Abstract
Agitation and aggression are frequently occurring and distressing behavioral and psychological symptoms of dementia (BPSD). These symptoms are disturbing for individuals with Alzheimer disease, commonly confer risk to the patient and others, and present a major management challenge for clinicians. The most widely prescribed pharmacological treatments for these symptoms—atypical antipsychotics—have a modest but significant beneficial effect in the short-term treatment (over 6–12 weeks) of aggression but limited benefits in longer term therapy. Benefits are less well established for other symptoms of agitation. In addition, concerns are growing over the potential for serious adverse outcomes with these treatments, including stroke and death. A detailed consideration of other pharmacological and nonpharmacological approaches to agitation and aggression in patients with Alzheimer disease is, therefore, imperative. This article reviews the increasing evidence in support of psychological interventions or alternative therapies (such as aromatherapy) as a first-line management strategy for agitation, as well as the potential pharmacological alternatives to atypical antipsychotics—preliminary evidence for memantine, carbamazepine, and citalopram is encouraging.
Key Points
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Agitation and aggression are frequent and distressing symptoms that present major management problems in people with Alzheimer disease (AD)
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Atypical antipsychotics are widely used in the pharmacological treatment of agitation and aggression, but their benefit is primarily limited to short-term management of aggression
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Serious adverse events are associated with atypical antipsychotics in AD, including increased risk of stroke and death
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An evidence base is emerging to support a variety of practical and easy-to-implement nonpharmacological treatments for the first-line treatment of agitation and aggression in AD
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Further clinical trials of pharmacotherapy for agitation and aggression in AD are urgently needed, but preliminary data indicate that memantine, citalopram and carbamazepine could be promising alternatives to atypical antipsychotics
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References
Prince, M. Epidemiology of Alzheimer's. Psychiatry 3, 11–13 (2004).
Steinberg, M. et al. Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study. Int. J. Geriatr. Psychiatry 23, 170–177 (2008).
Lyketsos, C. G. Neuropsychiatric symptoms (behavioral and psychological symptoms of dementia) and the development of dementia treatments. Int. Psychogeriatr. 19, 409–420 (2007).
Ballard, C. & Fossey, J. Clinical management of dementia. Psychiatry 7, 88–93 (2008).
Rabins, P. V., Mace, N. L. & Lucas, M. J. The impact of dementia on the family. JAMA 248, 333–335 (1982).
Ballard, C. G., Eastwood, C., Gahir, M. & Wilcock, G. A follow up study of depression in the carers of dementia sufferers. BMJ 312, 947 (1996).
Steele, C., Rovner, B., Chase, G. A. & Folstein, M. Psychiatric symptoms and nursing home placement of patients with Alzheimer's disease. Am. J. Psychiatry 147, 1049–1051 (1990).
Aalten, P. et al. Behavioral problems in dementia: a factor analysis of the neuropsychiatric inventory. Dement. Geriatr. Cogn. Disord. 15, 99–105 (2003).
Schneider, L. S., Pollock, V. E. & Lyness, S. A. A metaanalysis of controlled trials of neuroleptic treatment in dementia. J. Am. Geriatr. Soc. 38, 553–563 (1990).
Finkel, S. I. et al. A randomized, placebo-controlled trial of thiothixene in agitated, demented nursing home patients. Int. J. Geriatr. Psychiatry 10, 129–136 (1995).
De Deyn, P. P. et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 53, 946–955 (1999).
Teri, L. et al. Treatment of agitation in AD: a randomized, placebo-controlled clinical trial. Neurology 55, 1271–1278 (2000).
Lonergan, E., Luxenberg, J., Colford, J. M. & Birks, J. Haloperidol for agitation in dementia. Cochrane Database of Systematic Reviews 2002, Issue 2. Art. No.: CD002852. doi:10.1002/14651858.CD002852 (2002).
Tune, L. E., Steele, C. & Cooper, T. Neuroleptic drugs in the management of behavioral symptoms of Alzheimer's disease. Psychiatr. Clin. North Am. 14, 353–373 (1991).
Reilly, J. G., Ayis, S. A., Ferrier, I. N., Jones, S. J. & Thomas, S. H. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 355, 1048–1052 (2000).
Wang, P. S. et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N. Engl. J. Med. 353, 2335–2341 (2005).
Alldred, D. P., Petty, D. R., Bowie, P., Zermansky, A. G. & Raynor, D. K. Antipsychotic prescribing patterns in care homes and relationship with dementia. Psychiatr. Bull. R. Coll. Psychiatr. 31, 329–332 (2007).
Ballard, C. & Howard, R. Neuroleptic drugs in dementia: benefits and harm. Nat. Rev. Neurosci. 7, 492–500 (2006).
Schneider, L. S., Dagerman, K. & Insel, P. S. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am. J. Geriatr Psychiatry 14, 191–210 (2006).
Wooltorton, E. Olanzapine (Zyprexa): increased incidence of cerebrovascular events in dementia trials. CMAJ 170, 1395 (2004).
FDA Public Health Advisory. Deaths with antipsychotics in elderly patients with behavioral disturbances. [online] http://www.fda.gov/Cder/drug/advisory/antipsychotics.htm (2005).
Schneider, L. S., Dagerman, K. S. & Insel, P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 294, 1934–1943 (2005).
Ballard, C. et al. Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial. BMJ 330, 874 (2005).
Schneider, L. S. et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N. Engl. J. Med. 355, 1525–1538 (2006).
Ballard, C. et al. A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial). PLoS Med. 5, e76 (2008).
Cohen-Mansfield, J. et al. Withdrawal of haloperidol, thioridazine, and lorazepam in the nursing home: a controlled, double-blind study. Arch. Intern. Med. 159, 1733–1740 (1999).
Bridges-Parlet, S., Knopman, D. & Steffes, S. Withdrawal of neuroleptic medications from institutionalized dementia patients: results of a double-blind, baseline-treatment-controlled pilot study. J. Geriatr. Psychiatry Neurol. 10, 119–126 (1997).
Ballard, C. 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 65, 114–119 (2004).
Ballard, C. et al. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol. 8, 151–157 (2009).
Lyketsos, C. G. et al. Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia due to Alzheimer disease. Am. J. Geriatr. Psychiatry 14, 561–572 (2006).
Livingston, G. et al. Systematic review of psychological approaches to the management of neuropsychiatric symptoms of dementia. Am. J. Psychiatry 162, 1996–2021 (2005).
Neal, M. & Barton Wright, P. Validation therapy for dementia. Cochrane Database of Systematic Reviews Issue 3. Art. No.: CD001394. doi:10.1002/14651858.CD001394 (2003).
Cohen-Mansfield, J., Libin, A. & Marx, M. S. Nonpharmacological treatment of agitation: a controlled trial of systematic individualized intervention. J. Gerontol. A Biol. Sci. Med. Sci. 62, 908–916 (2007).
Ballard, C. et al. Brief psycho-social therapy (BPST) for the treatment of agitation in Alzheimer's disease (the CALM-AD trial). Am. J. Geriatr. Psychiatry (in press) (2009).
Bird, M., Llewellyn-Jones, R., Smithers, H. & Korten, A. Psychosocial approaches to challenging behaviour in dementia: a controlled trial. In Report to the Commonwealth Department of Health and Ageing. Sections 2.5 and 4.5. Canberra: Office for Older Australians (2002).
Fossey, J. et al. Effect of enhanced psychosocial care on antipsychotic use in nursing home residents with severe dementia: cluster randomised trial. BMJ 332, 756–758 (2006).
Rovner, B. W., Steele, C. D., Shmuely, Y. & Folstein, M. F. A randomized trial of dementia care in nursing homes. J. Am. Geriatr. Soc. 44, 7–13 (1996).
Akhondzadeh, S. et al. Melissa officinalis extract in the treatment of patients with mild to moderate Alzheimer's disease: a double blind, randomised, placebo controlled trial. J. Neurol. Neurosurg. Psychiatry 74, 863–886 (2003).
Ancoli-Israel, S. et al. Effect of light on agitation in institutionalized patients with severe Alzheimer disease. Am. J. Geriatr. Psychiatry 11, 194–203 (2003).
Ballard, C. G., O'Brien, J. T., Reichelt, K. & Perry, E. K. 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 63, 553–558 (2002).
Dowling, G. A. et al. Melatonin and bright-light treatment for rest-activity disruption in institutionalized patients with Alzheimer's disease. J. Am. Geriatr. Soc. 56, 239–246 (2008).
Lin, P. W., Chan, W. C., Ng, B. F. & Lam, L. C. Efficacy of aromatherapy (Lavandula angustifolia) as an intervention for agitated behaviours in Chinese older persons with dementia: a cross-over randomized trial. Int. J. Geriatr. Psychiatry 22, 405–410 (2007).
Burns, A., Byrne, J., Ballard, C. & Holmes, C. Sensory stimulation in dementia. BMJ 325, 1312–1313 (2002).
Gauthier, S. et al. Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer's disease. Int. Psychogeriatr. 14, 389–404 (2002).
Cummings, J. L., McRae, T., Zhang, R. & Donepezil-Sertraline Study Group. Effects of donepezil on neuropsychiatric symptoms in patients with dementia and severe behavioral disorders. Am. J. Geriatr. Psychiatry 14, 605–612 (2006).
McKeith, I. et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 356, 2031–2036 (2000).
Erkinjuntti, T. et al. Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial. Lancet 359, 1283–1290 (2002).
Ames, D. et al. For debate: is the evidence for the efficacy of cholinesterase inhibitors in the symptomatic treatment of Alzheimer's disease convincing or not? Int. Psychogeriatr. 20, 259–292 (2008).
Trinh, N. H., 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 289, 210–216 (2003).
Holmes, C. et al. The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology 63, 214–219 (2004).
Howard, R. J. et al. Donepezil for the treatment of agitation in Alzheimer's disease. N. Engl. J. Med. 357, 1382–1392 (2007).
Cummings, J. L., Schneider, E., Tariot, P. N., Graham, S. M. & Memantine MEM-MD-02 Study Group. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology 67, 57–63 (2006).
Gauthier S., Wirth, Y. & Möbius, H. J. Effects of memantine on behavioral symptoms in Alzheimer's disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomized, controlled studies. Int. J. Geriatr. Psychiatry 20, 459–464 (2005).
McShane, R., Areosa Sastre, A. & Minakaran, N. Memantine for dementia. Cochrane Database of Systematic Reviews Issue 2. Art. No.: CD003154. doi:10.1002/14651858.CD003154.pub5 (2006).
Gauthier, S., Loft, H. & Cummings, J. Improvement in behavioural symptoms in patients with moderate to severe Alzheimer's disease by memantine: a pooled data analysis. Int. J. Geriatr. Psychiatry 23, 537–545 (2008).
Wilcock, G. K., Ballard, C. G., Cooper, J. A. & Loft, H. Memantine for agitation/aggression and psychosis in moderately severe to severe Alzheimer's disease: a pooled analysis of 3 studies. J. Clin. Psychiatry 69, 341–348 (2008).
Fillit, H. et al. Memantine discontinuation in nursing home residents with Alzheimer's disease is associated with increased psychotropic drug use and decreased body weight. Poster presented at the XXVI Collegium Internationale Neuro-Psychopharmacologicum (CINP): 13–17 July 2008, Munich, Germany (2008).
Vidal, J. S. et al. Evaluation of the impact of memantine treatment initiation on psychotropics use: a study from the French national health care database. Neuroepidemiology 31, 193–200 (2008).
Finkel, S. I. 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. Geriatr. Psychiatry 19, 9–18 (2004).
Pollock, B. G. et al. Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. Am. J. Psychiatry 159, 460–465 (2002).
Pollock, B. G. 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 15, 942–952 (2007).
Sultzer, D. L., Gray, K. F., Gunay, I., Berisford, M. A. & Mahler, M. E. A double-blind comparison of trazodone and haloperidol for treatment of agitation in patients with dementia. Am. J. Geriatr. Psychiatry 5, 60–69 (1997).
Martin, B. K. et al. Design of Depression in Alzheimer's Disease Study-2. Am. J. Geriatr. Psychiatry 14, 920–930 (2006).
Tariot, P. N., Loy, R., Ryan, J. M., Porsteinsson, A. & Ismail, S. Mood stabilizers in Alzheimer's disease: symptomatic and neuroprotective rationales. Adv. Drug Deliv. Rev. 54, 1567–1577 (2002).
Konovalov, S., Muralee, S. & Tampi, R. R. Anticonvulsants for the treatment of behavioral and psychological symptoms of dementia: a literature review. Int. Psychogeriatr. 20, 293–308 (2008).
Tariot, P. N. et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am. J. Psychiatry 155, 54–61 (1998).
Olin, J. T., Fox, L. S., Pawluczyk, S., Taggart, N. A. & Schneider, L. S. A pilot randomized trial of carbamazepine for behavioral symptoms in treatment-resistant outpatients with Alzheimer disease. Am. J. Geriatr. Psychiatry 9, 400–405 (2001).
Hollis, J. et al. Antipsychotic medication dispensing and risk of death in veterans and war widows 65 years and older. Am. J. Geriatr. Psychiatry 15, 932–941 (2007).
Tariot, P. N. et al. Divalproex sodium in nursing home residents with possible or probable Alzheimer disease complicated by agitation: a randomized, controlled trial. Am. J. Geriatr. Psychiatry 13, 942–949 (2005).
Herrmann N., Lanctôt, K. L., Rothenburg, L. S. & Eryavec, G. A placebo-controlled trial of valproate for agitation and aggression in Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 23, 116–119 (2007).
Jeste, D. V. et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 33, 957–970 (2008).
Holmes, C., Arranz, M. J., Powell, J. F., Collier, D. A. & Lovestone, S. 5-HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer's disease. Hum. Mol. Genet. 7, 1507–1509 (1998).
Pritchard, A. L., Pritchard, C. W., Bentham, P. & Lendon, C. L. Role of serotonin transporter polymorphisms in the behavioural and psychological symptoms in probable Alzheimer disease patients. Dement. Geriatr. Cogn. Disord. 24, 201–206 (2007).
Sweet, R. A. et al. The 5-HTTPR polymorphism confers liability to a combined phenotype of psychotic and aggressive behaviour in Alzheimer disease. Int. Psychogeriatr. 13, 401–409 (2001).
Sweet, R. A. et al. Dopamine receptor genetic variation, psychosis, and aggression in Alzheimer disease. Arch. Neurol. 55, 1335–1340 (1998).
Förstl, H., Burns, A., Levy, R. & Cairns, N. Neuropathological correlates of psychotic phenomena in confirmed Alzheimer's disease. Br. J. Psychiatry 165, 53–59 (1994).
Sharp, S. I., Ballard, C. G., Chen, C. P. & Francis, P. T. Aggressive behavior and neuroleptic medication are associated with increased number of α1-adrenoceptors in patients with Alzheimer disease. Am. J. Geriatr. Psychiatry 15, 435–437 (2007).
Lyketsos, C. G., Breitner, J. C. & Rabins, P. V. An evidence-based proposal for the classification of neuropsychiatric disturbance in Alzheimer's disease. Int. J. Geriatr. Psychiatry 16, 1037–1042 (2001).
Birks J., Grimley Evans. J., Iakovidou, V. & Tsolaki, M. Rivastigmine for Alzheimer's disease. Cochrane Database of Systematic Reviews 2000, Issue 4. Art. No.: CD001191. doi:10.1002/14651858.CD001191 (2000).
Loy, C. & Schneider, L. Galantamine for Alzheimer's disease and mild cognitive impairment. Cochrane Database of Systematic Reviews Issue 1. Art. No.: CD001747. doi:10.1002/14651858.CD001747.pub3 (2006).
Birks, J. & Harvey, R. J. Donepezil for dementia due to Alzheimer's disease. Cochrane Database of Systematic Reviews Issue 1. Art. No.: CD001190. doi:10.1002/14651858.CD001190.pub2 (2006).
Martinón-Torres, G., Fioravanti, M. & Grimley, E. J. Trazodone for agitation in dementia. Cochrane Database of Systematic Reviews Issue 3. Art. No.: CD004990. doi:10.1002/14651858.CD004990 (2004).
Lonergan, E. T. & Luxenberg, J. Valproate preparations for agitation in dementia. Cochrane Database of Systematic Reviews Issue 2. Art. No.: CD003945. doi:10.1002/14651858.CD003945.pub2 (2004).
Herrmann, N. & Lanctôt, K. L. Pharmacologic management of neuropsychiatric symptoms of Alzheimer disease. Can. J. Psychiatry 52, 630–646 (2007).
Thorgrimsen, L. M., Spector, A. E., Wiles, A. & Orrell, M. Aroma therapy for dementia. Cochrane Database of Systematic Reviews Issue 3. Art. No.: CD003150. doi:10.1002/14651858.CD003150 (2003).
Ballard, C. Alternative therapies for behavioral problems. Presented at the International Conference on Alzheimer's Disease (ICAD): 26–31 July 2008, Chicago, USA (2008).
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We thank Cambridge Medical Communication Ltd for expert editorial assistance and Dr. Florinda Rosa for advice on content.
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C. G. Ballard has acted as a consultant for Arcadia, Esai, Lundbeck A/S, Novartis and Shire, has received honoraria from Esai, Lundbeck A/S, Novartis and Shire, and has received research support from Lundbeck A/S, Novartis, Shire and Wyeth. S. Gauthier has acted a consultant for and has received grants from Lundbeck and has acted as a consultant for Merz Pharmaceuticals. J. L. Cummings has acted as a consultant for and received honoraria from Forest, Lundbeck, Merz Pharmaceuticals, Pfizer, Janssen and Novartis and holds the copyright for the Neuropsychiatric Inventory (NPI). H. Brodaty has acted as a consultant for and received honoraria and grants from Lundbeck. G. T. Grossberg has acted as a consultant for Forest, Pfizer, Novartis, Medivation and PAM Labs and received grants from Elan and Wyeth. P. Robert has acted as a consultant for and received honoraria and grants from Lundbeck AIS, acted as a consultant for and received grants from Wyeth, received honoraria and grants from Esai Pharma, and received honoraria from Novartis and Janssen. C. G. Lyketsos has acted as a consultant for and received grants from Forest, Wyeth, Novartis and Lilly and has received grants from Pfizer.
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Ballard, C., Gauthier, S., Cummings, J. et al. Management of agitation and aggression associated with Alzheimer disease. Nat Rev Neurol 5, 245–255 (2009). https://doi.org/10.1038/nrneurol.2009.39
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DOI: https://doi.org/10.1038/nrneurol.2009.39
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