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For our next update, let’s look at patients with Alzheimer’s.
Is there a means to pharmacologically help them with apathy? Apathy is one of the most significant symptoms of Alzheimer’s in terms of lowering quality of life. If there is a way to improve this, it might be one of the most important interventions we could consider. It may be that we can do so by prescribing methylphenidate, for example, or modafinil. But what are the effects on apathy of the acetylcholinesterase inhibitors? Finally, what is the impact of use of antipsychotics or antidepressants when we look specifically at apathy as a symptom of Alzheimer’s?
For this, we have a new meta-analysis as of 2018 from the Cochrane system by Ruthirakuhan and colleagues. As you know, in a Cochrane meta-analysis, a very, very rigorous approach is taken to determine whether a study is qualified for the analysis. This makes it one of our most reliable sources. And, of course, a meta-analysis helps us not be swayed by particular individual studies because we have the advantage of many.
What was found? First, for methylphenidate, not very many studies made it through to analysis. Only 2 that lasted less than 12 weeks, and 1 that lasted more than 12 weeks; thus, data are limited. Again, fewer studies are available when you use very rigorous measures of outcomes, for example, and tight analysis of criteria, like adequacy of blinding. So, we have limited data. Methylphenidate does appear to produce a small signal in this meta-analysis, particularly in the longer study, but overall, the data were really quite weak. Nevertheless, there might be a little signal there.
Only 1 study for modafinil was available that met their criteria, with a sample size of 23. There, almost no conclusions can be reached. And in that study, no difference was seen from placebo. With acetylcholinesterase inhibitors, the data were of relatively low quality. There were no statistically significant findings in the outcome of the meta-analysis, including specifically that no one acetylcholinesterase inhibitor was any better than any of the rest. There are some pretty large studies of this, but overall, per the Cochrane team, the data were still of relatively low quality.
And then finally, antipsychotics and antidepressants were examined because we use them so commonly. With antipsychotics, there was a hint of perhaps a slight worsening of apathy. But because of the data limitations, no conclusions were reached on that. With antidepressants, no effect was seen in the limited data available using the tight measures of outcomes for measurement of apathy.
In summary, methylphenidate has a weak signal in favor of its use. Of course, you’d be comparing that possible benefit to the risks of increasing agitation, exacerbating hypertension, and increasing cardiovascular disease risk and the risk of open-angle glaucoma. For acetylcholinesterase inhibitors, the team concluded that they “may have benefit” with one no greater than another, and the signal there was also not strong.
Abstract
Pharmacological Interventions for Apathy in Alzheimer’s Disease
Myuri T Ruthirakuhan, Nathan Herrmann, Eleenor H Abraham, Sarah ChanKrista, L Lanctôt
Background: Despite the high prevalence of apathy in Alzheimer’s disease (AD), and its harmful effects, there are currently no therapies proven to treat this symptom. Recently, a number of pharmacological therapies have been investigated as potential treatments for apathy in AD.
Objectives: Objective 1: To assess the safety and efficacy of pharmacotherapies for the treatment of apathy in Alzheimer’s disease (AD).
Objective 2: To assess the effect on apathy of pharmacotherapies investigated for other primary outcomes in the treatment of AD.
Search methods: We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), MEDLINE, Embase, CINAHL, PsycINFO, LILACS, ClinicalTrials.gov and the World Health Organization (WHO) portal, ICTRP on 17 May 2017.
Selection criteria: Eligible studies were double‐blind, randomized, placebo‐controlled trials (RCTs) investigating apathy as a primary or secondary outcome in people with AD.
Data collection and analysis Three review authors extracted data. We assessed the risks of bias of included studies using Cochrane methods, and the overall quality of evidence for each outcome using GRADE methods. We calculated mean difference (MD), standardized mean difference (SMD) or risk ratio (RR) with 95% confidence intervals on an intention‐to‐treat basis for all relevant outcome measures.
Main results: We included 21 studies involving a total of 6384 participants in the quantitative analyses. Risk of bias is very low to moderate. All studies reported appropriate methods of randomization and blinding. Most studies reported appropriate methods of allocation concealment. Four studies, three with methylphenidate and one with modafinil, had a primary aim of improving apathy. In these studies, all participants had clinically significant apathy at baseline. Methylphenidate may improve apathy compared to placebo. This finding was present when apathy was assessed using the apathy evaluation scale (AES), which was used by all three studies investigating methylphenidate: MD ‐4.99, 95% CI ‐9.55 to ‐0.43, n = 145, 3 studies, low quality of evidence, but not when assessed with the neuropsychiatric inventory (NPI)‐apathy subscale, which was used by two of the three studies investigating methylphenidate: MD ‐0.08, 95% CI ‐3.85 to 3.69, n = 85, 2 studies, low quality of evidence. As well as having potential benefits for apathy, methylphenidate probably also slightly improves cognition (MD 1.98, 95% CI 1.06 to 2.91, n = 145, 3 studies, moderate quality of evidence), and probably improves instrumental activities of daily living (MD 2.30, 95% CI 0.74 to 3.86, P = 0.004, n = 60, 1 study, moderate quality of evidence), compared to placebo. There may be no difference between methylphenidate and placebo in the risk of developing an adverse event: RR 1.28, 95% CI 0.67 to 2.42, n = 145, 3 studies, low quality of evidence. There was insufficient evidence from one very small study of modafinil to determine the effect of modafinil on apathy assessed with the FrSBe‐apathy subscale: MD 0.27, 95% CI ‐3.51 to 4.05, n = 22, 1 study, low quality of evidence. In all other included studies, apathy was a secondary outcome and participants were not selected on the basis of clinically significant apathy at baseline. We considered the evidence on apathy from these studies to be indirect and associated with publication bias. There was low or very low quality of evidence on cholinesterase inhibitors (ChEIs) (six studies), ChEI discontinuation (one study), antipsychotics (two studies), antipsychotic discontinuation (one study), antidepressants (two studies), mibampator (one study), valproate (three studies) and semagacestat (one study).
Authors’ conclusions: Methylphenidate may demonstrate a benefit for apathy and may have slight benefits for cognition and functional performance in people with AD, but this finding is associated with low‐quality evidence. Our meta‐analysis is limited by the small number of studies within each drug class, risk of bias, publication bias, imprecision and inconsistency between studies. Additional studies should be encouraged targeting people with AD with clinically significant apathy which investigate apathy as a primary outcome measure, and which have a longer duration and a larger sample size. This could increase the quality of evidence for methylphenidate, and may confirm whether or not it is an effective pharmacotherapy for apathy in AD.
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Reference
Ruthirakuhan, M. T., Herrmann, N., Abraham, E. H., Chan, S., & Lanctôt, K. L. (2018). Pharmacological interventions for apathy in Alzheimer’s disease. Cochrane Database of Systematic Reviews.
