Methylphenidate, the most widely studied catecholaminergic compound in older adults, is safe and may have modest but noticeable benefits on apathy in patients with Alzheimer disease (AD), according to study findings published in JAMA Neurology.

Apathy is considered to be one of the most common neuropsychiatric symptoms in patients with AD. It’s defined as diminished well and initiative, and a general disinterest in activities with a limited affective response to events that is ongoing for at least 4 weeks. Significant caregiver burden, excess disability, increased medical costs, and mortality are associated apathy. Currently, there are no proven treatments for apathy, but methylphenidate tends to have a good safety profile in older adults.

To clarify the clinical efficacy of methylphenidate for apathy in AD, the study authors compared methylphenidate vs placebo in older adults with AD.


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The study included 200 patients (median age, 76 years) with AD, mild-to-moderate cognitive impairment, and frequent and/or severe apathy from 10 specialty clinics across North America.

Patients were randomly assigned to either 10 mg methylphenidate twice daily (n=99) or matching placebo (n=101). Researchers assessed changes from baseline to 6 months in the Neuropsychiatric Inventory (NPI) apathy subscale or improved rating on the AD Cooperative Study Clinical Global Impression of Change. Additionally, the researchers also compared groups in terms of safety, cognition changes, and quality of life (QoL).

Patients in the methylphenidate treatment arm demonstrated a significantly larger decrease over the 6-month treatment period in the NPI apathy score (mean difference, −1.25; 95% CI, −2.03 to −0.47; P =.002). Researchers found that the largest decrease in the NPI apathy score was reported in the first 100 days. During this time, there was a significant difference between the 2 groups in the hazard ratio (HR) change (HR, 2.16; 95% CI, 1.19-3.91; P =.01).

At the 6-month follow-up, the odds ratio of experiencing an improved rating on the AD Cooperative Study Clinical Global Impression of Change for methylphenidate vs placebo was 1.90 (95% CI, 0.95-3.84; P =.07). Additionally, the difference in the mean change from baseline, as estimated with a longitudinal model, was 1.43 (95% CI, 1.00-2.04; P =.048).

There was no significant difference between the methylphenidate and placebo groups regarding changes in cognitive measures and QoL. While 17 serious adverse events occurred during the 6 months, none of these events were deemed related to methylphenidate.

Given that the study population comprised mostly White patients from the US and Canadian academic centers, the researchers note that the findings may lack generalizability across other settings and patient populations. Additionally, the relatively short treatment period may further limit the findings.

Despite the potential benefits of methylphenidate on apathy in patients with AD, the researchers wrote that “clinicians should be aware of the small to medium treatment effects sizes and the lack of effect on activities of daily living.”

Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.

Reference

Mintzer J, Lanctôt KL, Scherer RW, et al. Effect of methylphenidate on apathy in patients with Alzheimer disease: The ADMET 2 randomized clinical trial. JAMA Neurol. Published online September 27, 2021. doi:10.1001/jamaneurol.2021.3356