In an 82‑year‑old African‑American male with recurrent moderate major depressive disorder and Alzheimer’s disease who is taking mirtazapine 7.5 mg nightly and shows agitation, should I start donepezil (Aricept)?

Should You Start Donepezil in This Patient?

Yes, you should start donepezil (Aricept) 5 mg nightly in this 82-year-old patient with Alzheimer's disease and moderate depression, as cholinesterase inhibitors are indicated for his stage of dementia and may help stabilize both cognitive decline and behavioral symptoms including agitation. 1, 2

Rationale for Starting Donepezil

Donepezil is the appropriate first-line cholinesterase inhibitor for this patient because it offers once-daily dosing (improving adherence in cognitively impaired patients), has no hepatotoxicity, and produces statistically significant improvements in cognition and global function in patients with mild-to-moderate Alzheimer's disease. 1, 3

Key Supporting Evidence:

• Donepezil improves cognition (mean 2.67-point improvement on ADAS-Cog) and global function compared to placebo over 24-26 weeks. 4
• Approximately 32-38% of patients demonstrate clinically meaningful improvement versus 18% on placebo. 5
• The drug delays functional deterioration by approximately 55 weeks compared to placebo. 6

Addressing the Agitation

The self-talk and clapping you describe represent behavioral symptoms that are common in Alzheimer's disease. 1 Importantly:

• Donepezil may cause an initial increase in agitation during the first few weeks of treatment, but this typically subsides after a few weeks. 1
• If agitation persists or worsens beyond 3-4 weeks, non-pharmacologic interventions should be exhausted before adding antipsychotic medications. 1
• The current mirtazapine 7.5 mg addresses depression but does not treat the core cognitive and functional decline of Alzheimer's disease. 2

Practical Prescribing Algorithm

Step 1: Initial Dosing

• Start donepezil 5 mg once daily at bedtime (taking just prior to retiring reduces sleep disturbances). 7, 3
• Administer with food to minimize gastrointestinal side effects (nausea, vomiting, diarrhea). 1, 7

Step 2: Dose Titration

• After 4-6 weeks, increase to 10 mg once daily if the patient tolerates the 5 mg dose well. 1, 2, 7
• The 10 mg dose provides superior cognitive and functional benefits compared to 5 mg, though with higher rates of gastrointestinal side effects (relative risk 2.5-3.2 for nausea/vomiting/diarrhea). 7, 4

Step 3: Assessment Timeline

• Evaluate response at 6-12 months using physician global assessment, caregiver reports of functional and behavioral changes, and cognitive testing. 1, 2
• Brief mental status tests (like MMSE) are relatively insensitive to cholinesterase inhibitor effects; comprehensive functional assessments are essential. 1, 3

Step 4: Continuation Criteria

Continue donepezil if:

• Cognitive function stabilizes or declines more slowly than pre-treatment rate 1
• Caregiver reports improved or stable function in activities of daily living 2
• Behavioral symptoms remain manageable 1

Discontinue donepezil if:

• Side effects develop and do not resolve after dose adjustment 1
• Deterioration continues at the pre-treatment rate after 6-12 months 1, 3
• Poor medication adherence persists 1

Safety Considerations for This Patient

No Dose Adjustment Needed:

• Age 82 is not a contraindication; donepezil has been extensively studied in elderly patients with mean age ~75 years. 4
• No renal dose adjustment required even with severe renal impairment (CrCl ~30 mL/min). 7

Monitor For:

• Cardiac conduction abnormalities (sick sinus syndrome, significant bradycardia), as cholinesterase inhibitors can exacerbate bradyarrhythmias. 2
• Active gastrointestinal conditions (peptic ulcer disease, severe GERD) that may worsen with cholinergic effects. 2
• Weight loss, which can occur with cholinesterase inhibitors and should be monitored. 1

Reassuring Safety Profile:

• No hepatotoxicity (unlike tacrine, which requires liver monitoring). 1, 3, 5
• No statistically significant difference in serious adverse events compared to placebo, aside from expected cholinergic side effects. 2, 4
• Withdrawal rates due to adverse events are 5-20%, comparable to placebo rates of 7-13%. 2, 4

Drug Interactions to Consider

The patient is taking mirtazapine and an unspecified medication (possibly "typical sprinkles" 500 mg bedtime/250 mg morning—clarify this medication). 1

• Donepezil has conflicting evidence about interactions with cimetidine, theophylline, warfarin, and digoxin. 1
• If the patient is on any of these medications, monitor more closely during initiation.

What to Tell the Patient and Caregiver

Set Realistic Expectations:

• Donepezil does not cure or reverse Alzheimer's disease; it may temporarily stabilize cognition or modestly slow the rate of decline. 2
• Benefits are equivalent to delaying cognitive decline by approximately one year. 2
• Only 20-35% of patients achieve clinically meaningful improvement, but stabilization (not worsening) also constitutes success. 2

Common Side Effects:

• Mild, transient gastrointestinal symptoms (nausea, vomiting, diarrhea) occur in the first few weeks but can be minimized by taking with food. 1, 7
• Initial agitation may occur but typically subsides within a few weeks. 1

Common Pitfalls to Avoid

Pitfall 1: Premature Discontinuation

• Do not stop donepezil before 6-12 months unless intolerable side effects occur; some patients require up to 12 months to demonstrate benefit. 1, 2

Pitfall 2: Inadequate Dose Titration

• Do not keep patients on 5 mg indefinitely without attempting to increase to 10 mg after 4-6 weeks, as the higher dose provides additional cognitive and functional benefits. 7, 4

Pitfall 3: Relying Solely on MMSE Scores

• Use comprehensive assessments including caregiver reports and functional measures, not just brief cognitive tests. 1, 3

Pitfall 4: Ignoring Non-Pharmacologic Interventions

• Implement behavioral strategies concurrently: predictable routines, simplified tasks, safe environment modifications, calendars/clocks for orientation, and reduction of excess stimulation. 1

If Donepezil Fails After 6-12 Months

If the patient continues to decline at the pre-treatment rate after 6-12 months on optimized donepezil (10 mg/day):

• Add memantine 20 mg/day (start at 5 mg/day, increase by 5 mg weekly) while continuing donepezil. 2
• Combination therapy produces additional improvements of ~3.4 points on cognitive scales and ~1.4 points on activities-of-daily-living scales compared to donepezil alone. 2
• Switching to another cholinesterase inhibitor (rivastigmine or galantamine) is reasonable only if the patient cannot tolerate donepezil, as there is no convincing evidence that one is more effective than another. 1, 2