Addressing Neuropsychiatric Symptoms of Alzheimer Disease

Jacobo Mintzer, MD, MPA

Methylphenidate, a central nervous system stimulant, has demonstrated its ability to improve apathy in patients with Alzheimer disease (AD) in the phase 3 ADMET 2 (NCT02346201) study. Results of the placebo-controlled, multicenter trial presented at the 2021 Alzheimer’s Association International Conference (AAIC), July 26-30, showed that the therapy had a small to medium benefit observed at 2 months that was sustained throughout the 6 months of the study.

A larger difference in Neuropsychiatric Inventory Apathy (NPI-A) subscale scores, the primary end point, was observed in the methylphenidate group compared with placebo (mean difference, –1.25 [95% CI, –2.03 to –0.47]; P = .002). Additionally, 43.8% (39 of 89) of participants treated with methyphenidate improved on AD Cooperative Study Clinical Global Impression of Change compared with 35.2% (32 of 91) of study participants in the placebo group. Though these findings favored methyphenidate, they did not reach statistical significance.

Lead author Jacobo Mintzer, MD, MPA, professor of health science, Medical University of South Carolina, shared his thoughts on methylphenidate’s clinical potential and other research opportunities within the space. He also shared his biggest takeaways from this year’s AAIC meeting and the controversial approval of aducanumab (Aduhelm; Biogen).

How is this drug currently utilized in clinical practice?

Jacobo Mintzer, MD, MPA: Both our investigator team and I use it in clinical practice every day. The big deterrent at this point for clinicians is that it is a scheduled drug that needs review for use every month. We still believe that it is very important for the treatment of this debilitating and common disorder. We are looking forward to opportunities like this, and to watch what’s going to happen after our publication. Hopefully this drug will be adopted more by the clinicians on the frontline.

Based on your findings in this study, what are the next steps in your research?

Our team is committed to the study of neuropsychiatric symptoms, but I believe that we’re moving into a research field that has drugs that not just help the average patient but help the individual specifically. We have obtained a fair number of biomarkers in this study. When we process biomarkers and associate them with clinical markers, we must hypothesize which patient is going to get the most benefit. The next steps for the team will be to use these biomarkers to identify those subjects that are more likely to respond to the treatment, and indirectly verify it in a clinical trial.

What were your overall takeaways from AAIC 2021?

Let me start by saying it was wonderful for us to be able to see part of the program in-person. I would like to congratulate the organizers who did a masterful job in blending the virtual and in-person parts. It was a miracle of technology that we have people in person giving a lecture to people watching virtually around the world. We had about 200-300 people in the audience when we did the presentation. Still, I think there was a large audience virtually learning and participating. That mixed type of meeting is definitely a model that can be used in the future. There were many other things of relevance, but I was personally impressed by the increasing studies and role of immune and inflammatory processes in Alzheimer disease. There was a layer of interest to understand how these fit better and develop compounds that may help in these aspects of the disease.

What are your thoughts on the approval of aducanumab, and will you use it in your practice?

Drugs should be used on the populations that the data was produced and supported efficacy for. If people choose to use aducanumab, it should be done by the subjects that have shown to have efficacy from it. The second thing that’s important to remember is that it was approved for the change of a critical biomarker called amyloid. Therefore, it will be critical to ensure that the subjects that participate and receive this treatment indeed have amyloid in their brain. It’s going to be very important to understand the clinical implications of reducing amyloid in the brain and the correlation between the clinical change and the amyloid among real patients in practice. Personally, I would have felt better if both conducted studies were positive. I would have felt more confident if the study was also not interrupted. That being said, patients are getting desperate. They don’t have too many options. As clinicians, we have the obligation to share all the information we have with the patients, but also to make treatments available.

I’m a strong believer that patients with Alzheimer disease are educated people. They follow the news very closely. Our job as physicians is to contribute to the certification and give all the information that’s available. If asked, give our opinion for this specific case, and try to facilitate access to the state-of-the-art treatments for our patients.

Transcript was edited for clarity.