Cholinesterase inhibitors in the treatment of dementia
- Daniel Press, MD
Daniel Press, MD
- Assistant Professor in Neurology
- Harvard Medical School
- Michael Alexander, MD
Michael Alexander, MD
- Professor of Neurology
- Harvard Medical School
- Section Editors
- Steven T DeKosky, MD, FAAN, FACP, FANA
Steven T DeKosky, MD, FAAN, FACP, FANA
- Section Editor — Dementia
- Professor of Neurology
- Deputy Director
- McKnight Brain Institute
- University of Florida College of Medicine
- Kenneth E Schmader, MD
Kenneth E Schmader, MD
- Editor in Chief — Geriatric Medicine
- Section Editor — Geriatrics
- Chief, Division of Geriatrics
- Duke University
- Director, Geriatric Research Education and Clinical Center
- Durham VA Medical Centers
Patients with Alzheimer disease (AD) have reduced cerebral production of choline acetyl transferase, which leads to a decrease in acetylcholine synthesis and impaired cortical cholinergic function. This early discovery of a marked cholinergic deficit in the brains of patients with AD led to the study of therapeutically augmenting cholinergic activity . However, acetylcholine precursors were found to be ineffective [2,3], while postsynaptic cholinergic receptor agonists had unacceptable side effects . By contrast, cholinesterase inhibitors, which increase cholinergic transmission by inhibiting cholinesterase at the synaptic cleft, have a more favorable side effect profile and are of some benefit in patients with AD as well as other non-AD dementias, albeit modest in most cases.
This topic will discuss the use of cholinesterase inhibitors in the treatment of dementia. Other treatments of dementia are discussed elsewhere. (See "Treatment of dementia".)
Three cholinesterase inhibitors, donepezil, rivastigmine, and galantamine, are currently approved for use in Alzheimer disease (AD) by the US Food and Drug Administration (FDA). The choice among the three available agents is based largely upon cost, individual patient tolerability, and physician experience, as efficacy appears to be similar (table 1) [5-7].
Donepezil — Donepezil has relatively little peripheral anticholinesterase activity and is generally well tolerated. This combined with its once-daily dosing has made it a popular drug in patients with AD. The recommended dose for donepezil is 5 mg per day for 4 weeks, then increasing to 10 mg per day. Donepezil is available in pill form and also as an oral disintegrating tablet for those unable or unwilling to swallow a pill.
The efficacy of donepezil was demonstrated in a 24-week double-blind study in which patients with mild to moderate AD were randomly assigned to donepezil (5 or 10 mg/day) or placebo . Cognition, as measured by the Alzheimer Disease Assessment Scale, cognitive subscale (ADAS-cog) , and the Clinician's Global Impression of Change (CGIC) ratings were significantly improved in both treatment groups compared with placebo. There was no consistent effect noted on patient-related quality of life measures.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Whitehouse PJ, Price DL, Struble RG, et al. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science 1982; 215:1237.
- Etienne P, Dastoor D, Gauthier S, et al. Alzheimer disease: lack of effect of lecithin treatment for 3 months. Neurology 1981; 31:1552.
- Thal LJ, Rosen W, Sharpless NS, Crystal H. Choline chloride fails to improve cognition of Alzheimer's disease. Neurobiol Aging 1981; 2:205.
- Bodick NC, Offen WW, Levey AI, et al. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol 1997; 54:465.
- Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis. JAMA 2003; 289:210.
- Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 2008; 148:379.
- Qaseem A, Snow V, Cross JT Jr, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 2008; 148:370.
- 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; 50:136.
- Weyer G, Erzigkeit H, Kanowski S, et al. Alzheimer's Disease Assessment Scale: reliability and validity in a multicenter clinical trial. Int Psychogeriatr 1997; 9:123.
- Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004; 363:2105.
- Birks JS, Harvey R. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev 2003; :CD001190.
- Feldman H, Gauthier S, Hecker J, et al. Efficacy of donepezil on maintenance of activities of daily living in patients with moderate to severe Alzheimer's disease and the effect on caregiver burden. J Am Geriatr Soc 2003; 51:737.
- Seltzer B, Zolnouni P, Nunez M, et al. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Arch Neurol 2004; 61:1852.
- Farlow MR, Salloway S, Tariot PN, et al. Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, randomized, double-blind study. Clin Ther 2010; 32:1234.
- Doody RS, Geldmacher DS, Gordon B, et al. Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Arch Neurol 2001; 58:427.
- Mohs RC, Doody RS, Morris JC, et al. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology 2001; 57:481.
- 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.
- Hernandez RK, Farwell W, Cantor MD, Lawler EV. Cholinesterase inhibitors and incidence of bradycardia in patients with dementia in the veterans affairs new England healthcare system. J Am Geriatr Soc 2009; 57:1997.
- Gill SS, Anderson GM, Fischer HD, et al. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch Intern Med 2009; 169:867.
- Birks JS, Grimley Evans J. Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev 2015; :CD001191.
- Novartis Exelon labeling update reflects report of esophageal rupture. The Pink Sheet 2001; 63:24.
- Rösler 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; 318:633.
- Feldman HH, Lane R, Study 304 Group. Rivastigmine: a placebo controlled trial of twice daily and three times daily regimens in patients with Alzheimer's disease. J Neurol Neurosurg Psychiatry 2007; 78:1056.
- Winblad B, Cummings J, Andreasen N, et al. A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease--rivastigmine patch versus capsule. Int J Geriatr Psychiatry 2007; 22:456.
- Winblad B, Grossberg G, Frölich L, et al. IDEAL: a 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease. Neurology 2007; 69:S14.
- Isaacson RS, Ferris S, Velting DM, Meng X. Cognitive Efficacy (SIB) of 13.3 Versus 4.6 mg/24 h Rivastigmine Patch in Severe Alzheimer's Disease. Am J Alzheimers Dis Other Demen 2016; 31:270.
- Olin J, Schneider L. Galantamine for Alzheimer's disease. Cochrane Database Syst Rev 2001; :CD001747.
- Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ 2000; 321:1445.
- Tariot PN, Solomon PR, Morris JC, et al. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology 2000; 54:2269.
- Rockwood K, Mintzer J, Truyen L, et al. Effects of a flexible galantamine dose in Alzheimer's disease: a randomised, controlled trial. J Neurol Neurosurg Psychiatry 2001; 71:589.
- Rockwood K, Fay S, Song X, et al. Attainment of treatment goals by people with Alzheimer's disease receiving galantamine: a randomized controlled trial. CMAJ 2006; 174:1099.
- Raskind MA, Peskind ER, Truyen L, et al. The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial. Arch Neurol 2004; 61:252.
- Galasko D, Kershaw PR, Schneider L, et al. Galantamine maintains ability to perform activities of daily living in patients with Alzheimer's disease. J Am Geriatr Soc 2004; 52:1070.
- Mayor S. Regulatory authorities review use of galantamine in mild cognitive impairment. BMJ 2005; 330:276.
- 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.
- Tariot PN, Cummings JL, Katz IR, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting. J Am Geriatr Soc 2001; 49:1590.
- Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study. Lancet 2006; 367:1057.
- Black SE, Doody R, Li H, et al. Donepezil preserves cognition and global function in patients with severe Alzheimer disease. Neurology 2007; 69:459.
- Howard R, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer's disease. N Engl J Med 2012; 366:893.
- Howard R, McShane R, Lindesay J, et al. Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: secondary and post-hoc analyses. Lancet Neurol 2015; 14:1171.
- Burns A, Bernabei R, Bullock R, et al. Safety and efficacy of galantamine (Reminyl) in severe Alzheimer's disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurol 2009; 8:39.
- Sandson TA. Metrifonate for Alzheimer's disease: is the next cholinesterase inhibitor better? Neurology 1999; 52:675.
- Schneider LS. AD2000: donepezil in Alzheimer's disease. Lancet 2004; 363:2100.
- Erkinjuntti T, Román G, Gauthier S, et al. Emerging therapies for vascular dementia and vascular cognitive impairment. Stroke 2004; 35:1010.
- Langa KM, Foster NL, Larson EB. Mixed dementia: emerging concepts and therapeutic implications. JAMA 2004; 292:2901.
- Erkinjuntti T, Kurz A, Gauthier S, et al. Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial. Lancet 2002; 359:1283.
- Kumar V, Anand R, Messina J, et al. An efficacy and safety analysis of Exelon in Alzheimer's disease patients with concurrent vascular risk factors. Eur J Neurol 2000; 7:159.
- McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000; 356:2031.
- Aarsland D, Laake K, Larsen JP, Janvin C. Donepezil for cognitive impairment in Parkinson's disease: a randomised controlled study. J Neurol Neurosurg Psychiatry 2002; 72:708.
- Ravina B, Putt M, Siderowf A, et al. Donepezil for dementia in Parkinson's disease: a randomised, double blind, placebo controlled, crossover study. J Neurol Neurosurg Psychiatry 2005; 76:934.
- Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med 2004; 351:2509.
- Wesnes KA, McKeith I, Edgar C, et al. Benefits of rivastigmine on attention in dementia associated with Parkinson disease. Neurology 2005; 65:1654.
- Russ TC, Morling JR. Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database Syst Rev 2012; :CD009132.
- Cubo E, Shannon KM, Tracy D, et al. Effect of donepezil on motor and cognitive function in Huntington disease. Neurology 2006; 67:1268.
- Silver JM, Koumaras B, Chen M, et al. Effects of rivastigmine on cognitive function in patients with traumatic brain injury. Neurology 2006; 67:748.
- Wilkinson D, Doody R, Helme R, et al. Donepezil in vascular dementia: a randomized, placebo-controlled study. Neurology 2003; 61:479.
- Black S, Román GC, Geldmacher DS, et al. Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial. Stroke 2003; 34:2323.
- Doody RS, Stevens JC, Beck C, et al. Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001; 56:1154.
- Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, van den Bussche H. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ 2005; 331:321.
- Lopez OL, Becker JT, Wisniewski S, et al. Cholinesterase inhibitor treatment alters the natural history of Alzheimer's disease. J Neurol Neurosurg Psychiatry 2002; 72:310.
- Lanctôt KL, Herrmann N, Yau KK, et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. CMAJ 2003; 169:557.
- Cummings JL. Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. Am J Geriatr Psychiatry 2003; 11:131.
- Clark CM, Karlawish JH. Alzheimer disease: current concepts and emerging diagnostic and therapeutic strategies. Ann Intern Med 2003; 138:400.
- Grossberg GT, Desai AK. Management of Alzheimer's disease. J Gerontol A Biol Sci Med Sci 2003; 58:331.
- Sheffrin M, Miao Y, Boscardin WJ, Steinman MA. Weight Loss Associated with Cholinesterase Inhibitors in Individuals with Dementia in a National Healthcare System. J Am Geriatr Soc 2015; 63:1512.
- Soysal P, Isik AT, Stubbs B, et al. Acetylcholinesterase inhibitors are associated with weight loss in older people with dementia: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2016; 87:1368.
- Holmes C, Wilkinson D, Dean C, et al. The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology 2004; 63:214.
- Rainer M, Mucke HA, Krüger-Rainer C, et al. Cognitive relapse after discontinuation of drug therapy in Alzheimer's disease: cholinesterase inhibitors versus nootropics. J Neural Transm (Vienna) 2001; 108:1327.
- O'Regan J, Lanctôt KL, Mazereeuw G, Herrmann N. Cholinesterase inhibitor discontinuation in patients with Alzheimer's disease: a meta-analysis of randomized controlled trials. J Clin Psychiatry 2015; 76:e1424.
- Pariente A, Fourrier-Réglat A, Bazin F, et al. Effect of treatment gaps in elderly patients with dementia treated with cholinesterase inhibitors. Neurology 2012; 78:957.
- Lubeck DP, Mazonson PD, Bowe T. Potential effect of tacrine on expenditures for Alzheimer's disease. Med Interface 1994; 7:130.
- Henke CJ, Burchmore MJ. The economic impact of the tacrine in the treatment of Alzheimer's disease. Clin Ther 1997; 19:330.
- Neumann PJ, Hermann RC, Kuntz KM, et al. Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer's disease. Neurology 1999; 52:1138.
- Hauber AB, Gnanasakthy A, Mauskopf JA. Savings in the cost of caring for patients with Alzheimer's disease in Canada: an analysis of treatment with rivastigmine. Clin Ther 2000; 22:439.
- ALZHEIMER DISEASE
- Advanced disease
- OTHER DEMENTIAS
- Vascular dementia
- Mixed dementia
- Dementia with Lewy bodies
- Parkinson disease
- Frontotemporal dementia
- Mild cognitive impairment
- Huntington disease
- Traumatic brain injury
- Multiple sclerosis
- PRACTICE ISSUES
- Degree of benefit
- Duration of therapy
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS