Treatment of Alzheimer's disease in Brazil: II. Behavioral and psychological symptoms of dementia

Vale, Francisco de Assis Carvalho do; Corrêa Neto, Ylmar; Bertolucci, Paulo Henrique Ferreira; Machado, João Carlos Barbosa; Silva, Delson José da; Allam, Nasser; Balthazar, Márcio Luiz Figueredo; ,

doi:10.1590/S1980-57642011DN05030006

Abstract

This article reports the recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology for the treatment of Alzheimer's disease (AD) in Brazil, with special focus on behavioral and psychological symptoms of dementia (BPSD). It constitutes a revision and broadening of the 2005 guidelines based on a consensus involving researchers (physicians and non-physicians) in the field. The authors carried out a search of articles published since 2005 on the MEDLINE, LILACS and Cochrane Library databases. The search criteria were pharmacological and non-pharmacological treatment of the behavioral and psychological symptoms of AD. Studies retrieved were categorized into four classes, and evidence into four levels, based on the 2008 recommendations of the American Academy of Neurology. The recommendations on therapy are pertinent to the dementia phase of AD. Recommendations are proposed for the treatment of BPSD encompassing both pharmacological (including acetyl-cholinesterase inhibitors, memantine, neuroleptics, anti-depressives, benzodiazepines, anti-convulsants plus other drugs and substances) and non-pharmacological (including education-based interventions, physiotherapy, occupational therapy, music therapy, therapy using light, massage and art therapy) approaches. Recommendations for the treatment of cognitive disorders of AD symptoms are included in a separate article of this edition.

Key words:
Alzheimer's disease; dementia; behavioral and psychological symptoms of dementia; treatment

Resumo

Esse texto apresenta as recomendações da Academia Brasileira de Neurologia, por intermédio do seu Departamento Científico de Neurologia Cognitiva e do Envelhecimento, para o tratamento da doença de Alzheimer (DA) no Brasil, enfocando os sintomas comportamentais e psicológicos da demência (SCPD). Trata-se de uma revisão ampliada das diretrizes publicadas em 2005, resultada de um consenso envolvendo pesquisadores da área, médicos e não médicos. Os autores realizaram uma busca de artigos publicados a partir de 2005 nas bases MEDLINE, LILACS e Cochrane Library. A busca foi direcionada para tratamento farmacológico e não farmacológico dos sintomas comportamentais e psicológicos da DA. Os estudos foram categorizados em quatro classes e as evidências em quatro níveis, com base nas recomendações da Academia Americana de Neurologia publicadas em 2008. As recomendações terapêuticas referem-se à fase demencial da DA. Apresentam-se recomendações para o tratamento dos SCPD, tanto farmacológico (incluindo inibidores da acetilcolinesterase, memantina, neurolépticos, antidepressivos, benzodiazepínicos, anticonvulsivantes e outros fármacos e substâncias), como não farmacológico (incluindo intervenções educacionais, fisioterapia, terapia ocupacional, musicoterapia, terapia com luz, massagem e arterapia). As recomendações para o tratamento dos transtornos cognitivos da DA são apresentadas em outro artigo desse fascículo.

Palavras-chave:
doença de Alzheimer; demência; sintomas comportamentais e psicológicos da demência; tratamento

Texto completo disponível apenas em PDF.

Full text available only in PDF format.

References

Engelhardt E, Brucki SM, Cavalcanti JL, Forlenza OV, Laks J, Vale FA. Treatment of Alzheimer's disease: recommendations and suggestions of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology. Arq Neuropsiquiatr 2005;63:1104-1112.
Gronseth G, French J. Practice parameters and technology assessments: what they are, what they are not, and why you should care. Neurology 2008;71:1639-1643.
French J, Gronseth G. Lost in a jungle of evidence: we need a compass. Neurology 2008;71:1634-1638.
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging and the Alzheimer's Association workgroup. Alzheimers Dement 2011;7:263-269.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDAWork Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939-44.
Albert MS, Dekosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging and Alzheimer's Association workgroup. Alzheimers Dement 2011;7:270-279.
Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging and the Alzheimer's Association workgroup. Alzheimers Dement 2011;7:1-13.
Apostolova LG, Cummings JL. Neuropsychiatric manifestations in mild cognitive impairment: a systematic review of the literature. Dement Geriatr Cogn Disord 2008; 25:115-126.
Fillit HM. The pharmacoeconomics of Alzheimer's disease. Am J Manag Care. 2000;6(22 suppl):S1139-S1144.
Buhr GT, White HK. Difficult behaviors in long-term care patients with dementia. J Am Med Dir Assoc 2006;7:180-192.
Department of Health and Human Services. Interpretive guidelines for long-term care facilities. State Operations Manual, Appendix PP - Guidance to Surveyors for Long Term Care Facilities. http://cms.hhs.gov/manuals/downloads/som107_pp_guidelines_ltcf.pdf Accessed August 21, 2007.
» http://cms.hhs.gov/manuals/downloads/som107_pp_guidelines_ltcf.pdf
Shekelle P, Maglione M, Bagley S, et al. Comparative effectiveness of off-label use of atypical antipsychotics. Comparative Effectiveness Review No. 6. (Prepared by the Southern California/RAND Evidence-based Practice Center under Contract 290-02-003.) Rockville, MD:Agency for Healthcare Research and Quality; January 2007. Effectivehealthcare.ahrq.gov/repFiles/Atypical_Antipsychotics_Final_Report.pdf.
Sultzer DL, Davis SM, Tariot PN, et al. CATIE-AD Study Group. Clinical symptom responses to atypical antipsychotic medications in Alzheimer's disease: phase 1 outcomes from the CATIE-AD effectiveness trial. Am J Psychiatry 2008;165:844-54.
Carson S, McDonagh MS, Peterson K. A Systematic Review of the Efficacy and Safety of Atypical Antipsychotics in Patients with Psychological and Behavioral Symptoms of Dementia JAGS 2006;54:354-361.
Tran-Johnson TK, Sack DA, Marcus RN, Auby P, McQuade RD, Oren DA. Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2007;68:111-119.
Grossberg GT, Desai AK. Management of Alzheimer's Disease. J Gerontol 2003;58A:331-353.
Cummings JL, Benson DF. Dementia: A clinical approach. (2nd ed.). Boston, MA: Butterworth-Heinemann; 1992.
Lyketsos CG, Colenda CC, Beck C, et al. Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia resulting from Alzheimer disease. Am J Geriatr Psychiatry 2006;14:561-572.
Ballard CG, Thomas A, Fossey J, et al. A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: the neuropsychiatric inventory median cutoff is a predictor of clinical outcome. J Clin Psychiatry 2004;65: 114-119.
Ballard C, Lana MM, Theodoulou M. A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial). PLoS Med 2008;5:e76.
Sink KM, Holden KF, Yaffe K. Pharmacologic treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA 2005;293:596-608.
De Deyn PP, Katz IR, Brodaty H, Lyons B, Greenspan A, Burns A. Management of agitation, aggression, and psychosis associated with dementia: a pooled analysis including three randomized, placebo-controlled double blind trials in nursing home residents treated with risperidone. Clin Neurol Neurosurg 2005;107:497-508.
Katz I, de Deyn PP, Mintzer J, Greenspan A, Zhu Y, Brodaty H. The efficacy and safety of risperidone in the treatment of psychosis of Alzheimers disease and mixed dementia: a meta-analysis of 4 placebo controlled clinical trials. Int J Geriatr Psychiatry 2007;22:475-484.
Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005;294:1934-1943.
Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA 2005; 293:596-608.
Guidelines abstracted from the American Academy ofNeurology 's dementia guidelines for early detection, diagnosis and management of dementia. AGS Clinical Practice Committee. J Am Geriatr Soc 2003;51:869-873.
American Academy for Geriatric Psychiatry. (2005). AAGP Atypical Position Statement. Retrieved March 26, 2008, from Retrieved March 26, 2008, from http://www.aagponline.org/prof/ antipsychstat_0705.asp
» http://www.aagponline.org/prof/ antipsychstat_0705.asp
Madhusoodanan S, Shah P, Brenner R, Gupta S. Pharmacological treatment of the psychosis of Alzheimer's Disease: what is the best approach? CNS Drugs 2007;21: 101-115.
Trinh N, 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;289:210-216.
Loy C, Schneider L. Galantamine for Alzheimer's disease and mild cognitive impairment. Cochrane Database of Systematic Reviews. In: The Cochrane Library 2011;4: Art. No. CD001747.
Cummings JL, Schneider L, Tariot PN, Kershaw PR, Yuan W. Reduction of behavioral disturbances and caregivers distress by galantamine in patients with Alzheimer's disease. Am J Psychiatry 2004;161:532-538.
Birks J, Grimley EJ, Iakovidou V, Tsolaki M. Rivastigmine for Alzheimer's disease. Cochrane Database of Systematic Reviews. In: The Cochrane Library 2011; 4: Art. No. CD001191.
Birks J, Harvey R. Donepezil for dementia due to Alzheimer's disease. Cochrane Database of Systematic Reviews. In: The Cochrane Library 2011; 4: Art. No. CD001190.
Gauthier S, Feldman H, Hecker J, et al. Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer's disease. Int Psychogeriatrics 2002;14: 389-404.
Feldman H, Gauthier S, Hecker J, et al. Efficacy and safety of donepezil in patients with more severe Alzheimer's disease: a subgroup analysis from a randomized, placebo-controlled trial. Int J Geriatric Psychiatry 2005;20:559-569.
Holmes C, Wilkinson D, Dean C, et al. The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology 2004;63:214-219.
Howard RJ, Juszczak E, Ballard CG, et al. Donepesil for the treatment of agitation in Alzheimer's disease. N Engl J Med 2007;357:1382-1392.
McShane R, Areosa SA N M. Memantine for dementia. Cochrane Database of Systematic Reviews. 2011(03): CD003154.
Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291:317-24.
Cummings JL, Schneider E, Tariot PN, et al. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology 2006;67:57-63.
Konovalov S, Muralle S, TAmpi RR. Anticonvulsants for the treatment of behavioral and psychological symptoms of dementia: a literature review. Int Psychogeriatrics 2008;20:293-308.
Tariot PN, Erb R, Podgorski CA, et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 1998;155:54-61.
Seitz D, Adunuri N, Gill SS, et al. Antidepressants for agitation and psychosis in dementia. Cochrane Database of Systematic Reviews . In: The Cochrane Library 2011; 4: Art. No. CD008191.
Weintraub D, Rosenberg PB, Drye LT, et al. Sertraline for the treatment of depression in Alzheimer's disease: week-24 outcomes. Am J Geriatr Psychiatry 2010;18:332-340.
Lyketsos CG, DelCampo L, Steinberg M, et al. Treating depression in Alzheimer disease. Arch Gen Psychiatry 2003;60:737-746.
Finkel SI, Mintzer JE, Dysken M, et al. A randomized, placebo-controlled study of the efficacy and safety of sertraline in the treatment of the behavioral manifestations of Alzheimer's disease in outpatients treated with donepezil. Int J Geriatric Psychiatry 2004;19:9-18.
Nyth AL, Gerhard G. The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders: a Nordic multicenter study. Br J Psychiatry 1990; 157:894-901.
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;159:460-465.
Suktzer DL, Gray KF, Gunay I, et al. Does behavioral improvement with haloperidol or trazodone treatment depend on psychosis or mood symptoms in patients with dementia? J Am Geriatrics Society 2001;49:1294-1300.
Barak Y, Plopski I, Tadger S, Paleacu D. Escitalopram versus risperidone for the treatment of behavioral and psychotic symptoms associated with Alzheimer's disease: a randomized double-blind pilot study. Int Psychogeriatrics 2011;15:1-5.
Chibnall JT, Tait RC, Harman B, Luebbert RA. Effect of acetaminophen on behavior, well-being, and psychotropic medication use in nursing home residents with moderate-to-severe dementia. J Am Geriatrics Society 2005;53:1921-1929.
Lu PH, Masterman DA, Mulnard R, et al. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and health elderly men. Arch Neurol 2006;63:177-185.
Gehrman PR, Connor DJ, Martin JL, et al. Melatonin fails to improve sleep or agitation in a double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer's disease. Am J Geriatr Psychiatry 2009;17:166-169.
Scripnikov A, Khomeno A, Napryeyenko O. Effects of ginkgo biloba extract EGb 761 on neuropsychiatric symptoms of dementia: findings from a randomized controlled trial. Wien Med Wochenschr 2007;157:295-300.
Doody RS, Gavrilova SI, Sano M, et al. Effect od dimebon on cognition, activities of daily living, behavior, and global function in patients with mild-to-moderate Alzheimer's disease: a randomized, double blind, placebo-controlled study. Lancet 2008;372:207-215.
Beer CD, Horner B, Almeida OP, et al. Dementia in residential care: education intervention trial (DIRECT); protocol for a randomised controlled trial. Trials 2010;11:63
Perry M, DraškoviĆ I, Achterberg T, et al. Can an EASYcare based dementia training programme improve diagnostic assessment and management of dementia by general practitioners and primary care nurses? The design of a randomized controlled trial. BMC Health Serv Res 2008;8:71.
Cerga-Pashoja A, Lowery D, Bhattacharya R, et al. Evaluation of exercise on individuals with dementia and their carers: a randomized controlled trial. Trials 2010;11:53.
Pitkala KH, Raivio MM, Laakkonen M, Tilvis RS, Kautiainen H, Strandberg TE. Exercise rehabilitation on home-dwelling patients with Alzheimer's disease - a randomized, controlled trial. Study protocol. Trials . 2010;11:92.
Graff M JL, Vernooil-Dassen MJM, Thijssen M, Dekker J, Hoefnagels WHL, Rikkert MGMO. Community based occupational therapy for patients with dementia and their care givers: randomised controlled trial. BMJ Online First bmj.com. 2006;1-6.
Ferrero-Arias J, Goñis-Imízcoz M, Gonzáles-Bernal J, Ortega-Lara F, Silva Gonzales A, Díez-Lopes M. The Efficacy of Nonpharmacological Treatment for Dementia-related Apathy. Alzheimer Dis Assoc Disord 2011;1-7.
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Publication Dates

Publication in this collection
Jul-Sep 2011

History

Received
17 Mar 2011
Accepted
17 June 2011

This is an open-access article distributed under the terms of the Creative Commons Attribution License

[1] Engelhardt E, Brucki SM, Cavalcanti JL, Forlenza OV, Laks J, Vale FA. Treatment of Alzheimer's disease: recommendations and suggestions of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology. Arq Neuropsiquiatr 2005;63:1104-1112.

[2] Gronseth G, French J. Practice parameters and technology assessments: what they are, what they are not, and why you should care. Neurology 2008;71:1639-1643.

[3] French J, Gronseth G. Lost in a jungle of evidence: we need a compass. Neurology 2008;71:1634-1638.

[4] McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging and the Alzheimer's Association workgroup. Alzheimers Dement 2011;7:263-269.

[5] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDAWork Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939-44.

[6] Albert MS, Dekosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging and Alzheimer's Association workgroup. Alzheimers Dement 2011;7:270-279.

[7] Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging and the Alzheimer's Association workgroup. Alzheimers Dement 2011;7:1-13.

[8] Apostolova LG, Cummings JL. Neuropsychiatric manifestations in mild cognitive impairment: a systematic review of the literature. Dement Geriatr Cogn Disord 2008; 25:115-126.

[9] Fillit HM. The pharmacoeconomics of Alzheimer's disease. Am J Manag Care. 2000;6(22 suppl):S1139-S1144.

[10] Buhr GT, White HK. Difficult behaviors in long-term care patients with dementia. J Am Med Dir Assoc 2006;7:180-192.

[11] Department of Health and Human Services. Interpretive guidelines for long-term care facilities. State Operations Manual, Appendix PP - Guidance to Surveyors for Long Term Care Facilities. http://cms.hhs.gov/manuals/downloads/som107_pp_guidelines_ltcf.pdf Accessed August 21, 2007.
» http://cms.hhs.gov/manuals/downloads/som107_pp_guidelines_ltcf.pdf

[12] Shekelle P, Maglione M, Bagley S, et al. Comparative effectiveness of off-label use of atypical antipsychotics. Comparative Effectiveness Review No. 6. (Prepared by the Southern California/RAND Evidence-based Practice Center under Contract 290-02-003.) Rockville, MD:Agency for Healthcare Research and Quality; January 2007. Effectivehealthcare.ahrq.gov/repFiles/Atypical_Antipsychotics_Final_Report.pdf.

[13] Sultzer DL, Davis SM, Tariot PN, et al. CATIE-AD Study Group. Clinical symptom responses to atypical antipsychotic medications in Alzheimer's disease: phase 1 outcomes from the CATIE-AD effectiveness trial. Am J Psychiatry 2008;165:844-54.

[14] Carson S, McDonagh MS, Peterson K. A Systematic Review of the Efficacy and Safety of Atypical Antipsychotics in Patients with Psychological and Behavioral Symptoms of Dementia JAGS 2006;54:354-361.

[15] Tran-Johnson TK, Sack DA, Marcus RN, Auby P, McQuade RD, Oren DA. Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2007;68:111-119.

[16] Grossberg GT, Desai AK. Management of Alzheimer's Disease. J Gerontol 2003;58A:331-353.

[17] Cummings JL, Benson DF. Dementia: A clinical approach. (2nd ed.). Boston, MA: Butterworth-Heinemann; 1992.

[18] Lyketsos CG, Colenda CC, Beck C, et al. Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia resulting from Alzheimer disease. Am J Geriatr Psychiatry 2006;14:561-572.

[19] Ballard CG, Thomas A, Fossey J, et al. A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: the neuropsychiatric inventory median cutoff is a predictor of clinical outcome. J Clin Psychiatry 2004;65: 114-119.

[20] Ballard C, Lana MM, Theodoulou M. A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial). PLoS Med 2008;5:e76.

[21] Sink KM, Holden KF, Yaffe K. Pharmacologic treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA 2005;293:596-608.

[22] De Deyn PP, Katz IR, Brodaty H, Lyons B, Greenspan A, Burns A. Management of agitation, aggression, and psychosis associated with dementia: a pooled analysis including three randomized, placebo-controlled double blind trials in nursing home residents treated with risperidone. Clin Neurol Neurosurg 2005;107:497-508.

[23] Katz I, de Deyn PP, Mintzer J, Greenspan A, Zhu Y, Brodaty H. The efficacy and safety of risperidone in the treatment of psychosis of Alzheimers disease and mixed dementia: a meta-analysis of 4 placebo controlled clinical trials. Int J Geriatr Psychiatry 2007;22:475-484.

[24] Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005;294:1934-1943.

[25] Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA 2005; 293:596-608.

[26] Guidelines abstracted from the American Academy ofNeurology 's dementia guidelines for early detection, diagnosis and management of dementia. AGS Clinical Practice Committee. J Am Geriatr Soc 2003;51:869-873.

[27] American Academy for Geriatric Psychiatry. (2005). AAGP Atypical Position Statement. Retrieved March 26, 2008, from Retrieved March 26, 2008, from http://www.aagponline.org/prof/ antipsychstat_0705.asp
» http://www.aagponline.org/prof/ antipsychstat_0705.asp

[28] Madhusoodanan S, Shah P, Brenner R, Gupta S. Pharmacological treatment of the psychosis of Alzheimer's Disease: what is the best approach? CNS Drugs 2007;21: 101-115.

[29] Trinh N, 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;289:210-216.

[30] Loy C, Schneider L. Galantamine for Alzheimer's disease and mild cognitive impairment. Cochrane Database of Systematic Reviews. In: The Cochrane Library 2011;4: Art. No. CD001747.

[31] Cummings JL, Schneider L, Tariot PN, Kershaw PR, Yuan W. Reduction of behavioral disturbances and caregivers distress by galantamine in patients with Alzheimer's disease. Am J Psychiatry 2004;161:532-538.

[32] Birks J, Grimley EJ, Iakovidou V, Tsolaki M. Rivastigmine for Alzheimer's disease. Cochrane Database of Systematic Reviews. In: The Cochrane Library 2011; 4: Art. No. CD001191.

[33] Birks J, Harvey R. Donepezil for dementia due to Alzheimer's disease. Cochrane Database of Systematic Reviews. In: The Cochrane Library 2011; 4: Art. No. CD001190.

[34] Gauthier S, Feldman H, Hecker J, et al. Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer's disease. Int Psychogeriatrics 2002;14: 389-404.

[35] Feldman H, Gauthier S, Hecker J, et al. Efficacy and safety of donepezil in patients with more severe Alzheimer's disease: a subgroup analysis from a randomized, placebo-controlled trial. Int J Geriatric Psychiatry 2005;20:559-569.

[36] Holmes C, Wilkinson D, Dean C, et al. The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology 2004;63:214-219.

[37] Howard RJ, Juszczak E, Ballard CG, et al. Donepesil for the treatment of agitation in Alzheimer's disease. N Engl J Med 2007;357:1382-1392.

[38] McShane R, Areosa SA N M. Memantine for dementia. Cochrane Database of Systematic Reviews. 2011(03): CD003154.

[39] Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291:317-24.

[40] Cummings JL, Schneider E, Tariot PN, et al. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology 2006;67:57-63.

[41] Konovalov S, Muralle S, TAmpi RR. Anticonvulsants for the treatment of behavioral and psychological symptoms of dementia: a literature review. Int Psychogeriatrics 2008;20:293-308.

[42] Tariot PN, Erb R, Podgorski CA, et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 1998;155:54-61.

[43] Seitz D, Adunuri N, Gill SS, et al. Antidepressants for agitation and psychosis in dementia. Cochrane Database of Systematic Reviews . In: The Cochrane Library 2011; 4: Art. No. CD008191.

[44] Weintraub D, Rosenberg PB, Drye LT, et al. Sertraline for the treatment of depression in Alzheimer's disease: week-24 outcomes. Am J Geriatr Psychiatry 2010;18:332-340.

[45] Lyketsos CG, DelCampo L, Steinberg M, et al. Treating depression in Alzheimer disease. Arch Gen Psychiatry 2003;60:737-746.

[46] Finkel SI, Mintzer JE, Dysken M, et al. A randomized, placebo-controlled study of the efficacy and safety of sertraline in the treatment of the behavioral manifestations of Alzheimer's disease in outpatients treated with donepezil. Int J Geriatric Psychiatry 2004;19:9-18.

[47] Nyth AL, Gerhard G. The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders: a Nordic multicenter study. Br J Psychiatry 1990; 157:894-901.

[48] 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;159:460-465.

[49] Suktzer DL, Gray KF, Gunay I, et al. Does behavioral improvement with haloperidol or trazodone treatment depend on psychosis or mood symptoms in patients with dementia? J Am Geriatrics Society 2001;49:1294-1300.

[50] Barak Y, Plopski I, Tadger S, Paleacu D. Escitalopram versus risperidone for the treatment of behavioral and psychotic symptoms associated with Alzheimer's disease: a randomized double-blind pilot study. Int Psychogeriatrics 2011;15:1-5.

[51] Chibnall JT, Tait RC, Harman B, Luebbert RA. Effect of acetaminophen on behavior, well-being, and psychotropic medication use in nursing home residents with moderate-to-severe dementia. J Am Geriatrics Society 2005;53:1921-1929.

[52] Lu PH, Masterman DA, Mulnard R, et al. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and health elderly men. Arch Neurol 2006;63:177-185.

[53] Gehrman PR, Connor DJ, Martin JL, et al. Melatonin fails to improve sleep or agitation in a double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer's disease. Am J Geriatr Psychiatry 2009;17:166-169.

[54] Scripnikov A, Khomeno A, Napryeyenko O. Effects of ginkgo biloba extract EGb 761 on neuropsychiatric symptoms of dementia: findings from a randomized controlled trial. Wien Med Wochenschr 2007;157:295-300.

[55] Doody RS, Gavrilova SI, Sano M, et al. Effect od dimebon on cognition, activities of daily living, behavior, and global function in patients with mild-to-moderate Alzheimer's disease: a randomized, double blind, placebo-controlled study. Lancet 2008;372:207-215.

[56] Beer CD, Horner B, Almeida OP, et al. Dementia in residential care: education intervention trial (DIRECT); protocol for a randomised controlled trial. Trials 2010;11:63

[57] Perry M, DraškoviĆ I, Achterberg T, et al. Can an EASYcare based dementia training programme improve diagnostic assessment and management of dementia by general practitioners and primary care nurses? The design of a randomized controlled trial. BMC Health Serv Res 2008;8:71.

[58] Cerga-Pashoja A, Lowery D, Bhattacharya R, et al. Evaluation of exercise on individuals with dementia and their carers: a randomized controlled trial. Trials 2010;11:53.

[59] Pitkala KH, Raivio MM, Laakkonen M, Tilvis RS, Kautiainen H, Strandberg TE. Exercise rehabilitation on home-dwelling patients with Alzheimer's disease - a randomized, controlled trial. Study protocol. Trials . 2010;11:92.

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