What intervention would you recommend for a patient on Aricept (donepezil) 10mg and memantine 5mg twice a day (BID) who exhibits yelling, agitation, aggression, and disruptive behavior?

Management of Refractory Agitation in a Patient on Donepezil and Memantine

First, rule out reversible medical causes of agitation including infection, metabolic derangements (hyperglycemia, electrolyte imbalances), urinary retention, constipation, and progression of neurological disease, then initiate an SSRI as first-line pharmacological treatment while implementing non-pharmacological interventions. 1, 2

Immediate Assessment

Before escalating pharmacotherapy, systematically evaluate for reversible causes that commonly precipitate or worsen agitation in dementia patients: 2

• Infectious causes: UTI, pneumonia, or other systemic infections 2
• Metabolic derangements: Check glucose, electrolytes, renal and hepatic function 2
• Neurological progression: Consider imaging if new focal deficits or sudden deterioration 2
• Basic comfort issues: Assess for urinary retention, constipation, pain 2
• Medication effects: Note that donepezil itself can cause initial agitation that typically subsides after the first few weeks, but persistent agitation at therapeutic doses suggests disease progression rather than drug effect 3, 4

The memantine dose of 5 mg BID is subtherapeutic—therapeutic dosing is 10 mg BID (20 mg/day total). 5 However, increasing memantine alone is unlikely to adequately address severe behavioral symptoms.

First-Line Pharmacological Intervention

Initiate an SSRI (such as citalopram or sertraline) as the primary pharmacological intervention for agitation in dementia. 1 SSRIs significantly improve overall neuropsychiatric symptoms and specifically target agitation with a more favorable safety profile compared to antipsychotics. 1

• Start with citalopram 10 mg daily or sertraline 25 mg daily, titrating gradually based on response 1
• Evaluate response within 4-6 weeks 1
• Monitor for serotonin syndrome if combining with other serotonergic medications 1
• Reassess need for continued medication after 6-9 months 1

Concurrent Non-Pharmacological Interventions

Implement these evidence-based behavioral strategies alongside medication: 1

• Simulated presence therapy: Use audio/video recordings of family members 1
• Massage therapy: Can reduce agitation 1
• Personally tailored behavioral interventions: Address specific triggers 1
• Physical activity: Reduces behavioral symptoms in cognitive impairment 1

If Agitation Persists or Escalates Acutely

For severe, persistent agitation unresponsive to SSRIs and non-pharmacological measures:

Add lorazepam 0.5-2 mg every 4-6 hours as needed for acute episodes. 2 Lorazepam provides rapid sedation and is particularly effective when combined with other agents. 3, 2

If agitation remains inadequately controlled after adding benzodiazepines:

Consider low-dose haloperidol 0.5-1 mg, titrating upward in 0.5-1 mg increments to a maximum of 10 mg/day. 2 The combination of benzodiazepines and haloperidol produces faster sedation than monotherapy. 2

Critical Safety Considerations with Antipsychotics

Both typical and atypical antipsychotics increase mortality risk in dementia patients, primarily from cardiac toxicities, and should only be used when other options have failed and agitation poses significant safety risks. 1

If antipsychotics are deemed necessary: 3, 6

• Atypical antipsychotics (risperidone, olanzapine, ziprasidone) have lower rates of extrapyramidal symptoms compared to typical agents 3, 7
• Risperidone 0.5-2 mg daily has evidence in behavioral disturbances with intellectual disability 3
• Olanzapine IM or oral formulations provide rapid onset (30 minutes IM, 1 hour oral) 6
• Monitor QTc interval, particularly with ziprasidone and haloperidol 3
• Use the lowest effective dose for the shortest duration possible 1

Monitoring and Reassessment

• Evaluate response every 1-2 hours during acute episodes 2
• Reassess need for medications daily with physical examination 2
• Adjust doses based on renal/hepatic function 2
• Consider psychiatry or palliative care consultation if agitation remains inadequately controlled 2

Common Pitfalls to Avoid

• Do not assume agitation is solely from disease progression without ruling out reversible medical causes 2
• Do not jump directly to antipsychotics without trying SSRIs first, given the mortality risk 1
• Do not continue ineffective medications—if no response after 6-12 months, discontinue and try alternatives 3
• Do not overlook the subtherapeutic memantine dose, though optimizing to 10 mg BID should be done alongside other interventions 5