Efficacy and Safety of Psychostimulants for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Abstract

Introduction Several reports of the effectiveness of the use of psychostimulants for the treatment of Alzheimer’s disease (AD) are available.

Methods A systematic review and meta-analysis was conducted including double-blind, randomized, placebo-controlled trials. Outcomes were the improvement of apathy scales score (primary), mini-mental state examination (MMSE) score, activities of daily living scale score, Zarit burden interview score, all-cause discontinuation, discontinuation due to adverse events, and incidence of at least 1 adverse event.

Results Three methylphenidate studies and 1 modafinil study were identified (n=156). Results from combined psychostimulants were superior to placebo in the improvement of apathy scales score (standardized mean differences [SMD]=−0.63 (−1.22, −0.04), p=0.04, all studies) and the MMSE score (SMD=−0.58 (−1.14, −0.02), p=0.04, 3 methylphenidate studies). The modafinil study was excluded from the meta-analysis for the improvement of apathy scales score; therefore, the effect size increased (SMD=−0.82 (−1.43, −0.20), p=0.009). However, no significant differences were observed in terms of other outcomes, including safety outcomes between the treatment groups.

Discussion Methylphenidate would be effective in treating apathy and cognitive impairment in AD patients.

Keywords

Alzheimer’s disease - psychostimulant - systematic review and meta-analysis - apathy - cognition impairment

• References

• 1 Rajan KB, Weuve J, Barnes LL. et al. Prevalence and incidence of clinically diagnosed Alzheimer’s disease dementia from 1994 to 2012 in a population study. Alzheimers Dement 2019; 15: 1-7
• 2 Scheltens P, Blennow K, Breteler MM. et al. Alzheimer’s disease. Lancet 2016; 388: 505-517
• 3 Kishi T, Matsunaga S, Iwata N. The effects of memantine on behavioral disturbances in patients with Alzheimer’s disease: A meta-analysis. Neuropsychiatr Dis Treat 2017; 13: 1909-1928
• 4 Ruthirakuhan MT, Herrmann N, Abraham EH. et al. Pharmacological interventions for apathy in Alzheimer’s disease. Cochrane Database Syst Rev 2018; 5: CD012197
• 5 Martorana A, Koch G. Is dopamine involved in Alzheimer’s disease?. Front Aging Neurosci 2014; 6: 252
• 6 Nobili A, Latagliata EC, Viscomi MT. et al. Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease. Nat Commun 2017; 8: 14727
• 7 Lanctot KL, Herrmann N, Black SE. et al. Apathy associated with Alzheimer disease: Use of dextroamphetamine challenge. Am J Geriatr Psychiatry 2008; 16: 551-557
• 8 Clarke DE, Reekum R, Simard M. et al. Apathy in dementia: An examination of the psychometric properties of the apathy evaluation scale. J Neuropsychiatry Clin Neurosci 2007; 19: 57-64
• 9 Padala PR, Padala KP, Lensing SY. et al. Methylphenidate for apathy in community-dwelling older veterans with mild Alzheimer’s disease: A double-blind, randomized, placebo-controlled trial. Am J Psychiatry 2018; 175: 159-168
• 10 Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the apathy evaluation scale. Psychiatry Res 1991; 38: 143-162
• 11 Rosenberg PB, Lanctot KL, Drye LT. et al. Safety and efficacy of methylphenidate for apathy in Alzheimer’s disease: a randomized, placebo–controlled trial. J Clin Psychiatry 2013; 74: 810-816
• 12 Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. In: Collaboration TC ed. http://handbookcochraneorg2011
• 13 Moher D, Liberati A, Tetzlaff J. et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535
• 14 Grace J, Malloy P. Frontal Systems Behavior Scale (FrSBe): Professional Manual. Psychological Assessment Resources; Lutz, Florida: 2001
• 15 Frakey LL, Salloway S, Buelow M. et al. A randomized, double-blind, placebo-controlled trial of modafinil for the treatment of apathy in individuals with mild-to-moderate Alzheimer’s disease. J Clin Psychiatry 2012; 73: 796-801
• 16 Herrmann N, Rothenburg LS, Black SE. et al. Methylphenidate for the treatment of apathy in Alzheimer disease: prediction of response using dextroamphetamine challenge. J Clin Psychopharmacol 2008; 28: 296-301
• 17 Folstein MF, Robins LN, Helzer JE. The mini-mental state examination. Arch Gen Psychiatry 1983; 40: 812
• 18 Lawton MP, Brody EM. Assessment of older people: Self-maintaining and instrumental activities of daily living. Gerontologist 1969; 9: 179-186
• 19 Zarit SH, Reever KE, Bach-Peterson J. Relatives of the impaired elderly: Correlates of feelings of burden. Gerontologist 1980; 20: 649-655
• 20 Cummings JL, Mega M, Gray K. et al. The neuropsychiatric inventory: Comprehensive assessment of psychopathology in dementia. Neurology 1994; 44: 2308-2314
• 21 Higgins JP, Thompson SG, Deeks JJ. et al. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557-560
• 22 FDA Methylphenidate. https://wwwaccessdatafdagov/drugsatfda_docs/label/2007/010187s069,018029s040,021284s011lblpdf
• 23 Moreno SG, Sutton AJ, Ades AE. et al. Assessment of regression-based methods to adjust for publication bias through a comprehensive simulation study. BMC Med Res Methodol 2009; 9: 2