Treatment with methylphenidate (Ritalin), a stimulant approved for attention deficit-hyperactivity disorders (ADHD) and narcolepsy, led to a small to medium reduction in apathy in people with Alzheimer's disease, the phase III ADMET 2 trial showed.
At 6 months, methylphenidate 10 mg twice daily led to a larger decrease on the 12-point Neuropsychiatric Inventory (NPI) apathy scale compared with placebo, with a mean difference of -1.25 points (95% CI -2.03 to -0.47, P=0.002), equivalent to a Cohen d of 0.365, reported Jacobo Mintzer, MD, MBA, of the Ralph H. Johnson VA Medical Center in Charleston, South Carolina, and co-authors.
This effect was first seen 2 months after starting treatment and was sustained over 6 months, the researchers wrote in JAMA Neurology.
On the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), a co-primary endpoint, methylphenidate did not show a statistically significant difference over placebo but trended favorably, the researchers noted.
There were no treatment differences in cognitive measures, or in activities of daily living or quality-of-life scores. No new safety signals emerged with methylphenidate treatment.
"Methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers," Mintzer and colleagues wrote. "Clinicians should be aware of the small to medium treatment effects sizes and the lack of effect on activities of daily living."
Apathy affects anywhere from 20% to 90% of people in the dementia stages of Alzheimer's disease, noted Carolyn Fredericks, MD, of Yale University in New Haven, Connecticut, in an accompanying editorial. "Despite the severity of apathy's impact on patients with dementia and their caregivers, it is notoriously difficult to treat, and no therapies to date have proven to be effective," she wrote.
"The magnitude of the effect of methylphenidate reported in this trial is likely to be of clinical significance for many patients and represents the first phase III randomized clinical trial showing efficacy of any treatment for apathy in Alzheimer's disease," Fredericks pointed out.
"While methylphenidate will not be an option for those individuals with medical or psychiatric contraindications to stimulants, the present study demonstrates that it is generally safe and well tolerated for the target population," she added.
Two smaller trials of shorter duration, including the first ADMET study, showed that methylphenidate led to positive outcomes in treating apathy in Alzheimer's disease, with minimal adverse events.
In ADMET 2, Mintzer and co-authors studied 200 patients clinically diagnosed with Alzheimer's disease, mild to moderate cognitive impairment, and frequent or severe apathy from August 2016 to July 2020, assigning 99 participants to methylphenidate 10 mg twice daily and 101 people to placebo.
People with major depression or significant agitation, aggression, delusions, or hallucinations were excluded from the study. Participants had a median age of 76, and two-thirds were men.
Two co-primary outcomes were prespecified: mean change in NPI apathy score and odds of improved ADCS-CGIC rating, both assessed from baseline to 6 months. A significant result for either outcome indicated efficacy.
NPI apathy scores had the largest decrease in the first 100 days, favoring methylphenidate (HR 2.16, 95% CI 1.19-3.91, P=0.01).
At 6 months, ADCS-CGIC ratings improved for 43.8% in the methylphenidate group and 35.2% in the placebo group (OR 1.90, 95% CI 0.95-3.84, P=0.07).
More people in the methylphenidate group reported weight loss of more than 7% during the trial. Of 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile emerged between treatment groups.
"Many study participants were taking acetylcholinesterase inhibitors, selective serotonin reuptake inhibitors (SSRIs) and other antidepressants, and/or memantine [Namenda] at the time of participation; the authors found no confounding effects of these medications on the study's primary outcomes," Fredericks observed.
"Apathy in the context of Alzheimer's disease often occurs without concomitant depressed mood and is not simply a symptom of depression," she wrote. "That said, depression is also common both in older adulthood and as a neuropsychiatric symptom of Alzheimer's disease, and it can be difficult to untangle which patients are experiencing Alzheimer's disease-related apathy, Alzheimer's disease-related depression, or co-occurring late-life major depression."
ADMET 2 has limitations, Fredericks noted: it did not assess whether methylphenidate meaningfully relieved caregiver burden and relied on "notoriously nonspecific" clinical criteria for Alzheimer's diagnoses, not biomarkers. Future studies should assess methylphenidate treatment on specific forms of apathy, she added.
Disclosures
Funding was provided by the National Institute on Aging.
Mintzer reported being an advisor for Praxis Bioresearch and Cerevel Therapeutics. Other authors reported relationships with NIH, BioXcel Therapeutics, Cerevel, Praxis, Eisai, Kondor Pharma, Eli Lilly, Vaccinex, Functional Neuromodulation, Alzheimer's Therapeutic Research Institute, Alzheimer's Clinical Trials Consortium, Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease, Gerson Lehrman Group, SVB Leerink, Cerevance, Acadia Pharmaceuticals, Sunovion, FDA, Roche, Ono Pharmaceutical, Biogen, Biohaven, Novartis, Janssen, Genentech, Merck, VA, Cadent Therapeutics, Syneos, Avanir Pharmaceuticals, Athira, Alzheon, MapLight Therapeutics, Premier Healthcare Solutions, and IQVIA.
