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.
-
Judy George
covers neurology and neuroscience news for MedPage Today, writing about
brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy,
autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep,
pain, and more. Follow
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.