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Pharmacological Treatment of Dementia

Summary (continued)

Question 2: Does Pharmacotherapy Delay Cognitive Deterioration or Delay Disease Onset of Dementia Syndromes?

Delay of Onset of Dementia

The concept of "delay onset" was operationalized to imply conversion from a state of cognitive impairment, classified as MCI, CLoND or CIND, to a true dementia state. No studies with this population met the final eligibility criteria, although four trials^109-112 advanced to the full text screening stage. The lack of studies eligible for evaluation in this systematic review points to a gap in the literature for pharmacological interventions (attempting to demonstrate a delay in disease onset) in MCI-type populations.

Delay of Progression of Dementia

The need for good evaluation of disease progression in trials was also identified. In general, few studies evaluated subjects in more severe states of the disease. This suggests that a bias exists towards evaluating mild to moderate disease in the trials eligible in this systematic review; this may reflect an underlying assumption that the less severe groups are most likely to benefit from drug trials. Since so few studies have evaluated the more severe groups, this assumption may require some empirical justification in future research. A consensus is required regarding the diagnostic criteria to be used to establish levels of severity.

Three studies evaluating cerebrolysin, selegiline and vitamin E, and donepezil have shown statistically significant effects in delaying disease progress in mild to moderate and moderately severe disease in patients with AD. This delay in progress was expressed in terms of delay in days to primary event or statistical differences between placebo at a specified time interval. Although these trials coincidentally evaluated dementia patients over the longest time interval, their protocol did not withdraw the drug at the end of the study. Theoretically, conclusive evidence of disease delay would be demonstrated if the treatment groups did not return to the level of the placebo. Thus, distinguishing between symptomatic and disease modifying effects is not possible unless the drug is withdrawn and the treatment groups are observed for these changes.

When studies attempted to evaluate disease progression, long-term (1 year or greater) trials continued in an "open-label fashion," where blinding was no longer maintained. This limits the confidence that bias did not affect the subsequent changes in the outcomes. It was observed that increasing levels of dropout (for a variety of reasons) also plagued these open-label phases of evaluation. From a practical perspective, maintaining adherence in longer-term trials in dementia patients is challenging, particularly for those in the placebo arm or for those with interventions that have a high proportion of adverse events. Although this practical challenge exists, the findings of this review suggest that there is a gap in the literature showing delay of the disease process of dementia related disorders.

Question 3: Are Certain Drugs, Including Alternative Medicines (Non-pharmaceutical) More Effective Than Others?

Head-to-head Comparisons of Drugs in the Treatment of Dementia

A total of 26^{18,39,47,60,61,65,66,68,69,73,113-128} studies compared efficacy of the two or more pharmacological agents relative to each other. In general, few drugs showed statistically significant differences relative to each other. Those that did include (listed in declining order of performance):

Sulphomucopolysaccharides versus CDP-choline:¹¹⁷ Statistically significant differences were seen in favor of sulphomucopolysaccharides in measures of behavior and global assessment in 30 institutionalized patients with mild to moderate MID.
Donepezil and vitamin E:¹⁸ Statistically significant differences were seen in favor of donepezil in general cognitive function 54 patients with mild AD.
Antagonic stress versus nicergoline:³⁹ Statistically significant differences were seen in favor of antagonic stress in cognition as well as a global assessments in 62 subjects with mild to moderate AD.
Antagonic stress versus meclofenate:¹²⁴ Statistically significant differences were seen in favor of antagonic stress in measures of cognition and global assessment in 63 patients with mild to moderate AD.
Posatirelin versus citicoline:⁴⁷ Statistically significant differences were seen in favor of posatirelin in general cognitive measure and mood in 222 community living patients with mild to moderate AD.
Pyritinol versus hydergine:¹²⁵ A significant difference in favor of pyritinol in a global assessment measure in 102 Hispanic patients with mild to moderate AD.
Idebenone⁶¹ versus tacrine: Mixed results were observed; the Efficacy Index Score showing a statistically significant benefit over tacrine, while the global assessment showed no difference in 203 individuals with AD, 44 of whom completed the study.

Current Drugs Approved in the United States for the Treatment of Dementia

What may be most relevant to clinicians are head to head comparison of the cholinergic modifying neurotransmitter pharmacological agents, particularly those currently approved for the treatment of dementia (tacrine, rivastigmine, galantamine, donepezil) in the United States. The evidence for each of these drugs has been extensively detailed, and the relative merits and handicaps of each are outlined in the results section of the full report (Chapter 3). Relative effectiveness as demonstrated by effect sizes for the ADAS-cog and the CIBIC are also compared in Chapter 3. Although the psychometric properties of these two outcomes are commonly accepted, comparison across the populations in these pooled estimates may not lend themselves to direct comparison across these four different specific drugs; populations may be different and reporting of adverse events is not consistent. Inferences about the relative efficacy of these four medications specific for the treatment of dementia should be made cautiously as head to head comparisons were not undertaken.

Question 4: Do Certain Patient Populations Benefit More from Pharmacotherapy Than Others?

In general, very few trials examined the efficacy of dementia drugs across different populations or described the population characteristics in sufficient detail. From the 15 studies ^{2,3,8,10-12,23-24,61,84,93,129-132} that reported stratified analyses, eight different variables were identified, which included age, gender, Apolipoprotein E gene (APOE) genotype, disease type, disease severity (as determined by MMSE/ ADAS-cog threshold levels), treatment center, care dependence, and presence of depression. Additionally, three trials were identified that evaluated efficacy in:

Patients with Down's syndrome and dementia.
Different races as a function of treatment center of a multicenter trial.
Depressed patients.

Given the relatively small number of trials evaluating these variables within different populations and different pharmacological interventions, the findings of this review are inconclusive with respect to these variables. A significant gap in the literature has been identified.

Question 5: What Is the Evidence-base for the Treatment of Ischemic Vascular Dementia?

A total of 20 pharmacological interventions in 29 studies ^{17,36,38,44,46,70-72,81,92,96,98,102-104,106-107,117,126,128,133-141} were applied specifically to VaD classified dementias. The majority of these pharmacological interventions (n=14) were represented by single trials, limiting the ability to judge the evidence; these interventions included:

Ateroid.
Buflomedil.
Cerebrolysin.
Sulphomucopolysaccharides (CDP choline).
Citalopram.
Donepezil.
Ginkgo biloba.
Idebenone.
Minaprine.
Nimodipine.
Oxiracetam.
5-THF (trazodone).
Vincamine.
Xantinolnicotinate.

Six interventions had more than a single trial, and these included:

Choto-san (n=2).
Memantine (n=3).
Nicergoline (n=2).
Pentoxifylline (n=4).
Posatirelin (n=2).
Propentofylline (n=2).

In general, when the drug interventions were shown to be effective, it was in the domains of cognitive function (both general and specific) and global assessment. Other domains were less frequently evaluated. Several trials attempted to test for differences between VaD groups and other dementia types.

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Discussion

The findings of this report suggest several important areas for future research using pharmacological treatments for dementia and these include:

Analytic Framework of the Intended Aim of the Therapy on the Disease

Better conceptualization and research design to capture "delay in progression."
Clearer consensus on defining efficacy (benefits and clinically important change).
Longer term studies (> 12 months).

Potential for Bias

Clarification of the role of industry sponsorship; one recommendation should be that all studies are required to disclose such information in future, including who analyzed the results.
More concerted effort to incorporate unpublished studies and negative trials in future reviews.

Population

Inclusion of the spectrum of severity in the patient populations (nothing to suggest that severe patients may not benefit from pharmacotherapy aimed at cognitive function improvement).
The need for validation of trials and testing processes within cultures other than the traditional white population.
Examining the efficacy of interventions in different sub-populations (age, disease severity levels, etc.).
Better measurement and reporting of important patient characteristics (including baseline cognition scores, co-morbid conditions, the use of other medications, etc.).
Inclusion of MCI type groups of subjects to evaluate "delay of onset" (studies in progress).

Outcomes

Expansion of outcomes collected to include more than just cognitive function, and especially include caregiver burden and quality of life/ADL.
Clear operational definitions for determining critical outcomes (delay to onset, delay to progression, important effect size, etc.).
Understanding of how therapies are addressed and what outcomes are produced in different cultures.
Production of other testing tools to detect both onset and responses to therapies across varied cultural groups.
Improvement in the reporting of adverse events to evaluate harm and risk vs. benefit.
Improvement in detailing adverse events associated with the duration period and those occurring following this period.

Analysis

Appropriate analytical strategies that take into account intention to treat (ITT)/last observation carried forward (LOCF) analyses; where possible both observed case and ITT/LOCF analyses should be presented.
Sufficient data to estimate effect size, taking into account variability in both treated and control populations on the primary measures.
Reporting the power of the study when findings are statistically non-significant.

Intervention

Undertake more studies with direct comparison of drugs to determine the relative efficacy of agents.
Improved description of the titration process.
Improved collection of adverse events undertaken in a systematic fashion with standardized instruments.

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Availability of Full Report

The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Research and Quality (AHRQ) by McMaster University Evidence-based Practice Center under Contract No. 290-02-0020. It is expected to be available in April 2004. At that time, printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment No. 97, Pharmacological Treatment of Dementia.

The Evidence Report is also online on the National Library of Medicine Bookshelf, or can be downloaded as a PDF File (PDF File, 13 MB). PDF Help.

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References

1. Thal LJ, Calvani M, Amato A, et al. A 1-year controlled trial of acetyl-l-carnitine in early-onset AD. Neurology 2000a; 55(6):805-10.

2. Thal LJ, Carta A, Clarke WR, et al. A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's disease. Neurology 1996a; 47(3):705-11.

3. Sano M, Bell K, Cote L, et al. Double-blind parallel design pilot study of acetyl levocarnitine in patients with Alzheimer's disease. Arch Neurol 1992 Nov; 49(11):1137-41.

4. Livingston GA, Sax KB, McClenahan Z, et al. Acetyl-l-carnitine in dementia. Int J Geriatr Psychiatry 1991; 6(12):853-60.

5. Spagnoli A, Lucca U, Menasce G, et al. Long-term acetyl-L-carnitine treatment in Alzheimer's disease. Neurology 1991 Nov; 41(11):1726-32.

6. Rai G, Wright G, Scott L, et al. Double-blind, placebo-controlled study of acetyl-l-carnitine in patients with Alzheimer's disease. Curr Med Res Opin 1990; 11(10):638-47.

7. Dunne MP, Hartley LR. Scopolamine and the control of attention in humans. Psychopharmacologia 1986; 89(1):94-7.

8. Prasher VP, Huxley A, Haque MS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Down syndrome and Alzheimer's disease: Pilot study. Int J Geriatr Psychiatry 2002 Mar; 17(3):270-8.

9. 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 Aug 14; 57(3):481-8.

10. 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 2001b; 57(3):489-95.

11. 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 Aug 28; 57(4):613-20.

12. Tariot PN, Cummings JL, Katz IR, et al. A randomised, 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 2001a; 49(12):1590-9.

13. Burns A, Rossor M, Hecker J, et al. The effects of donepezil in Alzheimer's disease—results from a multinational trial. Dement Geriatr Cogn Disord 1999 May; 10(3):237-44.

14. Rogers SL, Farlow MR, Doody RS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Neurology 1998b; 50(1):136-45.

15. 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. Arch Intern Med 1998a; 158(9):1021-31.

16. Rogers SL, Friedhoff LT. The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. The Donepezil Study Group. Dementia 1996 Nov; 7(6):293-303.

17. Pratt RD, Perdomo CA. Donepezil-treated patients with probable vascular dementia demonstrate cognitive benefits. Ann N Y Acad Sci 2002 Nov; 977:513-22.

18. Thomas A, Iacono D, Bonanni L, et al. Donepezil, rivastigmine, and vitamin E in Alzheimer disease: a combined P300 event-related potentials/neuropsychologic evaluation over 6 months. Clin Neuropharmacol 2001 Jan; 24(1):31-42.

19. 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 Apr 13; 359(9314):1283-90.

20. 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(5):589-95.

21. Wilkinson D, Murray J. Galantamine: a randomized, double-blind, dose comparison in patients with Alzheimer's disease. Int J Geriatr Psychiatry 2001 Sep; 16(9):852-7.

22. 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 Jun 27; 54(12):2269-76.

23. 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 Dec 9; 321(7274):1445-9.

24. 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 Jun 27; 54(12):2261-8.

25. Schulz R, O'Brien A, Czaja S, et al. Dementia caregiver intervention research: in search of clinical significance. Gerontologist 2002 Oct; 42(5):589-602.

26. Jann MW, Cyrus PA, Eisner LS, et al. Efficacy and safety of a loading-dose regimen versus a no-loading-dose regimen of metrifonate in the symptomatic treatment of Alzheimer's disease: a randomized, double-masked, placebo-controlled trial. Clin Ther 1999; 21(1):88-102.

27. Raskind MA, Cyrus PA, Ruzicka BB, et al. The effects of metrifonate on the cognitive, behavioral, and functional performance of Alzheimer's disease patients. J Clin Psychiatry 1999; 60(5):318-25.

28. Becker RE, Colliver JA, Markwell SJ, et al. Effects of metrifonate on cognitive decline in Alzheimer's disease: a double-blind, placebo-controlled, 6-month study. Alzheimer Dis Assoc Disord 1998 Mar; 12(1):54-7.

29. Morris JC, Cyrus PA, Orazem J, et al. Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer's disease. Neurology 1998 May; 50(5):1222-30.

30. Cummings JL, Cyrus PA, Bieber F, et al. Metrifonate treatment of the cognitive deficits of Alzheimer's disease. Neurology 1998b; 50(5):1214-21.

31. Pettigrew LC, Bieber F, Lettieri J, et al. Pharmacokinetics, pharmacodynamics, and safety of metrifonate in patients with Alzheimer's disease. J Clin Pharmacol 1998 Mar; 38(3):236-45.

32. Becker RE, Colliver JA, Markwell SJ, et al. Double-blind, placebo-controlled study of metrifonate, an acetylcholinesterase inhibitor, for Alzheimer's disease. Alzheimer Dis Assoc Disord 1996; 10(3):124-31.

33. Cummings J, Bieber F, Mas J, et al. Metrifonate in Alzheimer's disease: results of a dose finding study. Alzheimers Dis Biol Diagn Ther 1997:665-9.

34. Nordberg A, Svensson AL. Cholinesterase inhibitors in the treatment of Alzheimer's disease: a comparison of tolerability and pharmacology. Drug Saf 1998 Dec; 19(6):465-80.

35. Winblad B, Bonura ML, Rossini BM, et al. Nicergoline in the treatment of mild-to-moderate Alzheimer's disease: a European multicentre trial. Clin Drug Investig 2001a(9):621-32.

36. Herrmann WM, Stephan K, Gaede K, et al. A multicenter randomized double-blind study on the efficacy and safety of nicergoline in patients with multi-infarct dementia. Dement Geriatr Cogn Disord 1997 Jan; 8(1):9-17.

37. Nappi G, Bono G, Merlo P, et al. Long-term nicergoline treatment of mild to moderate senile dementia. Results of a multicentre, double-blind, placebo-controlled study. Clin Drug Investig 1997(6):308-16.

38. Saletu B, Paulus E, Linzmayer L, et al. Nicergoline in senile dementia of Alzheimer type and multi-infarct dementia: a double-blind, placebo-controlled, clinical and EEG/ERP mapping study. Psychopharmacologia 1995 Feb; 117(4):385-95.

39. Schneider F, Popa R, Mihalas G, et al. Superiority of antagonic-stress composition versus nicergoline in gerontopsychiatry. Ann N Y Acad Sci 1994 Jun; 717:332-42.

40. Moller HJ, Hampel H, Hegerl U, et al. Double-blind, randomized, placebo-controlled clinical trial on the efficacy and tolerability of a physostigmine patch in patients with senile dementia of the Alzheimer type. Pharmacopsychiatry 1999 May; 32(3):99-106.

41. Thal LJ, Schwartz G, Sano M, et al. A multicenter double-blind study of controlled-release physostigmine for the treatment of symptoms secondary to Alzheimer's disease. Neurology 1996b; 47(6):1389-95.

42. Van Dyck CH, Newhouse P. Extended-release physostigmine in Alzheimer's disease: a multicenter, double-blind, 12-week study with dose enrichment. Arch Gen Psychiatry 2000; 57(2):157-64.

43. Thal LJ, Ferguson JM, Mintzer J, et al. A 24-week randomized trial of controlled-release physostigmine in patients with Alzheimer's disease. Neurology 1999 Apr 12; 52(6):1146-52.

44. Ferrari E, Cucinotta D, Albizatti MG, et al. Effectiveness and safety of posatirelin in the treatment of senile dementia: a multicenter, double-blind, placebo-controlled study. Arch Gerontol Geriatr 1998; 27(Suppl 6):163-74.

45. Gasbarrini G, Stefanini G, Addolorato G, et al. Posatirelin for the treatment of degenerative and vascular dementia: results of explanatory and pragmatic efficacy analyses. Arch Gerontol Geriatr 1997; 26(1):33-47.

46. Parnetti L, Ambrosoli L, Agliati G, et al. Posatirelin in the treatment of vascular dementia: a double-blind multicentre study vs placebo. Acta Neurol Scand 1996 Jun; 93(6):456-63.

47. Parnetti L, Ambrosoli L, Abate G, et al. Posatirelin for the treatment of late-onset Alzheimer's disease: a double-blind multicentre study vs citicoline and ascorbic acid. Acta Neurol Scand 1995 Aug; 92(2):135-40.

48. Potkin SG, Anand R, Fleming K, et al. Brain metabolic and clinical effects of rivastigmine in Alzheimer's disease. Int J Neuropsychopharmacol 2001 Sep; 4(3):223-30.

49. 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 Dec 16; 356(9247):2031-6.

50. Forette F, Anand R, Gharabawi G. A phase II study in patients with Alzheimer's disease to assess the preliminary efficacy and maximum tolerated dose of rivastigmine (Exelon registered). Eur J Neurol 1999; 6(4):423-9.

51. 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 Mar 6; 318(7184):633-8.

52. Agid Y, Dubois B, Anand R, et al. Efficacy and tolerability of rivastigmine in patients with dementia of the Alzheimer type. Curr Ther Res Clin Exp 1998; 59(12):837-45.

53. Corey-Bloom JR, Anand JV, Veach J, et al. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease. Int J Geriatr Psychopharmacol 1998; 1:55-65.

54. Knapp MJ, Knopman DS, Solomon PR, et al. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group. JAMA 1994b; 271(13):985-91.

55. Maltby N, Broe GA, Creasey H, et al. Efficacy of tacrine and lecithin in mild to moderate Alzheimer's disease: double blind trial. BMJ 1994 Apr 2; 308(6933):879-83.

56. Prentice N, Van BM, Dougall NJ, et al. A double-blind, placebo-controlled study of tacrine in patients with Alzheimer's disease using SPET. J Psychopharmacol (Oxf) 1996; 10(3):175-81.

57. Weinstein HC, Teunisse S, Van Gool WA. Tetrahydroaminoacridine and lecithin in the treatment of Alzheimer's disease. Effect on cognition, functioning in daily life, behavioural disturbances and burden experienced by the carers. J Neurol 1991 Feb; 238(1):34-8.

58. Wong WJ, Liu HC, Fuh JL, et al. A double-blind, placebo-controlled study of tacrine in Chinese patients with Alzheimer's disease. Dement Geriatr Cogn Disord 1999 Jul; 10(4):289-94.

59. Wood PC, Castleden CM. A double-blind, placebo controlled, multicentre study of tacrine for Alzheimer's disease. Int J Geriatr Psychiatry 1994; 9(8):649-54.

60. Allain H, Schuck S, Lebreton S, et al. Aminotransferase levels and silymarin in de novo tacrine-treated patients with Alzheimer's disease. Dement Geriatr Cogn Disord 1999 May; 10(3):181-5.

61. Gutzmann H, Kuhl KP, Hadler D, et al. Safety and efficacy of idebenone versus tacrine in patients with Alzheimer's disease: results of a randomized, double-blind, parallel-group multicenter study. Pharmacopsychiatry 2002 Jan; 35(1):12-8.

62. Antuono PG. Effectiveness and safety of velnacrine for the treatment of Alzheimer's disease. A double-blind, placebo-controlled study. Mentane Study Group. Arch Intern Med 1995 Sep 11; 155(16):1766-72.

63. Huff FJ, Antuono P, Murphy M, et al. Potential clinical use of an adrenergic/cholinergic agent (HP 128) in the treatment of Alzheimer's disease. Ann N Y Acad Sci 1991; 640:263-7.

64. Zemlan FP, Folks DG, Goldstein BJ, et al. Velnacrine for the treatment of Alzheimer's disease: a double-blind, placebo-controlled trial. J Neural Transm Gen Sect 1996; 103(8-9):1105-16.

65. Allain H, Dautzenberg PH, Maurer K, et al. Double blind study of tiapride versus haloperidol and placebo in agitation and aggressiveness in elderly patients with cognitive impairment. Psychopharmacologia 2000 Mar; 148(4):361-6.

66. Teri L, Logsdon RG, Peskind E, et al. Treatment of agitation in AD: a randomized, placebo-controlled clinical trial. Neurology 2000 Nov 14; 55(9):1271-8.

67. Petrie WM, Ban TA, Berney S, et al. Loxapine in psychogeriatrics: a placebo- and standard-controlled clinical investigation. J Clin Psychopharmacol 1982 Apr; 2(2):122-6.

68. De Deyn PP, Rabheru K. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999 Sep 22; 53(5):946-55.

69. Auchus AP, Bissey-Black C. Pilot study of haloperidol, fluoxetine, and placebo for agitation in Alzheimer's disease. J Neuropsychiatry Clin Neurosci 1997; 9(4):591-3.

70. 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 Psychiatry 1999 Feb; 14(2):135-46.

71. Orgogozo J, Rigaud AS, Stoffler A, et al. Efficacy and safety of memantine in patients with mild to moderate vascular dementia. Stroke 2002; 33:1834-9.

72. Wilcock G, Mobius HJ, Stoffler A. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol 2002; 17(6):297-305.

73. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med 1997; 336(17):1216-22.

74. Mangoni A, Grassi MP, Frattola L, et al. Effects of a MAO-B inhibitor in the treatment of Alzheimer disease. Eur Neurol 1991; 31(2):100-7.

75. Agnoli A, Fabbrini G, Fioravanti M, et al. CBF and cognitive evaluation of Alzheimer type patients before and after IMAO-B treatment: a pilot study. Eur Neuropsychopharmacol 1992 Mar; 2(1):31-5.

76. Burke WJ, Roccaforte WH, Wengel SP, et al. L-deprenyl in the treatment of mild dementia of the Alzheimer type: results of a 15-month trial. J Am Geriatr Soc 1993a; 41(11):1219-25.

77. Filip V, Kolibas E. Selegiline in the treatment of Alzheimer's disease: a long-term randomized placebo-controlled trial. Czech and Slovak Senile Dementia of Alzheimer Type Study Group. J Psychiatry Neurosci 1999 May; 24(3):234-43.

78. Freedman M, Rewilak D, Xerri T, et al. L-deprenyl in Alzheimer's disease: cognitive and behavioral effects. Neurology 1998; 50(3):660-8.

79. Ruether E, Ritter R, Apecechea M, et al. Efficacy of the peptidergic nootropic drug cerebrolysin in patients with senile dementia of the Alzheimer type (SDAT). Pharmacopsychiatry 1994 Jan; 27(1):32-40.

80. Bae CY, Cho CY, Cho K, et al. A double-blind, placebo-controlled, multicenter study of Cerebrolysin for Alzheimer's disease. J Am Geriatr Soc 2000 Dec; 48(12):1566-71.

81. Xiao S, Yan H, Yao P, et al. The efficacy of cerebrolysin in patients with vascular dementia: results of a Chinese multicentre, randomised, double-blind, placebo-controlled trial. Hong Kong Journal of Psychiatry 1999(2):13-9.

82. Xiao S, Yan H, Yao P, et al. Efficacy of FPF 1070 (cerebrolysin) in patients with Alzheimer's disease: a multicentre, randomised, double-blind, placebo-controlled trial. Clin Drug Investig 2000(1):43-53.

83. Ruether E, Husmann R, Kinzler E, et al. A 28-week, double-blind, placebo-controlled study with Cerebrolysin in patients with mild to moderate Alzheimer's disease. Int Clin Psychopharmacol 2001 Sep; 16(5):253-63.

84. Panisset M, Gauthier S, Moessler H, et al. Cerebrolysin in Alzheimer's disease: a randomized, double-blind, placebo-controlled trial with a neurotrophic agent. J Neural Transm Gen Sect 2002; 109(7-8):1089-104.

85. Asthana S, Baker LD, Craft S, et al. High-dose estradiol improves cognition for women with AD: results of a randomized study. Neurology 2001 Aug 28; 57(4):605-12.

86. Wang PN, Liao SQ, Liu RS, et al. Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study. Neurology 2000 Jun 13; 54(11):2061-6.

87. Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial. Neurology 2000 Jan 25; 54(2):295-301.

88. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. JAMA 2000(8):1007-15.

89. Kyomen HH, Satlin A, Hennen J, et al. Estrogen therapy and aggressive behavior in elderly patients with moderate-to-severe dementia: results from a short-term, randomized, double-blind trial. Am J Geriatr Psychiatry 1999; 7(4):339-48.

90. Le Bars PL, Katz MM, Berman N, et al. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. JAMA 1997(16):1327-32.

91. Maurer K, Ihl R, Dierks T, et al. Clinical efficacy of Ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type. J Psychiatr Res 1997 Nov; 31(6):645-55.

92. Kanowski S, Herrmann WM, Stephan K, et al. Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Pharmacopsychiatry 1996 Mar; 29(2):47-56.

93. Weyer G, Babej-Dolle RM, Hadler D, et al. A controlled study of 2 doses of idebenone in the treatment of Alzheimer's disease. Neuropsychobiology 1997; 36(2):73-82.

94. Gutzmann H, Hadler D. Sustained efficacy and safety of idebenone in the treatment of Alzheimer's disease: update on a 2-year double-blind multicentre study. J Neural Transm Suppl 1998; 54:301-10.

95. Bergamasco B, Scarzella L, La Commare P. Idebenone, a new drug in the treatment of cognitive impairment in patients with dementia of the Alzheimer type. Funct Neurol 1994 May; 9(3):161-8.

96. Marigliano V, Abate G, Barbagallo-Sangiorgi G, et al. Randomized, double-blind, placebo controlled, multicentre study of idebenone in patients suffering from multi-infarct dementia. Arch Gerontol Geriatr 1992; 15(3):239-48.

97. Bottini G, Vallar G, Cappa S, et al. Oxiracetam in dementia: a double-blind, placebo-controlled study. Acta Neurol Scand 1992 Sep; 86(3):237-41.

98. Maina G, Fiori L, Torta R, et al. Oxiracetam in the treatment of primary degenerative and multi-infarct dementia: a double-blind, placebo-controlled study. Neuropsychobiology 1989; 21(3):141-5.

99. Mangoni A, Perin C, Smirne S, et al. A double-blind, placebo-controlled study with oxiracetam in demented patients administered the Luria-Nebraska Neuropsychological Battery. Drug Dev Res 1988; 14(3-4):217-4.

100. Rozzini R, Zanetti O, Bianchetti A. Effectiveness of oxiracetam therapy in the treatment of cognitive deficiencies secondary to primary degenerative dementia. Acta Neurol (Napoli) 1992 Apr; 14(2):117-26.

101. Burgio LD, Reynolds CFI, Janosky JE, et al. A behavioral microanalysis of the effects of haloperidol and oxazepam in demented psychogeriatric inpatients. Int J Geriatr Psychiatry 1992; 7(4):253-62.

102. Ghose K. Oxpentifylline in dementia: a controlled study. Arch Gerontol Geriatr 1987 Apr; 6(1):19-26.

103. Black RS, Barclay LL, Nolan KA, et al. Pentoxifylline in cerebrovascular dementia. J Am Geriatr Soc 1992 Mar; 40(3):237-44.

104. Knezevic S. European Pentoxifylline Multi-Infarct Dementia Study. Eur Neurol 1996; 36(5):315-21.

105. Mielke R, Ghaemi M, Kessler J, et al. Propentofylline enhances cerebral metabolic response to auditory memory stimulation in Alzheimer's disease. JNS 1998 Jan 21; 154(1):76-82.

106. Mielke R, Kittner B, Ghaemi M, et al. Propentofylline improves regional cerebral glucose metabolism and neuropsychologic performance in vascular dementia. JNS 1996 Sep 15; 141(1-2):59-2.

107. Marcusson J, Rother M, Kittner B, et al. A 12-month, randomized placebo-controlled trial of propentofylline (HWA 285) in patients with dementia according to DSM III-R. Dement Geriatr Cogn Disord 1997; 8(5):320-8.

108. Saletu B, Moller HJ, Grunberger J, et al. Propentofylline in adult-onset cognitive disorders: double-blind, placebo-controlled, clinical, psychometric and brain mapping studies. Neuropsychobiology 1990 Sep; 24(4):173-84.

109. Convit A, de Asis J, de Leon MJ, et al. Atrophy of the medial occipitotemporal, inferior, and middle temporal gyri in non-demented elderly predict decline to Alzheimer's disease. Neurobiol Aging 2000 Jan; 21(1):19-26.

110. Rapp S, Brenes G, Marsh AP. Memory enhancement training for older adults with mild cognitive impairment: a preliminary study. Aging Ment Health 2002 Feb; 6(1):5-11.

111. Johnson SA, Simmon VF. Randomized, double-blind, placebo-controlled international clinical trial of the AMPAKINE CX516 in elderly participants with mild cognitive impairment. A progress report. J Mol Neurosci 2002; 19(1-2):197-200.

112. Sherwin BB. Estrogen and cognitive functioning in men with mild cognitive impairment. J Mol Neurosci 2002; 19(1-2):219-23.

113. Meehan KM, Wang H, David SR, et al. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double-blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology 2002 Apr; 26(4):494-504.

114. Carlyle W, Ancill RJ, Sheldon L. Aggression in the demented patient: a double-blind study of loxapine versus haloperidol. Int Clin Psychopharmacol 1993; 8(2):103-8.

115. Ancill RJ, Carlyle WW, Liang RA, et al. Agitation in the demented elderly: a role for benzodiazepines? Int Clin Psychopharmacol 1991; 6(3):141-6.

116. Coccaro EF, Kramer E, Zemishlany Z, et al. Pharmacologic treatment of noncognitive behavioral disturbances in elderly demented patients. Am J Psychiatry 1990 Dec; 147(12):1640-5.

117. Cucinotta D, Romagnoli S, Godoli G, et al. Comparison of sulfomucopolysaccharides and cytidine diphosphocholine in the treatment of multi-infarct dementia: a randomized double-blind test. Curr Ther Res Clin Exp 1988; 43(1):12-20.

118. Karlsson I, Godderis J, Augusto De Mendonca LC, et al. A randomised, double-blind comparison of the efficacy and safety of citalopram compared to mianserin in elderly, depressed patients with or without mild to moderate dementia. Int J Geriatr Psychiatry 2000 Apr; 15(4):295-305.

119. Pollock BG, Mulsant BH, Rosen J, et al. Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. Am J Psychiatry 2002; 159(3):460-5.

120. Barnes R, Veith R, Okimoto J. Efficacy of antipsychotic medications in behaviorally disturbed dementia patients. Am J Psychiatry 1982; 139(9):1170-4.

121. Chan WC, Lam LC, Choy CN, et al. A double-blind randomised comparison of risperidone and haloperidol in the treatment of behavioural and psychological symptoms in Chinese dementia patients. Int J Geriatr Psychiatry 2001 Dec; 16(12):1156-62.

122. Katona CL, Hunter BN, Bray J. A double-blind comparison of the efficacy and safely of paroxetine and imipramine in the treatment of depression with dementia. Int J Geriatr Psychiatry 1998 Feb; 13(2):100-8.

123. Taragano FE, Lyketsos CG, Mangone CA, et al. A double-blind, randomized, fixed-dose trial of fluoxetine vs. amitriptyline in the treatment of major depression complicating Alzheimer's disease. Psychosomatics 1997 May; 38(3):246-52.

124. Popa R, Schneider F, Mihalas G, et al. Antagonic-stress superiority versus meclofenoxate in gerontopsychiatry. Arch Gerontol Geriatr 1994; 18(Suppl 4):197-206.

125. Spilich GJ, Wannenmacher W, Duarte A, et al. Efficacy of pyritinol versus hydergine upon cognitive performance in patients with senile dementia of the Alzheimer's type: a double-blind multi-center trial. Alzheimers Res 1996(3):79-84.

126. Parnetti L, Mari D, Abate G, et al. Vascular dementia Italian sulodexide study (VA.D.I.S.S.). Clinical and biological results. Thromb Res 1997 Jul 15; 87(2):225-33.

127. Gutzmann H, Kuhl KP, Kanowski S, et al. Measuring the efficacy of psychopharmacological treatment of psychomotoric restlessness in dementia: clinical evaluation of tiapride. Pharmacopsychiatry 1997 Jan; 30(1):6-11.

128. Passeri M, Cucinotta D, Abate G, et al. Oral 5'-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging (Milano) 1993 Feb; 5(Milano):63-71.

129. Alvarez XA, Pichel V, Perez P, et al. Double-blind, randomized, placebo-controlled pilot study with anapsos in senile dementia: effects on cognition, brain bioelectrical activity and cerebral hemodynamics. Methods Find Exp Clin Pharmacol 2000 Sep; 22(7):585-94.

130. Ruether E, Alvarez XA, Rainer M, et al. Sustained improvement of cognition and global function in patients with moderately severe Alzheimer's disease: a double-blind, placebo-controlled study with the neurotrophic agent Cerebrolysin. J Neural Transm Suppl 2002(62):265-75.

131. Schellenberg R, Todorova A, Wedekind W, et al. Pathophysiology and psychopharmacology of dementia: a new study design. Neuropsychobiology 1997; 35(3):132-42.

132. Reifler BV, Teri L, Raskind M, et al. Double-blind trial of imipramine in Alzheimer's disease patients with and without depression. Am J Psychiatry 1989 Jan; 146(1):45-9.

133. Ban TA, Morey LC, Santini V. Clinical investigations with ateroid in old-age dementias. Semin Thromb Hemost 1991b; 17(Suppl 2):161-3.

134. Cucinotta D, Aveni Casucci MA, Pedrazzi F, et al. Multicentre clinical placebo-controlled study with buflomedil in the treatment of mild dementia of vascular origin. J Int Med Res 1992 Apr; 20(2):136-49.

135. Shimada Y, Terasawa K, Yamamoto T, et al. A well-controlled study of Choto-san and placebo in the treatment of vascular dementia. J Tradit Med 1994; 11:246-55.

136. Terasawa K, Shimada Y, Kita T, et al. Choto-san in the treatment of vascular dementia: a double-blind, placebo-controlled study. Phytomedicine 1997; 4(1):15-22.

137. Nyth AL, Gottfries CG. The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders: a Nordic multicentre study. Br J Psychiatry 1990 Dec; 157:894-901.

138. Passeri M, Cucinotta D, de Mello M, et al. Comparison of minaprine and placebo in the treatment of Alzheimer's disease and multi-infarct dementia. Int J Geriatr Psychiatry 1987; 2(2):97-103.

139. Saletu B, Anderer P, Semlitsch HV. Relations between symptomatology and brain function in dementias: double-blind, placebo-controlled, clinical and EEG/ERP mapping studies with nicergoline. Dement Geriatr Cogn Disord 1997; Vol 8(Suppl 1):12-21.

140. Pantoni L, Rossi R, Inzitari D, et al. Efficacy and safety of nimodipine in subcortical vascular dementia: a subgroup analysis of the Scandinavian Multi-Infarct Dementia Trial. JNS 2000b; 175(2):124-34.

141. Fischhof PK, Moslinger-Gehmayr R, Herrmann WM, et al. Therapeutic efficacy of vincamine in dementia. Neuropsychobiology 1996; 34(1):29-35.

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AHRQ Publication Number 04-E018-1
Current as of April 2004

Internet Citation:

Santaguida PS, Raina P, Booker L, et al. Pharmacological Treatment of Dementia. Summary, Evidence Report/Technology Assessment: Number 97. AHRQ Publication Number 04-E018-1, April 2004. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/demphsum.htm