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Cholinesterase inhibitors in the treatment of dementia

INTRODUCTION

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 [1]. However, acetylcholine precursors were found to be ineffective [2,3], while postsynaptic cholinergic receptor agonists had unacceptable side effects [4]. By contrast, the results of studies with cholinesterase inhibitors, which increase cholinergic transmission by inhibiting cholinesterase at the synaptic cleft, have been more encouraging, and these drugs may even have some utility in the non-AD dementias.

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".)

ALZHEIMER DISEASE

Four cholinesterase inhibitors, tacrine, donepezil, rivastigmine, and galantamine are currently approved for use in Alzheimer disease (AD) by the US Food and Drug Administration (FDA). Tacrine was the first agent approved for use in AD, but it can cause hepatotoxicity and is rarely used [5]. The choice between the other three agents is largely based upon cost, individual patient tolerability, and physician experience, as efficacy appears to be similar [6-8]. (table 1).

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.

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 [9]. Cognition, as measured by the Alzheimer Disease Assessment Scale, cognitive subscale (ADAS-cog) [10], and the Clinician's global ratings were significantly improved in both treatment groups compared with placebo. There was no consistent effect noted on patient-related quality of life measures.
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References Top
  1. 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.
  2. Etienne, P, Dastoor, D, Gauthier, S, et al. Alzheimer disease: Lack of effect of lecithin treatment for 3 months. Neurology 1981; 31:1552.
  3. Thal, LJ, Rosen, W, Sharpless, NS, Crystal, H. Choline chloride fails to improve cognition of Alzheimer's disease. Neurobiol Aging 1981; 2:205.
  4. 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.
  5. Watkins, PB, Zimmerman, HJ, Knapp, MJ, et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease [see comments]. JAMA 1994; 271:992.
  6. 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.
  7. 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.
  8. 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.
  9. 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 [see comments]. Neurology 1998; 50:136.
  10. 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.
  11. 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.
  12. Birks, JS, Harvey, R. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev 2003; :CD001190.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. Birks, J, Grimley Evans, J, Iakovidou, V, Tsolaki, M. Rivastigmine for Alzheimer's disease (Cochrane Review). Cochrane Database Syst Rev 2000; 4:CD001191.
  20. Novartis Exelon labeling update reflects report of esophageal rupture. The Pink Sheet 2001; 63:24.
  21. Rosler, M, Anand, R, Cicin-Sain, A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial [see comments]. BMJ 1999; 318:633.
  22. Feldman, HH, Lane, R. 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.
  23. 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.
  24. Winblad, B, Grossberg, G, Frolich, L, et al. IDEAL: a 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease. Neurology 2007; 69:S14.
  25. Olin, J, Schneider, L. Galantamine for Alzheimer's disease (Cochrane review). Cochrane Database Syst Rev 2001; 1:CD001747.
  26. Wilcock, GK, Lilienfeld, S, Gaens, E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. BMJ 2000; 321:1445.
  27. 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.
  28. Rockwood, K, Mintzer, J, Truyen, L, Wessel, T. Effects of a flexible galantamine dose in Alzheimer's disease: a randomised, controlled trial. J Neurol Neurosurg Psychiatry 2001; 71:589.
  29. 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.
  30. 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.
  31. 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.
  32. Mayor, S. Regulatory authorities review use of galantamine in mild cognitive impairment. BMJ 2005; 330:276.
  33. 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.
  34. 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.
  35. 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.
  36. Black, SE, Doody, R, Li, H, et al. Donepezil preserves cognition and global function in patients with severe Alzheimer disease. Neurology 2007; 69:459.
  37. 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.
  38. Sandson, TA. Metrifonate for Alzheimer's disease: is the next cholinesterase inhibitor better? [letter; comment]. Neurology 1999; 52:675.
  39. Schneider, LS. AD2000: donepezil in Alzheimer's disease. Lancet 2004; 363:2100.
  40. Erkinjuntti, T, Roman, G, Gauthier, S, et al. Emerging therapies for vascular dementia and vascular cognitive impairment. Stroke 2004; 35:1010.
  41. Langa, KM, Foster, NL, Larson, EB. Mixed dementia: emerging concepts and therapeutic implications. JAMA 2004; 292:2901.
  42. 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.
  43. 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.
  44. McKeith, I, Del Ser, T, Spano, P, Emre, M. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000; 356:2031.
  45. 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.
  46. 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.
  47. Emre, M, Aarsland, D, Albanese, A, et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med 2004; 351:2509.
  48. Wesnes, KA, McKeith, I, Edgar, C, et al. Benefits of rivastigmine on attention in dementia associated with Parkinson disease. Neurology 2005; 65:1654.
  49. Cubo, E, Shannon, KM, Tracy, D, et al. Effect of donepezil on motor and cognitive function in Huntington disease. Neurology 2006; 67:1268.
  50. Silver, JM, Koumaras, B, Chen, M, et al. Effects of rivastigmine on cognitive function in patients with traumatic brain injury. Neurology 2006; 67:748.
  51. Kertesz, A, Morlog, D, Light, M, et al. Galantamine in frontotemporal dementia and primary progressive aphasia. Dement Geriatr Cogn Disord 2008; 25:178.
  52. Mendez, MF, Shapira, JS, McMurtray, A, Licht, E. Preliminary findings: behavioral worsening on donepezil in patients with frontotemporal dementia. Am J Geriatr Psychiatry 2007; 15:84.
  53. Moretti, R, Torre, P, Antonello, RM, et al. Rivastigmine in frontotemporal dementia: an open-label study. Drugs Aging 2004; 21:931.
  54. Wilkinson, D, Doody, R, Helme, R, et al. Donepezil in vascular dementia: A randomized, placebo-controlled study. Neurology 2003; 61:479.
  55. Black, S, Roman, 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.
  56. 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.
  57. 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.
  58. 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.
  59. Lanctot, KL, Herrmann, N, Yau, KK, et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. CMAJ 2003; 169:557.
  60. Cummings, JL. Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. Am J Geriatr Psychiatry 2003; 11:131.
  61. Clark, CM, Karlawish, JH. Alzheimer disease: current concepts and emerging diagnostic and therapeutic strategies. Ann Intern Med 2003; 138:400.
  62. Grossberg, GT, Desai, AK. Management of Alzheimer's disease. J Gerontol A Biol Sci Med Sci 2003; 58:331.
  63. 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.
  64. Rainer, M, Mucke, HA, Kruger-Rainer, C, et al. Cognitive relapse after discontinuation of drug therapy in Alzheimer's disease: cholinesterase inhibitors versus nootropics. J Neural Transm 2001; 108:1327.
  65. Lubeck, DP, Mazonson, PD, Bowe, T. Potential effect of tacrine on expenditures for Alzheimer's disease. Med Interface 1994; 7:130.
  66. Henke, CJ, Burchmore, MJ. The economic impact of the tacrine in the treatment of Alzheimer's disease. Clin Ther 1997; 19:330.
  67. Neumann, PJ, Hermann, RC, Kuntz, KM, et al. Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer's disease [see comments]. Neurology 1999; 52:1138.
  68. 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.
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