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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Mintzer reported being an advisor for Praxis Bioresearch and Cerevel Therapeutics outside the submitted work. Dr Lanctôt reported grants from the National Institutes of Health during the conduct of the study and personal fees for serving on the advisory boards of BioXcel Therapeutics, Cerevel Therapeutics, Praxis, Eisai, and Kondor Pharma outside the submitted work. Dr Scherer reported grants from Johns Hopkins University during the conduct of the study. Dr Rosenberg reported grants from National Institute on Aging during the conduct of the study; grants from Eli Lilly and Company, Vaccinex, Functional Neuromodulation, Alzheimer’s Therapeutic Research Institute, Alzheimer’s Clinical Trials Consortium, and Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease outside the submitted work; and personal fees for consulting for Gerson Lehrman Group, SVB Leerink, Cerevel Therapeutics, Cerevance, Acadia Pharmaceuticals, BioXcel Therapeutics, Sunovion, and the US Food and Drug Administration outside the submitted work. Dr Herrmann reported grants from the National Institute on Aging during the conduct of the study. Dr van Dyck reported grants from the National Institute on Aging during the conduct of the study; personal fees for consulting for Roche, Eisai, and Ono Pharmaceutical outside the submitted work; and grants from Roche, Eisai, Eli Lilly and Company, Biogen, Biohaven Pharmaceuticals, Novartis, Janssen, Genentech, and Merck outside the submitted work. Dr Padala reported grants from Office of Research Development, Department of Veterans Affairs and National Institutes of Health during the conduct of the study. Dr Brawman-Mintzer reported grants from the National Institute on Aging during the conduct of the study. Dr Porsteinsson reported grants from the National Institutes of Health during the conduct of the study; personal fees for serving on the data and safety monitoring boards of Acadia Pharmaceuticals, Cadent Therapeutics, Functional Neuromodulation, Novartis, and Syneos outside the submitted work; grants from Avanir Pharmaceuticals, Biogen, Eisai, Eli Lilly and Company, Genentech/Roche, Biohaven, Athira, Alector, Vaccinex, and Novartis outside the submitted work; and personal fees from Avanir, Biogen, Eisai, Alzheon, MapLight Therapeutics, Premier Healthcare Solutions, Sunovion, IQVIA, and Ono Pharmaceuticals outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flowchart

AD indicates Alzheimer disease.

Figure 2.. Mean (SE) Change in Neuropsychiatric Inventory (NPI) Apathy Subscale Score by Visit

Figure 3.. Kaplan-Meier Estimates of Proportion of Participants Achieving a Neuropsychiatric Inventory Apathy Score of 0

Censored events are noted by X’s. Over the complete follow-up period of 6 months, the methylphenidate group had a 57% increase in the hazard ratio compared with the placebo group (hazard ratio, 1.57; 95% CI, 0.97-2.53; P = .07). For the first 100 days of follow-up, the methylphenidate group had more than twice the increase in the hazard ratio compared with the placebo group (hazard ratio, 2.16; 95% CI, 1.19-3.91; P = .01). The model was adjusted for age, sex, and presence of diabetes.