Disclosures: Mintzer reports being an advisor for Cereval Therapeutics and Praxis Bioresearch outside the submitted work. Fredericks reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
October 04, 2021
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Methylphenidate may reduce apathy in AD

Disclosures: Mintzer reports being an advisor for Cereval Therapeutics and Praxis Bioresearch outside the submitted work. Fredericks reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
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Methylphenidate safely and effectively treated apathy in Alzheimer’s disease, according to results of a randomized placebo-controlled clinical trial published in JAMA Neurology.

“Apathy is the most prevalent neuropsychiatric symptom of dementia, yet there is very limited research available to provide guidance to clinicians on how to care for patients suffering from apathy in dementia,” Jacobo Mintzer, MD, MBA, of the South Carolina Institute for Brain Health, a division of the Lowcountry Center for Veterans Research, told Healio Neurology. "This study offers a potential treatment approach to this very prevalent neuropsychiatric symptom of dementia." 

old woman with head in hands
Source: Adobe Stock

Prior trials were limited due to small size and short durations of 6 and 12 weeks. In the current larger and longer trial, ADMET 2, Mintzer and colleagues used more robust measures to investigate whether methylphenidate vs. placebo decreased apathy severity among 200 individuals (median age, 76 years; 34% women) with AD. They conducted the study between August 2016 and July 2020 at nine U.S. clinics and one Canadian clinic that specialized in dementia care. They included patients with AD, mild to moderate cognitive impairment and frequent and/or severe apathy according to the Neuropsychiatric Inventory (NPI).

Jacobo Mintzer

Interventions consisted of 10 mg of methylphenidate (n = 99) compared with matched placebo (n = 101). Change from baseline to 6 months in the NPI apathy subscale or improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change served as the co-primary outcomes. Researchers used safety, change in cognition and quality of life as the other outcomes

Result showed a larger decrease in the NPI apathy score from baseline to 6 months among participants who received methylphenidate vs. placebo (mean difference = 1.25; 95% CI, 2.03 to 0.47). Mintzer and colleagues noted the largest decrease in the NPI apathy score in the first 100 days, with a significant HR for the proportion of patients with no apathy symptoms who received methylphenidate vs. placebo (HR = 2.16; 95% CI, 1.19-3.91). The OR of having an improvement on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change for methylphenidate vs. placebo at 6 months was 1.9 (95% CI, 0.95-3.84).

Based on estimates from a longitudinal model, researchers reported a difference in mean change from baseline to 6 months of 1.43 (95% CI, 1-2.04). The groups did not have significantly different cognitive measures and quality of life. None of the 17 serious adverse events that occurred during the study appeared related to the study drug. Mintzer and colleagues observed no significant differences in the safety profile between treatment groups.

"These findings show a clinically significant difference between drug and placebo as measured by a standardized measure," Mintzer said. "Of interest is the fact that the improvement in the primary outcome measure was strongly associated with improvement in Clinical Global Impression of Change score and caregiver burden, both measures of clinical relevance."

In a related editorial, Carolyn Fredericks, MD, of the department of neurology at Yale University, underscored the potential of methylphenidate for treating apathy in those with AD.

“Despite its near-ubiquity, apathy is far from a benign neuropsychiatric symptom, and its impact on the clinical course of AD is devastating,” Fredericks wrote. “Clinicians who have struggled to treat apathy in their patients with AD should take heart at this evidence that methylphenidate may be a safe and efficacious option.”