March 22, 2023

Jacobo E. Mintzer, MD, of the Medical University of South Carolina, shares the results of the Phase III ADMET2 trial (NCT02346201) of methylphenidate to reduce apathy in patients with Alzheimer’s disease (AD). Apathy is a syndrome seen in 71% of AD patients, characterized by a lack of expression of emotion, initiative, and interest in surroundings. After two positive short preliminary studies, the Phase III randomized, placebo controlled trial examined the effects of methylphenidate on approximately 200 AD subjects over 6 months. Changes in the neuropsychiatric inventory apathy subscale (NPIa) and clinical global impression of change (CGIC) were assessed as primary outcome measures. At 6 months, the ADCS-CGIC showed that 43.8% of methylphenidate treated participants improved compared with 35.2% receiving placebo, favoring methylphenidate but not reaching statistical significance. A statistically significant difference in NPIa improvement from baseline compared to placebo was observed. Effects of the drug were seen after approximately 2 months of use, and these effects remained after the 6-month period of the study. The information provided is a summary of the presentation given at the AAIC 2021 meeting in Denver, CO on July 29, 2021.

Apathy is the most common neuropsychiatric symptom observed in dementias especially in alzheimer’s disease with 71 percent of the people suffering from dementia presenting symptoms of apathy at some point during the disease apathy is not just a symptom but has negative consequences it causes excess disability in patients causes increasing the risk of

Institutionalization and increasing the risk of death and also causes increase in burden and stress in caregivers so uh is a common problem with major consequences now we don’t have today any treatment for apathy and until recently we didn’t have a definition so just to be clear with a we’re talking an apathy and when we talk about about apathy we talk about

A syndrome characterized by lack of effect or lack of expression of emotion to positive or negative events lack of initiative lack of interest in their surroundings so many people will say okay what’s the difference between apathy and depression and the two syndromes could not be more different depression is a very strong emotional response that is associated

Uh with negative events so it’s a very strong negative emotion on the other hand apathy is the lack of emotion so could not be more different one is an extreme of emotion on the negative side the second one is the lack of emotion so now what causes happiness well we don’t know the theology of apathy however many studies have shown a strong association between

Deficits in the dopamine catecholamine pathways and the onset of apathy in patients with alzheimer’s disease so if you were to think about how to treat it the thinking process will be that you would like to treat with something that will enhance the catecholamine dopaminergic pathway now ritalin happens to be the most studied dopamine catecholamine enhancer in

The elderly and therefore we choose to study the effects of ritalin which is a catecholamine dopamine dopamine enhancer in patients with alzheimer’s disease that present with apathy and we did two studies to preliminary studies one that was six weeks and the other one was 12 weeks each one of the two studies lasted included about 60 subjects both studies show

Positive results therefore we felt encouraged to move forwards to a phase three trial now the goal of the phase three trial was to do a very similar study with the larger population and in more sites to test general generalizability and also to do it for a longer period of time in this case we chose six months and we did manage to uh recruit 200 subjects which

Was what the study was powerful the primary outcome measures were either the npia the neuropsychiatric inventory apathy subscale or a modified version for apple with apathy anchored of the cjic or the a which is a global clinical scale and what we found was that the uh npia was very positive 0.02 p value and that meant that the study was positive because we

Said either or rather than and to consider the selling positive we split the alpha so subjects have to be positive in either one of the two consider positive but have to be at the 0.025 or below and the cgic came out that the 0.048 so that was not considered to be a positive outcome however there was a very strong association between improvement in a npia or

Improving innopathy and improvement in cgic there were also significant association between improvement in equity and improving in uh caregiver distress both items suggest the presence of a clinical meaningless meaningfulness to the results that result is not that you have a change in the scale but actually seems to have a positive effect in the subject and

In the caregiver now there were no uh meaningful side effects what we call in clinical research advancements there were no death and non-minimum no meaningful serious adverse events uh and those were no known of those that were present that were um considered to be related to the study medication so we concluded that the uh treatment from ritalin or medial

Phenidate in patients with alzheimer’s disease suffering from apathy is moderate multimodally effective has clinic and meaningless meaningfulness and appears to be uh associated with improved improvements in clinical uh response and caregiver stress now of interest is that the effects were seen started to become meaningful in about two months and these strong

Response remain over the six months period of the study

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Phase III ADMET2 trial of methylphenidate for apathy in Alzheimer's Disease By VJDementia