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A Drug for Attention-Deficit Disorder Helps Ameliorate Apathy in Alzheimer's Disease

Article In Brief

Methylphenidate reduced symptoms of apathy in patients with Alzheimer's disease. Experts agreed that apathy is a symptom that is often overlooked and which can impact caregivers as well as patients.

A drug used for decades for attention deficit-hyperactivity disorder is a safe and effective treatment for apathy related to Alzheimer's disease (AD), according to a November 1 study in JAMA Neurology that builds on previous research.

This latest randomized, placebo-controlled clinical trial found that those patients who received methylphenidate (Ritalin) had a larger decrease in symptoms of apathy compared with patients taking a placebo, and the improvements were seen fairly quickly.

The findings could have wide-reaching implications given that an estimated 70 percent of AD patients experience apathy, which can worsen disability and cause frustration for families and caregivers who want to keep their loved ones engaged in life.

The study authors defined apathy as “diminished will and initiative, lack of interest in activities, and limited affective response to positive or negative events that is present for at least 4 weeks.” It is different than depression, which can also cause a person to be apathetic or low energy, they said.

Apathy is associated with caregiver burden and distress, increased service utilization, accelerated institutionalization, increased mortality risk, and financial burden,” the study authors noted.

“Apathy robs you of the natural human inclination to interact with others and it causes suffering for the patient and suffering for the family,” said the study's lead author Jacobo Mintzer, MD, MBA, a geriatric psychiatrist and professor in the College of Health Sciences at the Medical University of South Carolina.

Dr. Mintzer said apathy is often overlooked in AD care, in part because so much focus is placed on memory loss and also because apathy “is a passive and not an active symptom,” like aggression or volatility. “I argue that it may be more relevant in your life to be able to interact with others than to be able to memorize a few more words,” he said.

Dr. Mintzer and his colleagues pointed out that although no treatments have been proven to treat apathy in AD, findings from two previous small clinical trials suggested a benefit from methylphenidate, a central nervous system stimulant.

Study Details

This latest study of methylphenidate for AD-related apathy was larger and lasted longer than the two prior trials. It followed patients for six months and was conducted from August 2016 to July 2020 at nine US clinics and one Canadian clinic specializing in dementia care.

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“It is one of the most common symptoms we see and it can happen early on. For a family it can be very hard to hear ‘Dad doesnt want to see the grandkids or ’Dad doesnt want to come over for Christmas. There can be misunderstandings and hurt feelings, especially when a family thinks they are doing everything possible for their loved one.”—DR. CAROLYN FREDERICKS

Of 307 persons screened for the trial, 52 did not pass the screening and 55 were not eligible to participate based on baseline eligibility visits. The 200 participants had a diagnosis of possible or probable AD, mild to moderate cognitive impairment, frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI), and the availability of a caregiver who spent at least 10 hours a week with the patient. The median age of the participants was 76, 66 percent were men, and 90 percent were White.

The 200 participants were randomized—99 to methylphenidate and 101 to placebo. They were given identical-appearing capsules containing either 5 mg of generic methylphenidate or placebo twice a day for three days, followed by two capsules twice a day for the remainder of the study. The participants continued to take their regular medications, which often included the dementia drugs, cholinesterase inhibitors and memantine. Ten participants in the methylphenidate group and seven in the placebo group withdrew from the study, and there were some missed follow-up visits—which took place monthly, including some by phone due to COVID-19—and occasional missed doses.

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“Its symptom-focused and is certainly not a panacea for Alzheimers” but getting patients motivated and back involved in life at least a bit more is such a wonderful thing.”—DR. ALAN J. LERNER

The coprimary outcomes were a change from baseline to six months in the NPI apathy subscale or improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADSC-CGIC), which assesses clinically meaningful change in apathy. Other outcomes included safety, change in cognition and quality of life. The NPI, which is given as a structured interview with the caregiver, assesses the severity of 12 neuropsychiatric symptoms, including apathy.

From baseline to six months, there was a larger decline in apathy in those receiving methylphenidate compared with placebo, with a mean difference of -1.25 on the NPI scale. The largest change in the NPI apathy scores occurred during the first two months of treatment, though the changes persisted throughout the study.

At six months, 27 percent of participants in the methylphenidate group had an NPI apathy score of 0 compared with 14 percent of the placebo group. Also at six months, 43.8 percent of those in the methylphenidate group showed improvement as measured by the ADCS-CGIC scale compared with 35.2 percent of the placebo group. At the same time, however, cognitive measures and quality-of-life measures were not significantly different between the two groups.

Of 17 serious adverse events that occurred during the trial, none were related to the study drug and the safety profile between the two treatment groups was similar. A few more of the people who took methylphenidate experienced weight loss.

“Apathy is a prevalent and clinically significant neuropsychiatric symptom in AD,” the authors concluded. “Methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers.”

Brain Chemistry

The authors said the idea to test methylphenidate as a potential drug for AD apathy is based “on the understanding that motivated behavior relies on subregions of the prefrontal cortex (dorsolateral, orbital-ventromedial, dorsomedial) which degenerate in AD resulting in apathetic behavior.”

“Methylphenidate treatment may ameliorate apathy symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits,” they wrote.

The study authors acknowledged the trial had limitations, including the fact that the participants were nearly all White and drawn from US and Canadian academic medical centers, which means the findings are necessarily generalizable to other patient groups and settings. The study only focused on AD patients with apathy and did not include people with other forms of dementia. It's also not known whether methylphenidate would continue to be effective over a long period of time.

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“Apathy robs you of the natural human inclination to interact with others and it causes suffering for the patient and suffering for the family.”—DR. JACOBO MINTZER

Expert Commentary

Carolyn Fredericks, MD, assistant professor of neurology at Yale School of Medicine, who wrote an editorial accompanying the study, said apathy can keep AD patients from socializing, keeping up with hobbies and physical activities or just taking part in everyday life in their family or community.

“It is one of the most common symptoms we see and it can happen early on,” perhaps before cognitive issue become apparent, said Dr. Fredericks, who sees patients at Yale's Memory Clinic. “For a family it can be very hard to hear ‘Dad doesn't want to see the grandkids or ’Dad doesn't want to come over for Christmas. There can be misunderstandings and hurt feelings, especially when a family thinks they are doing everything possible for their loved one.”

Dr. Fredericks noted in her editorial that “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,” she wrote.

Meredith Bock, MD, a fellow at the Weill Institute for Neurosciences at University of California, San Francisco, said, “While the decline in apathy measured in the study participants taking methylphenidate was not huge, because apathy is so debilitating, even a modest benefit would make a huge difference in some patients.”

She said families and caregivers can become discouraged if they are constantly met with apathy, perhaps getting no reply at all to a comment or suggestion. “They feel as though ‘I am working so hard to help this person. Why can't they work with me?’”

Dr. Bock said she believed apathy in AD and other neurodegenerative diseases is an under-researched area, and would be interested in learning whether methylphenidate would be helpful in Parkinson's disease, for instance. In the case of Alzheimer's, “I think it is equally important to focus on symptom management and quality of life while searching for disease-modifying treatment,” she said.

Alan J. Lerner, MD, a study coauthor and professor of neurology at Case Western Reserve University, said he was pleased that the findings turned out positive given how the many negative study findings related to AD.

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“While the decline in apathy measured in the study participants taking methylphenidate was not huge, because apathy is so debilitating, even a modest benefit would make a huge difference in some patients.”—DR. MEREDITH BOCK

Dr. Lerner said apathy in AD is often misdiagnosed as depression and patients are put on antidepressants, which probably won't help, though it's possible to have both apathy and depression. Making a correct diagnosis is key.

Dr. Lerner was part of an international group of clinicians, scientists and pharmaceutical industry researchers that compiled a set of criteria for the diagnosis of apathy in neurocognitive disorders, published online on May 5 in Alzheimer's & Dementia.

Dr. Lerner said the next step is to understand why some AD patients with apathy respond to methylphenidate and why others don't. He said the research team is looking at a variety of factors, including biomarkers.

In his own practice, Dr. Lerner said he has begun suggesting methylphenidate when he thinks it's appropriate and is finding “patients and families are very open” to the idea.

“It's symptom-focused and is certainly not a panacea for Alzheimer's,” he said, “but getting patients motivated and back involved in life at least a bit more is such a wonderful thing.”

Disclosures

Dr. Mintzer reported being an advisor for Praxis Bioresearch and Cerevel Therapeutics outside the submitted work. Dr. Lerner reported no relevant disclosures. Dr. Frederick had no disclosures.

Link Up for More Information

• Mintzer J, Lanctot KL, Scherer RW, et al; for the ADMET 2 Research Group. Effect of methylphenidate on apathy in patients with Alzheimer disease: The ADMET 2 randomized clinical trial https://jamanetwork.com/journals/jamaneurology/article-abstract/2784538. JAMA Neurol 2021;78(11):1324–1332.
    • Fredericks C. Editorial: Methylphenidate for apathy in Alzheimer disease—Why should we care https://jamanetwork.com/journals/jamaneurology/article-abstract/2784541. JAMA Neurol 2021;78(11):1311–1313.
      • Miller DS, Robert P, Ereshefsky L, et al. Diagnostic criteria or apathy in neurocognitive disorders https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12358. Alzheimers Dement 2021: Epub 2021 May 5.