Hostname: page-component-cd9895bd7-8ctnn Total loading time: 0 Render date: 2024-12-22T18:51:56.610Z Has data issue: false hasContentIssue false
  • English
  • Français

Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design

Published online by Cambridge University Press:  16 September 2014

Maria Soto ,
Sandrine Andrieu ,
Fati Nourhashemi ,
Pierre Jean Ousset ,
Clive Ballard ,
Philippe Robert ,
Bruno Vellas ,
Constantine G. Lyketsos  and
Paul B. Rosenberg
Maria Soto*
Affiliation:
Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France
Sandrine Andrieu
Affiliation:
Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France Department of Epidemiology, Toulouse University Hospital Toulouse, France
Fati Nourhashemi
Affiliation:
Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France
Pierre Jean Ousset
Affiliation:
Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France
Clive Ballard
Affiliation:
Wolfson Centre for Age-Related Diseases, King's College, London, UK
Philippe Robert
Affiliation:
EA CoBTeK / ICMRR University of Nice Sophia Antipolis -CHU, France
Bruno Vellas
Affiliation:
Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France
Constantine G. Lyketsos
Affiliation:
Department of Psychiatry, The Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
Paul B. Rosenberg
Affiliation:
Department of Psychiatry, The Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
*
Correspondence should be addressed to: Maria Soto, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, 170 avenue de Casselardit, 31059 Toulouse, Cedex 9, France. Phone: +33 5 61 77 96 65; Fax: +33 5 61 49 71 09. E-mail: [email protected].
Get access

Abstract

Background:

The management of disruptive neuropsychiatric symptom (NPS) such as agitation and aggression (A/A) is a major priority in caring for people with Alzheimer's disease (AD). Few effective pharmacological or non-pharmacological options are available. Results of randomized clinical trials (RCTs) of drugs for A/A have been disappointing. This may result from the absence of biological efficacy for medications tested in treating A/A. It may also be related to methodological issues such as the choice of outcomes. The aim of this review was to highlight key methodological issues pertaining to RCTs of current and emerging medications for the treatment of A/A in AD.

Methods:

We searched PubMed/Medline, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for RCTs comparing medications with either placebo or other drugs in the treatment of A/A in AD, between January 2008 and December 2013.

Results:

We identified a total of 18 RCTs; of these, 11 were completed and 7 ongoing. Of the ongoing RCTs, only one is in Phase III. Seven of 10 completed RCTs with reported results did not report greater benefit from drug than placebo. Each of the completed RCTs used a different definition of “clinically significant A/A.” There was considerable heterogeneity in study design. The primary endpoints were largely proxy-based but a variety of scales were used. The definition of caregiver and scales used to assess caregiver outcomes were similarly heterogeneous. Placebo response was notable in all trials.

Conclusions:

This review highlights a great heterogeneity in RCTs design of drugs for A/A in AD and some key methodological issues such as definition of A/A, choice of outcome measures and caregiver participation that could be addressed by an expert consensus to optimize future trials design.

Keywords

behavioragitationaggressionAlzheimer’smeasurementtherapeuticsclinical trial
Type
Review Article
Information
International Psychogeriatrics , Volume 27 , Issue 2 , February 2015 , pp. 181 - 197
Copyright
Copyright © International Psychogeriatric Association 2014 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ballard, C., Francis, P. and Corbett, A. (2013). Randomized controlled trial of mibampator for behavioral and psychological symptoms of dementia: comments on the trial and thoughts for future studies. International Psychogeriatrics, 25, 687–689.Google Scholar
Ballard, C. and Howard, R. (2006). Neuroleptic drugs in dementia: benefits and harm. Nature Reviews Neuroscience, 7, 492–500.CrossRefGoogle ScholarPubMed
Ballard, C. et al. (2009). Management of agitation and aggression associated with Alzheimer's disease. Nature Reviews Neurology, 2, 245–255.Google Scholar
Benoit, M. et al. (2006). Professional consensus on the treatment of agitation, aggressive behaviour, oppositional behaviour and psychotic disturbances in dementia. Journal of Nutrition Health and Aging, 10, 410–415.Google Scholar
Blanchard, B. J., Chen, A., Rozeboom, L. M., Stafford, K. A., Weigele, P. and Ingram, V. M. (2004). Efficient reversal of Alzheimer's disease fibril formation and elimination of neurotoxicity by a small molecule. Proceedings of the National Academy of Sciences USA, 101, 14326–14332.Google Scholar
Brodaty, H. and Arasaratnam, C. (2012). Meta-analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia. American Journal of Psychiatry, 169, 946–953.Google Scholar
Canevelli, M. et al. (2013). Behavioral and psychological subsyndromes in Alzheimer's disease using the neuropsychiatric inventory. International Journal of Geriatric Psychiatry, 28, 795–803.Google Scholar
Cohen-Mansfield, J. (1996). Conceptualization of agitation: results based on the Cohen-Mansfield agitation inventory and the agitation behavior mapping instrument. International Psychogeriatrics, 8, 309–315.Google Scholar
Cohen-Mansfield, J., Werner, P., Watson, V. and Pasis, S. (1995). Agitation among elderly persons at adult day-care centers: the experiences of relatives and staff members. International Psychogeriatrics, 7, 447–458.Google Scholar
Cummings, J. L. (1997). The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology, 48, S10–S16.Google Scholar
Cummings, J. L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D. A. and Gornbein, J. (1994). The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology, 44, 2308–2314.CrossRefGoogle ScholarPubMed
Cummings, J. L. et al. (2013). Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet, 383, 533–540.Google Scholar
de Deyn, P. P. et al. (1999). A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology, 53, 946–955.Google Scholar
de Medeiros, K. et al. (2010). The neuropsychiatric inventory-clinician rating scale (NPI-C): reliability and validity of a revised assessment of neuropsychiatric symptoms in dementia. International Psychogeriatrics, 22, 984–994.Google Scholar
Dennehy, E. B., Kahle-Wrobleski, K., Sarsour, K. and Milton, D. R. (2012). Derivation of a brief measure of agitation and aggression in Alzheimer's disease. International Journal of Geriatric Psychiatry, 28, 182–189.CrossRefGoogle ScholarPubMed
Deudon, A. et al. (2009). Non-pharmacological management of behavioural symptoms in nursing homes. International Journal of Geriatric Psychiatry, 24, 1386–1395.Google Scholar
Donohue, M. C. and Ainsen, P. S. (2012). Mixed model of repeated measures versus slope models in Alzheimer's disease clinical trials. Journal of Nutrition Health and Aging, 16, 360–364.Google Scholar
Drye, L. T. et al. (2012). CitAD Research Group. Citalopram for agitation in Alzheimer's disease: design and methods. Alzheimer's and Dementia, 8, 121–130.Google Scholar
Folstein, M. F., Folstein, S. E. and McHugh, P. R. (1975). “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatry Research, 12, 196–198.CrossRefGoogle ScholarPubMed
Fox, C. et al. (2012). Efficacy of memantine for agitation in Alzheimer's dementia: a randomised double-blind placebo controlled trial. PLoS One, 7, e35185.Google Scholar
Frost, C., Michael, G., Kenward, I. and Fox, C. (2008). Optimizing the design of clinical trials where the outcome is a rate. Can estimating a baseline rate in a run-in period increase efficiency? Statistical Medicine, 27, 3717–3731.Google Scholar
Galasko, D. et al. (1997). An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. The Alzheimer's disease cooperative study. Alzheimer Disease and Associated Disorders, 11, S33–S39.Google Scholar
Garre-Olmo, J., López-Pousa, S., Vilalta-Franch, J., de Gracia Blanco, M. and Vilarrasa, A. B. (2010). Grouping and trajectories of neuropsychiatric symptoms in patients with Alzheimer's disease. Part II: two-year patient trajectories. Journal of Alzheimers Disease, 22, 1169–1180.Google Scholar
Gauthier, S. et al. (2010). Management of behavioral problems in Alzheimer's disease. International Psychogeriatrics, 22, 346–372.Google Scholar
Geda, Y. E. et al. (2013). Neuropsychiatric syndromes professional interest area of ISTAART. Neuropsychiatric symptoms in Alzheimer's disease: past progress and anticipation of the future. Alzheimer's and Dementia, 9, 602–608.CrossRefGoogle ScholarPubMed
Gehrman, P. R., Connor, D. J., Martin, J. L., Shochat, T., Corey-Bloom, J. and Ancoli-Israel, S. (2009). Melatonin fails to improve sleep or agitation in double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer disease. American Journal of Geriatric Psychiatry, 17, 166–169.CrossRefGoogle ScholarPubMed
Gitlin, L. N., Kales, C. K. and Lyketsos, C. G. (2012). Nonpharmacologic management of behavioral symptoms in dementia. Journal of the American Medical Association, 308, 2020–2029.Google Scholar
Gonfrier, S., Andrieu, S., Renaud, D., Vellas, B. and Robert, P. H. (2012). Course of neuropsychiatric symptoms during a 4-year follow up in the REAL-FR cohort. Journal of Nutrition Health and Aging, 16, 134–137.CrossRefGoogle ScholarPubMed
Guy, W. (1976). ECDEU Assessment Manual for Psychopharmacology, Revised. Bethesda, MD: US Department of Health, Education, and Welfare.Google Scholar
Herrmann, N., Gauthier, S., Boneva, N. and Lemming, O. M. (2013). A randomized, double-blind, placebo-controlled trial of memantine in a behaviorally enriched sample of patients with moderate-to-severe Alzheimer's disease. International Psychogeriatrics, 25, 919–927.Google Scholar
Howard, R. J. et al. (2007). Donepezil for the treatment of agitation in Alzheimer's disease. New England Journal of Medicine, 357, 1382–1392.CrossRefGoogle ScholarPubMed
Husebo, B. S., Ballard, C., Sandvik, R., Nilsen, O. B. and Aarsland, D. (2011). Efficacy of treating pain to reduce behavioural disturbances in residents of nursing homes with dementia: cluster randomised clinical trial. BMJ, 343, d4065.CrossRefGoogle ScholarPubMed
Iovieno, N. and Papakostas, G. I. (2012). Does the presence of an open-label antidepressant treatment period influence study outcome in clinical trials examining augmentation/combination strategies in treatment partial responders/nonresponders with major depressive disorder? Journal of Clinical Psychiatry, 73, 676–683.Google Scholar
Kairalla, J. A., Coffey, C. S., Thomann, M. A. and Muller, K. E. (2012). Adaptive trial designs: a review of barriers and opportunities. Trials, 13, 145.Google Scholar
Kales, H. C., Gitlin, L. N. and Lyketsos, C. (2014) (For the Detroit Expert Panel on the Assessment and Management of Neuropsychiatric Symptoms of Dementia). Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. Journal of the American Geriatrics Society, 62, 762–769.Google Scholar
Kales, H. C. et al. (2012). Risk of mortality among individual antipsychotics in patients with dementia. American Journal of Psychiatry, 169, 71–79.Google Scholar
Kirste, T. et al. (2014). Detecting the effect of Alzheimer's disease on everyday motion behavior. Journal of Alzheimers Disease, 38, 121–132.Google Scholar
Lai, M. K. et al. (2003). Reduced serotonin 5-HT1A receptor binding in the temporal cortex correlates with aggressive behavior in Alzheimer disease. Brain Research, 974, 82–87.Google Scholar
Langballe, E. M., Engdahl, B., Nordeng, H., Ballard, C., Aarsland, D. and Selbæk, G. (2013). Short- and long-term mortality risk associated with the use of antipsychotics among 26,940 dementia outpatients: a population-based study. American Journal of Geriatric Psychiatry, 22, 321–331.Google Scholar
Logsdon, R. G., Gibbons, L. E., McCurry, S. M. and Teri, L. (2002). Assessing quality of life in older adults with cognitive impairment. Psychosomatic Medicine, 64, 510–519.Google Scholar
Lonergan, E., Luxenberg, J., Colford, J. M. and Birks, J. (2002). Haloperidol for agitation in dementia. Cochrane Database of Systematic Reviews, Issue 2, CD002852.Google Scholar
Lyketsos, C. G., Steinberg, M., Tschanz, J. T., Norton, M. C., Steffens, D. C. and Breitner, J. C. (2000). Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. American Journal of Geriatric Psychiatry, 157, 708–714.Google Scholar
Lyketsos, C. G. et al. (2006). Task Force of American Association for Geriatric Psychiatry. Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia resulting from Alzheimer disease. American Journal of Geriatric Psychiatry, 14, 561–572.Google Scholar
Lyketsos, C. G. et al. (2011). Neuropsychiatric symptoms in Alzheimer's disease. Alzheimer's and Dementia, 7, 532–539.Google Scholar
Maher, A. R. et al. (2011). Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis. JAMA, 28, 306, 1359–1369.CrossRefGoogle Scholar
Mahlberg, R., Walther, S., Eichmann, U., Tracik, F. and Kunz, D. (2007). Effects of rivastigmine on actigraphically monitored motor activity in severe agitation related to Alzheimer's disease: a placebo-controlled pilot study. Archives of Gerontolology Geriatric, 45, 19–26.Google Scholar
McKhann, G. et al. (1984). 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, 34, 939–944.Google Scholar
McKhann, G. M. et al. (2011). 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. Alzheimer's and Dementia, 7, 263–269.CrossRefGoogle ScholarPubMed
Molnar, F., Man-Son-Hing, M. and Dean Fergusson, D. (2009). Systematic review of measures of clinical significance employed in randomized controlled trials of drugs for dementia. Journal of the American Geriatrics Society, 57, 536–546.Google Scholar
Mowla, A. and Pani, A. (2010). Comparison of topiramate and risperidone for the treatment of behavioral disturbances of patients with Alzheimer disease. A double-blind, randomized clinical trial. Journal of Clinical Psychopharmacology, 30, 40–43.Google Scholar
Mugno, R., Zhus, W. and Rosenberger, W. F. (2004). Adaptive urn designs for estimating several percentiles of a dose–response curve. Statistical Medicine, 23, 2137–2150.Google Scholar
Murman, D. L., Chen, Q., Powell, M. C., Kuo, S. B., Bradley, C. J. and Colenda, C. C. (2002). The incremental direct costs associated with behavioral symptoms in AD. Neurology, 59, 1721–1729.Google Scholar
Okura, T. and Langa, K. M. (2011). Caregiver burden and neuropsychiatric symptoms in older adults with cognitive impairment: the Aging, Demographics, and Memory Study (ADAMS). Alzheimer Disease and Associated Disorders, 25, 116–121.Google Scholar
Okura, T., Plassman, B. L., Steffens, D. C., Llewellyn, D. J., Potter, G. G. and Langa, K. M. (2010). Prevalence of neuropsychiatric symptoms and their association with functional limitations in older adults in the United States: the aging, demographics, and memory study. Journal of the American Geriatrics Society, 58, 330–337.Google Scholar
Okura, T., Plassman, B. L., Steffens, D. C., Llewellyn, D. J., Potter, G. G. and Langa, K. M. (2011). Neuropsychiatric symptoms and the risk of institutionalization and death: the aging, demographics, and memory study. Journal of the American Geriatrics Society, 59, 473–481.Google Scholar
O’Neill, M. J. (2004). SMi 4th Annual Conference on Neurodegenerative Disorders: a focus on Alzheimer's and Parkinson's disease. Expert Opinion on Investigational Drugs, 13, 1369–1373.Google Scholar
Porsteinsson, A. P. et al. (2014). Effect of citalopram on agitation in Alzheimer's disease–the CitAD randomized controlled trial. Journal of the American Medical Association, 311, 682–691.Google Scholar
Prince, M., Bryce, R., Albanese, E., Wimo, A., Ribeiro, W. and Cleusa, P. (2013). The global prevalence of dementia: a systematic review and meta-analysis. Alzheimer's and Dementia, 9, 63–75.CrossRefGoogle Scholar
Rabins, P. V. et al. (2007). APA work group on Alzheimer's disease and other dementias; steering committee on practice guidelines. American Psychiatric Association practice guideline for the treatment of patients with Alzheimer's disease and other dementias: second edition. American Journal of Psychiatry, 164 (S), 5–56.Google Scholar
Ramírez, B. G. et al. (2005). Prevention of Alzheimer's disease pathology by cannabinoids: neuro-protection mediated by blockade of microglial activation. Journal of Neurosciences, 25, 1904–1913.Google Scholar
Rappaport, S. A., Marcus, R. N., Manos, G., McQuade, R. D. and Oren, D. A. (2009). A randomized, double-blind, placebo-controlled tolerability study of intramuscular aripiprazole in acutely agitated patients with Alzheimer's, vascular, or mixed dementia. Journal of the American Medical Directors Association, 10, 21–27.Google Scholar
Richter, T. et al. (2012). Psychosocial interventions for reducing antipsychotic medication in care home residents. The Cochrane Database of Systemetic Reviews, 12, CD008634.Google Scholar
Rosen, W. G., Mohs, R. C. and Davis, K. L. (1984). A new rating scale for Alzheimer's disease. American Journal of Psychiatry, 141: 1356–1364.Google Scholar
Rosenberg, P. B. et al. (2010). Sertraline for the treatment of depression in Alzheimer disease: DIADS-2 Research Group. American Journal of Geriatric Psychiatry, 18, 136–145.Google Scholar
Salzman, C. et al. (2008). Elderly patients with dementia-related symptoms of severe agitation and aggression: consensus statement on treatment options, clinical trials methodology, and policy. Journal of Clinical Psychiatry, 69, 889–898.Google Scholar
Schneider, L. S., Dagerman, K. and Insel, P. (2006). Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. American Journal of Geriatric Psychiatry, 14, 191–210.Google Scholar
Schneider, L. S., Pollock, V. E. and Lyness, S. A. (1990). A meta-analysis of controlled trials of neuroleptic treatment in dementia. Journal of the American Geriatrics Society, 38, 553–563.Google Scholar
Schneider, L. S. et al. (1997). Validity and reliability of the Alzheimer's Disease Cooperative Study-clinical global impression of change. The Alzheimer's Disease Cooperative Study. Alzheimer Disease and Associated Disorders, 11, S22–S32.Google Scholar
Selbæk, G., Høgset, L. D., Söderhamn, U. and Kirkevold, O. (2013). The course of neuropsychiatric symptoms in nursing-home patients with dementia over a 53-month follow-up period. International Psychogeriatrics, 20, 1–9.Google Scholar
Siddiqui, O., hung, M. J. and O’neill, R. (2009). MMRM versus LOCF: a comprehensive comparison based on simulation study and 25 NDA datasets. Journal of Biopharmaceutical Statistics, 19, 227–246.Google Scholar
Sommer, O. H., Aga, O., Cvancarova, M., Olsen, I. C., Selbaek, G. and Engedal, K. (2009). Effect of oxcarbazepine in the treatment of agitation and aggression in severe dementia. Dementia and Geriatric Cognitive Disorders, 27, 155–163.Google Scholar
Soto, M. E. et al. (2012). Improving care of older adults with dementia: description of 6299 hospitalizations over 11 years in a special acute care unit. Journal of the American Medical Directors Association, 13, 486,.e1–6.Google Scholar
Steinberg, M. and Lyketsos, C. G. (2008). Neuropsychiatric measures for cognitive disorders. In Rush, A. J., First, M. B. and Blacker, D. (eds.), Handbook of Psychiatric Measures (p. 864). Arlington, VA: American Psychiatric Publishing.Google Scholar
Steinberg, M. et al. (Cache County Investigators). (2008). Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study. International Journal of Geriatric Psychiatry, 23, 170–177.Google Scholar
Szot, P., White, S. S., Greenup, J. L., Leverenz, J. B., Peskind, E. R. and Raskind, M. A. (2007). Changes in adrenoreceptors in the prefrontal cortex of subjects with dementia: evidence of compensatory changes. Neuroscience, 146, 471–480.Google Scholar
Tariot, P. et al. (2011). Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Archives of General Psychiatry, 68, 853–886.Google Scholar
Teri, L. et al. (2000). Treatment of agitation in AD: a randomized, placebo-controlled clinical trial. Neurology 55, 1271–1278.Google Scholar
Townsend, M. et al. (2006). Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-beta oligomers. Annals of Neurolology, 60, 668–676.Google Scholar
Trzepacz, P. T. et al. (2013a). Mibampator (LY451395) randomized clinical trial for agitation/aggression in Alzheimer's disease. International Psychogeriatrics, 25, 707–719.Google Scholar
Trzepacz, P. T. et al. (2013b) Alzheimer's disease neuroimaging initiative. Subscale validation of the neuropsychiatric inventory questionnaire: comparison of Alzheimer's disease neuroimaging initiative and national Alzheimer's coordinating center cohorts. American Journal of Geriatric Psychiatry, 21, 607–622.Google Scholar
Wang, L. Y. et al. (2009). Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression. American Journal of Geriatric Psychiatry, 17, 744–751.Google Scholar
Woodward, M. R., Harper, D. G., Stolyar, A., Forester, B. P. and Ellison, J. M. (2014). Dronabinol for the treatment of agitation and aggressive behavior in acutely hospitalized severely demented patients with noncognitive behavioral symptoms. American Journal of Geriatric Psychiatry, 22, 415–419.Google Scholar
Yamada, K. A. (2000). Therapeutic potential of positive AMPA receptor modulators in the treatment of neurological disease. Expert Opinion on Investigational Drugs, 9, 765–778.Google Scholar
Zarit, S. H., Reever, K. E. and Bach-Peterson, J. (1980). Relatives of the impaired elderly: correlates of feelings of burden. Gerontologist, 20, 649–655.Google Scholar