Treatment Options for Agitation in Dementia

  • John M. RingmanEmail author
  • Lon Schneider
Dementia (J Pillai, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Dementia


Purpose of review

The goal of the current review is to provide an update on the management of agitation in persons with dementia with a focus on pharmacological management of persons with Alzheimer’s disease.

Recent findings

As consistently effective and safe pharmacologic interventions are still lacking, identifying and addressing medical and environmental precipitants remain a priority. Acetylcholinesterase inhibitors and memantine should be initiated to enhance cognition, and if present, management of insomnia or sundowning with trazodone is indicated. If agitation persists, treatment with citalopram can be initiated with attention paid to potential prolongation of the QT interval. Treatment with low doses of atypical antipsychotics such as risperidone or quetiapine can be effective after appropriate consideration of and disclosure of potential adverse effects.


In light of the lack of consistently effective treatments for agitation in dementia, there have been renewed efforts to define the condition and improve the design of trials of medications to treat it. Considering the heterogeneity of patients and their comorbidities as well as the specific nature of their “agitation”, there is no “one-size fits all” approach to agitation in AD. However, many options exist that can be prudently pursued for this common problem in this delicate population.


Agitation Dementia Alzheimer’s disease Pharmacological Atypical antipsychotics, selective serotonin reuptake inhibitors 



Preparation of this manuscript was supported by NIH P50 AG-005142.

Compliance with Ethical Standards

Conflict of Interest

John M. Ringman declares no potential conflict of interest. Lon Schneider reports grants from NIH and grants from the State of California, during the conduct of the study, and grants from NIH, grants and personal fees from Eli Lilly, grants and other from Lundbeck, grants and personal fees from Roche/Genentech, personal fees from Merck, personal fees from AC Immune, personal fees from Avraham, personal fees from Takeda, personal fees from Cognition, grants from Novartis, grants from Biogen, personal fees and other from vTv, personal fees and other from Allergan, personal fees from Neurim, personal fees from Axovant, personal fees from Neuronix, personal fees from Eisai, and personal fees from Toyama, outside the submitted work.

Human and animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    •• Cummings J, Mintzer J, Brodaty H, Sano M, Banerjee S, Devanand DP, et al. Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. Int Psychogeriatr. 2015;27(1):7–17 In this review article, the expert panel of authors attempts to standardize the definition of agitation in dementia and its implementation in clinical studies.PubMedGoogle Scholar
  2. 2.
    Cohen-Mansfield J. Agitated behaviors in the elderly. II. Preliminary results in the cognitively deteriorated. J Am Geriatr Soc. 1986;34(10):722–7.PubMedGoogle Scholar
  3. 3.
    Reisberg B, Monteiro I, Torossian C, Auer S, Shulman MB, Ghimire S, et al. The BEHAVE-AD assessment system: a perspective, a commentary on new findings, and a historical review. Dement Geriatr Cogn Disord. 2014;38(1–2):89–146.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994;44(12):2308–14.PubMedGoogle Scholar
  5. 5.
    Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, et al. Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. J Neuropsychiatr Clin Neurosci. 2000;12(2):233–9.Google Scholar
  6. 6.
    Wood S, Cummings JL, Hsu MA, Barclay T, Wheatley MV, Yarema KT, et al. The use of the neuropsychiatric inventory in nursing home residents. Characterization and measurement. Am J Geriatr Psychiatry. 2000;8(1):75–83.PubMedGoogle Scholar
  7. 7.
    Yesavage JA, Taylor JL, Friedman L, Rosenberg PB, Lazzeroni LC, Leoutsakos JS, et al. Principal components analysis of agitation outcomes in Alzheimer’s disease. J Psychiatr Res. 2016;79:4–7.PubMedPubMedCentralGoogle Scholar
  8. 8.
    • Salzman C, Jeste DV, Meyer RE, Cohen-Mansfield J, Cummings J, Grossberg GT, et al. Elderly patients with dementia-related symptoms of severe agitation and aggression: consensus statement on treatment options, clinical trials methodology, and policy. J Clin Psychiatry. 2008;69(6):889–98 In this review article, the authors addressed potential underlying causes of the lack of consistent benefits for agitation in clinical trials, the adverse effects of atypical antipsychotics and the care with which they must be used in this context, and the need for safer and more effective treatments for agitation in dementia.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Halpern R, Seare J, Tong J, Hartry A, Olaoye A, Aigbogun MS. Using electronic health records to estimate the prevalence of agitation in Alzheimer’s disease/dementia. Int J Geriatr Psychiatry. 2019;34(3):420–31.PubMedGoogle Scholar
  10. 10.
    Chui HC, Zarow C, Mack WJ, Ellis WG, Zheng L, Jagust WJ, et al. Cognitive impact of subcortical vascular and Alzheimer’s disease pathology. Ann Neurol. 2006;60(6):677–87.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Wolf D, Rhein C, Geschke K, Fellgiebel A. Preventable hospitalizations among older patients with cognitive impairments and dementia. Int Psychogeriatr. 2018:1–9.Google Scholar
  12. 12.
    Ihara ES, Tompkins CJ, Inoue M, Sonneman S. Results from a person-centered music intervention for individuals living with dementia. Geriatr Gerontol Int. 2018.Google Scholar
  13. 13.
    Pedersen SKA, Andersen PN, Lugo RG, Andreassen M, Sutterlin S. Effects of Music on Agitation in Dementia: A Meta-Analysis. Front Psychol. 2017;8:742.PubMedPubMedCentralGoogle Scholar
  14. 14.
    van der Steen JT, Smaling HJ, van der Wouden JC, Bruinsma MS, Scholten RJ, Vink AC. Music-based therapeutic interventions for people with dementia. Cochrane Database Syst Rev. 2018;7:CD003477.PubMedGoogle Scholar
  15. 15.
    Romeo R, Zala D, Knapp M, Orrell M, Fossey J, Ballard C. Improving the quality of life of care home residents with dementia: cost-effectiveness of an optimized intervention for residents with clinically significant agitation in dementia. Alzheimers Dement. 2018.Google Scholar
  16. 16.
    Livingston G, Kelly L, Lewis-Holmes E, Baio G, Morris S, Patel N, et al. Non-pharmacological interventions for agitation in dementia: systematic review of randomized controlled trials. Br J Psychiatry. 2014;205(6):436–42.PubMedGoogle Scholar
  17. 17.
    Leng M, Liu P, Zhang P, Hu M, Zhou H, Li G, et al. Pet robot intervention for people with dementia: a systematic review and meta-analysis of randomized controlled trials. Psychiatry Res. 2018;271:516–25.PubMedGoogle Scholar
  18. 18.
    Dimitriou TD, Verykouki E, Papatriantafyllou J, Konsta A, Kazis D, Tsolaki M. Non-pharmacological interventions for agitation/aggressive behaviour in patients with dementia: a randomized controlled crossover trial. Funct Neurol. 2018;33(3):143–7.PubMedGoogle Scholar
  19. 19.
    Canevelli M, Valletta M, Trebbastoni A, Sarli G, D’Antonio F, Tariciotti L, et al. Sundowning in dementia: clinical relevance, pathophysiological determinants, and therapeutic approaches. Front Med (Lausanne). 2016;3:73.Google Scholar
  20. 20.
    Howard RJ, Juszczak E, Ballard CG, Bentham P, Brown RG, Bullock R, et al. Donepezil for the treatment of agitation in Alzheimer’s disease. N Engl J Med. 2007;357(14):1382–92.PubMedGoogle Scholar
  21. 21.
    Cummings JL, Koumaras B, Chen M, Mirski D, Rivastigmine Nursing Home Study T. Effects of rivastigmine treatment on the neuropsychiatric and behavioral disturbances of nursing home residents with moderate to severe probable Alzheimer’s disease: a 26-week, multicenter, open-label study. Am J Geriatr Pharmacother. 2005;3(3):137–48.PubMedGoogle Scholar
  22. 22.
    Mahlberg R, Walther S, Eichmann U, Tracik F, Kunz D. Effects of rivastigmine on actigraphically monitored motor activity in severe agitation related to Alzheimer’s disease: a placebo-controlled pilot study. Arch Gerontol Geriatr. 2007;45(1):19–26.PubMedGoogle Scholar
  23. 23.
    Herrmann N, Rabheru K, Wang J, Binder C. Galantamine treatment of problematic behavior in Alzheimer disease: post-hoc analysis of pooled data from three large trials. Am J Geriatr Psychiatry. 2005;13(6):527–34.PubMedGoogle Scholar
  24. 24.
    Gauthier S, Feldman H, Hecker J, Vellas B, Ames D, Subbiah P, et al. Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer’s disease. Int Psychogeriatr. 2002;14(4):389–404.PubMedGoogle Scholar
  25. 25.
    Mega MS, Masterman DM, O’Connor SM, Barclay TR, Cummings JL. The spectrum of behavioral responses to cholinesterase inhibitor therapy in Alzheimer disease. Arch Neurol. 1999;56(11):1388–93.PubMedGoogle Scholar
  26. 26.
    Fox C, Crugel M, Maidment I, Auestad BH, Coulton S, Treloar A, et al. Efficacy of memantine for agitation in Alzheimer’s dementia: a randomized double-blind placebo controlled trial. PLoS One. 2012;7(5):e35185.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Herrmann N, Gauthier S, Boneva N, Lemming OM. A randomized, double-blind, placebo-controlled trial of memantine in a behaviorally enriched sample of patients with moderate to severe Alzheimer’s disease. Int Psychogeriatr. 2013;25(6):919–27.PubMedGoogle Scholar
  28. 28.
    Vermeiren Y, Van Dam D, Aerts T, Engelborghs S, De Deyn PP. Brain region-specific monoaminergic correlates of neuropsychiatric symptoms in Alzheimer’s disease. J Alzheimers Dis. 2014;41(3):819–33.PubMedGoogle Scholar
  29. 29.
    Seitz DP, Adunuri N, Gill SS, Gruneir A, Herrmann N, Rochon P. Antidepressants for agitation and psychosis in dementia. Cochrane Database Syst Rev. 2011;2:CD008191.Google Scholar
  30. 30.
    Olin JT, Katz IR, Meyers BS, Schneider LS, Lebowitz BD. Provisional diagnostic criteria for depression of Alzheimer disease: rationale and background. Am J Geriatr Psychiatry. 2002;10(2):129–41.PubMedGoogle Scholar
  31. 31.
    Orgeta V, Tabet N, Nilforooshan R, Howard R. Efficacy of antidepressants for depression in Alzheimer’s disease: systematic review and meta-analysis. J Alzheimers Dis. 2017;58(3):725–33.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Rosenberg PB, Drye LT, Martin BK, Frangakis C, Mintzer JE, Weintraub D, et al. Sertraline for the treatment of depression in Alzheimer disease. Am J Geriatr Psychiatry. 2010;18(2):136–45. Scholar
  33. 33.
    Finkel SI, Mintzer JE, Dysken M, Krishnan KR, Burt T, McRae T. 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. 2004;19(1):9–18.PubMedGoogle Scholar
  34. 34.
    • Porsteinsson AP, Drye LT, Pollock BG, Devanand DP, Frangakis C, Ismail Z, et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. Jama. 2014;311(7):682–91 In this large controlled trial, a benefit of citalopram for agitation in AD was demonstrated, albeit with a risk of cardiotoxicity.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Schneider LS, Frangakis C, Drye LT, Devanand DP, Marano CM, Mintzer J, et al. Heterogeneity of treatment response to citalopram for patients With Alzheimer’s disease with aggression or agitation: the CitAD randomized clinical trial. Am J Psychiatr. 2016;173(5):465–72.PubMedGoogle Scholar
  36. 36.
    Schneider LS, Pollock VE, Lyness SA. A meta-analysis of controlled trials of neuroleptic treatment in dementia. J Am Geriatr Soc. 1990;38(5):553–63.PubMedGoogle Scholar
  37. 37.
    De Deyn PP, Rabheru K, Rasmussen A, Bocksberger JP, Dautzenberg PL, Eriksson S, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology. 1999;53(5):946–55.PubMedGoogle Scholar
  38. 38.
    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(3):191–210.PubMedGoogle Scholar
  39. 39.
    •• Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med. 2006;355(15):1525–38. This large randomized and controlled study was designed to mimic real-world prescribing practices and therefore the results are more easily generalizable.PubMedGoogle Scholar
  40. 40.
    Sultzer DL, Davis SM, Tariot PN, Dagerman KS, Lebowitz BD, Lyketsos CG, 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(7):844–54.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Rosenheck RA, Leslie DL, Sindelar JL, Miller EA, Tariot PN, Dagerman KS, et al. Cost-benefit analysis of second-generation antipsychotics and placebo in a randomized trial of the treatment of psychosis and aggression in Alzheimer disease. Arch Gen Psychiatry. 2007;64(11):1259–68.PubMedGoogle Scholar
  42. 42.
    Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials.[see comment]. JAMA. 2005;294(15):1934–43.PubMedGoogle Scholar
  43. 43.
    Streim JE, Porsteinsson AP, Breder CD, Swanink R, Marcus R, McQuade R, et al. A randomized, double-blind, placebo-controlled study of aripiprazole for the treatment of psychosis in nursing home patients with Alzheimer disease. Am J Geriatr Psychiatry. 2008;16(7):537–50.PubMedGoogle Scholar
  44. 44.
    Mintzer JE, Tune LE, Breder CD, Swanink R, Marcus RN, McQuade RD, et al. Aripiprazole for the treatment of psychoses in institutionalized patients with Alzheimer dementia: a multicenter, randomized, double-blind, placebo-controlled assessment of three fixed doses. Am J Geriatr Psychiatry. 2007;15(11):918–31.PubMedGoogle Scholar
  45. 45.
    Ballard C, Banister C, Khan Z, Cummings J, Demos G, Coate B, et al. Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2, randomized, placebo-controlled, double-blind study. Lancet Neurol. 2018;17(3):213–22.PubMedGoogle Scholar
  46. 46.
    Rabinovici GD, Carrillo MC, Forman M, DeSanti S, Miller DS, Kozauer N, et al. Multiple comorbid neuropathologies in the setting of Alzheimer’s disease neuropathology and implications for drug development. Alzheimers Dement (N Y). 2017;3(1):83–91.Google Scholar
  47. 47.
    Irwin DJ, Grossman M, Weintraub D, Hurtig HI, Duda JE, Xie SX, et al. Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis. Lancet Neurol. 2017;16(1):55–65.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Aarsland D, Perry R, Larsen JP, McKeith IG, O’Brien JT, Perry EK, et al. Neuroleptic sensitivity in Parkinson’s disease and parkinsonian dementias. J Clin Psychiatry. 2005;66(5):633–7.PubMedGoogle Scholar
  49. 49.
    Shea YF, Chu LW. Neuroleptic Malignant Syndrome Caused by Quetiapine in an Elderly Man with Lewy Body Dementia. J Am Geriatr Soc. 2016;64(9):e55–6.PubMedGoogle Scholar
  50. 50.
    Teng PR, Yeh CH, Lin CY, Lai TJ. Olanzapine-induced neuroleptic malignant syndrome in a patient with probable dementia with Lewy bodies. J Neuropsychiatr Clin Neurosci. 2012;24(4):E1–2.Google Scholar
  51. 51.
    McKeith I, Del Ser T, Spano P, Emre M, Wesnes K, Anand R, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomized, double-blind, placebo-controlled international study. Lancet. 2000;356(9247):2031–6.PubMedGoogle Scholar
  52. 52.
    Matsunaga S, Kishi T, Yasue I, Iwata N. Cholinesterase inhibitors for Lewy body disorders: a meta-analysis. Int J Neuropsychopharmacol. 2015;19(2).PubMedPubMedCentralGoogle Scholar
  53. 53.
    Emre M, Aarsland D, Albanese A, Byrne EJ, Deuschl G, De Deyn PP, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med. 2004;351(24):2509–18.PubMedGoogle Scholar
  54. 54.
    Takahashi H, Yoshida K, Sugita T, Higuchi H, Shimizu T. Quetiapine treatment of psychotic symptoms and aggressive behavior in patients with dementia with Lewy bodies: a case series. Prog Neuro-Psychopharmacol Biol Psychiatry. 2003;27(3):549–53.Google Scholar
  55. 55.
    Kurlan R, Cummings J, Raman R, Thal L, Alzheimer’s Disease Cooperative Study G. Quetiapine for agitation or psychosis in patients with dementia and parkinsonism. Neurology. 2007;68(17):1356–63.PubMedGoogle Scholar
  56. 56.
    Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomized, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533–40.PubMedGoogle Scholar
  57. 57.
    Lopez-Pousa S, Garre-Olmo J, Vilalta-Franch J, Turon-Estrada A, Pericot-Nierga I. Trazodone for Alzheimer’s disease: a naturalistic follow-up study. Arch Gerontol Geriatr. 2008;47(2):207–15.PubMedGoogle Scholar
  58. 58.
    Davies SJ, Burhan AM, Kim D, Gerretsen P, Graff-Guerrero A, Woo VL, et al. Sequential drug treatment algorithm for agitation and aggression in Alzheimer’s and mixed dementia. J Psychopharmacol. 2018;32(5):509–23.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Wang LY, Shofer JB, Rohde K, Hart KL, Hoff DJ, McFall YH, et al. Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression. Am J Geriatr Psychiatry. 2009;17(9):744–51.PubMedPubMedCentralGoogle Scholar
  60. 60.
    van den Elsen GA, Ahmed AI, Verkes RJ, Kramers C, Feuth T, Rosenberg PB, et al. Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: a randomized controlled trial. Neurology. 2015;84(23):2338–46.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Cummings JL, Lyketsos CG, Peskind ER, Porsteinsson AP, Mintzer JE, Scharre DW, et al. Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia: a randomized clinical trial. Jama. 2015;314(12):1242–54.PubMedGoogle Scholar
  62. 62.
    Borsje P, Wetzels RB, Lucassen PL, Pot AM, Koopmans RT. The course of neuropsychiatric symptoms in community-dwelling patients with dementia: a systematic review. Int Psychogeriatr. 2015;27(3):385–405.PubMedGoogle Scholar
  63. 63.
    Van Leeuwen E, Petrovic M, van Driel ML, De Sutter AI, Vander Stichele R, Declercq T, et al. Withdrawal versus continuation of long-term antipsychotic drug use for behavioral and psychological symptoms in older people with dementia. Cochrane Database Syst Rev. 2018;3:CD007726.PubMedGoogle Scholar
  64. 64.
    • Brodaty H, Aerts L, Harrison F, Jessop T, Cations M, Chenoweth L, et al. Antipsychotic deprescription for older adults in long-term care: the HALT study. J Am Med Dir Assoc. 2018;19(7):592–600 e7. In this study, the authors demonstrated that it is frequently possible to discontinue atypical antipsychotics in agitated persons with dementia without relapse of symptoms.PubMedGoogle Scholar
  65. 65.
    Kales HC, Zivin K, Kim HM, Valenstein M, Chiang C, Ignacio RV, et al. Trends in antipsychotic use in dementia 1999–2007. Arch Gen Psychiatry. 2011;68(2):190–7.PubMedGoogle Scholar
  66. 66.
    Bergh S, Selbaek G, Engedal K. Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double-blind, randomized, parallel group, placebo-controlled trial. BMJ. 2012;344:e1566.PubMedGoogle Scholar
  67. 67.
    Horowitz MA, Taylor D. Tapering of SSRI treatment to mitigate withdrawal symptoms. Lancet Psychiatry. 2019.Google Scholar
  68. 68.
    •• Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673–734 In this comprehensive article, the authors review many practical dimensions of care of patients with AD, including management of agitation.PubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Helene and Lou Galen Professor of Clinical Neurology, Department of Neurology, Center for Health ProfessionsKeck School of Medicine at USCLos AngelesUSA
  2. 2.Keck School of Medicine of USCLos AngelesUSA

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