Good rate of clinical response to cholinesterase inhibitors in mild and moderate Alzheimer's disease after three months of treatment: An open-label study

Miranda, Luis Felipe José Ravic de; Barbosa, Marilourdes do Amaral; Peles, Patrícia Regina Henrique; Pôças, Patrícia Hilar; Tito, Pedro Augusto Lopes; Matoso, Rafael de Oliveira; Lima, Thiago Oliveira Lemos de; Moraes, Edgar Nunes de; Caramelli, Paulo

doi:10.1590/S1980-57642013DN70200009

ABSTRACT

Life expectancy in Brazil has increased markedly over the last 30 years. Hence, age-related disorders, such as Alzheimer's disease (AD), warrant special attention due to their high prevalence in the elderly. Pharmacologic treatment of AD is based on cholinesterase inhibitors (ChEI) and memantine, leading to modest clinical benefits both in the short and long-term. However, clinical response is heterogeneous and needs further investigation. Objective: To investigate the rate of response to ChEI in AD after three months of treatment. Methods: Patients with mild or moderate dementia due to probable AD or to AD associated with cerebrovascular disease were included in the study. The subjects were assessed at baseline and again after three months of ChEI treatment. Subjects were submitted to the Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale, Katz Basic Activities of Daily Living, Pfeffer Functional Activities Questionnaire, Neuropsychiatric Inventory and Cornell Scale for Depression in Dementia. Good response was defined by a gain of ≥2 points on the MMSE after three months of treatment in relation to baseline. Results: Seventy-one patients, 66 (93%) with probable AD and five (7%) with AD associated with cerebrovascular disease, were evaluated. The good response rate at three months was 31.0%, being 37.2% and 21.4% in mild and moderate dementia, respectively. There were no significant differences on most tests, except for improvement in hallucinations, agitation and dysphoria in moderate dementia patients. Conclusion: The rate of good clinical response to ChEI was higher than usually reported. Specific behavioral features significantly improved in the subgroup of moderate dementia.

Key word:
cholinesterase inhibitors; Alzheimer disease; treatment; clinical trial; open-label

RESUMO

A expectativa de vida no Brasil aumentou significativamente nos últimos 30 anos. Desse modo, transtornos relacionados à idade, como a doença de Alzheimer (DA), merecem especial atenção, devido à elevada prevalência. O tratamento farmacológico da DA se baseia nos inibidores da colinesterase (IChE) e na memantina, com melhora modesta em curto e longo prazo. Entretanto, a resposta clínica é heterogênea e necessita maior investigação. Objetivo: Investigar a taxa de resposta aos IChE em pacientes com DA após três meses de tratamento. Métodos: Pacientes com demência leve ou moderada devida à DA ou DA com doença cerebrovascular foram avaliados antes e após três meses de uso de IChE. Todos foram submetidos ao Mini-Exame do Estado Mental (MEEM), Escala de Demência Mattis, avaliação das atividades básicas de vida diária de Katz, Questionário de Pfeffer, Inventário Neuropsiquiátrico e Escala de Depressão de Cornell. Boa resposta foi definida pelo ganho de ≥2 pontos no MEEM em relação à primeira consulta, após três meses. Resultados: Setenta e um pacientes, 66 (93%) com DA provável e cinco (7%) com DA associada à doença cerebrovascular, foram avaliados. A taxa de boa resposta clínica em três meses foi de 31.0%, sendo 37,2% e 21,4% na demência leve e moderada, respectivamente. Não houve diferença significativa na maioria dos testes, exceto para melhora de alucinação, agitação e depressão em pacientes com demência moderada. Conclusão: A taxa de boa resposta clínica aos IChE foi superior à encontrada na literatura. Observou-se melhora de alguns sintomas comportamentais em pacientes com DA moderada.

Palavras-chave:
inibidores da colinesterase; doença de Alzheimer; tratamento; ensaio clínico aberto

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REFERENCES

Nitrini R, Bottino CM, Albala C, et al. Prevalence of dementia in Latin America: a collaborative study of population-based cohorts. Int Psychogeriatrics 2009;21:622-630.
Lopes MA, Hototian SR, Reis GC, Elkis H, Bottino CMC. 2007. Systematic review of dementia prevalence 1994 to 2000. Dement Neuropsychol 2007;1:230-240.
Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomized controlled trial. Galantamine International-1 Study Group. BMJ 2000; 321(7274):1445-1449. Erratum in: BMJ 2001;322(7283):405.
Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med 1998;158:1021-1031.
Kavanagh S, Howe I, Brashear HR, et al. Long-Term Response to Galantamine in Relation to Short-Term Efficacy Data: Pooled Analysis in Patients with Mild to Moderate Alzheimer's Disease. Curr Alzheimer Res 2011;8:175-186.
Förstl H, Stamouli SS, Janetzky W, Galanopoulo A, Karageorgiou C, Tzanakaki M. A Comparison of Studies in Germany and Greece. Dement Geriatr Cogn Disord 2011;32:267-272.
Lanctôt KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM, Einarson TR. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. CMAJ 2003;169:557-564.
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.
Raschetti R, Maggini M, Sorrentino GC, Martini N, Caffari B, Vanacore N. A cohort study of effectiveness of acetylcholinesterase inhibitors in Alzheimer's disease. Eur J Clin Pharmacol 2005;61:361-336.
Wattmo C, Wallin AK, Londos E, Minthon L. Predictors of long-term cognitive outcome in Alzheimer's disease. Alzheimers Res Ther 2011;3:23.
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:263-269.
Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993;43:250-260.
Folstein MF, Folstein SE, McHugh PR."Mini-mental state": A practical method for grading the cognitive state of patients for the clinician.J Psychiatr Res 1975;12:189-198.
Bertolucci P, Brucki S, Campacci S, Juliano Y. Mini-Exame do Estado Mental em uma população Geral. Impacto da escolaridade. Arq Neuropsiquiatr 1994;52:1-7.
Mattis S. Dementia Rating Scale. Professional Manual. Florida: Psychological Assessment Resources, 1988.
Porto CS, Fichman HC, Caramelli P, Bahia VS, Nitrini R. Brazilian version of the Mattis dementia rating scale: diagnosis of mild dementia in Alzheimer's disease. Arq Neuropsiquiatr2003;61:339-345.
Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of Illness in the Aged. The Index of ADL: A Standardized Measure of Biological and Psychosocial Function. JAMA 1963;185:914-919.
Pfeffer RI, Kurosaki TT, Harrah CH, et al. Measurement of functional activities in older adults in the community. J Gerontol 1982;37:323-329.
Cummings J, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia. Neurology 1994;44:230.
Alexopoulos GS, Abrams RC, Young RC, Shamoian CA. Cornell Scale for Depression in Dementia. Biol Psychiatry 1988;23:271-284.
Carthery-Goulart MT, Areza-Fegyveres R, Schultz RR, et al. Versão Brasileira da Escala Cornell de Depressão em Demência (Cornell Depression Scale in Dementia). Arq Neuropsiquiatr2007;65:912-915.
Carrasco MM, Agüera L, Gil P, Moríñigo A, Leon T. Safety and Effectiveness of Donepezil on Behavioral Symptoms in Patients with Alzheimer Disease. Alzheimer Dis Assoc Disord 2011;25:333-340
Wilkinson D, Schindler R, Schwam E, et al. Effectiveness of Donepezil in Reducing Clinical Worsening in Patients with Mild-to-Moderate Alzheimer's Disease. Dement Geriatr Cogn Disord2009;28:244-251.
Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med1998158:1021-1031.
Lopez OL, Becker JT, Saxton J, Sweet RA, Klunk W, DeKosky ST. Alteration of a clinically meaningful outcome in the natural history of Alzheimer's disease by cholinesterase inhibition. J Am Geriatr Soc 2005; 53:83-87.
Howard RJ, Juszczak E, Ballard CG, et al. Donepezil for the Treatment of Agitation in Alzheimer's Disease. N Engl J Med 2007;357:1382-1392.
Griffith P, Lichtenberg P, Goldman R, Payne-Parrish J. Safety and Efficacy of Donepezil in African Americans with Mild-to-Moderate Alzheimer's Disease. J Natl Med Assoc 2006;98:1590-1597.
Vogel A, Waldorff FB, Waldemar G. Impaired Awareness of Deficits and Neuropsychiatric Symptoms in Early Alzheimer's Disease: The Danish Alzheimer Intervention Study (DAISY). J Neuropsychiatry Clin Neurosci. 2010;22:93-99.
Kavanagh S, Gaudig M, VanBaelen B. Galantamine and behavior in Alzheimer disease: analysis of four trials. Acta Neurol Scand 2011;124: 302-308.
Rodda J, Morgan S, Walker Z. Are cholinesterase inhibitors effective in the management of the behavioral and psychological symptoms of dementia in Alzheimer's disease? A systematic review of randomized, placebo controlled trials of donepezil, rivastigmine and galantamine. Int Psychogeriatr 2009;21:813-824.
Cummings JL, Mackell J, Kaufer D. Behavioral effects of current Alzheimer's disease treatments: a descriptive review. Alzheimers Dement2008;4:49-60.

Publication Dates

Publication in this collection
Apr-Jun 2013

History

Received
12 Dec 2012
Accepted
18 Mar 2013

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

[1] Nitrini R, Bottino CM, Albala C, et al. Prevalence of dementia in Latin America: a collaborative study of population-based cohorts. Int Psychogeriatrics 2009;21:622-630.

[2] Lopes MA, Hototian SR, Reis GC, Elkis H, Bottino CMC. 2007. Systematic review of dementia prevalence 1994 to 2000. Dement Neuropsychol 2007;1:230-240.

[3] Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomized controlled trial. Galantamine International-1 Study Group. BMJ 2000; 321(7274):1445-1449. Erratum in: BMJ 2001;322(7283):405.

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

[5] Kavanagh S, Howe I, Brashear HR, et al. Long-Term Response to Galantamine in Relation to Short-Term Efficacy Data: Pooled Analysis in Patients with Mild to Moderate Alzheimer's Disease. Curr Alzheimer Res 2011;8:175-186.

[6] Förstl H, Stamouli SS, Janetzky W, Galanopoulo A, Karageorgiou C, Tzanakaki M. A Comparison of Studies in Germany and Greece. Dement Geriatr Cogn Disord 2011;32:267-272.

[7] Lanctôt KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM, Einarson TR. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. CMAJ 2003;169:557-564.

[8] 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.

[9] Raschetti R, Maggini M, Sorrentino GC, Martini N, Caffari B, Vanacore N. A cohort study of effectiveness of acetylcholinesterase inhibitors in Alzheimer's disease. Eur J Clin Pharmacol 2005;61:361-336.

[10] Wattmo C, Wallin AK, Londos E, Minthon L. Predictors of long-term cognitive outcome in Alzheimer's disease. Alzheimers Res Ther 2011;3:23.

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

[12] Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993;43:250-260.

[13] Folstein MF, Folstein SE, McHugh PR."Mini-mental state": A practical method for grading the cognitive state of patients for the clinician.J Psychiatr Res 1975;12:189-198.

[14] Bertolucci P, Brucki S, Campacci S, Juliano Y. Mini-Exame do Estado Mental em uma população Geral. Impacto da escolaridade. Arq Neuropsiquiatr 1994;52:1-7.

[15] Mattis S. Dementia Rating Scale. Professional Manual. Florida: Psychological Assessment Resources, 1988.

[16] Porto CS, Fichman HC, Caramelli P, Bahia VS, Nitrini R. Brazilian version of the Mattis dementia rating scale: diagnosis of mild dementia in Alzheimer's disease. Arq Neuropsiquiatr2003;61:339-345.

[17] Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of Illness in the Aged. The Index of ADL: A Standardized Measure of Biological and Psychosocial Function. JAMA 1963;185:914-919.

[18] Pfeffer RI, Kurosaki TT, Harrah CH, et al. Measurement of functional activities in older adults in the community. J Gerontol 1982;37:323-329.

[19] Cummings J, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia. Neurology 1994;44:230.

[20] Alexopoulos GS, Abrams RC, Young RC, Shamoian CA. Cornell Scale for Depression in Dementia. Biol Psychiatry 1988;23:271-284.

[21] Carthery-Goulart MT, Areza-Fegyveres R, Schultz RR, et al. Versão Brasileira da Escala Cornell de Depressão em Demência (Cornell Depression Scale in Dementia). Arq Neuropsiquiatr2007;65:912-915.

[22] Carrasco MM, Agüera L, Gil P, Moríñigo A, Leon T. Safety and Effectiveness of Donepezil on Behavioral Symptoms in Patients with Alzheimer Disease. Alzheimer Dis Assoc Disord 2011;25:333-340

[23] Wilkinson D, Schindler R, Schwam E, et al. Effectiveness of Donepezil in Reducing Clinical Worsening in Patients with Mild-to-Moderate Alzheimer's Disease. Dement Geriatr Cogn Disord2009;28:244-251.

[24] Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med1998158:1021-1031.

[25] Lopez OL, Becker JT, Saxton J, Sweet RA, Klunk W, DeKosky ST. Alteration of a clinically meaningful outcome in the natural history of Alzheimer's disease by cholinesterase inhibition. J Am Geriatr Soc 2005; 53:83-87.

[26] Howard RJ, Juszczak E, Ballard CG, et al. Donepezil for the Treatment of Agitation in Alzheimer's Disease. N Engl J Med 2007;357:1382-1392.

[27] Griffith P, Lichtenberg P, Goldman R, Payne-Parrish J. Safety and Efficacy of Donepezil in African Americans with Mild-to-Moderate Alzheimer's Disease. J Natl Med Assoc 2006;98:1590-1597.

[28] Vogel A, Waldorff FB, Waldemar G. Impaired Awareness of Deficits and Neuropsychiatric Symptoms in Early Alzheimer's Disease: The Danish Alzheimer Intervention Study (DAISY). J Neuropsychiatry Clin Neurosci. 2010;22:93-99.

[29] Kavanagh S, Gaudig M, VanBaelen B. Galantamine and behavior in Alzheimer disease: analysis of four trials. Acta Neurol Scand 2011;124: 302-308.

[30] Rodda J, Morgan S, Walker Z. Are cholinesterase inhibitors effective in the management of the behavioral and psychological symptoms of dementia in Alzheimer's disease? A systematic review of randomized, placebo controlled trials of donepezil, rivastigmine and galantamine. Int Psychogeriatr 2009;21:813-824.

[31] Cummings JL, Mackell J, Kaufer D. Behavioral effects of current Alzheimer's disease treatments: a descriptive review. Alzheimers Dement2008;4:49-60.

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