NeuroVoices: Jacobo Mintzer, MD, MPA, on Methylphenidate’s Impact on Alzheimer Apathy


The professor of health science at the Medical University of South Carolina discussed robust results from the phase 3 ADMET 2 study evaluating methylphenidate to treat apathy in Alzheimer disease.

Jacobo Mintzer, MD, MPA

Jacobo Mintzer, MD, MPA

At the 2021 Alzheimer’s Association International Conference (AAIC), July 26-30, results from ADMET 2 (NCT02346201), a phase 3, placebo-controlled, multi-center study were presented. A total of 200 individuals with Alzheimer disease (AD) and apathy were randomized to receive methylphenidate 20 mg per day or placebo for up to 6 months. Investigators used Neuropsychiatric Inventory Apathy (NPI-A) subscale and modified AD Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) as primary end points of the study.

Methylphenidate, a central nervous system stimulant, had shown efficacy and safety in 2 previous trials; however, the results were only for 6 weeks each. At the end of ADMET 2, there was a larger difference in the methylphenidate group compared with the placebo group on NPI-A score using a mixed model (mean difference, –1.25 [95% CI, –2.03 to –0.47] P = .002) with the largest change observed during the first 2 months. Additionally, 43.8% of participants in the methylphenidate group improved ADCS-CGIC scores compared to 35.2% of study participants in the placebo group. Despite favoring methylphenidate, this was deemed not significant.

Lead author Jacobo Mintzer, MD, MPA, professor of health science, Medical University of South Carolina, sat down with NeurologyLive on a new iteration of NeuroVoices to discuss ADMET 2, the prevalence of apathy and its similar, but distinct differences from depression. He also provided context on the challenges associated with apathy and the triggers caregivers should be cognizant of.

NeurologyLive: What is the prevalence of apathy among this patient population?

Jacobo Mintzer, MD, MBA: Apathy is the most common neuropsychiatric symptom in Alzheimer disease and other dementias, occurring in about 70% to 71% of patients. Apathy is defined as a lack of responsiveness, lack of effective response, or lack of effective initiative. That’s very important because it distinguishes well from depression. Many people who I converse with ask about depression, but depression is very different. Depression is a strong emotional response in a negative way. Apathy is lack of emotional response.

Can you discuss the phase 2/3 ADMET study and its findings?

This study was performed on the background of 2 previously reported studies, both of which had 60 subjects each using the same dose of methylphenidate b.i.d. One study used 6 weeks of treatment whereas the other was 12 weeks. Both studies showed encouraging results. Although we don’t know the etiology of our apathy and remain with no treatments, we believe there’s a strong association between the catecholamine dopaminergic networks and the onset of apathy. Therefore, we decided to do this trial.

The second trial, headed by Prasad Padala, MD, MS, had encouraging results. We tried to look at the limitations of the available data to move forward from research to clinical practice. There were 2 issues that were critical. First, the study was done in a small sample size and was done for a limited amount of time. ADMET 2 was developed to meet these 2 main limitations: looking at a very much larger sample size and for it to be a longer period. The sample size had 200 people, as per the power calculations based on the preliminary data, and the length was set for 6 months. It was a double-blind, placebo controlled, multi-center trial that used 10 mg b.i.d. of generic methylphenidate. It was required that the patients have a level of apathy, at least a 4 on the Neuropsychiatric Inventory Apathy (NPI-A) subscale, which is a combination of moderate, severe, and very frequent. At this point, it has some negative impact on the patient.

The study was executed in 10 academic sites, and the findings were positive regarding the drug and the NPI-A subscale. The study called for 1 of the 2 co-primary end points to be right. On the NPI-A, the outcome was positive; however, to be able to do this type of design, you must split the alpha. Even with a reduced P value, the NPI-A was positive at 6 months. The second outcome, CGI-I, showed clear differences between drug and placebo. These differences were not statistically significant after correction (P <.048), which was just shy of the .05 that we were expecting. We wanted to know the clinical impact of the finding. The CGI-I was strongly correlated with the improvement in NPI-A and caregiver distress.

In conclusion, we believe that this study shows that methylphenidate has a mild to moderate effect size in improving apathy in Alzheimer disease. The effect started at around 2 months and continued over 6 months. As for safety, the drug appears to be quite safe. There were many SAEs of which were not meaningfully different between the drug and placebo. None of the SAEs were deemed related to the study medication by investigators. Overall, we have a new tool that is in people’s hands that appears to be safe and moderately effective for the treatment of apathy.

What are some of the challenges associated with apathy in this patient population?

Apathy by itself is a low impact symptom. Patients with apathy will not complain about apathy because they are apathetic. People do not distinguish apathy as a symptom. Oftentimes, they confused it with depression, or assume that that’s the way the patient is. When you talk to a caregiver and ask them to describe the way this person used to be versus how they are now, and they point and say, ‘your mother/spouse used to be a person who was out and going but now spends most of the day watching TV.’ The person who used to have a lot of initiative is now passive. The person that wanted to engage in conversations but is now not. A person that used to have an emotional affective connection is now blunted. When you point out these differences with caregivers, they say ‘wow that’s true!’

Apathy increases suffering in this patient and causes excess disability. There are things that the patients could do but choose not to because of the apathy. It also increases your chances of being in an institution as well as increased risk of death. For the caregiver, it clearly increases the burden of providing care for a person. This burden has 2 different venues. One, is the fact that the patient becomes more dependent, but the second is that the patient becomes less responsive. As a caregiver, you feel reinforced when a patient says, ‘thank you,’ will engage, or will collaborate. Apathetic patients do not have an emotion or expression and therefore increases emotional burden.

Transcript edited for clarity. For more segments of NeuroVoices, click here.

Mintzer JE, Scherer R, Drye LT, et al. Apathy in dementia methylphenidate trial 2 (ADMET2): results of a phase 3, placebo-controlled, double-blind, 6-month, multi-center, randomized clinical trial. Presented at 2021 AAIC Annual Meeting; June 26-29. Abstract
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