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High-Dose Donepezil Or Memantine: Next Step for Alzheimer’S Disease?

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High-Dose Donepezil Or Memantine: Next Step for Alzheimer’S Disease? High-dose donepezil or memantine: Next step for Alzheimer’s disease? Larger dosages may benefit patients who have ‘maxed out’ existing therapies lthough cholinesterase inhibitors (ChEIs) and me- mantine at standard doses may slow the progres- Asion 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 © 2012 THINKSTOCK memantine (28 mg/d) for managing moderate to severe AD and their safety and tolerability profiles. Indrapal Singh, MD Assistant Professor Department of Geriatric Mental Health Chhattrapati Shahuji Maharaj Medical University Current treatments offer modest benefits Lucknow, Uttar Pradesh, India AD treatments comprise 2 categories: ChEIs (donepezil, riv- George T. Grossberg, MD astigmine, and galantamine) and the N-methyl-d-aspartate Samuel W. Fordyce Professor (NMDA) receptor antagonist memantine (Table 1).3,4 All ChEIs Department of Neurology and Psychiatry are FDA-approved for mild to moderate AD; donepezil also is Division of Geriatric Psychiatry Saint Louis University School of Medicine approved for severe AD. Memantine is approved for moderate St. Louis, MO 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 de- mentia.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 Current Psychiatry 20 June 2012 in patients with moderate to severe AD.7,8 Table 1 FDA-approved treatments for Alzheimer’s disease Maximum Mechanism Drug daily dose of action Indication Common side effects/comments Tacrine 160 mg/d ChEI Mild to Nausea, vomiting, loss of appetite, moderate AD diarrhea. First ChEI to be approved, but rarely used because of associated possible hepatotoxicity Donepezil 10 mg/d ChEI All stages Nausea, vomiting, loss of appetite, of AD diarrhea, sleep disturbance Rivastigmine 12 mg/d ChEI Mild to Nausea, vomiting, diarrhea, weight loss, moderate AD loss of appetite Galantamine 24 mg/d ChEI Mild to Nausea, vomiting, diarrhea, weight loss, moderate AD loss of appetite Memantine 20 mg/d NMDA Moderate to Dizziness, headache, constipation, receptor severe AD confusion antagonist Clinical Point Galantamine 24 mg/d ChEI Mild to Nausea, vomiting, diarrhea, weight loss, ER moderate AD loss of appetite AChE inhibition may Rivastigmine 9.5 mg/d ChEI Mild to Nausea, vomiting, diarrhea, weight loss, be suboptimal with transdermal moderate AD loss of appetite system donepezil, 10 mg/d, Donepezil 23 mg/d ChEI Moderate to Nausea, vomiting, diarrhea and higher doses 23 severe AD may be beneficial Memantine 28 mg/d NMDA Moderate to Dizziness, headache, constipation, for patients with ER receptor severe AD confusion antagonist advanced AD AD: Alzheimer’s disease; ChEI: cholinesterase inhibitor; ER: extended release; NMDA: N-methyl-d-aspartate Source: References 3,4 Recently, the FDA approved higher tion.15 Randomized clinical trials assessing daily doses of donepezil (23 mg) and me- dose-response with donepezil, 5 mg/d and mantine (28 mg) for moderate to severe 10 mg/d, have demonstrated more benefit AD on the basis of positive phase III trial in cognition with either dose than placebo. results.9-11 Donepezil, 23 mg/d, currently The 10 mg/d dose was more effective than is marketed in the United States; the avail- 5 mg/d in patients with mild to moderate ability date for memantine, 28 mg/d, was and severe AD.16-18 In patients with advanced undetermined at press time. AD who are stable on 5 mg/d, increasing to 10 mg/d could slow the progression of cog- nitive decline.18 High-dose donepezil (23 mg/d) Cognitive decline with AD has been associ- Rationale for higher doses. Positron ated with increasing loss of cholinergic neu- emission tomography studies have shown rons and cholinergic activities, particularly that at stable doses of donepezil, 5 mg/d or in areas associated with memory/cognition 10 mg/d, average cortical acetylcholinester- and learning, including cortical areas in- ase (AChE) inhibition was <30%.19,20 Based Discuss this article at volving the temporal lobe, hippocampus, on these findings, researchers thought that www.facebook.com/ CurrentPsychiatry and nucleus basalis of Meynert.12-14 In ad- cortical AChE inhibition may be subop- dition, evidence suggests that increasing timal with donepezil, 10 mg/d, and that levels of acetylcholine by using ChEIs can higher doses of ChEI may be required in enhance cognitive function.13,15 patients with more advanced AD—and Donepezil is a selective, reversible ChEI therefore more cholinergic loss—for ad- Current Psychiatry believed to enhance central cholinergic func- equate cholinesterase inhibition. In a pilot Vol. 11, No. 6 21 Table 2 study of patients with mild to moderate AD, higher doses of donepezil (15 mg/d High-dose vs standard-dose and 20 mg/d) were reported to be safe and donepezil: Treatment-emergent well tolerated.21 adverse events The 23-mg/d donepezil formulation Donepezil, Donepezil, was developed to provide a higher dose Adverse event 23 mg/d 10 mg/d administered once daily without a sharp High-dose Nausea 12% 3% rise in peak concentration. The FDA ap- Alzheimer’s drugs Vomiting 9% 3% proved donepezil, 23 mg/d, for patients Diarrhea 8% 5% with moderate to severe AD on the basis 9,22 Anorexia 5% 2% of phase III trial results. In a random- Dizziness 5% 3% ized, double-blind, multicenter, head-to- head clinical trial, >1,400 patients with Weight decrease 5% 3% moderate to severe AD (Mini-Mental State Headache 4% 3% Exam [MMSE]: 0 to 20) on a stable dose of Insomnia 3% 2% donepezil, 10 mg/d, for ≥3 months were Clinical Point Urinary 3% 1% randomly assigned to receive high-dose incontinence Patients receiving donepezil (23 mg/d) or standard-dose Fatigue 2% 1% donepezil (10 mg/d) for 24 weeks.9,22 donepezil, 23 mg/d, Weakness 2% 1% Patients in the 23-mg/d group showed a showed a statistically Somnolence 2% 1% statistically significant improvement in significant Contusion 2% 0% cognition compared with the 10-mg/d improvement in Source: Reference 22 group. The difference between groups on cognition compared with 10 mg/d a measure of global improvement was Table 3 not significant.9,22 However, in a post-hoc analysis, it was demonstrated that a sub- High-dose memantine: group of patients with more severe cogni- Treatment-emergent adverse a tive impairment (baseline MMSE: 0 to 16), events showed significant improvement in cogni- Placebo Memantine tion as well as global functioning.9 Adverse event (n = 335) ER (n = 341) Overall, treatment-emergent adverse Any TEAE 214 214 (62.8%) events (TEAEs) during the study were (63.9%) higher in patients receiving 23 mg/d (74%) Fall 26 (7.8%) 19 (5.6%) than those receiving 10 mg/d (64%). The Urinary tract 24 (7.2%) 19 (5.6%) infection most common TEAEs in the 23-mg/d and Headache 17 (5.1%) 19 (5.6%) 10-mg/d groups were nausea (12% vs 3%, respectively), vomiting (9% vs 3%), and Diarrhea 13 (3.9%) 17 (5.0%) diarrhea (8% vs 5%) (Table 2).22 These gas- Dizziness 5 (1.5%) 16 (4.7%) trointestinal adverse effects were more fre- Influenza 9 (2.7%) 15 (4.4%) quent during the first month of treatment Insomnia 16 (4.8%) 14 (4.1%) Clinical Point and were relatively infrequent beyond 1 Agitation 15 (4.5%) 14 (4.1%) Memantine ER may be month. Serious TEAEs, such as falls, uri- Hypertension 8 (2.4%) 13 (3.8%) better tolerated than nary tract infection, pneumonia, syncope, Anxiety 9 (2.7%) 12 (3.5%) aggression, and confusional state, were Depression 5 (1.5%) 11 (3.2%) the IR formulation noted in a similar proportion of patients in Weight increased 3 (0.9%) 11 (3.2%) because of less plasma the 23-mg/d and 10-mg/d groups; most of Constipation 4 (1.2%) 10 (2.9%) fluctuation during these were considered unrelated to treat- Somnolence 4 (1.2%) 10 (2.9%) steady-state dosing ment. No drug-related deaths occurred Back pain 2 (0.6%) 9 (2.6%) during the study. High-dose (23 mg/d) intervals Aggression 5 (1.5%) 8 (2.3%) donepezil generally was well tolerated, Hypotension 5 (1.5%) 7 (2.1%) with a typical ChEI safety profile but su- Vomiting 4 (1.2%) 7 (2.1%) perior efficacy. Abdominal pain 2 (0.6%) 7 (2.1%) A recent commentary discussed the is- sue of effect size and whether a 2.2-point Nasopharyngitis 10 (3.0%) 6 (1.8%) difference on a 100-point scale (the Severe Confusional state 7 (2.1%) 6 (1.8%) Impairment Battery [SIB]) is clinically Weight decreased 11 (3.3%) 5 (1.5%) meaningful.23 As with all anti-dementia Nausea 7 (2.1%) 5 (1.5%) therapies, in any cohort some patients will Irritability 8 (2.4%) 4 (1.2%) gain considerably more than 2.2 points on Cough 8 (2.4%) 3 (0.9%) the SIB, which is clinically significant.
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