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A systematic review of adverse events in the placebo arm of donepezil trials: the role of cognitive impairment

  • Martina Amanzio (a1) (a2), Fabrizio Benedetti (a3) (a4) and Lene Vase (a5) (a6)


Background: In randomized clinical trials, adverse events (AEs) are reported for the drug under evaluation and compared with the placebo group. Patients who receive placebo treatment report a high frequency of AEs, but little is understood about the nature of these. No study has yet analyzed the level of cognitive impairment as a crucial aspect for the AEs reported by patients.

Methods: The rates of AEs reported by patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) in the placebo arms of donepezil trials were compared using a systematic review approach. PubMed was searched with the terms “MCI and donepezil” as well as “AD and donepezil” from January 1989 to December 2010. Nineteen studies fulfilled the selection criteria (3 MCI, n = 783; 16 AD, n = 2,059).

Results: An overall comparison of 81 categories of AEs in the placebo arm of MCI versus AD trials showed that patients in AD trials experienced a significantly higher number of AEs than patients in MCI trials (p < 0.001).

Conclusions: This is the first study showing that AD patients may be at a greater risk of developing AEs than MCI patients. This may be related to a greater presence of somatic comorbidity predisposing them to express emotional distress as physical symptoms and/or to AD patients being frailer and therefore more susceptible to AEs. The phenomena we observed may be interpreted in terms of the “nocebo effect”.


Corresponding author

Correspondence should be addressed to: Dr. Martina Amanzio, Department of Psychology, University of Turin, Via Verdi 10, 10123, Turin, Italy. Phone: +39-11-6702468; Fax: +39-11-6702061. Email:


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*An asterisk indicates studies that were included in the analysis.

Amanzio, M. (2011). Do we need a new procedure for the assessment of adverse events in anti-migraine clinical trials? Recent Patents on CNS Drug Discovery, 6, 4147.
Amanzio, M., Latini Corazzini, L., Vase, L. and Benedetti, F. (2009). A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain, 146, 261269.
Amanzio, M. et al. (2011). Unawareness of deficits in Alzheimer's disease: role of the cingulate cortex. Brain, 134, 10611076.
Andrykowski, M. and Redd, W. (1987). Longitudinal analysis of the development of anticipatory nausea. Journal of Consulting & Clinical Psychology, 55, 3641.
Benedetti, F. and Amanzio, M. (1997). The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin. Progress in Neurobiology, 52, 109125.
Benedetti, F., Lanotte, M., Lopiano, L. and Colloca, L. (2007). When words are painful: unraveling the mechanisms of the nocebo effect. Neuroscience, 147, 260271.
*Black, S. E. et al. (2007). Donepezil preserves cognition and global function in patients with severe Alzheimer disease. Neurology, 69, 459469.
*Burns, A. et al. (1999). The effects of donepezil in Alzheimer's disease – results from a multinational trial. Dementia & Geriatric Cognitive Disorders, 10, 237244.
Cepeda, M. S., Farrar, J. T., Baumgarten, M., Boston, R., Carr, D. B. and Strom, B. L. (2003). Side effects of opioids during short-term administration: effect of age, gender and race. Clinical Pharmacology & Therapeutics, 74, 102112.
Davis, C., Ralevski, E., Kennedy, S. H. and Neitzert, C. S. (1995). The role of personality factors in the reporting of side effect complaints to moclobemide and placebo. Journal of Clinical Psychopharmacology, 15, 347352.
de la Cruz, M., Hui, D., Parsons, H. A. and Bruera, E. (2010). Placebo and nocebo effects in randomized double-blind clinical trials of agents for the therapy for fatigue in patients with advanced cancer. Cancer, 116, 766774.
*Doody, R. S. et al. (2009). Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial. Neurology, 72, 15551561.
Doody, R. S. et al. (2010). Safety and tolerability of donepezil in mild cognitive impairment: open-label extension study. American Journal of Alzheimers Disease & Other Dementias, 25, 155159.
Doraiswamy, M., Leon, J., Cummings, J. L., Martin, D. and Neumann, PJ. (2002). Prevalence and impact of medical comorbidity in Alzheimer's disease. The Journals of Gerontology Series A, Biological Sciences and Medical Sciences, 57, 7377.
*Feldman, H., Gauthier, S., Hecker, J., Vellas, B., Subbiah, P. and Whalen, E. (2001). Donepezil MSAD study investigators group: a 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. Neurology, 57, 613620.
Ferguson, J. M. (1993). Alprazolam XR: patient acceptability, safety, and tolerability. Psychiatric Annals, 23, 2026.
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, 189198.
Fried, L. P. et al. (2001). Cardiovascular health study collaborative research group. Frailty in older adults: evidence for a phenotype. Journals of Gerontology Series A, Biological Sciences and Medical Sciences, 56, M146M156.
Harrington, A. (ed.) (1997) The Placebo Effect: An Interdisciplinary Exploration. Cambridge, MA: Harvard University Press.
Hilmer, S. N., McLachlan, A. J. and Le Couteur, D. G. (2007). Clinical pharmacology in the geriatric patient. Fundamental Clinical Neuropharmacology, 21, 217230.
*Homma, A. et al. (2000). Clinical efficacy and safety of donepezil on cognitive and global function in patients with Alzheimer's disease: a 24-week, multicenter, double-blind, placebo-controlled study in Japan. E2020 study group. Dementia and Geriatric Cognitive Disorders, 11, 299313.
*Homma, A. et al. (2008). Donepezil treatment of patients with severe Alzheimer's disease in a Japanese population: results from a 24-week, double-blind, placebo-controlled, randomized trial. Dementia and Geriatric Cognitive Disorders, 25, 399407.
*Howard, R. J. et al. (2007). CALM-AD trial group. Donepezil for the treatment of agitation in Alzheimer's disease. New England Journal of Medicine, 357, 13821392.
Jadad, A. R. et al. (1996). Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials, 17, 112.
*Johannsen, P. et al. (2006). Assessing therapeutic efficacy in a progressive disease: a study of donepezil in Alzheimer's disease. CNS Drugs, 20, 311325.
*Mazza, M., Capuano, A., Bria, P. and Mazza, S. (2006). Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study. European Journal of Neurology, 13, 981985.
McLean, A. J. and Le Couteur, D. G. (2004). Ageing biology and geriatric clinical pharmacology. Pharmacological Reviews, 56, 163184.
*Mohs, R. C. et al. (2001). “312” study group. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology, 57, 481488.
*Petersen, R. C. et al. (2005). Alzheimer's Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. New England Journal of Medicine, 352, 23792388.
Raschetti, R., Albanese, E., Vanacore, N. and Maggini, M. (2007). Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomized trials. PLoS Medicine, 4, 18181828.
Rief, W. et al. (2009). Differences in adverse effect reporting in placebo groups in SSRI and tricyclic antidepressant trials: a systematic review and meta-analysis. Drug Safety, 32, 10411056.
*Rogers, S. L. and Friedhoff, L.T. (1996). The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. The Donepezil Study Group. Dementia, 7, 293303.
*Rogers, S. L., Doody, R. S., Mohs, R. C. and Friedhoff, L. T. (1998a). Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Archives of Internal Medicine, 158, 10211031.
*Rogers, S. L., Farlow, M. R., Doody, R. S., Mohs, R. and Friedhoff, LT. (1998b). A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group. Neurology, 50, 136–45.
*Salloway, S. et al. (2004). Donepezil 401 study group. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology, 63, 651657.
*Seltzer, B. et al. (2004). Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Archives of Neurology, 61, 18521856.
Standaert, D. G. and Young, A. B. (1996). Treatment of central nervous system degenerative disorders. In Hardman, J. G. and Limbird, L. E. (eds.), Goodman & Gilman's The Pharmacological Basis of Therapeutics (pp. 503519). New York: Mc Graw-Hill.
*Tariot, P. N. et al. (2001). A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting. Journal of the American Geriatrics Society, 49, 15901599.
Waldemar, G. et al. (2007). Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guidelines. European Journal of Neurology, 14, e1e26.
Walston, J. et al. (2006). Research agenda for frailty in older adults: toward a better understanding of physiology and etiology. Summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. Journal of the American Geriatrics Society, 54, 9911001.
*Winblad, B. et al. (2001). Donepezil Nordic study group. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology, 57, 489495.
*Winblad, B. et al. (2006). Severe Alzheimer's disease study group. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study. Lancet, 367, 10571065.
Wolf, S. and Pinsky, R. M. (1954). Effects of placebo administration and occurrence of toxic reactions. JAMA, 155, 339341.


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