Nonpharmacological Therapies in Alzheimers Disease a Systematic Review of Efficacy
Geriatric medicine
Research
Interventions to delay functional reject in people with dementia: a systematic review of systematic reviews
Abstruse
Objective To summarise existing systematic reviews that appraise the effects of non-pharmacological, pharmacological and alternative therapies on activities of daily living (ADL) function in people with dementia.
Design Overview of systematic reviews.
Methods A systematic search in the Cochrane Database of Systematic Reviews, Cartel, Medline, EMBASE and PsycInfo in April 2015. Systematic reviews of randomised controlled trials conducted in people with Alzheimer's disease or dementia measuring the impact on ADL office were included. Methodological quality of the systematic reviews was independently assessed by two authors using the AMSTAR tool. The quality of evidence of the primary studies for each intervention was assessed using GRADE.
Results A full of 23 systematic reviews were included in the overview. The quality of the reviews varied; all the same about (65%) scored eight/11 or more on the AMSTAR tool, indicating loftier quality. Interventions that were reported to be effective in minimising decline in ADL part were: exercise (6 studies, 289 participants, standardised mean divergence (SMD) 0.68, 95% CI 0.08 to 1.27; GRADE: low), dyadic interventions (8 studies, 988 participants, SMD 0.37, 95% CI 0.05 to 0.69; Course: low) acetylcholinesterase inhibitors and memantine (12 studies, 4661 participants, donepezil 10 mg SMD 0.18, 95% CI 0.03 to 0.32; GRADE: moderate), selegiline (7 studies, 810 participants, SMD 0.27, 95% CI 0.xiii to 0.41; Class: low), huperzine A (2 studies, seventy participants, SMD 1.48, 95% CI 0.95 to ii.02; Grade: very low) and Ginkgo biloba (7 studies, 2530 participants, SMD 0.36, 95% CI 0.28 to 0.44; GRADE: very depression).
Conclusions Healthcare professionals should ensure that people with dementia are encouraged to exercise and that chief carers are trained and supported to provide condom and constructive care for the person with dementia. Acetylcholinesterase inhibitors or memantine should exist trialled unless contraindicated.
Trial registration number CRD42015020179.
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Strengths and limitations of this written report
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This overview examines the efficacy for a number of different treatment approaches in delaying functional decline.
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The effect sizes of the different treatment approaches are compared providing clinicians and policymakers with data regarding treatments that should be prioritised.
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The quality of the included reviews is appraised using AMSTAR and the quality of evidence for each intervention is appraised using Class.
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There is a fence regarding the most advisable methodology for conducting overviews including how authors should capture the most recent evidence and avoid including overlapping reviews.
Introduction
Dementia affects approximately 35.6 meg people worldwide.one This figure is expected to nearly double every 20 years due to population ageing.ii It is one of the leading causes of mortality and morbidity, particularly in people aged sixty years or over in which information technology affects approximately v–seven% of the population.ane
The trajectory of dementia is associated with gradual functional decline whereby the person with dementia requires more aid to manage activities over time due to cognitive and physical impairment. Functional pass up is associated with reduced quality of life in people with dementia3 and increased care costs.4 It is also associated with increased demand for breezy intendance and can increment the carer burden, peculiarly when the rate of reject is rapid.5
While dementia is a terminal condition, the length of time between diagnosis and death can exist many years.half-dozen Therefore, one of the goals of treatment, particularly in the earlier stages of the disease, is to promote independence and reduce functional decline.7 Consumers have chosen for a greater focus on rehabilitation and restorative care in order to maximise the quality of life.eight
There are a number of intervention approaches that have been trialled to manage the symptoms of dementia including pharmacological approaches (such every bit acetylcholinesterase inhibitors) and non-pharmacological approaches (such as exercise). The vast amount of research literature means that it can exist hard for health professionals to keep themselves upwardly to date in understanding which interventions are idea to exist effective overall and the relative efficacy of unlike intervention approaches. Systematic reviews of systematic reviews (overviews) are useful in that they examine the effectiveness of a number of dissimilar interventions for a detail health condition.ix Systematic reviews practise not traditionally attempt to do this due to time and resources involved in conducting such a review.
The aim of this review was to summarise systematic reviews that appraise the effects of intervention for functional decline in people with dementia.
Methods
An a priori review protocol was developed and registered on the PROSPERO International prospective register of systematic reviews (http://world wide web.crd.york.ac.united kingdom/PROSPERO; registration number CRD42015020179). The protocol provides full details of the methods used. In that location were no changes made to the protocol during the review.
Inclusion and exclusion criteria
Types of studies
This overview included the most recent and comprehensive systematic reviews. Systematic reviews were defined as 'a review of the evidence on a conspicuously formulated question that uses systematic and explicit methods to place, select and critically assess relevant chief research, and to extract and analyse data from the studies that are included in the review'.10 In lodge to be eligible, the systematic review must take included randomised controlled trials (RCTs). Cochrane Reviews and systematic reviews published in other peer-reviewed journals were eligible. Systematic reviews that overlapped with the most up to date and comprehensive review in terms of the intervention arroyo were excluded to avoid double counting of studies where possible. Reviews published in non-English languages were excluded.
Population
Reviews which included populations of people with a diagnosis of dementia (any cause) or Alzheimer's disease were included. Reviews were excluded if they included people with not-Alzheimer's dementia only (eg, people with vascular dementia). Studies conducted in whatever setting, whether community or residential, were included.
Intervention and comparison
All interventions intended to treat or manage the symptoms of dementia were eligible; this included non-pharmacological interventions (such as exercise, counselling or instruction), pharmacological interventions (such as acetylcholinesterase inhibitors) and alternative therapies (such as Ginkgo biloba). Reviews including RCTs which compared the intervention to usual care, placebo or another form of intervention were included.
Upshot
The overview included reviews where functioning of global activities of daily living (ADL) was reported equally a primary or secondary outcome. ADL whether measured by observation, cocky-report or proxy study or tools such as the Functional Independence Measure out, Barthel Alphabetize, Alzheimer's Disease Co-operative Study—ADL Inventory, Disability Assessment for Dementia or Cleveland Scale for ADL were eligible.
Search methods for identification of reviews
Searches were conducted in the Cochrane Database of Systematic Reviews Dementia and Cognitive Improvement Group domain, Cochrane Dare, Medline, EMBASE and PsycINFO in Apr 2015. The Medline search strategy is fastened equally an online supplementary file and was adapted for the other databases. The search strategy was formulated including the dementia search string used past the Cochrane Dementia and Cognitive Improvement Group for dementia.
Supplemental material
Data collection and assay
Option of reviews
One author (KL) conducted the searches and assessed all retrieved citations coming together the inclusion criteria on the basis of title and abstruse. A second author (SD) independently reviewed 10% of the excluded articles. Potentially eligible reviews were reviewed in full text. Two authors (KL and SD) independently assessed all articles obtained in full text. A third author was consulted in cases of disagreement. Eligible reviews were classified based on intervention approach (eg, exercise) and discussion occurred regarding the most appropriate review to include (based on recency and quality). We used methods consistent with the Cochrane Handbook; nosotros did not echo the searches, determine eligibility, assess run a risk of bias, comport additional meta-analysis or aim to identify whatsoever additional studies.ix Thus, we accepted included reviews as being 'consummate' and did not cheque other reviews for missing studies.
Information extraction and management
One author (KL) extracted the data which was checked by a 2d researcher. Disagreements were resolved past a third author. A information drove form was developed and tested prior to starting the review. Fields extracted included review details (author, championship, year), review aims, inclusion criteria, date of concluding search and information from included RCTs that provided a comparing to usual care, placebo or another course of treatment. If the review included data from RCTs and other study designs, we extracted the data for the RCTs only. Where RCTs and quasi-RCTs were included, we extracted only the RCT data when possible (ie, when individually reported). We extracted details on the number of RCTs included in the review, population size and characteristics, intervention and comparator characteristics and outcomes (on an individual study basis or pooled values equally reported in the included review). Authors of the included reviews were non contacted for further information.
Assessment of quality of included reviews
Two people (KL and a 2nd researcher) independently assessed the methodological quality of the included reviews using the AMSTAR checklist.eleven The AMSTAR checklist includes a number of criteria which reflect whether the review was guided by a protocol, whether at that place was duplicate study selection and data extraction, the comprehensiveness of the search, inclusion of grey literature, use of quality assessment, ceremoniousness of data synthesis and documentation of conflict of interest. Disagreements regarding AMSTAR score were resolved by discussion or a decision made past a 3rd author.
Cess of quality of the body of evidence for each intervention
Class was used to rate the quality of the testify for each intervention.12 The GRADE level was determined based on information provided in the systematic review. The level considers the risk of bias of included studies, indirectness of evidence, inconsistency of results (heterogeneity), imprecision of results and possibility of publication bias.12
Data synthesis
Data was synthesised in tables and a narrative synthesis was used to provide a summary of results. Effect sizes were also expressed graphically using standardised mean divergence. Where meta-analysis had already been conducted within the review, we used the meta-analysis performed by the authors. Nosotros did not conduct boosted meta-analyses, however where the results were presented as mean difference, we calculated the standardised mean deviation to enable comparison of effect sizes across reviews.
Results
The study selection process is presented in effigy 1 (PRISMA). There were 23 systematic reviews meeting all inclusion criteria and included in this overview.13–35 An additional 10 reviews were identified that listed ADL every bit an consequence of involvement; however the reviews failed to identify whatever applicative studies. These reviews were for socially assistive robots, brute-assisted therapy, transcutaneous electrical nerve stimulation, social back up groups for the person with dementia, naftidrofuryl, respite intendance, smart home technologies, metal poly peptide-attenuating compounds, ibuprofen and educational interventions for the person with dementia.36–45 Ane review evaluated the efficacy of metrifonate, however identified serious harms associated with apply; metrifonate was since withdrawn from the market.46 These reviews are not discussed further. In most cases, the most recent comprehensive review (ie, dementia or Alzheimer's disease) reporting ADL outcomes was accounted every bit being of acceptable quality for inclusion. There were 2 intervention categories where this was non the case. Nosotros excluded two reviews of cerebral rehabilitation which were published more recently than the included Cochrane Review simply involved a search engagement that was not as recent as the included review.47 ,48 We also excluded 2 systematic reviews of exercise that were published more recently than the included review. One of the excluded reviews was of lower quality than the Cochrane Review and included non-randomised trials, merely involved a search date that was 6 months more recent.49 A second review included studies where practise was included as one component of a multifactorial programme.l
Characteristics of the included reviews
Characteristics of the included reviews are summarised in table 1. Xv (65%) of the reviews were Cochrane Reviews. Eleven reviews addressed non-pharmacological approaches. These were cognitive training, cerebral stimulation therapy, light therapy, exercise, aromatherapy, nutritional supplementation, validation therapy, psychological treatment, example management, music therapy and intervention for the person with dementia and carer dyad. Eight reviews addressed pharmacological approaches. These were acetylcholinesterase inhibitors and memantine, pharmacotherapies to improve sleep, latrepirdine, melatonin, statins, selegiline, lecithin and nimodipine. Iv reviews addressed alternative therapies. These were vitamin B supplementation, G. biloba, huperzine A and acupuncture.
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Table one
Characteristics of included reviews
Most (65%) of the reviews included people with any course of dementia. The remaining reviews included merely people with Alzheimer's disease. The hateful age of participants in all reviews was people in their 70s or 80s with the exception of the G. biloba and huperzine A reviews which involved younger participants. Most participants had mild-to-moderate severity dementia, although some reviews of pharmacological interventions (eg, acetylcholinesterase inhibitors) included a big number of participants with astringent dementia. The duration of unlike interventions varied from days to months and a large number of outcome assessment measures were used to assess ADL function.
Methodological quality of included reviews
The quality of the included review reflects the rigour and transparency of the review team rather than the quality of evidence for the intervention arroyo. Well-nigh of the reviews (65%) were of high quality (scores ≥viii/11) every bit assessed using the AMSTAR tool (tabular array 1). High-quality reviews were for latrepirdine, light therapy, exercise, aromatherapy, pharmacotherapies for sleep, example management, cognitive stimulation therapy, huperzine A, lecithin, selegiline and nimodipine. Still, in that location were besides ii lower quality reviews (scoring 5 or less on AMSTAR). Low-quality reviews were for M. biloba and dyadic interventions.
Quality of testify in included reviews
While the authors of this overview did non reassess the risk of bias of principal studies included in the reviews, it was necessary to examine the quality of these studies equally adamant by the original review authors to determine the overall quality of the evidence using Class. It can be seen from figure 2 that studies in well-nigh of the reviews had a risk of bias resulting in downgrading of the quality overall.
The quality of evidence for all non-pharmacological interventions was low with the exception of nutritional supplementation for which the evidence base was of moderate quality. The quality of testify for pharmacological interventions ranged from depression (latrepirdine) to high (statins). In dissimilarity, culling therapies had very low (huperzine A, One thousand. biloba, acupuncture)-to-moderate (vitamins B) evidence.
Effect of interventions
Effects are presented in table 2. Non-pharmacological interventions: two not-pharmacological interventions demonstrated a meaning issue in reducing to functional decline in people with dementia. Exercise had a big magnitude of effect (vi studies, 289 participants, SMD 0.69, 95% CI 0.08 to 1.27) withal the quality of prove was depression due to a risk of bias in some studies and the limited number of participants in the assay. Dyadic interventions, in which the therapeutic intervention aims to engage the person with dementia and their carer in maximising quality of life (utilising interventions, defined broadly as psychosocial simply which too included meaningful activities, daily living activities and ecology adaptations) were also associated with a pregnant positive effect on ADL (eight studies, 988 participants, SMD 0.37, 95% CI 0.05 to 0.69). Again, a number of studies were at risk of bias and there were mixed findings amongst studies. There was insufficient evidence to conclude whether or not the other intervention approaches were effective due to the small number of studies and the low quality of evidence.
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Table 2
Furnishings of interventions as reported in the included systematic reviews
Pharmacological interventions: two pharmacological interventions demonstrated a pregnant effect on ADL function. The use of acetylcholinesterase inhibitors or memantine was associated with a pocket-size simply statistically pregnant effect on role (12 studies, 4661 participants, donepezil 5 mg SMD 0.xviii, 95% CI 0.10 to 0.46; donepezil 10 mg SMD 0.xviii, 95% CI 0.03 to 0.32; galantamine 24 mg SMD 0.15, 95% CI 0.04 to 0.25; rivastigmine 12 mg SMD 0.19, 95% CI 0.02 to 0.36). Overall, the testify for acetylcholinesterase inhibitors and memantine was of moderate quality. Effect sizes varied slightly according to the specific amanuensis and dose used, although the effect size was consistently pocket-sized. Selegiline was also found to accept a small-scale statistically significant consequence on ADL function at 8–17-calendar week follow-up (vii studies, 810 participants, SMD 0.27, 95% CI 0.13 to 0.41). Studies were at gamble of bias and at that place were mixed findings between studies hence the quality of bear witness was low.
Alternative therapies: 2 of the alternative therapies were reported to significantly better ADL office. Huperzine A was reported to be effective although this was based on merely two studies (ii studies, 70 participants, SMD ane.48, 95% CI 0.95 to 2.02). Furthermore, the studies included in the review were at a high gamble of bias due to unclear allotment concealment, possible selective reporting and gamble of incomplete outcome data in both of the studies, and possible non-blinded upshot assessor in one of the studies. In addition, the outcome measure used in the pooled analysis in the review is not clearly reported. Overall, the quality of evidence for huperzine A was considered very low. G. biloba was also reported to exist effective in the included systematic review, however it was as well associated with very low-level evidence; the quality of the systematic review (AMSTAR=3/11) and the included studies was low (seven studies, 2530 participants, SMD 0.36, 95% CI 0.28 to 0.44). Furthermore, although in that location were vii included studies in the review, the findings were inconsistent between the studies.
Discussion
This overview identified 23 systematic reviews (including 84 studies reporting on ADL performance outcomes). These reviews addressed a range of dissimilar interventions that may be considered for use in people with dementia. Of the 23 interventions reviewed, only six were reported to be successful in reducing functional decline. Acetylcholinesterase inhibitors and memantine, pharmacological agents that are widely used in treating dementia, were assuredly demonstrated to improve the ADL (based on moderate quality evidence), although the effect sizes were small. The quality of the evidence was considered depression for two non-pharmacological approaches (practice and dyadic psychosocial interventions), nonetheless the effect sizes were small-to-moderate, suggesting that more research is required to confirm effect on ADL. Evidence was very low for the two alternative therapies (huperzine A and G. biloba) indicating that the findings of improving ADL should be interpreted with extreme caution for these therapies. In addition, we establish insufficient evidence to conclude that the remaining intervention approaches are ineffective due to the lack of studies examining each arroyo and poor methodological quality of existing studies. While caution is required, due to the absenteeism of effective treatment options and trajectory of functional turn down associated with dementia, it is recommended that after consideration of potential benefits, harms and costs, health professionals consider prescription of acetylcholinesterase inhibitors/memantine as a method of reducing functional decline. Furthermore, the furnishings of exercise and dyadic interventions are thought to be greater and they are not associated with side effects, therefore these interventions should be routinely recommended for people with dementia.
The magnitude of the effect sizes of the interventions demonstrated to be constructive were considered pocket-size to moderate.51 Thus, while the intervention may significantly improve performance of the ADL, the effect may non be strong plenty to impact on outcomes of institutionalisation, carer impact or quality of life. Two recent systematic reviews revealed that but a small number of studies have been shown to amend quality of life for people with dementia.52 ,53 The reviews constitute that carer interventions and dyadic interventions for people living in private dwellings and cognitive stimulation therapy for people in group homes had the best evidence for positively impacting on quality of life.52
The number of studies, peculiarly of pharmacological agents, that measured the impact on ADL was generally small. Interventional studies in dementia research frequently focus on outcomes of cerebral role equally the key symptoms of dementia, specially in the earlier phases of the condition, are cognitive. All the same, studies should as well examine impact on ADL office every bit improvements in cognitive role may not translate to gains in ADL performance or other patient-important outcomes such as quality of life. For example, the included review of acetylcholinesterase inhibitors and memantine included 23 studies of which only 12 looked at the result of the interventions on ADL function.27 Similarly, the included review of practise comprised 16 RCTs; nine of the studies reported cognitive outcomes, whereas merely six reported ADL office outcomes despite the expectation that this would exist a key expected result of any exercise programme.16
The interventions that were constitute to have a significant effect on ADL function should not be difficult to implement routinely for people with dementia as they are accessible in most Western countries. However, health professionals should note that the non-pharmacological interventions that were effective (exercise and dyadic interventions) involved regular participation. Exercise programmes ranged in frequency from 2 to 5 times per week and were programmed over a minimum of vii weeks. Dyadic interventions were scheduled over a number of handling sessions. Information technology should be noted that the interventions reduced functional decline relative to the control group rather than leading to improvements in functional operation compared with the baseline, indicating a slowing of functional decline rather than prevention.
The number of research trials evaluating the efficacy of acetylcholinesterase inhibitors is big relative to research conducted in other aspects of dementia treatment. Published studies consistently demonstrate a positive consequence on noesis and ADL function. Clinicians need to consider the potential bias of the inquiry in this field given that many of the studies were funded by pharmaceutical companies. Killin et al54 conducted a meta-analysis examining the differences in findings betwixt industry-funded and independent RCTs of donepezil and found that studies sponsored past pharmaceutical companies reported a larger outcome on standardised cognitive tests than independent research groups.
Policymakers should consider the results of this review and implications for practice. For example, in Australia, while the government spends a large corporeality of money subsidising acetylcholinesterase inhibitors and memantine (over $threescore million per year55), there is less money invested in ensuring people with dementia tin can access appropriate exercise programmes or dyadic interventions, which may be associated with other benefits such as improved cardiovascular health, reduced carer burden and increased community participation.
The benefit of conducting an overview is that it provides a wide-ranging perspective on the intervention approaches available and their relative efficacy. Ane of the limitations of this arroyo is that the most recently published primary studies are not captured. However, the search dates of the included reviews were relatively contempo in virtually cases. Furthermore, while the body of enquiry for interventions in dementia care is slowly accumulating, in that location take not been any significant advances in the past couple of years that would alter routine intendance. Another limitation is that systematic reviews tend to examine unmarried-intervention approaches and therefore more circuitous multifactorial interventions (eg, physical exercise plus cognitive stimulation) take non been captured. In add-on, the detail of participants, intervention and results are less prominent at the level of overview and at that place is a niggling scope to delve into the details of the individual interventions. The findings of this review suggest that clinicians should familiarise themselves with the details of the type of exercise and dyadic interventions thought to be most effective.16 ,thirty
This particular overview did not seek to identify boosted trials that may take been missed in the 'included' systematic review and excluded reviews in languages published other than English language. Furthermore, we merely included RCTs which restricted the number of studies included and data that tin be drawn upon. The results of this overview highlight effective approaches but practise not provide much needed information around price-effectiveness equally economic evaluations in dementia care are scarce.56
At that place is clearly more work to be performed in both developing interventions to filibuster functional turn down and testing interventions to provide more show around the type of approaches that are most constructive and for whom. For instance, the review on exercise failed to provide recommendations about the type of exercise or population most probable to benefit due to the heterogeneity of studies.
In decision, at the current time in the absence of disease-modifying treatments for dementia, health professionals should attempt to minimise functional decline in people with dementia by considering prescription of acetylcholinesterase inhibitors and memantine, and recommending exercise and dyadic interventions.
Acknowledgments
The authors thank Dr Enwu Liu for creating the graphic (figure 2).
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