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Comparisons of Alzheimer’s treatment options

Depression, Men's Health, Age related illnesses, Mental Health, Women's Health | May 17, 2016 | Author: The Super Pharmacist

age related, mental health, depression

Comparisons of Alzheimer’s treatment options

The U.S. Food and Drug Administration (FDA) has approved five medications (listed below) to treat the cognitive symptoms (memory loss, confusion, and problems with thinking and reasoning) of Alzheimer's disease. To date, only symptomatic therapies for Alzheimer disease are available. All drugs approved by the US Food and Drug Administration (FDA) for the treatment of Alzheimer disease (AD) modulate neurotransmitters, either acetylcholine or glutamate. The standard medical treatment for AD includes cholinesterase inhibitors and a partial N-methyl-D-aspartate (NMDA) antagonist.Donepezil, galantamine, and rivastigmine all belong to the class of medications called acetylcholinesterase inhibitors. Memantine is an NMDA (N-methyl-D-aspartate) receptor antagonist. The medicines which are subsidised through the Pharmaceutical Benefits Scheme (PBS) for treating dementia in Alzheimer’s disease include the cholinesterase inhibitors (donepezil, rivastigmine and galantamine) and the N-methyl-D-aspartate receptor antagonist, memantine.

How Do These Drugs Work?

Cholinesterase Inhibitors

Acetylcholine helps to send messages between certain nerve cells. In Alzheimer’s there is also a loss of the nerve cells that use acetylcholine. Falling acetylcholine levels and progressive loss of these nerve cells are linked to worsening symptoms. There have been clear demonstrations that cholinergic neurons are diminished in critical areas of the brain of AD patients. While acetylcholine deficiency plays a role in AD, there is increased recognition that this occurs within a complex milieu of neurotransmitter changes in the brains of AD patients.The cholinesterase inhibitors all prevent an enzyme called acetylcholinesterase from breaking down acetylcholine in the brain. As a result, an increased concentration of acetylcholine leads to increased communication between nerve cells. This may temporarily alleviate or stabilise some symptoms of Alzheimer disease.

NMDA receptor antagonist

The action of memantine is different from that of donepezil, rivastigmine and galantamine. Glutamate is another chemical that helps to send messages between nerve cells. Glutamate is released in excessive amounts when brain cells are damaged by Alzheimer disease. This causes the brain cells to be damaged further. Memantine protects brain cells by blocking the effects of excess glutamate. The current Pharmaceutical Benefits Scheme (PBS) restriction allows subsidised cholinesterase inhibitors and memantine for patients who have a specialist diagnosis of Alzheimer’s disease and a score of >10 in the Mini-Mental State Examination (MMSE), a commonly used test of mental function. Continuing treatment beyond six months is restricted to patients who show an improvement of 2 or more points in the MMSE (or equivalent cognitive improvement in the AD Assessment Scale–Cognitive sub-scale [ADAS-Cog]).

How Well Do These Drugs Work?

Cholinesterase inhibitors

Outcome measures that show benefit with cholinesterase inhibitor therapy include cognition (as measured by the Alzheimer Disease Assessment Scale cognitive subscale and the Mini-Mental Status Examination), clinician's interview-based impression of change, activities of daily living (ADL), disability, quality of life and nursing home placement. The magnitude of response appears to be a stabilisation or slowing of disease progression that is equivalent to 6 months of cognitive decline with this disease.While most of these are short-term studies, there are several studies demonstrating durability of response for 1 to 2 years.11,12,15,16 Emerging evidence suggests that long-term treatment with cholinesterase inhibitors not only improves cognitive and behavioural domains, but may influence neuronal function and survival. There are no randomised double-blind trials comparing cholinesterase inhibitors to one another. Two open label studies have been recently published. The first showed no difference in efficacy between donepezil and rivastigmine, while the second suggested that patients on donepezil performed better on cognitive testing and ADL functioning than patients on galantamine. While these open label results are suggestive, double-blind studies are necessary before concluding that one cholinesterase inhibitor is superior to another.

NMDA receptor antagonist

There is increasing evidence that disturbances in glutamatergic neurotransmission contribute to the pathogenesis and cognitive deficits in AD. Glutamine is an excitatory neurotransmitter that activates the N -methyl-d-aspartate receptor. Glutamatergic transmission is thought to be important in learning and memory, but glutamatergic overstimulation appears to be toxic to neurons.28 Based on this theory, the N -methyl-d-aspartate receptor antagonist, memantine, has been tested in the treatment of AD. There have been three randomised placebo-controlled trials demonstrating that memantine is moderately effective in slowing the progression of AD. In the first study, 166 demented nursing home patients (49% AD; 51% vascular dementia) were randomised to 10 mg of memantine or placebo. At 12 weeks the treated patients had improved clinician's global impression scores independent of the etiology of dementia.29 In another study, 252 patients with moderate to severe AD were randomized to memantine or placebo. At 28 weeks, patients treated with memantine had better ADL function and disability scores. Clinician's impression scores were also improved in the treatment group, but this difference did not reach statistical significance.30 In the most recent study, 403 patients with moderate to severe AD who were already taking donepezil (stable dose of 5 or 10 mg) were randomised to an additional therapy with memantine or placebo in a blinded fashion. After 24 weeks of follow-up, the memantine-treated group had better cognitive, functional, and behavioural scores compared with the monotherapy group. Whether memantine is effective with other cholinesterase inhibitors is unproven, but there is no reason to expect different results with other cholinesterase inhibitors. Clinical trials are under way to address this issue. Memantine is well tolerated with a side effect profile similar to placebo. The beneficial effects seen with memantine reflect a slower decline in treated patients rather than improvement, which is sometimes seen in patients treated with cholinesterase inhibitors. Thus, cholinesterase inhibitors remain the treatment of choice for patients with AD, although treatment with memantine may be a useful adjunct in later stage disease. There is limited data regarding memantine use in early AD, and it is not recommended for these patients. Since the beneficial effects of cholinesterase inhibitors are only modest, there has been interest in whether combinations of therapies may have additive or even synergistic effects in the treatment of AD. As seen above, the addition of memantine to donepezil in later stage disease has benefit.30 Unfortunately, adding vitamin E or hormone replacement therapy to cholinesterase therapy has not resulted in further benefit over monotherapy.

What Are the Side Effects of these Drugs?

Donepezil, rivastigmine, and galantamine share common cholinergic-mediated side effects. The most common cholinergic side effects include nausea, vomiting, diarrhea, anorexia, and abdominal pain. Slow titration of these drugs to therapeutic doses may alleviate many of these symptoms since patients tend to develop tolerance to these gastrointestinal symptoms.Two small open label studies have suggested that of the three commonly used cholinesterases, donepezil is associated with fewer side effects leading to discontinuation of the drug, but these studies require confirmation with prospective randomized double-blinded studies. Because the cholinesterase inhibitors increase acetylcholine and may increase parasympathetic tone, these drugs should be used cautiously in patients with bronchospasm, active peptic ulcer disease, bradycardia or cardiac conduction disturbances. In addition, care should be exercised if patients taking cholinesterase inhibitors undergo general anaesthesia since these drugs may prolong the effects of neuromuscular blocking agents.

What Are the Specific Indications for these Drugs?

Treatment of Mild to Moderate Disease: Early diagnosis and treatment allows AD patients to maintain the highest levels of cognitive and functional ability possible. Cholinesterase inhibitors and mental exercises are used in an attempt to prevent or delay the deterioration of cognition in patients with AD. All cholinesterase inhibitors have shown modest benefit on measures of cognitive function and activities of daily living. Patients on cholinesterase inhibitors have shown slower declines on cognitive and functional measures than patients on placebo. However, cholinesterase inhibitors do not address the underlying cause of the degeneration of cholinergic neurons, which continues during the disease. The cholinesterase inhibitors may also alleviate the non-cognitive manifestations of AD, such as agitation, wandering, and socially inappropriate behavior. Although the usefulness of cholinesterase inhibitors was originally expected to be limited to the early and intermediate stages of AD (because the cholinergic deficit becomes more severe later in disease and because fewer intact cholinergic synapses are present), they are also helpful in advanced disease. are also helpful in patients with AD with concomitant infarcts and in patients with dementia with Lewy bodies. Frequently, AD and dementia with Lewy bodies occur in the same patient; this is sometimes called the Lewy body variant of AD. In summary, donepezil, rivastigmine and galantamine are moderately effective in the treatment of mild to moderate AD, but there is little evidence to recommend one drug over another. A realistic discussion of the benefits of therapy, focusing on disease stabilization, as well as side effects, is warranted in all patients diagnosed with mild to moderate AD. Cholinesterase inhibitor therapy should be started early and there is emerging data that efficacy extends to the late stages of the disease. When and if cholinesterase therapy should be discontinued remains controversial.


Treatment of Moderate to Severe Disease: The partial N -methyl-D-aspartate (NMDA) antagonist memantine is believed to work by improving the signal-to-noise ratio of glutamatergic transmission at the NMDA receptor. Blockade of NMDA receptors by memantine is thought to slow the intracellular calcium accumulation and thereby help prevent further nerve damage. This agent is approved by the FDA for treating moderate and severe AD. The beneficial effects seen with memantine reflect a slower decline in treated patients rather than improvement, which is sometimes seen in patients treated with cholinesterase inhibitors. Thus, cholinesterase inhibitors remain the treatment of choice for patients with AD, although treatment with memantine may be a useful adjunct in later stage disease. There is limited data regarding memantine use in early AD, and it is not recommended for these patients. Several studies have demonstrated that memantine can be safely used in combination with cholinesterase inhibitors. The combination of memantine with a cholinesterase inhibitor has been shown to significantly delay institutionalisation in AD patients. Studies suggest that the use of memantine with donepezil affects cognition in moderate to severe AD40 but not in mild to moderate AD. Dizziness, headache, and confusion are some of the most common side effects of memantine. In June 2013, the FDA approved rivastigmine transdermal for severe AD. Approval was based on the ACTION (ACTivities of Daily Living and CognitION in Patients with Severe Dementia of the Alzheimer's Type) study, in which a higher dose of the drug (13.3 mg/24 hr) demonstrated statistically significant improvement in overall cognition and function compared with a lower dose (4.6 mg/24 hr). Australia's best online pharmacy


What we know today about Alzheimer's disease. Alzheimer’s Association. Updated 2016. Accessed 26 Feb 2016.

Winslow BT, Onysko MK, Stob CM, Hazlewood KA. Treatment of Alzheimer disease. Am Fam Physician. 2011 Jun 15. 83(12):1403-12. 

Massoud F, Léger GC. Pharmacological treatment of Alzheimer disease. Can J Psychiatry. 2011 Oct. 56(10):579-88.

McGeer PL, McGeer EG, Suzuki J, et al. Aging, Alzheimer's disease, and the cholinergic system in the basal forebrain. Neurology 1984;34:741-745.

Rossor MN, Iversen LL, Reynolds GP, et al. Neurochemical characteristics of early and late onset types of Alzheimer's disease. BMJ 1984;288:961-964.

Arai H, Ichimiya Y, Kosaka K, et al. Neurotransmitter changes in early- and late-onset Alzheimer type dementia. Prog Neuropsychopharmacol Biol Psychiatry 1992;16:883-890.

Report to the PBAC - Review of Pharmaceutical Benefits Scheme anti-dementia drugs to treat Alzheimers Disease. The Pharmaceutical Benefits Scheme. Updated 1 Nov 2012. Accessed 26 Feb 2016.

Rogers SL, Farlow MR, Doody RS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group Neurology 1998;50:1136-1145.

Rogers SL, Doody RS, Mohs RC, et al. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Int Med 1998;158:1021-1031.

Burns A, Rossor M, Hecker J, et al. The effects of donepezil in Alzheimer disease. Results from a multinational trial. Dementia and Geriatr Cogn Disorders 1999;10:237-244.

Winblad B, Engedal K, Soininen H, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001;57:489-495.

Mohs RC, Doody RS, Morris JC, et al. A 1-year, placebo-controlled preservation of function study of donepezil in AD patients. Neurology 2001;57:481-488.

13 Feldman H, Gauthier S, Hecker J, et al. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. Neurology 2001;57:613-620.

Geldmacher DS, Provenzano G, McRae, et al. Donepezil is associated with delayed nursing home placement in patients with Alzheimer's disease. J Am Geriatr Soc 2003;51:937-944.

Cummings JL, Donahue JA, Brooks RL. Ther between donepezil and behavioral disturbances in patients with Alzheimer's disease. Am J. Geriatr Psych 2000;8:134-140.

Corey-Bloom J, Anand R, Veach J, for ENA 713 B352 Study Group. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease. Int J Geriatr Psychopharmacol 1998;1:55-65.

Rosler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ 1999;319:633-638.

Farlow M, Anand R, Messina J, et al. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease. Eur Neurol 2000;46:236-241.

Raskind MA, Peskind ER, Wessel T, et al. Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 2000;54:2261-2268.

Tariot PN, Solomon PR, Morris JC, et al. A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology 2000;54:2269-2276.

Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer disease: multicentre randomized trial. BMJ 2000;321:1445-1449.

Hock C, Maddalena A, Raschig A, et al. Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of A beta 42 in patients with Alzheimer's disease. Amyloid 2003;10:1-6.

Sadot E, Gurwitz D, Barg J, et al. Activation of m1 muscarinic acetylcholine receptor regulates tau phosphorylation in transfected PC12 cells. J Neurochem 1996;66:877-880.

Neumann PJ, Hermann RC, Kuntz KM, et al. Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer's disease. Neurology 1999;25:1138-1145.

Livingston G, Katona C. How useful are cholinesterase inhibitors in the treatment of Alzheimer's disease? A number needed to treat analysis. Int J Geriatr Psychiatry 2000;15:203-207.

Wilkinson D, Passmore P, Bullock R, et al. A multinational, randomized, 12-week comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer's disease. Int J Clin Practice 2002;56:441-446.

Jones RW, Soininen H, Hager K, et al. First head-to-head study comparing the tolerability, ease of use and efficacy of donepezil and galantamine in Alzheimer's disease. Poster Presentation at: The 7th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy (AAT); April 4, 2002; Geneva, Switzerland.

Butterfield DA, Pocernich CB. The glutamatergic system and Alzheimer's disease: therapeutic implications. CNS Drugs 2003;17:641-652.

Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Pysch 1999;14:135-146.

Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer disease. NEJM 2003;348:1333-1341.

Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291:317-324.

Sobow TM, Kloszewska I, Karlinska I. Addition of vitamin E to donepezil as a treatment for Alzheimer's disease. Alzheimer's Reports 1999;2:143-146.

Rigaud AS, Andre G, Vellas B, et al. No additional benefit of HRT on response to rivastigmine in menopausal women with AD. Neurology 2003;60:148-149.

Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291:317-324.

Nordberg A, Svensson AL. Cholinesterase inhibitors in the treatment of Alzhiemer's disease: a compariason of tolerability and pharmacology. Drug Safety 1998;19:465-480.

Wilkinson D, Passmore P, Bullock R, et al. A multinational, randomized, 12-week comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer's disease. Int J Clin Practice 2002;56:441-446.

Kavanagh S, Gaudig M, Van Baelen B, et al. Galantamine and behavior in Alzheimer disease: analysis of four trials. Acta Neurol Scand. 2011 Nov. 124(5):302-8.

Farlow M, Veloso F, Moline M, et al. Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease. BMC Neurol. 2011 May 25. 11:57.

Lachaine J, Beauchemin C, Legault M, Bineau S. Economic evaluation of the impact of memantine on time to nursing home admission in the treatment of Alzheimer disease. Can J Psychiatry. 2011 Oct. 56(10):596-604.

Schmitt FA, van Dyck CH, Wichems CH, Olin JT. Cognitive response to memantine in moderate to severe Alzheimer disease patients already receiving donepezil: an exploratory reanalysis. Alzheimer Dis Assoc Disord. 2006 Oct-Dec. 20(4):255-62.

Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT. Memantine treatment in patients with mild to moderate Alzheimer's disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial. Curr Alzheimer Res. 2008 Feb. 5(1):83-9.

Schneider LS, Dagerman KS, Higgins JP, et al. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. 2011 Aug. 68(8):991-8.

Jeffrey S. FDA Approves Exelon Patch for Severe Alzheimer's. Medscape [serial online]. Available at: Accessed 26 Feb 2016.

Farlow MR, Grossberg G, Gauthier S, Meng X, Olin JT. The ACTION study: methodology of a trial to evaluate safety and efficacy of a higher dose rivastigmine transdermal patch in severe Alzheimer's disease.Curr Med Res Opin. 2010 Oct. 26(10):2441-7.

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