Although cholinesterase inhibitors (ChEIs) and memantine at standard doses may slow the progression of Alzheimer’s disease (AD) as assessed by cognitive, functional, and global measures, this effect is relatively modest. For the estimated 5.4 million Americans with AD1—more than one-half of whom have moderate to severe disease2—there is a great need for new approaches to slow AD progression.
High doses of donepezil or memantine may be the next step in achieving better results than standard pharmacologic treatments for AD. This article presents the possible benefits and indications for high doses of donepezil (23 mg/d) and memantine (28 mg/d) for managing moderate to severe AD and their safety and tolerability profiles.
Current treatments offer modest benefits
AD treatments comprise 2 categories: ChEIs (donepezil, rivastigmine, and galantamine) and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Table 1).3,4 All ChEIs are FDA-approved for mild to moderate AD; donepezil also is approved for severe AD. Memantine is approved for moderate to severe AD, either alone or in combination with ChEIs. Until recently, the maximum FDA-approved doses were donepezil, 10 mg/d, and memantine, 20 mg/d. However, these dosages are associated with only modest beneficial effects in managing cognitive deterioration in patients with moderate to severe dementia.5,6 Studies have reported that combining a ChEI, such as donepezil, and memantine is well tolerated and may result in synergistic benefits by affecting different neurotransmitters in patients with moderate to severe AD.7,8
Recently, the FDA approved higher daily doses of donepezil (23 mg) and memantine (28 mg) for moderate to severe AD on the basis of positive phase III trial results.9-11 Donepezil, 23 mg/d, currently is marketed in the United States; the availability date for memantine, 28 mg/d, was undetermined at press time.
Table 1
FDA-approved treatments for Alzheimer’s disease
| Drug | Maximum daily dose | Mechanism of action | Indication | Common side effects/comments |
|---|---|---|---|---|
| Tacrine | 160 mg/d | ChEI | Mild to moderate AD | Nausea, vomiting, loss of appetite, diarrhea. First ChEI to be approved, but rarely used because of associated possible hepatotoxicity |
| Donepezil | 10 mg/d | ChEI | All stages of AD | Nausea, vomiting, loss of appetite, diarrhea, sleep disturbance |
| Rivastigmine | 12 mg/d | ChEI | Mild to moderate AD | Nausea, vomiting, diarrhea, weight loss, loss of appetite |
| Galantamine | 24 mg/d | ChEI | Mild to moderate AD | Nausea, vomiting, diarrhea, weight loss, loss of appetite |
| Memantine | 20 mg/d | NMDA receptor antagonist | Moderate to severe AD | Dizziness, headache, constipation, confusion |
| Galantamine ER | 24 mg/d | ChEI | Mild to moderate AD | Nausea, vomiting, diarrhea, weight loss, loss of appetite |
| Rivastigmine transdermal system | 9.5 mg/d | ChEI | Mild to moderate AD | Nausea, vomiting, diarrhea, weight loss, loss of appetite |
| Donepezil 23 | 23 mg/d | ChEI | Moderate to severe AD | Nausea, vomiting, diarrhea |
| Memantine ER | 28 mg/d | NMDA receptor antagonist | Moderate to severe AD | Dizziness, headache, constipation, confusion |
| AD: Alzheimer’s disease; ChEI: cholinesterase inhibitor; ER: extended release; NMDA: N-methyl-D-aspartate Source: References 3,4 | ||||
High-dose donepezil (23 mg/d)
Cognitive decline with AD has been associated with increasing loss of cholinergic neurons and cholinergic activities, particularly in areas associated with memory/cognition and learning, including cortical areas involving the temporal lobe, hippocampus, and nucleus basalis of Meynert.12-14 In addition, evidence suggests that increasing levels of acetylcholine by using ChEIs can enhance cognitive function.13,15
Donepezil is a selective, reversible ChEI believed to enhance central cholinergic function.15 Randomized clinical trials assessing dose-response with donepezil, 5 mg/d and 10 mg/d, have demonstrated more benefit in cognition with either dose than placebo. The 10 mg/d dose was more effective than 5 mg/d in patients with mild to moderate and severe AD.16-18 In patients with advanced AD who are stable on 5 mg/d, increasing to 10 mg/d could slow the progression of cognitive decline.18
Rationale for higher doses. Positron emission tomography studies have shown that at stable doses of donepezil, 5 mg/d or 10 mg/d, average cortical acetylcholinesterase (AChE) inhibition was <30%.19,20 Based on these findings, researchers thought that cortical AChE inhibition may be suboptimal with donepezil, 10 mg/d, and that higher doses of ChEI may be required in patients with more advanced AD—and therefore more cholinergic loss—for adequate cholinesterase inhibition. In a pilot study of patients with mild to moderate AD, higher doses of donepezil (15 mg/d and 20 mg/d) were reported to be safe and well tolerated.21
The 23-mg/d donepezil formulation was developed to provide a higher dose administered once daily without a sharp rise in peak concentration. The FDA approved donepezil, 23 mg/d, for patients with moderate to severe AD on the basis of phase III trial results.9,22 In a randomized, double-blind, multicenter, head-to-head clinical trial, >1,400 patients with moderate to severe AD (Mini-Mental State Exam [MMSE]: 0 to 20) on a stable dose of donepezil, 10 mg/d, for ≥3 months were randomly assigned to receive high-dose donepezil (23 mg/d) or standard-dose donepezil (10 mg/d) for 24 weeks.9,22 Patients in the 23-mg/d group showed a statistically significant improvement in cognition compared with the 10-mg/d group. The difference between groups on a measure of global improvement was not significant.9,22 However, in a post-hoc analysis, it was demonstrated that a subgroup of patients with more severe cognitive impairment (baseline MMSE: 0 to 16), showed significant improvement in cognition as well as global functioning.9