Background

This drug is a mild CNS stimulant that is being tested as a treatment for apathy in people with Alzheimer’s disease. It increases dopamine levels in the brain, and improves memory and attention. Available as a generic, it is widely prescribed to treat ADHD and it is also approved for narcolepsy. Widely misused by students to improve concentration while studying, methylphenidate carries a risk for addiction. It is available in rapid or extended-release tablet, capsule, and suspension formulations, and as a transdermal patch. Side effects include weight loss, elevated heart rate and blood pressure, and insomnia. 

Apathy, which manifests as loss of interest and motivation, is a prevalent noncognitive symptom of AD. It occurs early in the disease course, contributes to caregiver burden, and diminishes the patient's quality of life. Apathy in people with AD is proposed to stem from decreased dopaminergic neurotransmission (for review, see van Dyck et al., 2020).

Only one preclinical study of methylphenidate for AD appears in the literature. In 9-month-old male 5XFAD mice, acute injection just before behavioral testing did not alter anxiety or memory, but did increase locomotion and exploration (Schneider et al., 2015).

Findings

In two small, open-label studies, 10 to 20 mg per day methylphenidate reportedly eased apathy in people with AD and clinically significant apathy (Galynker et al.,1997; Padala et al., 2010). A placebo-controlled crossover trial in 13 AD patients reported improvement on the Apathy Evaluation Scale (AES) after two weeks of treatment (Herrmann et al., 2008).

In 2007, a placebo-controlled trial enrolled 60 male veterans with apathy and a clinical diagnosis of AD at the Veteran’s Administration Medical Center in Omaha, Nebraska. Participants received 20 mg methylphenidate daily, or placebo, for 12 weeks. By four weeks, the treated group saw significant improvement on the AES compared to placebo, which was sustained at 12 weeks. Participants also improved on measures of cognition, functional status, caregiver burden, clinical global impression, and depression at 12 weeks. Adverse events were similar between drug and placebo groups, with no serious adverse events reported (Padala et al., 2018).

In 2010, a second study, called the Apathy in Dementia Methylphenidate Trial (ADMET), enrolled 60 people with AD and significant apathy at three academic medical centers in North America, to compare a six-week course of 20 mg methylphenidate daily to placebo (Drye et al., 2013). On the primary outcomes—change in AES and ADCS-Clinical Global Impression of Change—results were mixed. Methylphenidate caused no change in the AES, but significant improvement on the ADCS-CGIC. On secondary outcomes, scores on the NPI apathy subscale improved, along with a trend to improvement on the MMSE. There was no difference in adverse events between drug and placebo groups. Study results have been published (Rosenberg et al., 2013).

In January 2016, the ADMET study group started a Phase 3 trial. Sponsored by the NIA, ADMET2 aimed to enroll 200 participants in 10 academic medical centers in the U.S. and Canada, and to randomize them to 20 mg methylphenidate or placebo per day for six months. Participants have clinically diagnosed possible or probable AD, and have had frequent or moderate to severe apathy for at least four weeks. The primary endpoints are changes in apathy subscale of the NPI and ADCS-CGIC; other outcomes include change in cognition, safety, and cost effectiveness. As of October 2017, 77 participants were enrolled, with a targeted end date for recruitment set at June 2018 (Scherer et al., 2018). One year in, the investigators added a substudy to measure blood markers of oxidative stress, inflammation, neuronal loss, microRNA and lipids. The trial was completed in July 2020. According to a July 2021 AAIC presentation, it met one of its primary objectives, posting a small improvement on the NPI apathy measure at six months compared to placebo. The effect was apparent by two months. The ADCS-CGIC also trended toward a benefit, but the difference was statistically insignificant. Methylphenidate did not improve measures of cognition, quality of life, or caregiver burden. The study found no serious adverse events related to drug, and similar side effects in drug and placebo groups (Mintzer et al., 2021, and commentary by Fredericks, 2021).

In November 2019, a Phase 4 pilot trial at Clinical Trials Center, Charlestown, Massachusetts, started enrolling eight people with mild cognitive impairment or mild dementia due to AD into a four-month course of slow-release methylphenidate. This crossover, placebo-controlled study was to measure cognition by way of Lumosity games and track activity via Fitbit (DesRuisseaux et al., 2020). It finished in January 2021.

Methylphenidate has been evaluated for its effect on gait and balance in people with Parkinson’s disease. In one trial, 30 mg/day improved walking and freezing left uncontrolled by dopaminergic drugs or subthalamic stimulation in people with advanced PD (Moreau et al., 2012), and another trial in 42 PD patients is currently testing 20 mg daily combined with physical therapy for a benefit on walking. This drug has also been studied for PTSD, multiple sclerosis, epilepsy, delayed waking from anesthesia, fatigue, smoking, neurofibromatosis, and several types of cancer.

For details on methylphenidate trials in Alzheimer's, see clinicaltrials.gov; for all trials see clinicaltrials.gov.