More than five million Americans suffer from Alzheimer’s disease (AD), and this number is expected to triple by 2050. While impairments in cognition, particularly memory, are typically the defining features of the clinical syndrome, behavioral symptoms are extremely common, affecting up to 90 % of patients. Behavioral symptoms in AD can be difficult to manage and may require a combination of non-pharmacological and pharmacological approaches. The latter is complicated by FDA “black-box warnings” for the medication classes most often used to target these symptoms, and currently there are initiatives in place to limit their use. In this review, we describe common behavioral symptoms of AD—with a particular focus on the challenging symptoms of “agitation” and “irritability”—and discuss evidence-based approaches to their management. Ultimately, multidimensional approaches must be tailored to the patient and their environment, though evidence-based practices should define the treatment of agitation and irritability in AD.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Similar content being viewed by others
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Alzheimer’s A. 2015 Alzheimer’s disease facts and figures. Alzheimers Dement. 2015;11:332–84.
Cerejeira J, Lagarto L, Mukaetova-Ladinska EB. Behavioral and psychological symptoms of dementia. Front Neurol. 2012;3:73.
Fong TG, Tulebaev SR, Inouye SK. Delirium in elderly adults: diagnosis, prevention and treatment. Nat Rev Neurol. 2009;5:210–20.
Cohen-Mansfield J. Measurement of inappropriate behavior associated with dementia. J Gerontol Nurs. 1999;25:42–51.
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994;44:2308–14.
Landes AM, Sperry SD, Strauss ME, Geldmacher DS. Apathy in Alzheimer’s disease. J Am Geriatr Soc. 2001;49:1700–7.
Rea R, Carotenuto A, Fasanaro AM, Traini E, Amenta F. Apathy in Alzheimer’s disease: any effective treatment? ScientificWorldJournal. 2014;2014:421385.
Mayor S. Signs of depression and apathy precede memory problems in Alzheimer’s disease, study shows. BMJ. 2015;350:h190.
Mograbi DC, Morris RG. On the relation among mood, apathy, and anosognosia in Alzheimer’s disease. J Int Neuropsychol Soc. 2014;20:2–7.
Van der Mussele S, Le Bastard N, Saerens J, Somers N, Marien P, Goeman J, et al. Agitation-associated behavioral symptoms in mild cognitive impairment and Alzheimer’s dementia. Aging Ment Health. 2015;19:247–57.
Charernboon T, Phanasathit M. Prevalence of neuropsychiatric symptoms in Alzheimer’s disease: a cross-sectional descriptive study in Thailand. J Med Assoc Thail. 2014;97:560–5.
Thyrian JR, Eichler T, Hertel J, Wucherer D, Dreier A, Michalowsky B, Killimann I, Teipel S, Hoffmann W. Burden of behavioral and psychiatric symptoms in people screened positive for dementia in primary care: results of the DelpHi-study. J Alzheimers Dis. 2015.
Kales HC, Gitlin LN, Lyketsos CG, Detroit Expert Panel on A, Management of Neuropsychiatric Symptoms of D. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc. 2014;62:762–9. Recommendations from expert panel, with excellent review of the DICE approach.
Conde-Sala JL, Turro-Garriga O, Pinan-Hernandez S, Portellano-Ortiz C, Vinas-Diez V, Gascon-Bayarri J, Rene-Ramirez R. Effects of anosognosia and neuropsychiatric symptoms on the quality of life of patients with Alzheimer’s disease: a 24-month follow-up study. Int J Geriatr Psychiatry. 2015.
Lee D, Heo SH, Yoon SS, Chang DI, Lee S, Rhee HY, et al. Sleep disturbances and predictive factors in caregivers of patients with mild cognitive impairment and dementia. J Clin Neurol. 2014;10:304–13.
Morris S, Patel N, Baio G, Kelly L, Lewis-Holmes E, Omar RZ, et al. Monetary costs of agitation in older adults with Alzheimer’s disease in the UK: prospective cohort study. BMJ Open. 2015;5:e007382.
Peters ME, Schwartz S, Han D, Rabins PV, Steinberg M, Tschanz JT, et al. Neuropsychiatric symptoms as predictors of progression to severe Alzheimer’s dementia and death: the Cache County Dementia Progression Study. Am J Psychiatry. 2015;172:460–5. Recently published analysis of data from the Cache County Dementia Progression Study, examining the relationship between neuropsychiatric symptoms and progression to severe dementia or death.
Stevens JR, Jarrahzadeh T, Brendel RW, Stern TA. Strategies for the prescription of psychotropic drugs with black box warnings. Psychosomatics. 2014;55:123–33. Excellent review and discussion of strategies for prescribing agents with block-box warnings.
Borisovskaya A, Pascualy M, Borson S. Cognitive and neuropsychiatric impairments in Alzheimer’s disease: current treatment strategies. Curr Psychiatry Rep. 2014;16:470.
Soto M, Andrieu S, Nourhashemi F, Ousset PJ, Ballard C, Robert P, Vellas B, Lyketsos CG, Rosenberg PB Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design. Int Psychogeriatr. 2014;1–17.
Stella F, Forlenza OV, Laks J, de Andrade LP, de Castilho Cacao J, Govone JS, de Medeiros K, Lyketsos CG. Caregiver report versus clinician impression: disagreements in rating neuropsychiatric symptoms in Alzheimer’s disease patients. Int J Geriatr Psychiatry. 2015.
Brodaty H, Connors MH, Xu J, Woodward M, Ames D, group Ps. The course of neuropsychiatric symptoms in dementia: a 3-year longitudinal study. J Am Med Dir Assoc. 2015;16:380–7.
Morra LF, Donovick PJ. Clinical presentation and differential diagnosis of dementia with Lewy bodies: a review. Int J Geriatr Psychiatry. 2014;29:569–76.
Bott NT, Radke A, Stephens ML, Kramer JH. Frontotemporal dementia: diagnosis, deficits and management. Neurodegener Dis Manag. 2014;4:439–54.
Cummings JL, Isaacson RS, Schmitt FA, Velting DM. A practical algorithm for managing Alzheimer’s disease: what, when, and why? Ann Clin Transl Neurol. 2015;2:307–23.
Weiner MF. Impact of delirium on the course of Alzheimer disease. Arch Neurol. 2012;69:1639–40.
Ballard C, O’Brien J. Treating behavioural and psychological signs in Alzheimer’s disease. BMJ. 1999;319:138–9.
Staedtler AV, Nunez D. Nonpharmacological therapy for the management of neuropsychiatric symptoms of Alzheimer’s disease: linking evidence to practice. Worldviews Evid-Based Nurs. 2015;12:108–15.
Karel MJ, Teri L, McConnell E, Visnic S, Karlin BE. Effectiveness of expanded implementation of STAR-VA for managing dementia-related behaviors among veterans. Gerontologist. 2015.
Gitlin LN, Mann WC, Vogel WB, Arthur PB. A non-pharmacologic approach to address challenging behaviors of Veterans with dementia: description of the tailored activity program-VA randomized trial. BMC Geriatr. 2013;13:96.
Figueiro MG, Plitnick BA, Lok A, Jones GE, Higgins P, Hornick TR, et al. Tailored lighting intervention improves measures of sleep, depression, and agitation in persons with Alzheimer’s disease and related dementia living in long-term care facilities. Clin Interv Aging. 2014;9:1527–37.
Burns A, Perry E, Holmes C, Francis P, Morris J, Howes MJ, et al. A double-blind placebo-controlled randomized trial of Melissa officinalis oil and donepezil for the treatment of agitation in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2011;31:158–64.
Raglio A, Bellandi D, Baiardi P, Gianotti M, Ubezio MC, Zanacchi E, et al. Effect of active music therapy and individualized listening to music on dementia: a multicenter randomized controlled trial. J Am Geriatr Soc. 2015;63:1534–9.
Cohen-Mansfield J. Nonpharmacologic interventions for inappropriate behaviors in dementia: a review, summary, and critique. Am J Geriatr Psychiatry. 2001;9:361–81.
Padilla R. Effectiveness of environment-based interventions for people with Alzheimer’s disease and related dementias. Am J Occup Ther. 2011;65:514–22.
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;355:1525–38.
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;294:1934–43.
FDA U. U.S. Government. 2008.
Dorsey ER, Rabbani A, Gallagher SA, Conti RM, Alexander GC. Impact of FDA black box advisory on antipsychotic medication use. Arch Intern Med. 2010;170:96–103.
Singh RR, Nayak R. Impact of FDA black box warning on psychotropic drug use in noninstitutionalized elderly patients diagnosed with dementia: a retrospective study. J Pharm Pract. 2015.
Maust DT, Kim HM, Seyfried LS, Chiang C, Kavanagh J, Schneider LS, et al. Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry. 2015;72:438–45. Recent retrospective case–control study suggesting that the effect of antipsychotics on mortality in elderly patients with dementia may be higher than previously reported.
Ma H, Huang Y, Cong Z, Wang Y, Jiang W, Gao S, et al. The efficacy and safety of atypical antipsychotics for the treatment of dementia: a meta-analysis of randomized placebo-controlled trials. J Alzheimers Dis. 2014;42:915–37.
M M, AR M, J H, Z W, R S, PG S, B R, L H, MJ S, BA E, A M, T. P. Agency for Healthcare Research and Quality (US), Rockville, MD. 2011.
Steinberg M, Lyketsos CG. Atypical antipsychotic use in patients with dementia: managing safety concerns. Am J Psychiatry. 2012;169:900–6.
Murray PS, Kumar S, Demichele-Sweet MA, Sweet RA. Psychosis in Alzheimer’s disease. Biol Psychiatry. 2014;75:542–52. Comprehensive review of the “AD with Psychosis” (AD + P) phenotype of Alzheimer’s disease.
Koppel J, Greenwald BS. Optimal treatment of Alzheimer’s disease psychosis: challenges and solutions. Neuropsychiatr Dis Treat. 2014;10:2253–62.
Moore AR, O’Keeffe ST. Drug-induced cognitive impairment in the elderly. Drugs Aging. 1999;15:15–28.
Pariente A, Dartigues JF, Benichou J, Letenneur L, Moore N, Fourrier-Reglat A. Benzodiazepines and injurious falls in community dwelling elders. Drugs Aging. 2008;25:61–70.
Carriere I, Fourrier-Reglat A, Dartigues JF, Rouaud O, Pasquier F, Ritchie K, et al. Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study. Arch Intern Med. 2009;169:1317–24.
Berryman SN, Jennings J, Ragsdale S, Lofton T, Huff DC, Rooker JS. Beers criteria for potentially inappropriate medication use in older adults. Medsurg Nurs. 2012;21:129–32. Quiz 133. Important update to Beers Criteria from the American Geriatrics Society, highlighting medications that should be prescribed with caution in the older adult population.
Pauszek ME. Propranolol for treatment of agitation in senile dementia. Indiana Med. 1991;84:16–7.
Hersch EC, Falzgraf S. Management of the behavioral and psychological symptoms of dementia. Clin Interv Aging. 2007;2:611–21.
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;311:682–91. Results from the CiTAD clinical trial, showing that citalopram significantly reduced agitation in individuals with Alzheimer’s disease (as compared to placebo).
Suzuki H, Gen K. Clinical efficacy of lamotrigine and changes in the dosages of concomitantly used psychotropic drugs in Alzheimer’s disease with behavioural and psychological symptoms of dementia: a preliminary open-label trial. Psychogeriatrics. 2015;15:32–7.
Porsteinsson AP, Smith JS, Keltz MA, Antonsdottir IM. Can antidepressant medication relieve agitation in Alzheimer’s disease? Expert Rev Neurother. 2014;14:969–71.
Ballard C, Thomas A, Gerry S, Yu LM, Aarsland D, Merritt C, et al. A double-blind randomized placebo-controlled withdrawal trial comparing memantine and antipsychotics for the long-term treatment of function and neuropsychiatric symptoms in people with Alzheimer’s disease (MAIN-AD). J Am Med Dir Assoc. 2015;16:316–22.
Voyer P, McCusker J, Cole MG, Monette J, Champoux N, Ciampi A, et al. Behavioral and psychological symptoms of dementia: how long does every behavior last, and are particular behaviors associated with PRN antipsychotic agent use? J Gerontol Nurs. 2015;41:22–37. quiz 38–29.
Neumann RD, Faris P, Klassen R. Examining trends in the administration of “as needed” medications to inpatients with behavioral and psychological symptoms of dementia. Am J Alzheimers Dis Other Demen. 2015;30:247–56.
Martin D, MacVicar S. Drugging dementia: are antipsychotics killing nursing home patients? Aljazeera America. 2015.
CMS. Center for Medicare & Medcaid Services, CMS.gov. 2014.
Mort JR, Sailor R, Hintz L. Partnership to decrease antipsychotic medication use in nursing homes: impact at the state level. S D Med. 2014;67:67–9.
Glezer A, Stern TA, Mort EA, Atamian S, Abrams JL, Brendel RW. Documentation of decision-making capacity, informed consent, and health care proxies: a study of surrogate consent. Psychosomatics. 2011;52:521–9.
Volicer L. Goals of care in advanced dementia: quality of life, dignity and comfort. J Nutr Health Aging. 2007;11:481.
Brendel RW, Wei MH, Schouten R, Edersheim JG. An approach to selected legal issues: confidentiality, mandatory reporting, abuse and neglect, informed consent, capacity decisions, boundary issues, and malpractice claims. Med Clin N Am. 2010;94:1229–40. xi-ii. Review of approaches to common medicolegal issues, including capacity decisions and informed consent.
Conflict of Interest
The authors declare that they have no competing interests.
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.
This work was supported, in part, by National Institutes of Health grant T32 MH1711929 (AMK).
This article is part of the Topical Collection on Geriatric Disorders
About this article
Cite this article
Koenig, A.M., Arnold, S.E. & Streim, J.E. Agitation and Irritability in Alzheimer’s Disease: Evidenced-Based Treatments and the Black-Box Warning. Curr Psychiatry Rep 18, 3 (2016). https://doi.org/10.1007/s11920-015-0640-7