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Original Investigation
September 27, 2021

Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease: The ADMET 2 Randomized Clinical Trial

Author Affiliations
  • 1Ralph H. Johnson VA Medical Center, Medical University of South Carolina, Charleston
  • 2Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada
  • 3Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
  • 4Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 5Yale School of Medicine, New Haven, Connecticut
  • 6Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock
  • 7University of Rochester School of Medicine and Dentistry, Rochester, New York
  • 8University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
  • 9Wake Forest University, Winston-Salem, North Carolina
  • 10Emory Goizueta Alzheimer’s Disease Research Center, Atlanta, Georgia
  • 11Banner Alzheimer’s Institute, Phoenix, Arizona
JAMA Neurol. 2021;78(11):1324-1332. doi:10.1001/jamaneurol.2021.3356
Key Points

Question  Does methylphenidate decrease apathy in individuals with Alzheimer disease?

Findings  In this randomized clinical trial of 200 participants, methylphenidate vs placebo was found to be safe and was associated with a decrease in apathy symptoms as measured by the Neuropsychiatric Inventory within 2 months that was sustained for 6 months.

Meaning  Methylphenidate may be useful for the treatment of apathy in individuals with Alzheimer disease, which can reduce symptoms and caregiver burden.


Importance  Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality.

Objective  To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease.

Design, Setting, and participants  This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included.

Interventions  Ten milligrams of methylphenidate, twice daily, vs matching placebo.

Main Outcomes and Measures  The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life.

Results  Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, −1.25; 95% CI, −2.03 to −0.47; P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91; P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84; P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04; P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups.

Conclusions and Relevance  This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease.

Trial Registration  ClinicalTrials.gov Identifier: NCT02346201

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    1 Comment for this article
    Suggestion on dosage frequency and effect of methylphenidate on Apathy in AD
    Stuart Garrie, MD | Retired Psychiatrist
    Since methylphenidate effectiveness in ameliorating ADHD symptoms diminishes after 3 1/2 to 4 hours, could methylphenidate show even more effectiveness for Apathy in AD if given q.I.d.?