Donepezil, Memantine, Amantadine, and Modafinil in Delirium
None of these medications—donepezil, memantine, amantadine, or modafinil—are appropriate for treating delirium, and some may cause harm. Management of delirium focuses on identifying and treating underlying causes, implementing non-pharmacological interventions, and using antipsychotics only when severe agitation poses imminent risk after behavioral measures fail.
Evidence Against These Agents
Cholinesterase Inhibitors (Donepezil)
The Society of Critical Care Medicine strongly recommends against using rivastigmine (another cholinesterase inhibitor) to treat delirium, as a randomized controlled trial was halted prematurely due to higher mortality (22% vs 8%) and longer delirium duration (5 vs 3 days) in the rivastigmine group 1.
While one retrospective database study suggested donepezil use in dementia patients was associated with reduced delirium during critical illness 2, this observational finding does not override the strong guideline recommendation against cholinesterase inhibitors for delirium treatment 1.
Donepezil should not be newly initiated for delirium prevention or treatment 1.
Memantine
No compelling evidence supports memantine for delirium prevention or treatment in ICU patients 1.
Memantine has been reported to cause myoclonus and delirium exacerbation, particularly when combined with drugs that interfere with renal elimination (such as trimethoprim) or in patients with renal impairment 3.
The 2013 Critical Care Medicine guidelines provide no recommendation for memantine in delirium due to lack of evidence 1.
Amantadine
Amantadine is not mentioned in any major delirium management guidelines 1.
Like memantine, amantadine can cause myoclonus and delirium, especially with renal impairment or drug interactions 3.
There is no evidence supporting its use for delirium.
Modafinil (Modalert)
Modafinil has been proposed theoretically for Alzheimer's disease to improve wakefulness and cognition 4, but there is no evidence supporting its use in delirium.
Delirium management guidelines do not mention modafinil as a treatment option 1.
Evidence-Based Delirium Management
First Priority: Identify and Treat Underlying Causes
Infection is the most common precipitating factor—particularly urinary tract infections and pneumonia—and must be systematically investigated and treated 1.
Address metabolic disturbances including hypoxia, dehydration, electrolyte abnormalities, hyperglycemia, constipation, and urinary retention 1.
Assess and treat pain, as it is a major contributor to delirium in patients who cannot verbally communicate discomfort 1.
Review all medications for deliriogenic agents, particularly anticholinergics and benzodiazepines 1.
Non-Pharmacological Interventions (First-Line)
The ABCDEF Bundle has been associated with reduced delirium and improved survival in implementation studies 1.
Implement environmental modifications: adequate lighting, reduced noise, reorientation strategies, early mobilization, and sleep promotion 1.
Use validated delirium screening tools (CAM-ICU or ICDSC) to monitor for delirium 1.
Pharmacological Approaches (When Necessary)
Sedation Strategy
Use short-acting sedatives (propofol or dexmedetomidine) rather than benzodiazepines in mechanically ventilated patients 1.
Dexmedetomidine may reduce delirium prevalence compared to benzodiazepines and can help resolve hyperactive delirium faster (median 23.3 vs 40.0 hours) 1.
Benzodiazepines are a risk factor for delirium development and should be avoided except for alcohol or benzodiazepine withdrawal 1.
Antipsychotics for Severe Agitation
Antipsychotics should not be used routinely for delirium prevention or treatment 1.
Reserve antipsychotics only for severe agitation with imminent risk of harm to self or others after non-pharmacological interventions have failed 1, 5.
When necessary, use haloperidol 0.5-1 mg (maximum 5 mg daily in elderly) or atypical antipsychotics at low doses 1, 5.
No published evidence demonstrates that haloperidol reduces delirium duration, though atypical antipsychotics may have modest benefit 1.
Avoid antipsychotics in patients at risk for torsades de pointes (baseline QTc prolongation, concurrent QT-prolonging medications) 1.
Common Pitfalls to Avoid
Do not initiate cholinesterase inhibitors for delirium treatment—they increase mortality and prolong delirium 1.
Do not use benzodiazepines as first-line treatment for delirium (except in withdrawal syndromes), as they worsen delirium incidence and duration 1.
Do not prescribe memantine, amantadine, or modafinil for delirium—there is no evidence of benefit and potential for harm 1, 3.
Do not use antipsychotics for hypoactive delirium or as routine prevention 1.
Always address reversible medical causes before considering any pharmacological intervention 1.