Therapeutics

Methylphenidate

Overview

Name: Methylphenidate
Synonyms: Ritalin, Concerta
Chemical Name: Methyl phenyl(piperidin-2-yl)acetate
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 4)
Approved for: Attention-deficit hyperactivity disorder (ADHD), narcolepsy

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. Often misused by young adults in the U.S. to improve concentration while studying, it 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 and occurs early in the disease course. Some evidence apathy in people with AD is associated with decreased dopaminergic neurotransmission (for review, see Mitchell et al., 2011).

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 aims to enroll 200 participants in 10 academic medical centers in the U.S. and Canada, and randomizing 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 will run through December 2019.

In December 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 will measure cognition by way of Lumosity games and track activity via Fitbit. It is expected to run until 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, neurofibrimatosis, and several types of cancer.

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

Last Updated: 02 Dec 2019

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References

Research Models Citations

  1. 5xFAD (C57BL6)

Paper Citations

  1. . Methylphenidate treatment of negative symptoms in patients with dementia. J Neuropsychiatry Clin Neurosci. 1997 Spring;9(2):231-9. PubMed.
  2. . Methylphenidate for apathy and functional status in dementia of the Alzheimer type. Am J Geriatr Psychiatry. 2010 Apr;18(4):371-4. PubMed.
  3. . Methylphenidate for the treatment of apathy in Alzheimer disease: prediction of response using dextroamphetamine challenge. J Clin Psychopharmacol. 2008 Jun;28(3):296-301. PubMed.
  4. . Methylphenidate for Apathy in Community-Dwelling Older Veterans With Mild Alzheimer's Disease: A Double-Blind, Randomized, Placebo-Controlled Trial. Am J Psychiatry. 2018 Feb 1;175(2):159-168. Epub 2017 Sep 15 PubMed.
  5. . Designing a Trial to Evaluate Potential Treatments for Apathy in Dementia: The Apathy in Dementia Methylphenidate Trial (ADMET). Am J Geriatr Psychiatry. 2013 Jun;21(6):549-59. PubMed.
  6. . Safety and efficacy of methylphenidate for apathy in alzheimer's disease: a randomized, placebo-controlled trial. J Clin Psychiatry. 2013 Aug;74(8):810-6. PubMed.
  7. . The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): study protocol for a randomized controlled trial. Trials. 2018 Jan 18;19(1):46. PubMed.
  8. . Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial. Lancet Neurol. 2012 Jul;11(7):589-596. PubMed.
  9. . The role of dopamine in symptoms and treatment of apathy in Alzheimer's disease. CNS Neurosci Ther. 2011 Oct;17(5):411-27. Epub 2010 Jun 16 PubMed.
  10. . Effects of methylphenidate on the behavior of male 5xFAD mice. Pharmacol Biochem Behav. 2015 Jan;128:68-77. Epub 2014 Nov 6 PubMed.

External Citations

  1. clinicaltrials.gov
  2. clinicaltrials.gov

Further Reading

Papers

  1. . Pharmacological interventions for apathy in Alzheimer's disease. Cochrane Database Syst Rev. 2018 May 4;5:CD012197. PubMed.
  2. . Pharmacological and Nonpharmacological Treatment for Apathy in Alzheimer Disease : A systematic review across modalities. J Geriatr Psychiatry Neurol. 2017 Jan;30(1):26-49. PubMed.
  3. . Apathy associated with neurocognitive disorders: Recent progress and future directions. Alzheimers Dement. 2017 Jan;13(1):84-100. Epub 2016 Jun 27 PubMed.
  4. . Drugs That Bind to α-Synuclein: Neuroprotective or Neurotoxic?. ACS Chem Neurosci. 2015 Dec 16;6(12):1930-40. Epub 2015 Sep 28 PubMed.
  5. . Effect of methylphenidate on attention in apathetic AD patients in a randomized, placebo-controlled trial. Int Psychogeriatr. 2014 Feb;26(2):239-46. Epub 2013 Oct 29 PubMed.