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ADMET 2: Apathy in dementia methylphenidate trial 2

Apathy is defined as a loss of will and initiative, lack of interest in activities, lack of productivity, as well as limited affective response to positive or negative events. Apathy is one of the most common neuropsychiatric symptoms of Alzheimer’s disease (AD); it affects about 70% of patients with AD and results in serious adverse consequences for patients and caregivers. Patients suffering from apathy experience decreased motivation and rely heavily on caregivers to initiate and oversee daily activities. Specifically, apathetic patients are 2.8 times more likely than non-apathetic patients to struggle with at least one activity of daily living. Apathetic patients are also more likely to require institutionalization, the largest single driver of direct costs in AD.

Despite the high prevalence of apathy in AD and its serious consequences, there are no proven treatments for this condition. Nonpharmacologic strategies appear to have limited effects on apathy in AD, as do current U.S. Food and Drug Administration-approved medications for AD such as cholinesterase inhibitors.

Recently, new research has suggested the involvement of dopamine pathways in the biology of apathy in AD and the potential value of dopamine enhancers, such as methylphenidate, for the treatment of this condition. Moreover, we have recently reported the results of three short-term, randomized controlled trials showing a clear benefit of methylphenidate over placebo in treating apathy in AD, as well as potential cognitive benefits of methylphenidate and a favourable safety/tolerability profile. Specifically, we found positive effects on certain attention measures and a borderline significant effect in general cognition as measured by the Mini Mental State Exam.

However, a number of key questions relevant for clinical practice were not answered by these studies. For example, is the treatment effective and safe beyond six weeks in a larger sample? Can the potential cognitive benefit of methylphenidate be reproduced and remain clinically significant in this population? Can the combination of a decrease in apathy and an improvement in cognition be translated into clinically significant functional change?

We propose to address these unresolved key questions by conducting a multi-site, parallel, randomized, double-blind, placebo-controlled study. The study would evaluate methylphenidate for the treatment of apathy in patients with AD (Apathy in Dementia Methylphenidate Trial-II (ADMET II)) in a larger sample over a longer period of time and employ a concise battery of neuropsychological tests optimized for apathetic AD patients. The ultimate goal is to collect evidence strong enough to support a change in clinical practice. This trial will bring together a team of investigators who have collaborated successfully in the execution of the first ADMET study as well as on other clinical trials exploring treatments for neuropsychiatric symptoms of dementia.