Methylphenidate reduced a measure of apathy in patients with clinically diagnosed possible or probable Alzheimer’s disease (AD) in the ADMET 2 phase III trial.
Larger decreases were seen from baseline to 6-month scores on the apathy subscale of the Neuropsychiatric Inventory (NPIP=0.002), according to Jacobo Mintzer, MD, MBA, of the VA Medical Center in Charleston, South Carolina, and co-authors.
The largest decrease was seen over the first 100 days (HR for proportion with no apathy symptom favoring methylphenidate 2.16, 95% CI 1.19-3.91, P=0.01).
“In this study, methylphenidate treatment was associated with a small to medium reduction in apathy in patients with AD as shown by the NPI apathy subscale,” Mintzer and co-investigators wrote in JAMA Neurology. “These findings were first observed 2 months after treatment initiation and sustained over 6 months.”
A second primary outcome, 6-month change on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC), however, did not show a statistically significant difference, “but there was a trend favoring methylphenidate,” the researchers added.
There was no between-group difference on measures of caregiver distress, cognitive function, quality of life, or adverse effects, though more people in the methylphenidate than placebo group lost >7% body weight during the study. None of the 17 serious adverse events seen were related to the study drug.
“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,” Mintzer and colleagues wrote. “Adverse events were generally modest and consistent with those expected with methylphenidate.”
Methylphenidate (Ritalin), a central nervous system stimulant, is approved for the treatment of attention deficit hyperactivity disorders and narcolepsy in the U.S.
In the ADMET 2 study, researchers randomized patients with a caregiver from 10 AD clinics in North America with clinically diagnosed possible or probable AD (n=200, median age 76, 34% women) to methylphenidate (n=89 in intention-to-treat analysis) 10 mg twice daily or placebo (n=92 in intention-to-treat analysis) between August 2016 and July 2020. Mean Mini-Mental State Examination scores in the methylphenidate and placebo groups were 19.2 and 18.5, respectively, while baseline NPI apathy subscale scores were 8.0 and 7.6, respectively.
Overall, 79% of participants were being treated with dementia medications (cholinesterase inhibitors 73%; memantine 38%), and 36% were treated with selective serotonin reuptake inhibitors (SSRIs).
Mintzer and colleagues emphasized the difference between AD and depression, pointing out that although people with depression have some of the same symptoms as those with apathy, they are distinct clinical entities.
“Apathy is characterized by a lack of affect, while depression is characterized by an overwhelming presence of a negative affect and mood,” the researchers wrote. “Furthermore, literature has shown the lack of response of symptoms of apathy to selective serotonin reuptake inhibitors, supporting the importance of the distinction and providing evidence of two very different biological pathways.”
A 2017 review of behavioral symptoms in cognitively impaired older adults reported that apathy, with sleep problems, depression, and irritability, were prevalent, persistent, and associated with mortality and disability. Apathy also has been with significant caregiver burden, though evidence about the association is mixed. A 2013 review of apathy syndrome in AD estimated prevalence at 21% and incidence yearly of 10.5%, with 1-year persistence in 61.2%. A 2008 review reported 5-year depression and apathy prevalence of 77% and 71%, respectively, in patients with dementia.
Three domains of apathy are correlated with amyloid and tau in prefrontal cortex subregions, with a possible integrating role for anterior cingulate cortex. Methylphenidate has catecholamine-related and dopaminergic effects on the prefrontal cortex and basal ganglia.
Two smaller trials, ADMET and a 12-week study that found improvements in apathy, cognition, functional status, depression, and caregiver burden in Alzheimer’s patients, led to the present phase III investigation.
In an accompanying editorial, Carolyn Fredericks, MD, of Yale University, noted that apathy in the context of AD often occurs without concomitant depressed mood and is not simply a symptom of depression. “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.
“Previous studies evaluating the efficacy of acetylcholinesterase inhibitors, SSRIs, modafinil, antipsychotics, and valproic acid for the management of apathy in individuals with AD have been inconclusive at best,” she added. “What is clear is that apathy cannot be treated with antidepressants, such as SSRIs: these do not effectively relieve it and may in fact make symptoms of apathy worse.”
“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,” Fredericks noted.
“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 AD,” she wrote. “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.”
Limitations of the study included the use of clinical criteria for possible or probable AD diagnosis and indirect assessment of caregiver burden. “Whether methylphenidate can improve apathy to the extent that it meaningfully relieves caregiver burden is an important question, and one whose answer would help clinicians and families in their decision-making,” Fredericks noted.
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Methylphenidate reduced a measure of apathy in patients with clinically diagnosed possible or probable Alzheimer’s disease in ADMET2.
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ADMET 2 is the first phase III trial showing efficacy of any treatment for apathy in Alzheimer’s.
Paul Smyth, MD, Contributing Writer, BreakingMED™
Funding was provided by the National Institute on Aging.
Mintzer reported being an advisor for Praxis Bioresearch and Cerevel Therapeutics.
Fredericks reported no conflicts.
Cat ID: 130
Topic ID: 82,130,404,485,494,730,130,33,361,192,255,146,362,55,921,925
