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Change in agitation in Alzheimer's disease in the placebo arm of a nine-week controlled trial

Published online by Cambridge University Press:  25 August 2015

Paul B. Rosenberg ,
Lea T. Drye ,
Anton P. Porsteinsson ,
Bruce G. Pollock ,
D.P. Devanand ,
Constantine Frangakis ,
Zahinoor Ismail ,
Christopher Marano ,
Curtis L. Meinert  and
Jacobo E. Mintzer
...Show all authors
Paul B. Rosenberg*
Affiliation:
Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, USA
Lea T. Drye
Affiliation:
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Maryland, USA
Anton P. Porsteinsson
Affiliation:
Alzheimer's Disease Care, Research and Education Program (AD-CARE), University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Bruce G. Pollock
Affiliation:
Campbell Institute, CAMH, University of Toronto, Toronto, Ontario, Canada Campbell Family Mental Health Research Institute, Division of Geriatric Psychiatry, Faculty of Medicine University of Toronto, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
D.P. Devanand
Affiliation:
Psychiatry and Neurology, Division of Geriatric Psychiatry, College of Physicians and Surgeons, Columbia University, New York, USA
Constantine Frangakis
Affiliation:
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Zahinoor Ismail
Affiliation:
Psychiatry and Neurology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada Psychiatry, University of Toronto, Toronto, Ontario, Canada
Christopher Marano
Affiliation:
Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, USA
Curtis L. Meinert
Affiliation:
Epidemiology and Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Jacobo E. Mintzer
Affiliation:
Clinical Biotechnology Research Institute, Roper St. Francis Healthcare, Charleston, South Carolina, USA Department of Health Studies, Medical University of South Carolina, Charleston, South Carolina, USA Ralph H. Johnson VA Medical Center, Charleston, South Carolina, USA
Cynthia A. Munro
Affiliation:
Department of Psychiatry and Behavioral Sciences, Department of Neurology, Johns Hopkins Bayview and Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Gregory Pelton
Affiliation:
Psychiatry and Neurology, Division of Geriatric Psychiatry, College of Physicians and Surgeons, Columbia University, New York, USA
Peter V. Rabins
Affiliation:
Psychiatry and Behavioral Sciences Johns Hopkins School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
Lon S. Schneider
Affiliation:
Psychiatry, Neurology, and Gerontology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
David M. Shade
Affiliation:
Departments of Medicine (Pulmonary) and Epidemiology (Center for Clinical Trials), Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Daniel Weintraub
Affiliation:
Psychiatry and Neurology, Perelman School of Medicine at the University of Pennsylvania, Parkinson's Disease Research, Education and Clinical Center (PADRECC), Mental Illness Research, Education and Clinical Center (MIRECC), Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA
Jeffery Newell
Affiliation:
Clinical Science, Culture and Mental Health Lab, University of Southern California, Los Angeles, California, USA
Jerome Yesavage
Affiliation:
Aging Clinical Research Center, Director Mental Illness Research Education and Clinical Center, VA Palo Alto Health Care System, Virginia, USA Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California, USA
Constantine G. Lyketsos
Affiliation:
Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, USA
*
Correspondence should be addressed to: Paul B. Rosenberg, MD, Associate Professor of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins School of Medicine, Johns Hopkins Bayview Medical Center, 5300 Alpha Commons Dr. #429, Baltimore, Maryland 21224, USA. Phone: (410) 550 9883; Fax: (410) 550 1407. Email: prosenb9@jhmi.edu.
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Abstract

Background:

Placebo responses raise significant challenges for the design of clinical trials. We report changes in agitation outcomes in the placebo arm of a recent trial of citalopram for agitation in Alzheimer's disease (CitAD).

Methods:

In the CitAD study, all participants and caregivers received a psychosocial intervention and 92 were assigned to placebo for nine weeks. Outcomes included Neurobehavioral Rating Scale agitation subscale (NBRS-A), modified AD Cooperative Study-Clinical Global Impression of Change (CGIC), Cohen-Mansfield Agitation Inventory (CMAI), the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (NPI A/A) and Total (NPI-Total) and ADLs. Continuous outcomes were analyzed with mixed-effects modeling and dichotomous outcomes with logistic regression.

Results:

Agitation outcomes improved over nine weeks: NBRS-A mean (SD) decreased from 7.8 (3.0) at baseline to 5.4 (3.2), CMAI from 28.7 (6.7) to 26.7 (7.4), NPI A/A from 8.0 (2.4) to 4.9 (3.8), and NPI-Total from 37.3 (17.7) to 28.4 (22.1). The proportion of CGI-C agitation responders ranged from 21 to 29% and was significantly different from zero. MMSE improved from 14.4 (6.9) to 15.7 (7.2) and ADLs similarly improved. Most of the improvement was observed by three weeks and was sustained through nine weeks. The major predictor of improvement in each agitation measure was a higher baseline score in that measure.

Conclusions:

We observed significant placebo response which may be due to regression to the mean, response to a psychosocial intervention, natural course of symptoms, or nonspecific benefits of participation in a trial.

Keywords

Alzheimer’s diseaseagitationrandomized clinical trialneuropsychiatric symptoms
Type
Research Article
Information
International Psychogeriatrics , Volume 27 , Issue 12 , December 2015 , pp. 2059 - 2067
Copyright
Copyright © International Psychogeriatric Association 2015 

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References

APA Work Group on Alzheimer's Disease and other Dementias et al. (2007). American psychiatric association practice guideline for the treatment of patients with Alzheimer's disease and other dementias. 2nd edn. The American Journal of Psychiatry, 164, 5–56.Google Scholar
Baer, L. and Ivanova, A. (2013). When should the sequential parallel comparison design be used in clinical trials? Clinical Investigation, 3, 823–833.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 Association, 8 (Suppl. 3), 309–315, discussion 351–354.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
Drye, L. T. et al. (2012). Citalopram for agitation in Alzheimer's disease: design and methods. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 8, 121–130. DOI: 10.1016/j.jalz.2011.01.007.CrossRefGoogle ScholarPubMed
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 Psychiatric Research, 12, 189–198.Google Scholar
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. DOI: 10.1371/journal.pone.0035185.Google Scholar
Galasko, D. 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 (Suppl. 2), S33–S39.Google Scholar
Gauthier, S. et al. (2010). Management of behavioral problems in Alzheimer's disease. International Psychogeriatrics Association, 22, 346–372. DOI: 10.1017/S1041610209991505.CrossRefGoogle ScholarPubMed
Gitlin, L. N., Kales, H. C., Lyketsos, C. G. (2012). Nonpharmacologic management of behavioral symptoms in dementia. JAMA: The Journal of the American Medical Association, 308, 2020–2029. DOI: 10.1001/jama.2012.36918.Google Scholar
Gitlin, L. N., Marx, K. A., Stanley, I. H., Hansen, B. R. and Van Haitsma, K. S. (2014). Assessing neuropsychiatric symptoms in people with dementia: a systematic review of measures. International Psychogeriatrics Association, 26, 1805–1848. DOI: 10.1017/S1041610214001537.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. The Journal of Nutrition, Health & Aging, 16, 134–137.CrossRefGoogle ScholarPubMed
Herrmann, N., Gauthier, S., Boneva, N., Lemming, O. M. 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 Association, 25, 919–927. DOI: 10.1017/S1041610213000239.Google Scholar
Kales, H. C., Gitlin, L. N., Lyketsos, C. G. and Lyketsos, C. G. (2014). Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. Journal of the American Geriatrics Society, 62, 762–769. DOI: 10.1111/jgs.12730.Google Scholar
Kales, H. C. et al. (2007). Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications. The American Journal of Psychiatry, 164, 1568–1576; quiz 1623. DOI: 10.1176/appi.ajp.2007.06101710.Google Scholar
Kales, H. C. et al. (2012). Risk of mortality among individual antipsychotics in patients with dementia. The American Journal of Psychiatry, 169, 71–79. DOI: 10.1176/appi.ajp.2011.11030347.CrossRefGoogle ScholarPubMed
Khan, A., Faucett, J., Lichtenberg, P., Kirsch, I. and Brown, W. A. (2012). A systematic review of comparative efficacy of treatments and controls for depression. PloS One, 7, e41778. DOI: 10.1371/journal.pone.0041778.Google Scholar
Levin, H. S. et al. (1987). The neurobehavioural rating scale: assessment of the behavioural sequelae of head injury by the clinician. Journal of Neurology, Neurosurgery, and Psychiatry, 50, 183–193.Google Scholar
Lyketsos, C. G., Lopez, O., Jones, B., Fitzpatrick, A. L., Breitner, J. and DeKosky, S. (2002). Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA : The Journal of the American Medical Association, 288, 1475–1483.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. The American Journal of Psychiatry, 157, 708–714.CrossRefGoogle Scholar
Lyketsos, C. G. et al. (2011). Neuropsychiatric symptoms in Alzheimer's disease. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 7, 532–539. DOI: 10.1016/j.jalz.2011.05.2410.Google Scholar
Martin, B. K. et al. (2006). Design of depression in Alzheimer's disease study-2. The American Journal of Geriatric Psychiatry, 14, 920–930. DOI: 10.1097/01.JGP.0000240977.71305.ee.CrossRefGoogle ScholarPubMed
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D. and Stadlan, E. M. (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
Morris, S.B. (2000). Distribution of the standardized mean change effect size for meta-analysis on repeated measures. The British Journal of Mathematical and Statistical Psychology, 53 (Pt 1), 17–29.CrossRefGoogle ScholarPubMed
National Research Council. (2010). The Prevention and Treatment of Missing Data in Clinical Trials. Panel on Handling Missing Data in Clinical Trials. Committee on National Statistics, Division of Behavioral and Social Sciences and Education. Washington, DC: The National Academies Press.Google Scholar
Pollock, B.G. et al. (2002). Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. The American Journal of Psychiatry, 159, 460–465.CrossRefGoogle ScholarPubMed
Pollock, B.G. et al. (2007). A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. The American Journal of Geriatric Psychiatry, 15, 942–952.Google Scholar
Porsteinsson, A.P. et al. (2014). Effect of citalopram on agitation in Alzheimer disease. JAMA : The Journal of the American Medical Association, 311, 682. DOI: 10.1001/jama.2014.93.Google Scholar
Rosenberg, P. B., Mielke, M. M. and Lyketsos, C. G. (2005). Caregiver assessment of patients’ depression in Alzheimer disease: longitudinal analysis in a drug treatment study. The American Journal of Geriatric Psychiatry, 13, 822–826. DOI: 10.1176/appi.ajgp.13.9.822.Google Scholar
Rosenberg, P. B. et al. (2010). Sertraline for the treatment of depression in Alzheimer disease. The American Journal of Geriatric Psychiatry, 18, 136–145. DOI: 10.1097/JGP.0b013e3181c796eb.Google Scholar
Rosenberg, P. B. et al. (2013). Safety and efficacy of methylphenidate for apathy in Alzheimer's disease: a randomized, placebo-controlled trial. The Journal of Clinical Psychiatry, 74, 810–816. DOI: 10.4088/JCP.12m08099.Google Scholar
Schneider, L. S., Dagerman, K. S. and Insel, P. (2005). Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA: The Journal of the American Medical Association, 294, 1934–1943. DOI: 10.1001/jama.294.15.1934.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 (Suppl. 2), S22–S32.CrossRefGoogle ScholarPubMed
Schneider, L. S. et al. (2006). Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. The New England Journal of Medicine, 355, 1525–1538. DOI: 10.1056/NEJMoa061240.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. DOI: 10.1159/000199236.Google Scholar
Steinberg, M. et al. (2006). Risk factors for neuropsychiatric symptoms in dementia: the cache county study. International Journal of Geriatric Psychiatry, 21, 824–830.Google Scholar
Steinberg, M. et al. (2008). Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the cache county study. International Journal of Geriatric Psychiatry, 23, 170–177. DOI: 10.1002/gps.1858.Google Scholar
Trzepacz, P. T. et al. (2013). Mibampator (LY451395) randomized clinical trial for agitation/aggression in Alzheimer's disease. International Psychogeriatrics Association, 25, 707–719. DOI: 10.1017/S1041610212002141.Google Scholar
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