Rexulti (Brexpiprazole) in Geriatric Patients: Benefits, Risks, and Clinical Considerations
Brexpiprazole (Rexulti) was FDA-approved in July 2015 for schizophrenia and major depressive disorder, with subsequent approval in May 2023 for agitation associated with Alzheimer's disease dementia 12. While brexpiprazole is NOT specifically listed on the 2019 AGS Beers Criteria, all antipsychotics as a class carry strong warnings for use in older adults, particularly those with dementia, due to increased mortality risk 33.
FDA Approval Timeline
- Initial approval: July 2015 for schizophrenia and adjunctive treatment of major depressive disorder 1
- Expanded indication: May 2023 for agitation associated with dementia due to Alzheimer's disease 2
Beers Criteria Status
Brexpiprazole itself is not individually named in the 2019 AGS Beers Criteria, but this does not mean it's safe for routine use in older adults. The Beers Criteria explicitly state that antipsychotics as a class should generally be avoided in older adults except for specific conditions (schizophrenia, bipolar disorder, or short-term use as antiemetic during chemotherapy) 33. The rationale is clear: antipsychotics in older adults increase risk of stroke, cognitive decline, mortality, falls, fractures, and delirium 33.
Critical Caveat
The 2019 Beers Criteria recognize limited exceptions for Parkinson's disease psychosis (quetiapine, clozapine, pimavanserin), but note that even these "excepted drugs" are far from ideal 33. Brexpiprazole's 2023 approval for Alzheimer's agitation came after the 2019 Beers update, so it was not specifically evaluated.
Benefits in Geriatric Populations
For Agitation in Alzheimer's Disease (Ages 51-90)
Brexpiprazole 2 mg daily demonstrates the most favorable benefit-risk profile for agitation associated with Alzheimer's dementia 4. In two 12-week placebo-controlled trials (N=503 patients aged 51-90):
- CMAI score improvement: -5.88 points versus placebo (95% CI: -8.13 to -3.63) 4
- CGI-S improvement: -0.48 points versus placebo 4
- NPI-NH improvement: -4.60 points with 2-3 mg doses 4
- Continuation rate: 94.4% completed treatment (only 5.6% discontinued due to adverse events) 5
For Schizophrenia in Elderly (≥65 years)
In a 56-week open-label study of elderly Japanese patients with schizophrenia 6:
- PANSS total score improvement: -13.8 points from baseline, maintained throughout 56 weeks
- Continuation rate: 54.5% at week 56
- Efficacy comparable to non-elderly patients
For Major Depressive Disorder (≥65 years)
In a 26-week open-label study of adjunctive brexpiprazole 7:
- MADRS improvement: -14.5 points from baseline
- CGI-S improvement: -1.8 points
- Completion rate: 66.7%
Risks and Adverse Events in Geriatric Patients
Common Problems (Incidence ≥2%)
From FDA-approved trials in Alzheimer's agitation (ages 51-90) 5:
| Adverse Event | Placebo | Brexpiprazole 2mg | Brexpiprazole 3mg |
|---|---|---|---|
| Headache | 8% | 9% | 9% |
| Somnolence/Sedation | 1% | 2% | 4% |
| Dizziness/Vertigo | 2% | 1% | 5% |
| Nasopharyngitis | 2% | 4% | 2% |
| Urinary Tract Infection | 1% | 2% | 3% |
| Insomnia | 3% | 5% | 5% |
How Common Are Serious Problems?
Treatment-emergent adverse events (TEAEs):
- Elderly patients with schizophrenia: 97.0% experienced any TEAE, but most were mild (75.8%) or moderate (18.2%) 6
- Elderly patients with MDD: 77.3% experienced any TEAE, mostly mild-moderate 7
- Alzheimer's agitation trials: Overall TEAE rate 1.20-1.33 times higher than placebo 4
Discontinuation due to adverse events:
- Alzheimer's agitation: 5.6% (vs 4.8% placebo) 5
- Elderly schizophrenia: 9.1% (lower than 13.1% in non-elderly) 6
- Elderly MDD: 18.2% 7
Extrapyramidal Symptoms (EPS)
EPS risk is lower than many antipsychotics but still present 5:
- Akathisia: 1% in Alzheimer's trials (vs 0% placebo)
- EPS-related events (excluding akathisia): 3% (vs 2% placebo)
- Shift from normal to abnormal on SAS: 6% (vs 2% placebo)
- In elderly schizophrenia: Most common were nasopharyngitis (30.3%) and worsening schizophrenia (27.3%) 6
Black Box Warnings (FDA Label) 5
1. Increased Mortality in Elderly Patients with Dementia-Related Psychosis
- This is a class-wide black box warning for all antipsychotics
- Elderly patients with dementia-related psychosis treated with antipsychotics have increased risk of death
- Brexpiprazole is NOT approved for dementia-related psychosis except specifically for agitation in Alzheimer's disease
2. Cerebrovascular Adverse Events
- Increased risk of stroke and transient ischemic attacks in elderly dementia patients 5
Other Serious Risks in Elderly 55:
- Orthostatic hypotension and falls: May cause dizziness, lightheadedness, syncope when rising from sitting/lying position
- Metabolic changes: Hyperglycemia, diabetes, dyslipidemia, weight gain
- Neuroleptic malignant syndrome (NMS): Rare but potentially fatal
- Tardive dyskinesia: May be irreversible, even after discontinuation
- Cognitive impairment: Increased sedation, drowsiness, difficulty thinking
- Aspiration pneumonia: Due to dysphagia
- Temperature dysregulation
- Seizures
Clinical Decision Algorithm for Geriatric Use
Step 1: Determine Indication
Is the patient's condition one of the following?
- Agitation associated with Alzheimer's dementia (FDA-approved)
- Schizophrenia (FDA-approved)
- Treatment-resistant major depressive disorder as adjunct (FDA-approved)
If NO: Do not use brexpiprazole. Consider non-pharmacological interventions first.
Step 2: Assess Contraindications
Screen for absolute contraindications:
- Known hypersensitivity to brexpiprazole
- Severe cardiovascular disease with recent stroke/TIA
- Uncontrolled diabetes or severe metabolic syndrome
- History of neuroleptic malignant syndrome
Step 3: Risk Stratification
High-risk patients (use extreme caution or avoid):
- Dementia-related psychosis other than Alzheimer's agitation
- History of falls or fractures
- Parkinson's disease (brexpiprazole not an exception like quetiapine/clozapine/pimavanserin)
- Orthostatic hypotension
- Swallowing difficulties
- Polypharmacy with CNS depressants
Step 4: Dosing Strategy for Alzheimer's Agitation
Start low, go slow, target 2 mg:
- Week 1-2: 0.5 mg once daily
- Week 3-4: 1 mg once daily
- Week 5+: 2 mg once daily (optimal dose per evidence) 4
- Maximum: 3 mg daily (only if 2 mg insufficient and well-tolerated)
Do NOT use 1 mg as maintenance dose—FDA label explicitly states this is not a recommended dosage 5.
Step 5: Monitoring Protocol
Baseline assessments:
- Fasting glucose and HbA1c
- Lipid panel
- Weight and BMI
- Blood pressure (sitting and standing)
- Movement disorder scales (AIMS, BARS, SAS)
- CBC with differential
Ongoing monitoring:
- Weeks 1-4: Weekly assessment for orthostatic hypotension, falls, sedation, EPS
- Weeks 4-12: Every 2 weeks for metabolic parameters, weight
- After 12 weeks: Every 3 months for metabolic monitoring, movement disorders
Step 6: Discontinuation Criteria
Stop brexpiprazole immediately if:
- Signs of NMS (fever, rigidity, altered mental status, autonomic instability)
- Severe EPS or akathisia unresponsive to dose reduction
- Stroke or TIA
- Severe orthostatic hypotension with falls
- Uncontrolled hyperglycemia
- Patient/family preference after informed discussion
Consider discontinuation if:
- No improvement in target symptoms after 8-12 weeks at therapeutic dose
- Intolerable sedation affecting quality of life
- Significant weight gain (>7% baseline weight)
- Development of tardive dyskinesia
Key Clinical Pitfalls to Avoid
Do not assume "not on Beers list" means "safe": The class-wide antipsychotic warnings apply 33
Do not use for general behavioral symptoms in dementia: Only FDA-approved for agitation specifically in Alzheimer's disease, not other dementias or other behavioral symptoms 2
Do not underdose: 1 mg is not a therapeutic maintenance dose; target 2 mg for Alzheimer's agitation 54
Do not ignore orthostatic vital signs: Check blood pressure sitting and standing at every visit during titration 5
Do not combine with multiple CNS depressants: Risk of excessive sedation, falls, and respiratory depression increases substantially
Do not forget informed consent: Discuss black box warnings about increased mortality risk with patient and family/caregivers before initiating 5
Do not continue indefinitely without reassessment: Periodically attempt dose reduction or discontinuation, especially if symptoms have improved
Comparative Context
Brexpiprazole's advantage over older antipsychotics: Lower EPS risk, more favorable metabolic profile than some alternatives, and specific FDA approval for Alzheimer's agitation 82.
Brexpiprazole's disadvantage: Still carries all class-wide antipsychotic risks including mortality, stroke, falls, and metabolic effects. The 2-3 mg doses show 20-33% higher TEAE rates than placebo 4.
Bottom line for clinical practice: Brexpiprazole represents a treatment option with regulatory approval for specific geriatric indications, but the evidence shows it is far from risk-free. The 2 mg dose offers the best balance of efficacy and tolerability for Alzheimer's agitation 4, but non-pharmacological interventions should always be attempted first, and ongoing monitoring is mandatory to detect adverse effects early.