What medications are recommended for treating dementia?

Medications for Dementia

Cholinesterase inhibitors (donepezil, galantamine, or rivastigmine) should be initiated for mild to moderate Alzheimer's disease, while memantine is the treatment of choice for moderate to severe disease, though clinicians must recognize these medications produce only statistically significant—not clinically important—improvements in cognition and global function. 1

FDA-Approved Medications

Cholinesterase Inhibitors for Mild to Moderate Dementia

• Donepezil is FDA-approved for mild to moderate Alzheimer's disease, started at 5 mg daily and increased to 10 mg daily after 4-6 weeks if tolerated 1, 2, 3

• Galantamine is FDA-approved for mild to moderate Alzheimer's disease 3, 1

• Rivastigmine is FDA-approved for mild to moderate Alzheimer's disease AND Parkinson's disease dementia, initiated at 1.5 mg twice daily with meals, titrated every 2-4 weeks to a maximum of 6 mg twice daily (12 mg/day total) 2

• All three cholinesterase inhibitors show equivalent efficacy—no convincing evidence demonstrates superiority of one over another 1

• Tacrine is not recommended due to serious hepatotoxicity despite FDA approval 1

Memantine for Moderate to Severe Dementia

• Memantine is FDA-approved for moderate to severe Alzheimer's disease 4, 1

• Memantine showed statistically significant but not clinically important improvements in cognition scores (ADAS-cog) for moderate to severe disease 1

• Combination therapy with memantine plus a cholinesterase inhibitor (typically donepezil) is recommended for severe Alzheimer's disease in US, China, and Japan guidelines 1

Critical Evidence Limitations

The Reality of Treatment Benefits

• The average improvement in cognition does not reach clinically significant levels (defined as ≥4 points on the 70-point ADAS-Cog scale), though statistical significance is consistently demonstrated 1

• Treatment effects on cognition average only -2.7 points (95% CI -3.0 to -2.3) on the ADAS-Cog scale—well below the 4-point threshold for clinical importance 5

• Global assessment improvements are "generally modest" and changes in quality of life show "mixed" evidence 1

• A subset of patients may achieve clinically important improvements, but there is no way to predict which patients will respond prior to treatment 1, 5

Study Duration Concerns

• Most trials lasted only 6 months or less, limiting ability to assess long-term disease modification 1

• The longest trials extended to 2 years, still insufficient to determine if these medications truly delay disease progression 1

Treatment Algorithm

Step 1: Initiate Treatment Based on Disease Severity

For mild to moderate Alzheimer's disease:

• Start with any cholinesterase inhibitor (donepezil, galantamine, or rivastigmine) based on tolerability profile, ease of dosing, and cost 1
• Donepezil may have fewer adverse events than rivastigmine, making titration more straightforward 1, 5

For moderate to severe Alzheimer's disease:

• Initiate memantine as monotherapy OR add memantine to existing cholinesterase inhibitor therapy 1, 4

For Parkinson's disease dementia or dementia with Lewy bodies:

• Use cholinesterase inhibitors (rivastigmine preferred given FDA approval) 2, 6, 7

For vascular dementia:

• No drugs are clearly effective, though cholinesterase inhibitors may benefit mixed dementia (Alzheimer's plus vascular) 7

For frontotemporal dementia:

• Do not use cholinesterase inhibitors—they are ineffective and may cause agitation 6, 7

Step 2: Assess Response at 3 Months

• A beneficial effect, if present, should be observed within 3 months and may manifest as improvement OR stabilization (not continued decline) 1

• Monitor cognitive function, activities of daily living, and behavioral symptoms 1

• If no benefit is observed at 3 months, discontinuation should be considered, though guidelines provide weak recommendations on this point 1

Step 3: Continue Treatment Decisions

• Do not stop medications solely because dementia severity increases—continue treatment as long as stabilization or slowing of decline remains a meaningful goal 7

• If quality of life is judged to be poor in advanced dementia, family or decision-makers may reasonably decline further treatment since stabilization may not be a desirable goal 1

Common Adverse Effects and Management

Cholinesterase Inhibitors

• Gastrointestinal effects are most common: nausea (9-12%), vomiting, diarrhea, and loss of appetite 1

• Rivastigmine causes higher rates of nausea during titration compared to donepezil, though serious adverse events are equivalent 1

• Approximately 29% of patients discontinue cholinesterase inhibitors due to adverse events versus 18% on placebo 5

• If adverse effects cause intolerance: discontinue for several doses, then restart at the same or lower dose 2

• If dosing interrupted >3 days: restart at the lowest dose (e.g., rivastigmine 1.5 mg twice daily) and re-titrate 2

Memantine

• Adverse effects include dizziness, agitation, and headache at rates of 7-13% (similar to placebo) 1

• Generally better tolerated than cholinesterase inhibitors 1

Special Populations

Patients with Low Body Weight (<50 kg)

• Carefully titrate and monitor for excessive nausea and vomiting 2

• Consider dose reduction if toxicities develop 2

Renal and Hepatic Impairment

• Patients with moderate to severe renal impairment may only tolerate lower doses of rivastigmine 2

• Patients with mild to moderate hepatic impairment (Child-Pugh 5-9) may only tolerate lower doses 2

• No data exist for severe hepatic impairment 2

Medications NOT Recommended

The following have insufficient evidence and should NOT be used for dementia treatment:

• Statins 1, 6, 7
• Anti-inflammatory drugs (NSAIDs) 1, 6, 7
• Vitamin E 1, 6, 7
• Ginkgo biloba 6, 7
• Lithium (not recommended by American Academy of Neurology or American College of Physicians; may be used only for comorbid mood disorders at low doses with careful monitoring) 8
• Citicoline (not included in guidelines; insufficient evidence as monotherapy) 9

Non-Pharmacologic Interventions

• Cognitive training, music therapy, reminiscence therapy, and physical exercise (aerobic and anaerobic) may positively impact cognition and function 1

• Mediterranean diet and brain-healthy foods (nuts, berries, green leafy vegetables, fish) are recommended 1

• Psychological interventions can be effective for both cognitive and non-cognitive symptoms as adjuncts to pharmacotherapy 6, 7