Methylphenidate Shows Small to Medium Benefit in Treating Alzheimer Apathy


The effect of methylphenidate on Alzheimer disease apathy was observed at 2 months and was sustained throughout the 6 months of the study.

Jacobo Mintzer, MD

Jacobo Mintzer, MD

Data from ADMET 2, a phase 3, 6-month study (NCT02346201) revealed that methylphenidate, a central nervous system (CNS) stimulant, had small to medium benefit in treating apathy in patients with Alzheimer disease (AD), supporting the notion that this drug may be a viable treatment for patients suffering from this condition. These results were presented at the 2021 Alzheimer’s Association International Conference (AAIC), June 26-30, by Jacobo Mintzer, MD, MBA, professor of health science, Medical University of South Carolina.1

A total of 200 individuals with AD and apathy were randomized 1:1 to 20-mg methylphenidate per day or placebo for up to 6 months. Mean difference on the Neuropsychiatric Inventory Apathy (NPI-A) subscale scores and odds of a rating of improvement on the modified AD Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) were used as primary outcomes.

Using a mixed model, a larger difference in the methylphenidate group compared with the placebo group on NPI-A score from baseline to 6 months was observed (mean difference, –1.25 [95% CI, –2.03 to –0.47]; P = .002). Notably, the largest change was observed during the first 2 months of treatment.

At 6 months, 43.8% (39 of 89) participants treated with methylphenidate had improved scores of ADCS-CGIC compared to 35.2% (32 of 91) of those in the placebo group (odds ratio [OR], 1.90 [95% CI, 0.95-3.84]. Despite slightly favoring the study drug, the difference in ADCS-GCIC scores were not statistically significant (P = .071). Secondary outcomes of the study, including change in cognition, safety, and cost-effectiveness measured monthly, were all not statistically significant. In addition, the safety profile was similar between the 2 groups, with the adverse events (AEs) being mild in nature.

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Methylphenidate was originally observed in ADMET, a 6-week, placebo-controlled multicenter trial that was conducted from June 2010 to December 2011. After 6 weeks of treatment, mean change in AES score was –1.9 (standard deviation [SD], 1.5) for methylphenidate and 0.6 (SD, 1.4) for placebo (P = .23).2 The OR for improvement in ADCS-GCIC was 3.7 (95% CI, 1.3-10.8; P = .02), with 21% of the methylphenidate group versus 3% of the placebo group rated as moderately or markedly improved. Investigators also observed a 1.8-point improvement (95% CI, 0.3-3.4) over placebo in NPI apathy score for patients treated with the therapy (P = .02).

A separate, 12-week, prospective study published in 2017 continued to highlight methylphenidate’s impact on improving apathy in a cohort of 60 community-dwelling veterans with mild AD.3 At 12 weeks, investigators observed a greater improvement in cognition, functional status, caregiver burden, CGI scores, and depression in the methylphenidate group compared with those on placebo.

Methylphenidate, which has several different brand names, is used to treat attention deficit disorder, attention deficit hyperactivity disorder, and narcolepsy. Mintzer recently sat down with NeurologyLive to discuss the need for more therapeutic approaches to treat some of the most difficult symptoms of dementia, including apathy. To watch his commentary, click the link below.

For more coverage of AAIC 2021, click here.

1. Mintzer JE, Scherer R, Drye LT, et al. Apathy in dementia methylphenidate trial 2 (ADMET2): results of a phase 3, placebo-controlled, double-blind, 6-month, multi-center, randomized clinical trial. Presented at 2021 AAIC Annual Meeting; June 26-29. Abstract
2. 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. Published online January 25, 2014. doi: 10.4088/JCP.12m08099
3. 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 Physiol. Published online September 15, 2017. doi: 10.1176/appi.ajp.2017.17030316
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