ADMET 2 Trial Shows Positive Impact With Methylphenidate on Alzheimer Apathy


Investigators observed a significant difference in the hazard ratio change on NPI apathy score within the first 100 days, suggesting an early treatment effect.

Jacobo Mintzer, MD, MBA

Jacobo Mintzer, MD, MBA

The full results from ADMET 2, a phase 3 trial (NCT02346201) evaluating methylphenidate, a central nervous system stimulant designed to treat apathy in Alzheimer disease (AD), have been published in JAMA Neurology. The findings showed that the medication is safe and effective in the treatment of apathy in AD, indicated by changes in Neuropsychiatric Inventory (NPI) scale.1

Lead author Jacobo Mintzer, MD, MBA, professor of health science, Medical University of South Carolina, and colleagues concluded that "methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers,” adding that “clinicians should be aware of the small to medium treatment effect sizes and the lack of effect on activities of daily living." Mintzer previously presented topline results at the 2021 Alzheimer’s Association International Conference, June 26-30.

In total, 99 patients with AD, mild to moderate cognitive impairment, and frequent and/or severe apathy were assigned to 5 mg of generic methylphenidate dosed as 1 capsule twice a day for 3 days, followed by 2 capsules twice a day (20 mg/day) for the remainder of the 6-month study period. A matched cohort of 101 patients were assigned to placebo as well. In addition to outcomes on NPI apathy subscale, Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) was used as the coprimary end point.

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In an adjusted longitudinal model, investigators observed a significant difference of –1.25 (95% CI, –2.03 to –0.47) between treatment groups in change in NPI apathy score from baseline to 6 months. Notably, the largest change in NPI apathy occurred during the first 2 months of treatment. At the conclusion of the study, 27% (24 of 89) of participants treated with methylphenidate had an NPI apathy score of 0 compared with 14% (13 of 90) in the placebo.

Over the entire follow-up period, investigators identified a hazard ratio (HR) of 1.57 (95% CI, 0.97-2.53; P = .07) for which participants achieved an NPI apathy score of 0. Furthermore, in the first 100 days, there was a significant difference observed in HR change (2.16 [95% CI, 1.19-3.91; P = .01), suggesting that the methylphenidate-treated group demonstrated a decrease in the NPI apathy subscale sooner than placebo during this time period.

On the ADCS-CGIC, 43.8% (39 of 89) participants in the methylphenidate group showed improvement, compared with 35.2% (32 of 91) of those in the placebo group, resulting in an OR of 1.90 (95% CI, 0.95-3.84; P = .07) favoring methylphenidate. Notably, investigators observed a strong association between improvement in NPI apathy subscale scores and overall ADCS-GCIC (OR, 6.10 [95% CI, 1.35-56.67]; P = .009).

At 6 months, decreases on the Dementia Apathy Interview and Rating assessment were observed for both the methylphenidate group (mean, –0.5 [standard deviation (SD), 0.8]) and placebo (–0.5 [SD, 0.7]) group. Overall, the differences seen between the groups were nonsignificant on race except for Whites, Mintzer and colleagues noted.

Increased NPI aberrant motor behavior was the only observed change among neuropsychiatric symptoms with treatment of methylphenidate compared with placebo (mean difference, 0.69 [95% CI, 0.09-1.25]; P = .03). Additionally, this treatment did not differ from placebo in cognitive measures such as Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale, Dependence Scale, and EuroQoL.

In total, 17 serious adverse events were observed in the methylphenidate group compared with 10 in the placebo group. In comparison, 10 and 6 participants in each group, respectively, lost more than 7% of their baseline body weight at follow-up. Of these, 4 in each group had a body mass index, calculated as weight in kilograms divided by height in meters squared, greater than 25 at baseline.

ADMET, the precursor study to ADMET 2, was a 6-week, placebo-controlled multicenter trial that was conducted from June 2010 to December 2011. At the conclusion of the treatment period, investigators recorded a change in Apathy Evaluation Scale score of –1.9 (SD, 1.5) for methylphenidate compared with 0.6 (SD, 1.4) for placebo (P = .23). The OR for improvement in ADCS-GCIC was 3.7 (95% CI, 1.3-10.8; = .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 (= .02).2

Mintzer recently sat down with NeurologyLive to discuss the need for more therapeutic options to treat symptoms of dementia, including apathy. Click the link below to watch his commentary.

1. Mintzer J, Lanctot KL, Scherer RW, et al. Effect of methylphenidate on apathy in patients with Alzheimer disease: the ADMET 2 randomized clinical trial. JAMA Neurol. Published online September 27, 2021. doi:10.1001/jamaneurol.2021.3356
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
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