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Methylphenidate offers apathy treatment hope for Alzheimer’s disease patients

By Lucy Piper, Senior medwireNews Reporter

Jacobo Mintzer (Lowcountry Center for Veterans Research, Charleston, South Carolina, USA) said that the benefit seen with the stimulant, compared with placebo, was “modest but potentially clinically significant”, explaining that the onset of effect was “relatively early” and “sustainable for at least 6 months.”

For the phase 3 ADMET 2 study, the team randomly assigned 200 patients with AD and frequent and/or severe apathy, aged a median of 76 years, to receive, in addition to psychosocial intervention, oral methylphenidate 20 mg/day given as two 5-mg tablets twice a day or placebo. Most of the patients were taking dementia medications, at 79%, primarily cholinesterase inhibitors.

Among the 180 patients who were analysed, the 89 given methylphenidate had significantly larger decreases in Neuropsychiatric Inventory (NPI) apathy scores at 6 months than the 91 given placebo, with an average 1.25 greater reduction.

The average NPI score in the methylphenidate group fell from 8.0 points at baseline to 3.5 points at 6 months, by which time 27% of patients had an NPI score of 0, compared with 14% of those taking placebo.

The greatest degree of change in NPI score occurred in the first 2 months of treatment and was sustained through the duration of the trial. During the first 100 days, people receiving methylphenidate were 2.16 times more likely to have no apathy symptoms than those taking placebo, suggesting a quicker decrease in apathy for this group.

The proportion of patients showing improvement on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change was also higher among those taking methylphenidate, at 43.8% compared with 35.2% of those taking placebo, but the odds of improvement did not significantly differ between the two groups.

Mintzer and colleagues comment that “the effect of treatment is specific to the treatment of apathy and not a secondary effect of improvement in cognition”, having found no group differences in any of the cognitive measures, and no effect on activities of daily living or caregiver distress.

As explanation, they suggest that methylphenidate may reduce the symptoms of apathy “by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits.”

They found no effect of concomitant medication on the efficacy of methylphenidate and adverse events were “generally modest and consistent with those expected with methylphenidate”, the researchers report. However, 10 patients in the methylphenidate group experienced more than 7% weight loss, compared with six in the placebo group, and there were increased ratings on the NPI aberrant motor behaviour measure for those taking the drug.

Commenting on the findings in an accompanying editorial, Carolyn Fredericks (Yale University, New Haven, Connecticut, USA) said “[t]he magnitude of the effect of methylphenidate in this trial is likely to be of clinical significance for many patients”.

She concluded: “Despite its near-ubiquity, apathy is far from a benign neuropsychiatric symptom, and its impact on the clinical course of AD is devastating.

“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.”

News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2021 Springer Healthcare Ltd, part of the Springer Nature Group

JAMA Neurol 2021; doi:10.1001/jamaneurol.2021.3356

JAMA Neurol 2021; doi:10.1001/jamaneurol.2021.2942