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Methylphenidate for Apathy

Dr Mark Rapoport, MD, FRCPC; IPA Bulletin Deputy Editor, Research and Practice

Key Highlights

  • Methylphenidate, a psychostimulant used to treat ADHD and narcolepsy, was found to improve apathy in men with mild Alzheimer’s disease in the United States, supporting further off-label use.
  • This 12-week double blind RCT at a Department of Veteran’s Affairs medical center is the longest in duration to date (two prior studies of methylphenidate in AD were of 2 or 6 weeks), and uses the Apathy Evaluation Scale caregiver version to reveal more robust between-group differences.

Men with mild Alzheimer’s disease (AD) in an American Department of Veteran’s Affairs medical centre were recruited from clinics, referrals and advertisements to participate in a 12-week double blind, randomized controlled single-site trial of methylphenidate versus placebo for the treatment of apathy. Diagnoses were clinically confirmed, and scored at least 18 on the Mini-Mental Status Examination (MMSE), and at least 41 on the Clinician Version of the Apathy Evaluation Scale (AES-C). Co-prescription with antidepressants was allowed if participants were on stable doses for at least two months, and cholinesterase inhibitors or memantine if on stable doses for four months. Antipsychotics, amphetamines, MAOIs and clonidine were exclusionary. Methylphenidate doses were 5mg twice daily for two weeks, then 10mg twice daily and the mean dose in the treatment arm was 9.5mg BID (most participants got the full dose). Sixty participants were randomized with 30 in each group. Apathy improved by four weeks and continued to improve by the end of the trial in the treatment arm, with robust between-group differences of -9.9 (95% CI -13.6 to -6.2) by 12 weeks on the AES-C. The treatment arm also improved relative to placebo at 12 weeks (and in some cases by 8 weeks) on the MMSE, a measure of IADLs (but not basic ADLs), and measures of depression in dementia, caregiver burden, global improvement and global severity. They found no statistically significant changes in weight, pulse, blood pressure or other adverse events.

The authors point out that only two prior studies of methylphenidate in AD were randomized studies, the earlier studies were of two or six weeks duration. The present study found more robust between-group differences, and the authors posit that potentially their use of the AES-C may account for this, as the earlier studies used the AES-I (informant version). Furthermore, they point out that men may respond to this medication better than women according to earlier studies in different populations, and this study included only men. The authors of this paper found that those with high baseline depression scores had bigger improvement, although that was not statistically significant, and the main analysis remained significant even when controlling for baseline depression and apathy. One interesting finding that was made in this trial is that the magnitude of MMSE improvement with methylphenidate was similar to that found in trials of cholinesterase inhibitors. It is notable that they used only the AES to measure apathy, and not the apathy measure in the Neuropsychiatric Inventory, as both of the earlier studies showed conflicting results between the two different measures. Furthermore, the authors did not address potential between-group differences in benzodiazepines which may have influenced the results. Nonetheless, this stimulant was well-tolerated, with all participants in the treatment arm completing the trial. This is likely the largest and longest randomized controlled trial of this medication in AD thus far, and lends clinical support to its use, although it remains off-label.

For further reading:

Padala, P.R. et al Methylphenidate for apathy in communitydwelling older veterans with mild Alzheimer’s disease: A doubleblind randomized, placebo-controlled trial. American Journal of Psychiatry 2017: Published online

Excerpted article as reprint from IPA's newsletter, the IPA Bulletin, Volume 34, Number 4
IPA Members can read the full issue on the members' site.


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