Methylphenidate associated with short-term reduction in symptoms of apathy in patients with Alzheimer disease

1. Methylphenidate provides a treatment approach with modest but potentially clinically significant benefit for apathy symptoms in patients with Alzheimer disease.

2. The efficacy of methylphenidate had a relatively short onset, and its effect was sustainable for at least 6 months.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Apathy is one of the most common distinguishing symptoms in individuals with Alzheimer disease (AD) characterized by executive cognitive dysfunction leading patients to suffer from decreased daily function and specific cognitive deficits over time. This gradual deterioration in executive function is associated with significant caregiver burden, excess disability, increased medical costs, and mortality. This placebo-controlled randomized clinical trial, the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2), sought to determine the clinical efficacy of methylphenidate compared to placebo for reducing the severity of apathy in patients with AD. The primary endpoints of the analysis included 1) change from baseline to 6 months in the Neuropsychiatric Inventory (NPI) apathy subscale or 2) improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change. Secondary endpoints included safety profile, change in cognition, and quality of life. Among 200 patients with AD, methylphenidate therapy vs placebo was safe and associated with a decrease in apathy symptoms and severity as measured via the NPI within 2 months and sustained for 6 months. These findings suggested that methylphenidate provides a treatment approach with modest but potentially clinically significant benefit for patients with AD and caregivers. The efficacy of methylphenidate had a relatively short onset, and its effect was sustainable for at least 6 months. A limitation of this study was that the majority of participants were White individuals from US and Canadian academic medical centers that may not generalize to other populations or non-AD forms of dementia

Click to read the study in JAMA Neurology

Click to read an accompanying editorial in JAMA Neurology

Relevant Reading: Methylphenidate for the treatment of apathy in Alzheimer disease: prediction of response using dextroamphetamine challenge

In-Depth [randomized controlled trial]: This multicenter, phase 3 randomized clinical trial included 200 patients with AD, mild to moderate cognitive impairment, and frequent and/or severe apathy randomized 1:1 to receive 10 mg of methylphenidate (n = 99) vs matching placebo (n = 101) (median age [IQR], 76 [71-81] years; 68 [34%] female). The trial was conducted between August 2016 and July 2020 from 1 Canadian and 9 US centers. Overall, methylphenidate therapy resulted in a larger decrease in the NPI apathy score from baseline to 6 months compared to placebo (mean difference, -1.25; 95%CI, -2.03 to -0.47; P = .002). The most significant decrease in NPI apathy score was observed in the initial 100 days, with a significant hazard ratio for the proportion of participants without apathy symptoms receiving methylphenidate compared to placebo (HR, 2.16; 95%CI, 1.19-3.91; P = .01). Using the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change, the odds ratio of an improvement in ratings at 6 months for methylphenidate therapy was 1.90 (95%CI, 0.95-3.84; P = .07). Using a longitudinal model, the difference in mean change from baseline to 6 months estimated was 1.43 (95%CI, 1.00-2.04; P = .048). There were no significant differences in the safety profile among treatment groups.

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