Which medication is pharmacologically similar to brexpiprazole (Rexulti) for managing agitation and irritability in an elderly patient with dementia?

Medications Pharmacologically Similar to Brexpiprazole (Rexulti) for Dementia-Related Agitation

Direct Recommendation

Quetiapine is the most pharmacologically similar atypical antipsychotic to brexpiprazole for managing agitation and irritability in elderly dementia patients, starting at 12.5 mg twice daily and titrating slowly to a maximum of 200 mg twice daily, though SSRIs (citalopram or sertraline) should be tried first for chronic agitation unless the patient is severely agitated with psychotic features. 1, 2, 3

Treatment Algorithm Based on Severity and Features

Step 1: Rule Out Reversible Causes (Mandatory Before Any Medication)

Before considering any pharmacological agent similar to brexpiprazole, you must systematically investigate and treat:

• Pain (major contributor in non-verbal patients) 1
• Infections (UTI, pneumonia) 1
• Metabolic disturbances (dehydration, electrolyte abnormalities, hypoxia, hyperglycemia) 1
• Constipation and urinary retention 1
• Anticholinergic medications that worsen agitation (diphenhydramine, oxybutynin, cyclobenzaprine) 1

Step 2: Implement Non-Pharmacological Interventions (Required First-Line)

• Structured daily routines, adequate lighting (especially late afternoon), reduced noise 1
• Calm tones, simple one-step commands, gentle touch 1
• Morning bright light exposure (2 hours at 3,000-5,000 lux) for sundowning 1
• At least 30 minutes daily sunlight exposure 1

Step 3: Pharmacological Options Based on Clinical Presentation

For Chronic Agitation WITHOUT Psychotic Features (First-Line)

SSRIs are preferred over any antipsychotic:

• Citalopram 10 mg/day (maximum 40 mg/day) 1
• Sertraline 25-50 mg/day (maximum 200 mg/day) 1
• Assess response at 4 weeks; if no benefit, taper and discontinue 1
• SSRIs significantly reduce neuropsychiatric symptoms, agitation, and depression in vascular dementia 1

For Severe Agitation WITH Psychotic Features (When SSRIs Fail)

Quetiapine is the closest alternative to brexpiprazole:

• Starting dose: 12.5 mg twice daily 1, 2, 3
• Titration: Increase slowly by 12.5-25 mg increments 2, 3
• Maximum dose: 200 mg twice daily 1, 2, 3
• Advantages: More sedating (beneficial for hyperactive agitation), lower EPS risk than risperidone 1
• Monitoring: Watch for orthostatic hypotension, sedation, falls 1, 2, 3

Risperidone is the second alternative:

• Starting dose: 0.25 mg at bedtime 1
• Target dose: 0.5-1.25 mg daily 1
• Maximum dose: 2-3 mg/day (EPS risk increases significantly above 2 mg/day) 1
• Advantages: Largest evidence base among atypicals for dementia agitation 4
• Disadvantages: Higher EPS risk than quetiapine, especially in Parkinson's dementia 3

Olanzapine is a third option:

• Starting dose: 2.5 mg at bedtime 1
• Maximum dose: 10 mg/day 1
• Critical limitation: Less effective in patients over 75 years 1
• Avoid in: Diabetic patients (significant hyperglycemia risk) 1

Why Quetiapine Is Most Similar to Brexpiprazole

Pharmacological similarities:

• Both are atypical antipsychotics with lower EPS risk 2, 3
• Both have sedating properties useful for agitation 2
• Both are appropriate for maintenance treatment (not PRN) 5
• Both require slow titration in elderly patients 2, 3

Key difference: Brexpiprazole is a partial dopamine D2 agonist with serotonin 5-HT1A partial agonism and 5-HT2A antagonism 5, while quetiapine is a full antagonist at multiple receptors. However, in clinical practice for dementia agitation, quetiapine's tolerability profile most closely matches brexpiprazole's 2, 3.

Critical Safety Warnings (Apply to ALL Antipsychotics)

Black Box Warning: All antipsychotics increase mortality 1.6-1.7 times higher than placebo in elderly dementia patients 1, 5, 6

Before prescribing, discuss with surrogate decision-makers:

• Increased mortality risk 1
• Cerebrovascular adverse events (stroke risk) 1
• Falls, QT prolongation, sudden death 1
• Expected modest benefits (approximately 5-point greater reduction on agitation scales versus placebo) 5, 6

Dosing principles:

• Use lowest effective dose for shortest duration 1
• Daily in-person evaluation of ongoing need 1
• Attempt taper within 3-6 months 1
• Approximately 47% continue antipsychotics without clear indication after discharge 1

Medications to AVOID

Typical antipsychotics (haloperidol, chlorpromazine):

• 50% risk of tardive dyskinesia after 2 years continuous use 1
• Reserve haloperidol only for acute severe agitation with imminent harm (0.5-1 mg, maximum 5 mg/day) 1

Benzodiazepines:

• Increase delirium incidence and duration 1
• Cause paradoxical agitation in 10% of elderly patients 1
• Risk of tolerance, addiction, cognitive impairment, falls 1
• Exception: alcohol or benzodiazepine withdrawal 1

Special Populations

Parkinson's Disease Dementia:

• Quetiapine is strongly preferred (12.5 mg twice daily) 3
• Avoid risperidone and olanzapine (severe EPS sensitivity) 3
• Consider SSRIs as first-line even before quetiapine 3

Lewy Body Dementia:

• Quetiapine at very low doses (12.5 mg twice daily) 2
• Extreme caution with all antipsychotics (severe sensitivity reactions) 2
• Avoid typical antipsychotics completely 2

Vascular Dementia:

• SSRIs are explicitly first-line (citalopram or sertraline) 1
• Risperidone and olanzapine carry three-fold increased stroke risk 1

Common Pitfalls to Avoid

• Do not add antipsychotics without first treating reversible medical causes 1
• Do not use antipsychotics for mild agitation, unfriendliness, poor self-care, repetitive questioning, or wandering (these behaviors do not respond to antipsychotics) 1
• Do not continue antipsychotics indefinitely—review need at every visit 1
• Do not combine high-dose benzodiazepines with antipsychotics (risk of fatal respiratory depression) 1
• Do not exceed recommended maximum doses (no additional benefit, markedly increased adverse effects) 1

Monitoring Requirements for All Antipsychotics

• Daily in-person examination initially 1
• ECG for QTc prolongation 1
• Falls risk assessment 1
• Extrapyramidal symptoms (tremor, rigidity, bradykinesia) 1
• Weight, metabolic parameters 1
• Cognitive function (ensure no worsening) 1
• Blood pressure (orthostatic changes) 1