Antipsychotics in Alzheimer's disease: A critical analysis

Silva, Eduardo Marques da; Braga, Rafaela de Castro Oliveira Pereira; Avelino-Silva, Thiago Junqueira; Gil Junior, Luiz Antonio

doi:10.1590/S1980-57642011DN05010007

Abstract

The estimated worldwide prevalence of dementia among adults older than 60 years of age was 3.9% in 2005. About 90% of demented patients will develop neuropsychiatric symptoms (NS) such as delirium, delusion, aggressiveness and agitation. The treatment of NS involves non-pharmacologic strategies (with varying degrees of success according to the scientific literature) and pharmacologic treatment (PT). The present review of literature examined the current role of AP in the management of NS in dementia.

Methods:

A thematic review of medical literature was carried out.

Results:

313 articles were found, 39 of which were selected for critical analysis. Until 2005, the best evidence for PT had supported the use of selective serotonin re-uptake inhibitors (SSRIs), anticholinesterases, memantine and antipsychotics (AP). In 2005, the U.S. Food and Drug Administration (FDA) disapproved the use of atypical APs to treat neuropsychiatric symptoms in individuals with dementia (the same occurred with the typical APs in 2008). After this, at least two important randomized placebo-controlled multicenter trials were published examining the effectiveness of atypical APs in Alzheimer's disease (CATIE-AD) and the effects of interrupting AP treatment (DART-AD).

Conclusions:

Based on the current evidence available, APs still have a place in treatment of the more serious psychotic symptoms, after the failure of non-pharmacological treatment and of an initial approach with selective inhibitors of serotonin uptake, anticholinesterases and memantine.

Key words:
antipsychotics; dementia; side effects; Alzheimer; neuropsychiatric symptoms

Resumo

A prevalência mundial de demencia entre idosos foi de 3,9% em 2005. Cerca de 90% dos dementados apresentarão sintomas como delirium, alucinações, agressividade e agitação. O tratamento dos sintomas não cognitivos envolve estratégias não farmacológicas - com sucesso variável de acordo com a literatura - e tratamento medicamentoso. A presente revisão de literatura discute o atual papel dos antipsicóticos nos sintomas neurocomportamentais de demência.

Métodos:

Conduzimos uma revisão temática nas principais bases de dados da literatura.

Resultados:

313 artigos sobre o tema foram encontrados e 39 selecionaos para compor uma análise crítica. Até 2005, as melhores evidências para tratamento medicamentoso indicavam o uso de inibidores da acetilcolinesterase memantina e antipsicóticos. Em 2005 o FDA desautorizou o uso de antipsicóticos atípicos em dementados (em 2008 fez o mesmo com os típicos). Após isto, 2 ensaios clínicos randomizados placebo-controlados foram concluídos avaliando a eficácia dos antipsicóticos atípicos em portadores de doença de Alzheimer (CATIE-AD) e os efeitos da interrupção destes (DART-AD).

Conclusões:

Considerando as evidências atuais, os antipsicóticos ainda têm importância no manejo dos sintomas psicóticos mais sérios, após falha de tratamento não farmacológico e de uma abordagem inicial com inibidores de receptação de serotonina, anticolinesterásicos e memantina.

Palavras-chave:
antipsicoticos; demencia; efeitos colaterais; Alzheimer; sintomas neuropsiquiátricos

Texto completo disponível apenas em PDF.

Full text available only in PDF format.

References

Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112-2117.
Bottino CM, Azevedo D Jr, Tatsch M, et al. Estimate of dementia prevalence in a community sample from Sao Paulo, Brazil. Dement Geriatr Cogn Disord 2008;26:291-299.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939-944.
Ballard C, Gray A, Ayre G. Psychotic symptoms, aggression and restlessness in dementia. Rev Neurol (Paris) 1999;155 (Suppl 4):S44-S52.
Tatsch MF, Bottino CM, Azevedo D, et al. Neuropsychiatric symptoms in Alzheimer disease and cognitively impaired, nondemented elderly from a community-based sample in Brazil: prevalence and relationship with dementia severity. Am J Geriatr Psychiatry, 2006;14:438-445.
Steele C, Rovner B, Chase GA, Folstein M. Psychiatric symptoms and nursing home placement of patients with Alzheimer's disease. Am J Psychiatry 1990;147:1049-1051.
Lopez OL, Wisniewski SR, Becker JT, Boller F, DeKosky ST. Psychiatric medication and abnormal behavior as predictors of progression in probable Alzheimer disease. Arch Neurol 1999;56:1266-1272.
Clyburn LD, Stones MJ, Hadjistavropoulos T, Tuokko H. Predicting caregiver burden and depression in Alzheimer's disease. J Gerontol B Psychol Sci Soc Sci 2000;55:S2-S13.
Coen RF, Swanwick GR, O'Boyle CA, Coakley D. Behaviour disturbance and other predictors of carer burden in Alzheimer's disease. Int J Geriatr Psychiatry 1997;12:331-336.
Ayalon L, Gum AM, Feliciano L, Areán PA. Effectiveness of nonpharmacological interventions for the management of neuropsychiatric symptoms in patients with dementia: a systematic review. Arch Intern Med 2006;166:2182-2188.
Opie J, Rosewarne R, O'Connor DW. The efficacy of psychosocial approaches to behaviour disorders in dementia: a systematic literature review. Aust N Z J Psychiatry 1999;33: 789-799.
Clark ME, Lipe AW, Bilbrey M. Use of music to decrease aggressive behaviors in people with dementia. J Gerontol Nurs 1998;24:10-17.
Gerdner LA. Effects of individualized versus classical "relaxation" music on the frequency of agitation in elderly persons with Alzheimer's disease and related disorders. Int Psychogeriatr 2000;12:49-65.
Witzke J, Rhone RA, Backhaus D, Shaver NA. How sweet the sound: research evidence for the use of music in Alzheimer's dementia. J Gerontol Nurs 2008;34:45-52.
Ballard CG, O'Brien JT, Reichelt K, Perry EK. Aromatherapy as a safe and effective treatment for the management of agitation in severe dementia: the results of a double-blind, placebo-controlled trial with Melissa. J Clin Psychiatry 2002;63: 553-558.
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;56:1154-1166.
Cohen-Mansfield J. Nonpharmacologic interventions for inappropriate behaviors in dementia: a review, summary, and critique. Am J Geriatr Psychiatry 2001;9:361-381.
Cohen-Mansfield J, Werner P. Management of verbally disruptive behaviors in nursing home residents. J Gerontol A Biol Sci Med Sci 1997; 52:M369-377.
Szulik J. Antipsychotics in geriatric institutions. Vertex 2007; 18:454-460.
Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA 2005;293:596-608.
Pollock BG, Mulsant BH, Rosen J, et al. A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr Psychiatry 2007;15:942-952.
Pollock BG, Mulsant BH, Rosen J. 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.
Cummings JL, Mackell J, Kaufer D. Behavioral effects of current Alzheimer's disease treatments: a descriptive review. Alzheimers Dement 2008;4:49-60.
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.
Pinheiro D. Anticonvulsant mood stabilizers in the treatment of behavioral and psychological symptoms of dementia (BPSD). Encephale 2008;34:409-415.
Kim Y, Wilkins KM, Tampi RR. Use of gabapentin in the treatment of behavioural and psychological symptoms of dementia: a review of the evidence. Drugs Aging 2008;25:187-196.
Lanctôt KL, Herrmann N, Mazzotta P, Khan LR, Ingber N. GABAergic function in Alzheimer's disease: evidence for dysfunction and potential as a therapeutic target for the treatment of behavioural and psychological symptoms of dementia. Can J Psychiatry 2004;49:439-453.
Alkhalil C, Hahar N, Alkhalil B, Zavros G, Lowenthal DT. Can gabapentin be a safe alternative to hormonal therapy in the treatment of inappropriate sexual behavior in demented patients? Int Urol Nephrol 2003;35:299-302.
Ballard C, Corbett A, Chitramohan R, Aarsland D. Management of agitation and aggression associated with Alzheimer's disease: controversies and possible solutions. Curr Opin Psychiatry 2009;22:532-540.
Schneider LS, Pollock VE, Lyness SA. A metaanalysis of controlled trials of neuroleptic treatment in dementia. J Am Geriatr Soc 1990;38:553-563.
Lonergan E, Luxenberg J, Colford J. Haloperidol for agitation in dementia. Cochrane Database Syst Rev 2002:CD002852.
Ballard C, Howard R. Neuroleptic drugs in dementia: benefits and harm. Nat Rev Neurosci 2006;7:492-500.
Ballard C, Waite J. The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease. Cochrane Database Syst Rev 2006:CD003476.
Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry 2006;14:191-210.
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.
Ballard C, Hanney ML, Theodoulou M. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol 2009;8:151-157.
Rappaport SA, Marcus RN, Manos G, McQuade RD, Oren DA. A randomized, double-blind, placebo-controlled tolerability study of intramuscular aripiprazole in acutely agitated patients with Alzheimer's, vascular, or mixed dementia. J Am Med Dir Assoc 2009;10:21-27.
Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med 2006;355:1525-1538.
Alanen HM, Finne-Soveri H, Noro A, Leinonen E. Use of antipsychotics among nonagenarian residents in long-term institutional care in Finland. Age Ageing 2006;35:508-513.
Rochon PA, Stukel TA, Sykora K, Gill S, et al., Atypical antipsychotics and parkinsonism. Arch Intern Med 2005;165: 1882-1888.
Liperoti R, Onder G, Lapane KL.et al. Conventional or atypical antipsychotics and the risk of femur fracture among elderly patients: results of a case-control study. J Clin Psychiatry 2007;68:929-934.
Percudani M, Barbui C, Fortino I, Tansella M, Petrovich L. Second-generation antipsychotics and risk of cerebrovascular accidents in the elderly. J Clin Psychopharmacol 2005;25:468-470.
Hoey J, Wooltorton E. Olanzapine (Zyprexa): increased incidence of cerebrovascular events in dementia trials. CMAJ 2004;170:1395.
Greenspan A, Eerdekens M, Mahmoud R. Is there an increased rate of cerebrovascular events among dementia patients? Poster presented at: 24^th Congress of the Collegium Internationale Neuro-Psychopharmacologicum (CINP); June 20-24, 2004; Paris, France.
Cavazzoni P, Young C, Polzer J, et al. Incidence of cerebrovascular adverse events and mortality during antipsychotic clinical trials of elderly patients with dementia. Poster presented at: 44^th Annual New Clinical Drug Evaluation Unit; June 1-4, 2004; Phoenix, Ariz.
Liperoti R, Gambassi G, Lapane KL, et al. Cerebrovascular events among elderly nursing home patients treated with conventional or atypical antipsychotics. J Clin Psychiatry 2005; 66:1090-1096.
Herrmann N, Mamdani M, Lanctot KL. Atypical antipsychotics and risk of cerebrovascular accidents. Am J Psychiatry 2004;161:1113-1115.
Herrmann N, Lanctot KL. Do atypical antipsychotics cause stroke? CNS Drugs 2005;19: 91-103.
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.
FDA. The Food and Drug Administration Public Health Advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. 2005 10/05/2009; Available from:Available from:http://www.fda.gov/cder/drug/advisory/antipsychotics.htm
» http://www.fda.gov/cder/drug/advisory/antipsychotics.htm
FDA. The Food and Drug Administration - Information for Healthcare Professionals - Antipsychotics. 2008 10/05/2009; >from: 2008 10/05/2009; >from: http://www.fda.gov/cder/drug/InfoSheets/HCP/antipsychotics_conventional.htm
» http://www.fda.gov/cder/drug/InfoSheets/HCP/antipsychotics_conventional.htm
Gill SS, Bronskill SE, Normand SL, et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med 2007;146:775-786.
Schneeweiss S, Setoguchi S, Brookhart A, Dormuth C, Wang PS. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ 2007;176:627-632.
Setoguchi S, Wang PS, Alan Brookhart M, Canning CF, Kaci L, Schneeweiss S. Potential causes of higher mortality in elderly users of conventional and atypical antipsychotic medications. J Am Geriatr Soc 2008;56:1644-1650.
Samuel C. Durso, L.G., Bernard Roos, and Martin Gorbien. Guidelines abstracted from the American Academy of Neurology's dementia guidelines for early detection, diagnosis and management of dementia. 2003 cited 2009 04/05/2009; Available from: Available from: http://www.americangeriatrics.org/products/positionpapers/aan_dementia.shtml
» http://www.americangeriatrics.org/products/positionpapers/aan_dementia.shtml
Zheng L, Mack WJ, Dagerman KS, et al. Metabolic changes associated with second-generation antipsychotic use in Alzheimer's disease patients: The CATIE-AD Study. Am J Psychiatry 2009;166:583-590
Sultzer DL, Davis SM, Tariot PN, et al. Clinical symptom responses to atypical antipsychotic medications in Alzheimer's disease: phase 1 outcomes from the CATIE-AD effectiveness trial. Am J Psychiatry 2008;165:844-854.

Publication Dates

Publication in this collection
Jan-Mar 2011

History

Received
08 Dec 2010
Accepted
10 Feb 2011

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

[1] Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112-2117.

[2] Bottino CM, Azevedo D Jr, Tatsch M, et al. Estimate of dementia prevalence in a community sample from Sao Paulo, Brazil. Dement Geriatr Cogn Disord 2008;26:291-299.

[3] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939-944.

[4] Ballard C, Gray A, Ayre G. Psychotic symptoms, aggression and restlessness in dementia. Rev Neurol (Paris) 1999;155 (Suppl 4):S44-S52.

[5] Tatsch MF, Bottino CM, Azevedo D, et al. Neuropsychiatric symptoms in Alzheimer disease and cognitively impaired, nondemented elderly from a community-based sample in Brazil: prevalence and relationship with dementia severity. Am J Geriatr Psychiatry, 2006;14:438-445.

[6] Steele C, Rovner B, Chase GA, Folstein M. Psychiatric symptoms and nursing home placement of patients with Alzheimer's disease. Am J Psychiatry 1990;147:1049-1051.

[7] Lopez OL, Wisniewski SR, Becker JT, Boller F, DeKosky ST. Psychiatric medication and abnormal behavior as predictors of progression in probable Alzheimer disease. Arch Neurol 1999;56:1266-1272.

[8] Clyburn LD, Stones MJ, Hadjistavropoulos T, Tuokko H. Predicting caregiver burden and depression in Alzheimer's disease. J Gerontol B Psychol Sci Soc Sci 2000;55:S2-S13.

[9] Coen RF, Swanwick GR, O'Boyle CA, Coakley D. Behaviour disturbance and other predictors of carer burden in Alzheimer's disease. Int J Geriatr Psychiatry 1997;12:331-336.

[10] Ayalon L, Gum AM, Feliciano L, Areán PA. Effectiveness of nonpharmacological interventions for the management of neuropsychiatric symptoms in patients with dementia: a systematic review. Arch Intern Med 2006;166:2182-2188.

[11] Opie J, Rosewarne R, O'Connor DW. The efficacy of psychosocial approaches to behaviour disorders in dementia: a systematic literature review. Aust N Z J Psychiatry 1999;33: 789-799.

[12] Clark ME, Lipe AW, Bilbrey M. Use of music to decrease aggressive behaviors in people with dementia. J Gerontol Nurs 1998;24:10-17.

[13] Gerdner LA. Effects of individualized versus classical "relaxation" music on the frequency of agitation in elderly persons with Alzheimer's disease and related disorders. Int Psychogeriatr 2000;12:49-65.

[14] Witzke J, Rhone RA, Backhaus D, Shaver NA. How sweet the sound: research evidence for the use of music in Alzheimer's dementia. J Gerontol Nurs 2008;34:45-52.

[15] Ballard CG, O'Brien JT, Reichelt K, Perry EK. Aromatherapy as a safe and effective treatment for the management of agitation in severe dementia: the results of a double-blind, placebo-controlled trial with Melissa. J Clin Psychiatry 2002;63: 553-558.

[16] 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;56:1154-1166.

[17] Cohen-Mansfield J. Nonpharmacologic interventions for inappropriate behaviors in dementia: a review, summary, and critique. Am J Geriatr Psychiatry 2001;9:361-381.

[18] Cohen-Mansfield J, Werner P. Management of verbally disruptive behaviors in nursing home residents. J Gerontol A Biol Sci Med Sci 1997; 52:M369-377.

[19] Szulik J. Antipsychotics in geriatric institutions. Vertex 2007; 18:454-460.

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

[21] Pollock BG, Mulsant BH, Rosen J, et al. A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr Psychiatry 2007;15:942-952.

[22] Pollock BG, Mulsant BH, Rosen J. 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.

[23] Cummings JL, Mackell J, Kaufer D. Behavioral effects of current Alzheimer's disease treatments: a descriptive review. Alzheimers Dement 2008;4:49-60.

[24] 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.

[25] Pinheiro D. Anticonvulsant mood stabilizers in the treatment of behavioral and psychological symptoms of dementia (BPSD). Encephale 2008;34:409-415.

[26] Kim Y, Wilkins KM, Tampi RR. Use of gabapentin in the treatment of behavioural and psychological symptoms of dementia: a review of the evidence. Drugs Aging 2008;25:187-196.

[27] Lanctôt KL, Herrmann N, Mazzotta P, Khan LR, Ingber N. GABAergic function in Alzheimer's disease: evidence for dysfunction and potential as a therapeutic target for the treatment of behavioural and psychological symptoms of dementia. Can J Psychiatry 2004;49:439-453.

[28] Alkhalil C, Hahar N, Alkhalil B, Zavros G, Lowenthal DT. Can gabapentin be a safe alternative to hormonal therapy in the treatment of inappropriate sexual behavior in demented patients? Int Urol Nephrol 2003;35:299-302.

[29] Ballard C, Corbett A, Chitramohan R, Aarsland D. Management of agitation and aggression associated with Alzheimer's disease: controversies and possible solutions. Curr Opin Psychiatry 2009;22:532-540.

[30] Schneider LS, Pollock VE, Lyness SA. A metaanalysis of controlled trials of neuroleptic treatment in dementia. J Am Geriatr Soc 1990;38:553-563.

[31] Lonergan E, Luxenberg J, Colford J. Haloperidol for agitation in dementia. Cochrane Database Syst Rev 2002:CD002852.

[32] Ballard C, Howard R. Neuroleptic drugs in dementia: benefits and harm. Nat Rev Neurosci 2006;7:492-500.

[33] Ballard C, Waite J. The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease. Cochrane Database Syst Rev 2006:CD003476.

[34] Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry 2006;14:191-210.

[35] 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.

[36] Ballard C, Hanney ML, Theodoulou M. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol 2009;8:151-157.

[37] Rappaport SA, Marcus RN, Manos G, McQuade RD, Oren DA. A randomized, double-blind, placebo-controlled tolerability study of intramuscular aripiprazole in acutely agitated patients with Alzheimer's, vascular, or mixed dementia. J Am Med Dir Assoc 2009;10:21-27.

[38] Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med 2006;355:1525-1538.

[39] Alanen HM, Finne-Soveri H, Noro A, Leinonen E. Use of antipsychotics among nonagenarian residents in long-term institutional care in Finland. Age Ageing 2006;35:508-513.

[40] Rochon PA, Stukel TA, Sykora K, Gill S, et al., Atypical antipsychotics and parkinsonism. Arch Intern Med 2005;165: 1882-1888.

[41] Liperoti R, Onder G, Lapane KL.et al. Conventional or atypical antipsychotics and the risk of femur fracture among elderly patients: results of a case-control study. J Clin Psychiatry 2007;68:929-934.

[42] Percudani M, Barbui C, Fortino I, Tansella M, Petrovich L. Second-generation antipsychotics and risk of cerebrovascular accidents in the elderly. J Clin Psychopharmacol 2005;25:468-470.

[43] Hoey J, Wooltorton E. Olanzapine (Zyprexa): increased incidence of cerebrovascular events in dementia trials. CMAJ 2004;170:1395.

[44] Greenspan A, Eerdekens M, Mahmoud R. Is there an increased rate of cerebrovascular events among dementia patients? Poster presented at: 24^th Congress of the Collegium Internationale Neuro-Psychopharmacologicum (CINP); June 20-24, 2004; Paris, France.

[45] Cavazzoni P, Young C, Polzer J, et al. Incidence of cerebrovascular adverse events and mortality during antipsychotic clinical trials of elderly patients with dementia. Poster presented at: 44^th Annual New Clinical Drug Evaluation Unit; June 1-4, 2004; Phoenix, Ariz.

[46] Liperoti R, Gambassi G, Lapane KL, et al. Cerebrovascular events among elderly nursing home patients treated with conventional or atypical antipsychotics. J Clin Psychiatry 2005; 66:1090-1096.

[47] Herrmann N, Mamdani M, Lanctot KL. Atypical antipsychotics and risk of cerebrovascular accidents. Am J Psychiatry 2004;161:1113-1115.

[48] Herrmann N, Lanctot KL. Do atypical antipsychotics cause stroke? CNS Drugs 2005;19: 91-103.

[49] 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.

[50] FDA. The Food and Drug Administration Public Health Advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. 2005 10/05/2009; Available from:Available from:http://www.fda.gov/cder/drug/advisory/antipsychotics.htm
» http://www.fda.gov/cder/drug/advisory/antipsychotics.htm

[51] FDA. The Food and Drug Administration - Information for Healthcare Professionals - Antipsychotics. 2008 10/05/2009; >from: 2008 10/05/2009; >from: http://www.fda.gov/cder/drug/InfoSheets/HCP/antipsychotics_conventional.htm
» http://www.fda.gov/cder/drug/InfoSheets/HCP/antipsychotics_conventional.htm

[52] Gill SS, Bronskill SE, Normand SL, et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med 2007;146:775-786.

[53] Schneeweiss S, Setoguchi S, Brookhart A, Dormuth C, Wang PS. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ 2007;176:627-632.

[54] Setoguchi S, Wang PS, Alan Brookhart M, Canning CF, Kaci L, Schneeweiss S. Potential causes of higher mortality in elderly users of conventional and atypical antipsychotic medications. J Am Geriatr Soc 2008;56:1644-1650.

[55] Samuel C. Durso, L.G., Bernard Roos, and Martin Gorbien. Guidelines abstracted from the American Academy of Neurology's dementia guidelines for early detection, diagnosis and management of dementia. 2003 cited 2009 04/05/2009; Available from: Available from: http://www.americangeriatrics.org/products/positionpapers/aan_dementia.shtml
» http://www.americangeriatrics.org/products/positionpapers/aan_dementia.shtml

[56] Zheng L, Mack WJ, Dagerman KS, et al. Metabolic changes associated with second-generation antipsychotic use in Alzheimer's disease patients: The CATIE-AD Study. Am J Psychiatry 2009;166:583-590

[57] Sultzer DL, Davis SM, Tariot PN, et al. Clinical symptom responses to atypical antipsychotic medications in Alzheimer's disease: phase 1 outcomes from the CATIE-AD effectiveness trial. Am J Psychiatry 2008;165:844-854.

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