Abstract: 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). 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.

Plain-language summary: We found 21 RCTs involving more than 6300 people with Alzheimer’s disease. Four trials of two different medicines (methylphenidate and modafinil) had been done specifically to study apathy, so all the people taking part were known to be significantly apathetic before the trial started. The other 17 trials had other primary aims, but reported some data on apathy. The trials were generally well designed and conducted. From the three trials with methylphenidate, we found that it may improve apathy, although this depended on how the apathy was measured. The people taking methylphenidate also did slightly better than those taking placebo on scales measuring cognition (thinking, remembering, etc.) and some daily activities, but it was not clear that these effects were big enough to be important in practice. We found no evidence that it caused more side effects than placebo. The quality of this evidence was low or moderate, so we cannot be certain that other similar studies would not have different results. There was only one very small trial with modafinil and there was no evidence that it was effective for apathy. The other 17 trials studied a variety of medicines and included people who were not necessarily significantly apathetic to start with. We therefore thought they were only indirectly relevant to our review question. It is also highly likely that other trials of the same drugs have measured apathy but have not published the results, so we were concerned about possible publication bias (that the studies we found could have been a biased subset). We therefore thought the quality of evidence for all these other medicines was low or very low, meaning that we can have limited or little confidence in the results. Current evidence suggests that methylphenidate may be useful for treating apathy in Alzheimer's disease. However, more trials should be done specifically targeting apathy in order to improve the overall quality of the evidence.