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      Pharmacological interventions for apathy in Alzheimer's disease

      1 , 2 , 1 , 3 , 4 , 1 , 5 , 1 , 2 , 3 , 4

      Cochrane Dementia and Cognitive Improvement Group

      Cochrane Database of Systematic Reviews

      Wiley

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          Abstract

          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. 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. 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. Eligible studies were double‐blind, randomized, placebo‐controlled trials (RCTs) investigating apathy as a primary or secondary outcome in people with AD. 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. 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. Review question We wanted to know whether there are any medications that are safe and effective for reducing apathy in people with Alzheimer's disease. Background Apathy is a state of reduced interest, lack of initiative and reduced activity. It is a very common symptom of Alzheimer's disease. It is often persistent and it is known to be linked to a lower quality of life, faster decline and more burden on caregivers. Effective treatments of apathy could improve the quality of life for people with Alzheimer's disease and their families. What we did We searched for randomized controlled trials (RCTs) up to May 2017 which had compared any medicine with a placebo (dummy pill) and measured the effect on apathy in people with Alzheimer's disease. We were only interested in trials in which it was decided randomly whether the people taking part got the drug of interest or the placebo; this was to make sure that the comparison was as fair as possible. What we found 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. Conclusions 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.

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          Most cited references 101

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          The cholinergic hypothesis of geriatric memory dysfunction.

          Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.
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            Pharmaceutical industry sponsorship and research outcome and quality: systematic review.

            To investigate whether funding of drug studies by the pharmaceutical industry is associated with outcomes that are favourable to the funder and whether the methods of trials funded by pharmaceutical companies differ from the methods in trials with other sources of support. Medline (January 1966 to December 2002) and Embase (January 1980 to December 2002) searches were supplemented with material identified in the references and in the authors' personal files. Data were independently abstracted by three of the authors and disagreements were resolved by consensus. 30 studies were included. Research funded by drug companies was less likely to be published than research funded by other sources. Studies sponsored by pharmaceutical companies were more likely to have outcomes favouring the sponsor than were studies with other sponsors (odds ratio 4.05; 95% confidence interval 2.98 to 5.51; 18 comparisons). None of the 13 studies that analysed methods reported that studies funded by industry was of poorer quality. Systematic bias favours products which are made by the company funding the research. Explanations include the selection of an inappropriate comparator to the product being investigated and publication bias.
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              Cholinesterase inhibitors for Alzheimer's disease.

              Since the introduction of the first cholinesterase inhibitor (ChEI) in 1997, most clinicians and probably most patients would consider the cholinergic drugs, donepezil, galantamine and rivastigmine, to be the first line pharmacotherapy for mild to moderate Alzheimer's disease.The drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. The most that these drugs could achieve is to modify the manifestations of Alzheimer's disease. Cochrane reviews of each ChEI for Alzheimer's disease have been completed (Birks 2005, Birks 2005b and Loy 2005). Despite the evidence from the clinical studies and the intervening clinical experience the debate on whether ChEIs are effective continues. To assess the effects of donepezil, galantamine and rivastigmine in people with mild, moderate or severe dementia due to Alzheimer's disease. The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' , 'Aricept' , galanthamin* galantamin* reminyl, rivastigmine, exelon, "ENA 713" and ENA-713 on 12 June 2005. This Register contains up-to-date records of all major health care databases and many ongoing trial databases. All unconfounded, blinded, randomized trials in which treatment with a ChEI was compared with placebo or another ChEI for patients with mild, moderate or severe dementia due to Alzheimer's disease. Data were extracted by one reviewer (JSB), pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment estimated. The results of 13 randomized, double blind, placebo controlled trials demonstrate that treatment for periods of 6 months and one year, with donepezil, galantamine or rivastigmine at the recommended dose for people with mild, moderate or severe dementia due to Alzheimer's disease produced improvements in cognitive function, on average -2.7 points (95%CI -3.0 to -2.3), in the midrange of the 70 point ADAS-Cog Scale. Study clinicians blind to other measures rated global clinical state more positively in treated patients. Benefits of treatment were also seen on measures of activities of daily living and behaviour. None of these treatment effects are large. There is nothing to suggest the effects are less for patients with severe dementia or mild dementia, although there is very little evidence for other than mild to moderate dementia.More patients leave ChEI treatment groups, approximately 29 %, on account of adverse events than leave the placebo groups (18%). There is evidence of more adverse events in total in the patients treated with a ChEI than with placebo. Although many types of adverse event were reported, nausea, vomiting, diarrhoea, were significantly more frequent in the ChEI groups than in placebo. There are four studies, all supported by one of the pharmaceutical companies, in which two ChEIs were compared, two studies of donepezil compared with galantamine, and two of donepezil compared with rivastigmine. In three studies the patients were not blinded to treatment, only the fourth, DON vs RIV/Bullock is double blind. Two of the studies provide little evidence, they are of 12 weeks duration, which is barely long enough to complete the drug titration. There is no evidence from DON vs GAL/Wilcock of a treatment difference between donepezil and galantamine at 52 weeks for cognition, activities of daily living, the numbers who leave the trial before the end of treatment, the number who suffer any adverse event, or any specific adverse event. There is no evidence from DON vs RIV/Bullock of a difference between donepezil and rivastigmine for cognitive function, activities of daily living and behavioural disturbance at two years. Fewer patients suffer adverse events on donepezil than rivastigmine. The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer's disease. It is not possible to identify those who will respond to treatment prior to treatment. There is no evidence that treatment with a ChEI is not cost effective. Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. There appears to be less adverse effects associated with donepezil compared with rivastigmine. It may be that galantamine and rivastigmine match donepezil in tolerability if a careful and gradual titration routine over more than three months is used. Titration with donepezil is more straightforward and the lower dose may be worth consideration.
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                Author and article information

                Journal
                Cochrane Database of Systematic Reviews
                Wiley
                14651858
                May 04 2018
                Affiliations
                [1 ]Sunnybrook Research Institute; Hurvitz Brain Sciences Research Program; 2075 Bayview Avenue Toronto ON Canada M4N 3M5
                [2 ]University of Toronto; Department of Pharmacology and Toxicology; 2075 Bayview Avenue Toronto Canada
                [3 ]University of Toronto; Department of Psychiatry; 2075 Bayview Avenue, Room H-185 Toronto ON Canada
                [4 ]Sunnybrook Health Sciences Centre; Geriatric Psychiatry; Toronto Canada
                [5 ]Sunnybrook Health Sciences Centre; Neuropsychopharmacology Research Group; 2075 Bayview Avenue Toronto Canada M4N 3M5
                Article
                10.1002/14651858.CD012197.pub2
                6494556
                29727467
                © 2018
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