhythms and reduce agitation. 2

Clinical Indications for Adding Brexpiprazole

When Brexpiprazole Is Appropriate

• Reserve brexpiprazole for severe, dangerous agitation that poses substantial risk of harm to the patient or others, causes significant distress, and has failed to respond adequately to non-pharmacologic interventions after a documented trial. 2, 4
• Brexpiprazole should NOT be used "as needed" or PRN—it is a maintenance medication requiring daily administration for efficacy. 5

When Brexpiprazole Should NOT Be Used

• Do not use for mild agitation or behaviors such as unfriendliness, poor self-care, repetitive questioning, wandering, or pacing, as these symptoms are unlikely to respond to antipsychotics. 3
• Avoid in patients with primarily hypoactive symptoms or when the agitation is clearly driven by untreated medical conditions. 3

Safety Considerations with Combination Therapy

Rivastigmine Continuation

• Continue the Exelon patch during brexpiprazole initiation, as cholinesterase inhibitors should be maintained in dementia patients regardless of frailty status, with careful monitoring of additive side effects. 2
• Monitor for additive adverse effects including dizziness and weight loss, as both medications can contribute to these symptoms. 2

FDA Black-Box Warning and Mortality Risk

• All antipsychotics, including brexpiprazole, carry a black-box warning for increased mortality in elderly patients with dementia-related psychosis (1.6-1.7 times higher than placebo). 1, 2
• Mandatory discussion with patient (if feasible) and surrogate decision-makers must occur before initiation, covering mortality risk, cardiovascular effects (QT prolongation, sudden death), cerebrovascular adverse events, falls risk, and metabolic changes. 2, 4

Dosing and Administration

Starting and Target Doses

• Initiate brexpiprazole at 0.5 mg once daily for the first week, then increase to 1 mg daily for week 2. 5
• Target therapeutic dose is 2-3 mg once daily, as clinical trials demonstrated significant efficacy at these doses with approximately 5-point greater reduction on Cohen-Mansfield Agitation Inventory (CMAI) compared to placebo at week 12. 5, 6
• Maximum dose is 3 mg daily for this indication. 5

Dose Adjustments

• Reduce dose by 50% in patients taking strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine) or strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole). 5
• Reduce dose in patients with moderate to severe renal or hepatic impairment, as brexpiprazole is a major substrate of CYP2D6 and CYP3A4. 5

Monitoring Protocol

Initial Assessment (Baseline)

• Use quantitative measures such as the Cohen-Mansfield Agitation Inventory (CMAI) or Neuropsychiatric Inventory Questionnaire (NPI-Q) to establish baseline severity and objective monitoring parameters. 2, 4
• Obtain baseline vital signs, weight, and metabolic parameters before starting treatment. 2

Ongoing Monitoring

• Assess response at 4 weeks using the same quantitative measure; if no clinically significant improvement after 4 weeks at adequate dosing (2-3 mg), taper and discontinue brexpiprazole. 2, 4
• Monitor for common adverse effects including dizziness (most common), headache, insomnia, nasopharyngitis, somnolence, and urinary tract infections. 5, 7
• Evaluate for extrapyramidal symptoms (though risk is low at therapeutic doses), orthostatic hypotension, falls, cognitive changes, and metabolic effects. 2, 4
• Conduct daily or frequent in-person assessments initially to evaluate ongoing need and detect adverse effects. 2

Duration of Treatment

• Use the lowest effective dose for the shortest duration necessary, with periodic reassessment (at least every 3-6 months) to determine if continued treatment is still warranted. 2, 4
• Attempt gradual taper within 3-6 months if agitation is controlled, as many patients can be successfully tapered without symptom recurrence. 2

Evidence Base and Efficacy

Clinical Trial Data

• Two phase 3 trials demonstrated efficacy of brexpiprazole 2 mg daily, with statistically significant improvements in CMAI total scores compared to placebo (adjusted mean difference -3.77 points in Study 1). 6
• Long-term extension trial (12 weeks) showed continued improvement in agitation with mean CMAI reduction of 9.1 points, with generally good tolerability. 7
• Brexpiprazole is the first and only FDA-approved medication specifically for agitation in Alzheimer's dementia, representing an important regulatory precedent. 8

Limitations of Evidence

• No head-to-head trials comparing brexpiprazole to other antipsychotics exist, and there is debate whether the magnitude of CMAI score reduction translates to clinically meaningful improvement in real-world practice. 5
• Benefits are modest—as with all antipsychotics in dementia, effect sizes are small (SMD -0.21 for atypical antipsychotics overall). 4

Critical Pitfalls to Avoid

• Do not initiate brexpiprazole without first addressing reversible medical causes of agitation, as this is the most common error leading to unnecessary antipsychotic exposure. 2, 3
• Do not use brexpiprazole as a PRN medication—it requires daily dosing to achieve therapeutic effect. 5
• Do not continue indefinitely without reassessment—approximately 47% of patients remain on antipsychotics after discharge without clear ongoing indication. 2
• Do not combine with benzodiazepines routinely, as this increases risk of oversedation, respiratory depression, and falls in elderly patients. 2, 3
• Do not exceed 3 mg daily or use in patients without documented failure of non-pharmacologic interventions. 5, 2