Which medications have FDA approval for treating agitation associated with dementia?

FDA-Approved Medications for Dementia-Related Agitation

As of 2024, brexpiprazole (Rexulti) is the only medication with FDA approval specifically for agitation associated with Alzheimer's dementia. 1

FDA-Approved Treatment

Brexpiprazole received FDA approval for agitation in Alzheimer's dementia and should be considered when non-pharmacological interventions have been systematically attempted and documented as insufficient, and the patient exhibits severe, dangerous agitation. 1

Prerequisites Before Initiating Brexpiprazole

Before starting any pharmacological treatment, you must:

• Systematically investigate and treat reversible medical causes including pain (a major contributor in non-communicative patients), urinary tract infections, pneumonia, constipation, dehydration, hypoxia, and metabolic disturbances 1
• Review all medications to identify and discontinue anticholinergic agents (diphenhydramine, oxybutynin, cyclobenzaprine) that worsen confusion and agitation 1
• Implement and document failure of non-pharmacological interventions including environmental modifications (adequate lighting, reduced noise), structured daily routines, calm communication with simple one-step commands, and caregiver education 1, 2

Brexpiprazole Considerations

• Can be continued alongside cholinesterase inhibitors like rivastigmine, though monitor for additive side effects (dizziness, weight loss) 1
• Requires pre-treatment discussion with patient/surrogate about increased mortality risk (1.6-1.7 times higher than placebo), cardiovascular effects, and cerebrovascular adverse events 1

Off-Label Alternatives When Brexpiprazole Is Not Suitable

While not FDA-approved for dementia-related agitation, the following have guideline support:

For Chronic Agitation Without Psychotic Features

SSRIs are first-line pharmacological treatment:

• Citalopram 10 mg/day (maximum 40 mg/day) 1, 3
• Sertraline 25-50 mg/day (maximum 200 mg/day) 1
• Assess response at 4 weeks using quantitative measures; taper and discontinue if no clinically significant benefit 1, 4

For Severe Agitation With Psychotic Features or Imminent Harm

When behavioral interventions have failed and patient poses substantial risk:

• Risperidone 0.25 mg once daily at bedtime (target 0.5-1.25 mg daily, maximum 2-3 mg/day) 1, 2

  • Extrapyramidal symptoms increase significantly above 2 mg/day 1
  • Three-fold increased stroke risk in vascular dementia 1

• Olanzapine 2.5 mg at bedtime (maximum 10 mg/day) 1, 2

  • Less effective in patients over 75 years 1
  • Avoid in diabetic patients due to FDA warnings about hyperglycemia and new-onset diabetes 1

• Quetiapine 12.5 mg twice daily (maximum 200 mg twice daily) 1, 2

  • More sedating with orthostatic hypotension risk 1
  • Low doses (≤25 mg) may paradoxically worsen nightmares and hallucinations 1

For Acute Severe Agitation Requiring Rapid Control

• Haloperidol 0.5-1 mg orally or subcutaneously (maximum 5 mg daily in elderly) 1
  • Higher initial doses (>1 mg) provide no additional benefit and increase adverse effects 1
  • Preferred over benzodiazepines except for alcohol/benzodiazepine withdrawal 1

Critical Safety Requirements for All Antipsychotics

• Use lowest effective dose for shortest duration with daily in-person evaluation 1
• Attempt taper within 3-6 months to determine ongoing need 1
• Monitor for: extrapyramidal symptoms, falls, QT prolongation, metabolic changes, cognitive worsening 1
• All antipsychotics increase mortality risk 1.6-1.7 times higher than placebo in elderly dementia patients 1, 5

Medications to Avoid

• Benzodiazepines should not be first-line (except for alcohol/benzodiazepine withdrawal) due to increased delirium incidence, paradoxical agitation in 10% of elderly patients, and respiratory depression risk 1
• Typical antipsychotics (other than haloperidol for acute situations) carry 50% risk of tardive dyskinesia after 2 years of continuous use 1
• Chlorpromazine is explicitly not recommended by WHO due to safety concerns 1
• Valproate preparations should not be used for agitation in dementia 6

Treatment Algorithm

1. Identify and treat reversible causes (pain, infection, metabolic disturbances, medication side effects) 1
2. Implement non-pharmacological interventions for adequate trial period (generally ≥30 days) 1, 2
3. If severe, dangerous agitation persists:
   • For chronic agitation without psychosis: SSRIs (citalopram or sertraline) 1, 4
   • For severe agitation with psychosis: Consider brexpiprazole (FDA-approved) or off-label risperidone 1, 2
   • For acute dangerous agitation: Haloperidol 0.5-1 mg 1
4. Reassess at 4 weeks using quantitative measures; discontinue if no benefit 1, 2
5. Attempt taper within 3-6 months if symptoms improve 1

Common Pitfalls

• Adding psychotropics without first addressing reversible medical causes (pain, infection, constipation) 1
• Using antipsychotics for mild agitation or behaviors unlikely to respond (unfriendliness, repetitive questioning, wandering) 1
• Continuing antipsychotics indefinitely without reassessment—47% of patients continue without clear indication 1
• Combining high-dose benzodiazepines with antipsychotics (risk of fatal respiratory depression) 1