ADHD Med May Reduce Apathy in Alzheimer's Disease

Erik Greb

October 04, 2021

Methylphenidate is safe and effective for treating apathy in patients with Alzheimer's disease (AD), new research suggests.

Results from a phase 3 randomized trial showed that, after 6 months of treatment, mean score on the Neuropsychiatric Inventory (NPI) apathy subscale decreased by 4.5 points for patients who received methylphenidate vs a decrease of 3.1 points for those who received placebo.

In addition, the safety profile showed no significant between-group differences.

"Methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers," say the investigators, led by Jacobo Mintzer, MD, MBA, professor of health studies at the Medical University of South Carolina in Charleston.  

The findings were published online September 27 in JAMA Neurology.

Common Problem

Apathy, which is common among patients with AD, is associated with increased risk for mortality, financial burden, and caregiver burden. No treatment has been proven effective for apathy in this population.

Two trials of methylphenidate, a catecholaminergic agent, have provided preliminary evidence of efficacy. Findings from the Apathy in Dementia Methylphenidate trial (ADMET) suggested the drug was associated with improved cognition and few adverse events. However, both trials had small patient populations and short durations.

The current investigators conducted ADMET 2, a 6-month, phase 3 trial, to investigate methylphenidate further. They recruited 200 patients (mean age,  76 years; 66% men; 90% White) at nine clinical centers that specialized in dementia care in the United States and one in Canada.

Eligible patients had a diagnosis of possible or probable AD and a Mini-Mental State Examination (MMSE) score between 10 and 28. They also had clinically significant apathy for at least 4 weeks and an available caregiver who spent more than 10 hours a week with the patient.

The researchers randomly assigned patients to receive methylphenidate (n = 99) or placebo (n = 101). For 3 days, participants in the active group received 10 mg/day of methylphenidate. After that point, they received 20 mg/day of methylphenidate for the rest of the study.

Patients in both treatment groups were given the same number of identical-appearing capsules each day.

In-person follow-up visits took place monthly for 6 months. Participants also were contacted by telephone at days 15, 45, and 75 after treatment assignment.

Participants underwent cognitive testing at baseline and at 2, 4, and 6 months. The battery of tests included the MMSE, Hopkins Verbal Learning Test, and Wechsler Adult Intelligence Scale—Revised Digit Span.

The trial's two primary outcomes were mean change in NPI apathy score from baseline to 6 months and the odds of an improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) between baseline and 6 months.

Significant change on either outcome was to be considered a signal of effective treatment.

Treatment-Specific Benefit

Ten patients in the methylphenidate group and seven in the placebo group withdrew during the study.

Mean MMSE score at baseline was 19.2 in the methylphenidate group vs 18.5 in the placebo group, indicating moderately severe dementia. Mean baseline score on the NPI apathy subscale was 8.0 vs 7.6, respectively.

In an adjusted, longitudinal model, mean between-group difference in change in NPI apathy score at 6 months was -1.25 (P = .002). The mean NPI apathy score decreased by 4.5 points in the methylphenidate group vs 3.1 points in the placebo group.

The largest change in apathy score occurred during the first 2 months of treatment. At 6 months, 27% of the methylphenidate group vs 14% of the placebo group had an NPI apathy score of 0.

In addition, 43.8% of the methylphenidate group had improvement on the ADCS-CGIC compared with 35.2% of the placebo group. The odds ratio (OR) for improvement on ADCS-CGIC for methylphenidate vs placebo was 1.90 (P = .07).

There was also a strong association between score improvement on the NPI apathy subscale and improvement on the ADCS-CGIC subscale (OR, 2.95; P = .002).

"It is important to note that there were no group differences in any of the cognitive measures, suggesting that the effect of the treatment is specific to the treatment of apathy and not a secondary effect of improvement in cognition," the researchers write.

In all, 17 serious adverse events occurred in the methylphenidate group and 10 occurred in the placebo group. However, all events were found to be hospitalizations for events not related to treatment.

"Enduring Effect"

Commenting on the findings for Medscape Medical News, Jeffrey L. Cummings, MD, ScD, professor of brain sciences at the University of Nevada, Las Vegas, noted that the reduction in NPI apathy subscale score of more than 50% was clinically meaningful.

A more robust outcome on the ADCS-CGIC would have been desirable, he added, although that instrument is not designed specifically for apathy.

Dr Jeffrey Cummings

Methylphenidate's effect on apathy observed at 2 months and remaining stable throughout the study makes it appear to be "an enduring effect, and not something that the patient accommodates to," said Cummings, who was not involved with the research. Such a change may manifest itself in a patient's greater willingness to help voluntarily with housework or to suggest going for a walk, he noted.

"These are not dramatic changes in cognition, of course, but they are changes in initiative and that is very important," Cummings said. Decreased apathy also may improve quality of life for the patient's caregiver, he added.

Overall, the findings raise the question of whether the US Food and Drug Administration should recognize apathy as an indication for which drugs can be approved, said Cummings.

"For me, that would be the next major step in this line of investigation," he concluded.

The study was funded by the National Institute on Aging. Mintzer has served as an advisor to Praxis Bioresearch and Cerevel Therapeutics on matters unrelated to this study. Cummings is the author of the Neuropsychiatric Inventory but does not receive payments for it from academic trials such as ADMET 2.

JAMA Neurol. Published online September 27, 2021. Abstract

Follow Erik Greb on Twitter: @MedscapeErik .

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