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A Literature Review of Methodologies Used in Randomized Clinical Trials of Agitation in Alzheimer’s Disease

  • Sanjay Dubé
  • J. T. Megerian
  • R. Malamut
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Abstract

Agitation is a common and burdensome symptom associated with Alzheimer’s disease (AD). This is a narrative literature review of the designs and methods used in randomized clinical trials of agitation in patients with AD; sources range from published, to completed but not published, to ongoing studies in the past 10 years. Selection for review included blinded, randomized trials conducted to assess the effect of a pharmacological intervention for which agitation in patients with AD was among the prespecified end points. Key criteria for exclusion included open-label studies, trials of dementia not specific to AD, or mixed populations of AD and unspecified dementia. A search of PubMed and clinicaltrials.gov databases identified 36 trials for which agitation was among the prespecified end points: 18 were published trials and 18 were completed but not published or ongoing. There was significant heterogeneity among AD studies in terms of diagnostic criteria, assessment of severity of disease and agitation, sample size and powering assumptions, treatment duration, patient age and cognitive status, and outcomes measurements. Few studies used a mitigation strategy for placebo response. Accumulating evidence suggests that it is important to consider the following in trial design: thresholds for baseline severity of agitation and AD; use of prespecified accepted criteria to define agitation; and use of standardized, validated tools to measure treatment effects during a trial. Adoption of these design strategies might help improve signal detection and bring us closer to identifying the most appropriate, effective, and safe treatments for agitation in patients with AD.

Key words

Alzheimer’s disease agitation assessment tools methodology trial design 

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References

  1. 1.
    Selbaek G, Engedal K, Bergh S. The prevalence and course of neuropsychiatric symptoms in nursing home patients with dementia: a systematic review. JJ Am Med Dir Assoc 2013;14(3):161–169.CrossRefGoogle Scholar
  2. 2.
    Steinberg M, Shao H, Zandi P, et al. Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry 2008;23(2):170–177.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Tschanz JT, Corcoran CD, Schwartz S, et al. Progression of cognitive, functional, and neuropsychiatric symptom domains in a population cohort with Alzheimer dementia: the Cache County Dementia Progression study. Am J Geriatr Psychiatry 2011;19(6):532–542.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Yaffe K, Fox P, Newcomer R, et al. Patient and caregiver characteristics and nursing home placement in patients with dementia. JAMA 2002;287(16):2090–2097.CrossRefPubMedGoogle Scholar
  5. 5.
    Okura T, Plassman BL, Steffens DC, Llewellyn DJ, Potter GG, Langa KM. Neuropsychiatric symptoms and the risk of institutionalization and death: the aging, demographics, and memory study. J Am Geriatr Soc 2011;59(3):473–481.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Khoo SA, Chen TY, Ang YH, Yap P. The impact of neuropsychiatric symptoms on caregiver distress and quality of life in persons with dementia in an Asian tertiary hospital memory clinic. Int Psychogeriatr 2013;25(12):1991–1999.CrossRefPubMedGoogle Scholar
  7. 7.
    Castro FA, Melegarejo JD, Lee JH, Maestre JE. Neuropsychiatric symptoms and their relationship with progression to severe dementia and death: findings of the MARACAIBO Aging Study (MAS). Alzheimers Dement 2016;12(7 Suppl):P495–P496.CrossRefGoogle Scholar
  8. 8.
    Knapp M, Chua KC, Broadbent M, et al. Predictors of care home and hospital admissions and their costs for older people with Alzheimer’s disease: findings from a large London case register. BMJ Open 2016;6(11):e013591.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    US Food and Drug Administration. Division of Neuropharmacological Drug Products (DNDP) Issues Paper for March 9, 2000 Meeting of the Psychopharmacological Drugs Advisory Committee Meeting on the Various Psychiatric and Behavioral Disturbances Associated with Dementia. Silver Spring, MA; 2000. Contract No.: Doc PDAC\AC030900.IP4.Google Scholar
  10. 10.
    Cummings J, Mintzer J, Brodaty H, et al. Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. Int Psychogeriatr 2015;27(1):7–17.CrossRefPubMedGoogle Scholar
  11. 11.
    Salzman C, Jeste DV, Meyer RE, 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):889–898.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    US National Institutes of Health. Clinicaltrials.gov website. US National Institutes of Health Web Site. 2014 11/16/2011. Available from: http://clinicaltrials.gov/.
  13. 13.
    Ballard C, Thomas A, Gerry S, et al. A double-blind randomized placebocontrolled 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(4):316–322.CrossRefPubMedGoogle Scholar
  14. 14.
    Cummings JL, Lyketsos CG, Peskind ER, et al. Effect of dextromethorphanquinidine on agitation in patients with alzheimer disease dementia: a randomized clinical trial. JAMA 2015;314(12):1242–1254.CrossRefPubMedGoogle Scholar
  15. 15.
    van den Elsen GA, Ahmed AI, Verkes RJ, et al. Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: a randomized controlled trial. Neurology 2015;84(23):2338–2346.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Porsteinsson AP, Drye LT, Pollock BG, et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA 2014;311(7):682–691.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Herrmann N, Gauthier S, Boneva N, Lemming OM. A randomized, doubleblind, placebo-controlled trial of memantine in a behaviorally enriched sample of patients with moderate-to-severe Alzheimer’s disease. Int Psychogeriatr 2013;25(6):919–927.CrossRefPubMedGoogle Scholar
  18. 18.
    Trzepacz PT, Cummings J, Konechnik T, et al. Mibampator (LY451395) randomized clinical trial for agitation/aggression in Alzheimer’s disease. Int Psychogeriatr 2013;25(5):707–719.CrossRefPubMedGoogle Scholar
  19. 19.
    Fox C, Crugel M, Maidment I, et al. Efficacy of memantine for agitation in Alzheimer’s dementia: a randomised double-blind placebo controlled trial. PLoS One 2012;7(5):e35185.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Barak Y, Plopski I, Tadger S, Paleacu D. Escitalopram versus risperidone for the treatment of behavioral and psychotic symptoms associated with Alzheimer’s disease: a randomized double-blind pilot study. Int Psychogeriatr 2011;23(9):1515–1519.CrossRefPubMedGoogle Scholar
  21. 21.
    Mowla A, Pani A. Comparison of topiramate and risperidone for the treatment of behavioral disturbances of patients with Alzheimer disease: a double-blind, randomized clinical trial. J Clin Psychopharmacol 2010;30(1):40–43.CrossRefPubMedGoogle Scholar
  22. 22.
    Gehrman PR, Connor DJ, Martin JL, Shochat T, Corey-Bloom J, Ancoli-Israel S. Melatonin fails to improve sleep or agitation in double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer disease. Am J Geriatr Psychiatry 2009;17(2):166–169.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Sommer OH, Aga O, Cvancarova M, Olsen IC, Selbaek G, Engedal K. Effect of oxcarbazepine in the treatment of agitation and aggression in severe dementia. Dement Geriatr Cogn Disord 2009;27(2):155–163.CrossRefPubMedGoogle Scholar
  24. 24.
    Wang LY, Shofer JB, Rohde K, et al. Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression. Am JJ Geriatr Psychiatry 2009;17(9):744–751.CrossRefGoogle Scholar
  25. 25.
    Streim JE, Porsteinsson AP, Breder CD, 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):537–550.CrossRefPubMedGoogle Scholar
  26. 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(14):1382–1392.CrossRefPubMedGoogle Scholar
  27. 27.
    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.CrossRefPubMedGoogle Scholar
  28. 28.
    Wilcock GK, Ballard CG, Cooper JA, 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 2008;69(3):341–348.CrossRefPubMedGoogle Scholar
  29. 29.
    Devanand DP, Mintzer J, Schultz SK, et al. Relapse risk after discontinuation of risperidone in Alzheimer’s disease. N Engl J Med 2012;367(16):1497–1507.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Tariot PN, Schneider LS, Cummings J, et al. Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry 2011;68(8):853–861.CrossRefPubMedGoogle Scholar
  31. 31.
    Drye LT, Ismail Z, Porsteinsson AP, et al. Citalopram for agitation in Alzheimer’s disease: design and methods. Alzheimers Dement 2012;8(2):121–130.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    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(7):939–944.CrossRefPubMedGoogle Scholar
  33. 33.
    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(3):263–269.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5®). Arlington, VA: American Psychiatric Publishing; 2013.Google Scholar
  35. 35.
    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(3):189–198.CrossRefPubMedGoogle Scholar
  36. 36.
    Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology 1997;48(5 Suppl 6):S10–S16.CrossRefPubMedGoogle Scholar
  37. 37.
    Cohen-Mansfield J. Instruction Manual for the Cohen-Mansfield Agitaion Inventory (CMAI). Rockville, MD: Author; 1991.Google Scholar
  38. 38.
    Guy W. Abnormal involuntary movement scale. In: ECDEU Assessment Manual For Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare; 1976.Google Scholar
  39. 39.
    Schneider LS, Raman R, Schmitt FA, et al. Characteristics and performance of a modified version of the ADCS-CGIC CIBIC+ for mild cognitive impairment clinical trials. Alzheimer Disease and Associated Disorders 2009;23(3):260–267.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Sultzer DL, Levin HS, Mahler ME, High WM, Cummings JL. Assessment of cognitive, psychiatric, and behavioral disturbances in patients with dementia: the Neurobehavioral Rating Scale. J Am Geriatr Soc 1992;40(6):549–555.CrossRefPubMedGoogle Scholar
  41. 41.
    Reisberg B, Auer SR, Monteiro IM. Behavioral pathology in Alzheimer’s disease (BEHAVE-AD) rating scale. Int Psychogeriatr 1996;8(Suppl 3):301–308; discussion 351-304.PubMedGoogle Scholar
  42. 42.
    Rosen J, Burgio L, Kollar M, et al. A user-friendly instrument for rating agitation in dementia patients. Am J Geriatr Psychiatry 1994;2(1):52–59.CrossRefGoogle Scholar
  43. 43.
    Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep 1962;10:799–812.CrossRefGoogle Scholar
  44. 44.
    Finkel SI, Lyons JS, Anderson RL. A brief agitation rating scale (BARS) for nursing home elderly. J Am Geriatr Soc 1993;41(1):50–52.CrossRefPubMedGoogle Scholar
  45. 45.
    Teri L, Truax P, Logsdon R, Uomoto J, Zarit S, Vitaliano PP. Assessment of behavioral problems in dementia: the revised memory and behavior problems checklist. Psychol Aging 1992;7(4):622–631.CrossRefPubMedGoogle Scholar
  46. 46.
    Soto M, Andrieu S, Nourhashemi F, et al. Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design. Int Psychogeriatr 2014:1–17.Google Scholar
  47. 47.
    Rosenberg PB, Drye LT, Porsteinsson AP, et al. Change in agitation in Alzheimer’s disease in the placebo arm of a nine-week controlled trial. Int Psychogeriatr 2015;27(12):2059–2067.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Enck P, Klosterhalfen S, Zipfel S. Novel study designs to investigate the placebo response. BMC Med Res Methodol 2011;11:90.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Weintraub D, Drye LT, Porsteinsson AP, et al. Time to response to citalopram treatment for agitation in Alzheimer disease. Am J Geriatr Psychiatry 2015;23(11):1127–1133.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Schneider LS, Frangakis C, Drye LT, 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 Psychiatry 2016;173(5):465–472.CrossRefPubMedGoogle Scholar
  51. 51.
    Leonpacher AK, Peters ME, Drye LT, et al. Effects of citalopram on neuropsychiatric symptoms in Alzheimer’s dementia: evidence from the CitAD Study. Am J Psychiatry 2016;173(5):473–480.CrossRefPubMedGoogle Scholar
  52. 52.
    Schneider LS, Dagerman KS, Higgins JP, McShane R. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol 2011;68(8):991–998.CrossRefPubMedGoogle Scholar
  53. 53.
    Transition Therapeutics announces results of clinical study of ELND005 in agitation and aggression in patients with Alzheimer’s disease [press release]. Toronto, Ontario, Canada: Transition Therapeutics Inc., June 24, 2015.Google Scholar
  54. 54.
    Transition Therapeutics announces results of data analysis from ELND005 phase 2/3 clinical study in agitation and aggression in Alzheimer’s disease Patients [press release]. Ontario, Canada: Transition Therapeutics Inc., October 15, 2015.Google Scholar
  55. 55.
    Robert P, Ferris S, Gauthier S, Ihl R, Winblad B, Tennigkeit F. Review of Alzheimer’s disease scales: is there a need for a new multi-domain scale for therapy evaluation in medical practice? Alzheimers Res Ther 2010;2(4):24.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Kales HC, Gitlin LN, Lyketsos CG. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc 2014;62(4):762–769.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Wang G, Kennedy RE, Cutter GR, Schneider LS. Effect of sample size re-estimation in adaptive clinical trials for Alzheimer’s disease and mild cognitive impairment. Alzheimers Dement 2015;1:63–71.Google Scholar
  58. 58.
    Mahajan R, Gupta K. Adaptive design clinical trials: methodology, challenges and prospect. Indian J Pharmacol 2010;42(4):201–207.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    US Department of Health and Human Services. US Food and Drug Administration. Critical path opportunities list. March 2006. https://www.fda.gov/downloads/scienceresearch/specialtopics/criticalpathinitiative/criticalpathopportunitiesreports/ucm077258.pdf. Accessed September 25, 2016.

Copyright information

© Serdi and Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Avanir Pharmaceuticals, Inc.Aliso ViejoUSA

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