Systematic reviews on behavioural and psychological symptoms in the older or demented population

Introduction Behavioural and psychological symptoms of dementia (BPS) include depressive symptoms, anxiety, apathy, sleep problems, irritability, psychosis, wandering, elation and agitation, and are common in the non-demented and demented population. Methods We have undertaken a systematic review of reviews to give a broad overview of the prevalence, course, biological and psychosocial associations, care and outcomes of BPS in the older or demented population, and highlight limitations and gaps in existing research. Embase and Medline were searched for systematic reviews using search terms for BPS, dementia and ageing. Results Thirty-six reviews were identified. Most investigated the prevalence or course of symptoms, while few reviewed the effects of BPS on outcomes and care. BPS were found to occur in non-demented, cognitively impaired and demented people, but reported estimates vary widely. Biological factors associated with BPS in dementia include genetic factors, homocysteine levels and vascular changes. Psychosocial factors increase risk of BPS; however, across studies and between symptoms findings are inconsistent. BPS have been associated with burden of care, caregiver's general health and caregiver depression scores, but findings are limited regarding institutionalisation, quality of life and disease outcome. Conclusions Limitations of reviews include a lack of high quality reviews, particularly of BPS other than depression. Limitations of original studies include heterogeneity in study design particularly related to measurement of BPS, level of cognitive impairment, population characteristics and participant recruitment. It is our recommendation that more high quality reviews, including all BPS, and longitudinal studies with larger sample sizes that use frequently cited instruments to measure BPS are undertaken. A better understanding of the risk factors and course of BPS will inform prevention, treatment and management and possibly improve quality of life for the patients and their carers.


Introduction
Behavioural and psychological symptoms (BPS) include depressive symptoms, anxiety, apathy, sleep problems, irritability, psychosis, wandering, elation and agitation. They are common in people with dementia, but are not restricted to this group [1]. BPS have public policy implications as they impact upon quality of life of older people and their carers, and influence prescribing and use of services [2,3].
Systematic reviews are an important tool for summarising the available evidence regarding a specific topic, permitting policy decisions to be based on representative literature. They allow researchers to focus on areas where information is most lacking, and allow more reliable interpretation of research findings. A review of reviews, therefore, serves two important purposes: first, summarising the evidence base on a subject beyond the scope of a single review, and second, highlighting areas where the literature is inadequate and where additional reviews are required. While the prevalence, course, biological and psychosocial associations, care and outcomes of BPS have been the subject of systematic reviews, the findings from these different reviews have not been brought together in this way. Given the broad research focus on BPS, including underlying causes, association with dementia risk, and impact on care, and the large number of studies published in this area, any single systematic review of the primary literature can only explore a narrow range of objectives. This paper presents a systematic 'review of reviews' of the literature on BPS in older people. Combining current knowledge across the multiple domains of BPS research provides a broad overview of what is known and identifies gaps where reviews have not been conducted [4]. Bringing together the conclusions of the reviews, we provide recommendations for future research and highlight areas where the evidence base with respect to BPS in the older population should be strengthened. In addition, we discuss the recommendations for future research made by the reviews.

Scope of review
BPS are related to cognitive impairment and dementia. So-called "behavioural and psychological symptoms of dementia", BPSD, are commonly studied within this subpopulation, but BPS can also occur in older people without significant cognitive impairment. Traditionally these are considered as phenomena distinct to BPSD; however, BPS in a cognitively healthy older person may indicate early dementia, and certain BPS, for example, depression, may be risk factors for dementia. Continuities in BPS are seen 'pre' and 'post' diagnosis, and common biological and psychosocial risk factors for BPS may exist among the cognitively healthy and cognitively impaired older populations. For this reason the scope of our review includes studies of BPS in the older population with or without cognitive impairment or dementia. We included reviews of the prevalence, the causes and consequences of BPS.
Owing to the breadth of literature and the specialist treatment required to review certain kinds of study, there are some limitations to the scope of this review. We did not include reviews that focused on pharmacological or non-pharmacological treatment of symptoms. Depression is a heterogeneous disorder ranging from mild symptoms to major depressive disorder. Depression is common in the older population with dementia and can be studied in the context of other BPS, but is also seen in the older population without dementia ( Figure 1). Depression in the older population without dementia has been studied widely since it was first described in 1896 [5,6]. The term BPSD was introduced by the International Psychogeriatric Association in 1996 [7]. Although they have been identified since the earliest descriptions of dementia, research only moved to BPSD in the 1980s with the development of instruments to measure BPSD [8,9]. Depression as a BPSD and depression in the older population without dementia have largely been separate research areas. Here, we focused on depressive symptoms below the threshold for depressive disorder. We excluded reviews that studied only major or clinical depression and included reviews that studied both major depression and minor depression, depressive symptoms or minor depression only or depressive symptoms in the context of other BPS.

Search methods
Embase and Medline were searched for potentially relevant articles published before 29 March 2012. Search terms included Emtree terms and text searches for each individual BPS and BPS in general (see Additional file 1), and Dementia (Emtree) or Aged (Emtree). Additional articles were identified from reference lists of included studies and relevant narrative reviews.

Data collection
All systematic reviews written in English of one or more BPS in the older non-demented or demented population were included. A systematic review was defined as used by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement: "A review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant research, and to collect and analyse data from the studies that are included in the review. Statistical methods (meta-analysis) may or may not be used to analyse and summarise the results of the included studies" [10]. Specific symptoms included depressive symptoms (including sadness, tearfulness, being unhappy, depressed feeling, suicidal feelings), anxiety (including feelings and physical signs of anxiety, worrying, being frightened), apathy (including listlessness, loss of interest, slowing), sleep problems (includes reduced sleep, increased sleep, change in sleep, tiredness), irritability (including being irritable or angry, verbal and physical aggression), psychosis (including delusion and hallucination), wandering (including wandering away, getting lost, aimless wandering), elation (including euphoria, inappropriate laughing) and non-aggressive agitation (including restlessness, repetitive behaviour).
RvdL selected articles through a multi-step screening process first based upon the assessment of the title and the abstract, followed by assessment of the article content. Information from each potential article was extracted by RvdL using a standardised form, recording: the BPS investigated, population, date of publication and literature search, number of studies reviewed and if a meta-analysis was performed. Reviews were divided by the following themes: prevalence, progression, course, biological associations, risk factors, care, quality of life and disease outcome. Results were summarised using the abstract. A list of recommendations for future research (for example, "future research should", "we recommend", "is needed") and limitations of the original studies and review as reported by the reviews in their discussion section was generated. The quality of the included reviews was assessed using AMSTAR, a validated measurement tool (Shea et al. 2007, Ottawa, Ontario, Canada) to assess the methodological quality of systematic reviews [11,12].

Quality
The quality assessment for each included review is shown in Table 3. Generally, review quality was low, with only 7 of the reviews scoring positive on 5 of the 11 components and meeting the criteria for moderate scientific quality (5 to 8 points). All other reviews scored less than five points.

Narrative description by theme Prevalence of BPS
Two reviews [21,22] of BPS in populations with mild cognitive impairment (MCI) reported an overall symptom prevalence ranging from 35 to 75% and 35 to 85%. Depressive symptoms, anxiety and irritability were the most commonly observed symptoms, followed by apathy and agitation. Hospital-based samples of MCI cases reported a higher mean prevalence of any BPS than population-based studies [21]. In people with dementia in long term care the prevalence of one or more BPS was 78% [23]. The mean reported prevalence of psychosis in dementia was 41% [27].
Reviews of the prevalence of BPS in the older population without dementia were available only for depression. The prevalence of depressive disorders in the older population without dementia has been estimated to be 17.1% (95% CI 9.7 to 26.1), in a meta-analysis of moderate scientific quality [28]. Other studies reported a high variability in the prevalence reported in included studies ranging from 14 to 82% [23], 14 to 16% [20], 0 to 35% [58] and 7 to 49% [31]. A lower prevalence has been reported in community settings than in primary care and long term care settings [30].
Most reviews found considerable variability in reported prevalence, possibly due to heterogeneity in methodology, thereby limiting the ability to compare  Original studies -Uncertainty of etiologic diagnosis of dementia        Can't answer Can't answer Alwahhabi [32] Can't answer Can't answer Apostolova [22] Can't answer Can't answer Can't answer Can't answer Can't answer Beekman [29] Can't answer Can't answer Black [52] Can't answer Can't answer Can't answer Djernes [31] Can't answer Can't answer Can't answer Can Fischer [55] Can't answer Can't answer Can't answer Floyd [40] Can't answer Can't answer Can't answer Floyd [39] Can't answer

Yes
Can't answer Kuo [41] Can't answer Can't answer  Table 3 Methodological quality of systematic reviews assessed with the AMSTAR measurement tool (Continued) Lee [54] Can't answer Can't answer Can't answer Ohayon [38] Can't answer Can't answer Can't answer Can't answer Can't answer Can't answer Shub [25] Can't answer Can't answer Vink [49] Can't answer Can't answer Can't answer Can't answer Can't answer

No
Can't answer No  Yes  No  No  Not applicable  No  No  2  Low Response options: yes, no, can't answer, not applicable.

Longitudinal course and association with cognitive decline
Monastero et al. reported that prospective studies showed that BPS, particularly depression, might represent risk factors for MCI or predictors of MCI conversion to dementia [21]. A review of moderate scientific quality failed to find evidence of an association between depressive symptoms and severity of dementia [34]. A review on psychotic symptoms suggested that these symptoms increase with the development of dementia but plateau after three years [59].
Few reviews on BPS course have been conducted in the older population. Huang et al. reported that compared to individuals without cognitive impairment, incidence and prevalence of depression was higher in those with cognitive impairment or dementia. Meeks et al. found that depression was relatively stable in the older population, with a median remission of 27% after more than one year [30]. Three reviews by Jorm et al. concluded that history of depression in cognitively normal persons was associated with increased risk of dementia [33,36,37,60]. Sleep problems including sleep latency and waking after sleep were common with increasing age, but only sleep efficiency continued to significantly decrease after age 60 [38][39][40].
The reviews identified a need for more longitudinal studies using standardised measures of cognitive function and BPS and appropriate adjustment for confounding factors.

Biopsychosocial associations
Biological factors A systematic review shows inconsistent results for genetic associations, including genes coding for APOE E, serotonin receptors and transporter, COMT, MAO-A, tryptophan hydroxylase and dopamine receptors with BPS in individuals with dementia [42]. No other reviews were found.
In the general older population, most reviews of biological correlates of BPS focus on depression. An association between high levels of homocysteine and depression and dementia has been reported [41,45]. Stetler et al. suggest an association between depression and cortisol and other hormones [46]. In addition, cerebral atherosclerotic changes may result in cognitive impairment and depression, possibly mediated by C-reactive protein but results were not consistent [47]. The association between vascular factors and depression was further studied and discussed in a review by Camus et al. [48].
Recommendations for future research include prospective studies with large sample sizes further investigating the association with biological factors. Risk factors In nursing home patients with cognitive impairment, BPS were associated with the psychosocial environment, in addition to dementia type and stage and medication use [24]. In dementia patients, psychosis has been associated with age, illness duration and functional impairment, whereas results are weak or inconsistent for sociodemographic variables [27].
In two moderate quality reviews of the older population by Huang et al., depression was reported to be common in those with poor self-rated health, disability and chronic disease, including stroke, sensory impairment, cardiac disease or chronic lung disease [43,44]. Depression is more common in women, and has been associated with many risk factors, including other diseases, low social support, cognitive impairment, disability, prior depression and bereavement [20,[29][30][31]49,50]. Vink et al. report that health factors were less clearly related to anxiety than to depression [49]. Psychosocial associations of other BPS have not been reviewed.
More research is recommended on risk factors for depression and randomised controlled trials to investigate if manipulation of risk factors reduces the onset of BPS.

Outcomes and care
Some evidence suggests that BPS predicts nursing home placement in those with dementia [51]. Burden of care, caregiver's general health and caregiver depression scores have been associated with BPS, but perhaps caregiver's perception of the BPS and caregiver's social and psychological resources prior to institutionalisation are more important factors [52]. Lee et al. concluded that there was no consensus regarding the association between BPS and increased mortality in individuals with dementia [54]. Studies of associations between delusions in dementia and functional outcome had inconsistent results [55]. Finally, depression has been associated with decreased health related quality of life in dementia, although the size of the association was moderate [53].
Depression in the general older population has been associated with increased health care utilisation and expenditure [30]. In addition, anxiety in the elderly has been reported to have negative consequences independently of depression [32].
The reviews recommend more research with better measurements of determinants and outcomes and more sophisticated techniques to analyse the association with disease outcomes.

Summary: limitations and recommendations
Overall, the reviews reported several limitations of the original studies, including heterogeneity in methodology, insufficient adjustment for confounders, heterogeneity in BPS instruments and definitions, small sample size and that most studies were cross-sectional ( Figure 2). This led to recommendations for prospective longitudinal studies, with a large sample size and using standardised BPS instruments and definitions. The following topics for future research were most often recommended, including intervention and treatment, mechanisms and underlying causes of BPS and the prevalence, incidence and persistence of BPS. Many reviews reported that comparison of results was limited due to heterogeneity of the included studies. Figure 3 gives an overview of the number of reviews that studied each BPS by the topic of the review. Most of the included reviews focused on individuals with dementia or cognitive impairment studied depression or psychotic symptoms, and they most often studied the prevalence of symptoms. Of the reviews of older populations, almost all studied depressive symptoms and some studied sleep problems or anxiety, whereas the other BPS were not investigated.

Summary of findings
• Prevalence. BPS occur in non-demented, cognitively impaired and demented populations, but there are large variations in reported prevalence estimates.
• Biological associations. Biological factors associated with BPS include health status, homocysteine levels and vascular disease.
• Risk factors. Associations have been found with psychosocial environment and dementia severity. Results are inconsistent, especially for socio-demographic factors, and differ between symptoms.
• Outcomes and care. BPS have been associated with increased burden of care, decreased caregiver's general health and increased caregiver depression scores, but

Methods recommended for future studies Topics recommended for future studies
Prospective longitudinal studies, n = 13 Large sample size, n = 8 Standardised instruments, n = 7 Different populations, n = 3 Include oldest old, n = 3 Improved comparability, n = 3 Interventions and treatment, n = 8 Mechanisms, biological factors and underlying causes BPS, n = 5 Prevalence, incidence and persistence, n = 3

Limitations of original studies Limitations of reviews as reported by the as reported by the included reviews reviews
Heterogeneity in methodology, n = 9 Confounder issues, n = 7 Heterogeneity in BPS instruments and definitions, n = 6 Small sample size, n = 5 Majority cross-sectional and correlational, n = 5 Selection bias, n = 4 Diagnosing of dementia and cognition, n = 3 Comparison or metaanalysis limited due to heterogeneity studies, n = 11 Limitations search, n = 7 Confounder issues, n = 4 Publication bias, n = 3 Figure 2 Overview of the recommendations and limitations reported by the included reviews. In total, 36 reviews were included in the review of reviews. Only recommendations and limitations reported by three or more reviews are included in the figures. Reviews that make multiple recommendations or limitations may be included more than once.
these conclusions come from a limited number of studies. Findings in relation to BPS and institutionalisation, quality of life and disease outcome are generally inconsistent.

Limitations of reviews
Over 97,000 articles have been published on BPS in recent years (up to July 2011). However, in total, only 36 systematic reviews were identified, published from Course Biological 3 or more reviews 1 or 2 reviews No reviews Figure 3 Number of reviews that reported on each symptom by the topic of the review. Agg, aggression; Agi, agitation; Anx, anxiety; BPS, behavioural and psychological symptoms; Dep, depressive symptoms; Ela, elation; Psy, psychosis; Sle, sleep problems; Wan, wandering; In total 36 reviews were included in the review of reviews. Reviews that report on multiple topics or more than one BPS are included more than once. 1989 to 2011, covering 6 to 244 papers, with only 10 reviews, including a meta-analysis. These covered a wide area of research and included studies with large differences in population characteristics, recruitment and definition of BPS. Depressive symptoms were most widely reviewed. Other symptoms, such as apathy, irritability, wandering and elation, are typically ignored, especially in studies of the older population. Aggression, psychosis and wandering have been identified as the BPS that are most difficult to cope with by caregivers [61]. Not all areas of BPS research have yet been adequately reviewed. For example, no review has yet appeared on the neuropathology underpinning BPS, although there are several recent studies on this subject and many possible biological mechanisms may underlie BPS, such as Alzheimer's disease pathology, lower neuronal counts, neurotransmitter changes, genetic risk factors and abnormal neuroendocrinology [62][63][64]. A high quality systematic review of the biological underpinnings of BPS would give direction to further research, particularly with regard to treatment development.

Reviews that reported on demented or cognitively impaired populations
The quality of the included reviews as measured with the AMSTAR tool was generally low. All except one did not report if the research question and inclusion criteria were established before the conduct of the review, or they did not provide a research question and/or inclusion criteria. Many reviews did not have two independent researchers who selected the studies and extracted the data, or did not report this. None of the reviews reported the potential conflict of interest of the included studies. Furthermore, the inclusion of grey literature and if the search was supplemented by consulting current contents, reviews, textbooks, specialised registers or experts were rarely reported.
Better and more systematic reporting would make it easier to compare the characteristics, results and strengths and limitations of reviews, and the use of reporting checklists, such as PRISMA, is recommended [65]. More details on the populations covered by the review and the characteristics of included studies would be particularly helpful.
Recommendations for future research made by the reviews were variable, with many recommendations made only by one or two reviews. Only more general recommendations were made by several reviews. This has been previously reported by Clark et al., who examined 2,535 Cochrane reviews and found that the characterisation of the needs for future research was less than explicit [66]. In addition, it has been previously found that reviews tend to be too optimistic when drawing conclusions from their results [67,68]. It has been recommended that research gaps should be identified more systematically, rating the reasons of research gaps in terms of population, intervention, comparison, outcome and setting (PICOS), including insufficient information, biased information, inconsistency or not the right information [69], although this tool has been designed for reviews of intervention studies and may not be suitable for reviews of observational studies.

Limitations of original studies
The reviews have included individual research studies with a large degree of heterogeneity in study design (for example, definition and measurement of BSP, level of cognitive impairment, population characteristics and recruitment of participants), making cross study comparisons difficult. Many different instruments are used to measure BPS, including the Neuropsychiatric Inventory (NPI) [70], CERAD-BRSD [71] and the Behavioral Pathology in Alzheimer's Disease scale (BEHAVE-AD) [72]. Symptom-specific instruments are also used, including the Geriatric Depression Scale (GDS) for depressive symptoms [73]. Some instruments use self-ratings (for example, GDS), while others are based on a caregiver interview (for example, NPI). Across instruments there is no consistency in the definition and severity of the symptoms.
Some studies focused on the general older population, while others selected only those with dementia or MCI. Even within impaired groups large differences exist in the measurement of cognitive function. Some study populations were divided by cognitive status (for example, normal, mild or other cognitive impairment and dementia) using diagnostic criteria applied independently of BPS. It may be that the phenotypes of BPS (for example, the causes of depression or agitation) have a different basis at different stages of cognitive impairment and, therefore, studies using different groups will have discrepant findings. Other features, such as the age and gender of participants, and the setting where they were recruited, also vary. If samples are not representative of the population (either that of older people in the community or people with dementia) conclusions may be difficult to generalise.

Limitations of our review of review
There is no Mesh or Emtree search term for BPS, so search terms for individual symptoms and text searches had to be combined. As many different terms are used to describe BPS, it is possible that we may have missed relevant reviews, though we have checked all reference lists of relevant papers. One author undertook data selection and extraction.
Many different definitions of BPS have been used in the literature. Here we used symptom definitions as used by the most commonly used instruments to measure BPS, including the NPI. However, symptom definitions may overlap and there was heterogeneity in symptom definitions that were used by the reviews. Depression is especially problematic. All of the reviews van der Linde et al. Alzheimer's Research & Therapy 2012, 4:28 http://alzres.com/content/4/4/28 included here that studied depression included studies investigating major depression as well as studies investigating depressive symptoms. In the original studies, decisions about depression can be made at recruitment, when applying the inclusion and exclusion criteria or during measurement at baseline and follow-up. In some studies, only people with or without depressive symptoms or major depression are recruited, or participants with major depression can be excluded from the study at the participant selection stage. At the data collection stage, the definition of depression can include both major depression and minor depression using a cut-off score (for example, a CES-D score higher than 16); it can include both depressive symptoms and major depression separately (for example, DSM definitions for major and minor depression or CES-D scores 16 to 20 and CES-D higher than 20), or either depressive symptoms only (for example, using the Neuropsychiatric Inventory to measure depressive symptoms in the context of BPSD) or major depression only (for example, DSM definition for major depression).
By reviewing reviews and not the original studies, it is likely that noise has been introduced. Furthermore, with the diverse and generally qualitative outcomes of the majority of reviews, we were unable to combine results quantitatively and, therefore, a meta-meta-analysis was not possible.

Recommendations for future research
Recommendations for future reviews on BPS: • More reviews on BPS are needed, for example, on neuropathological associations • Improve the quality of reporting of reviews • Choose reviews that include all BPS not just symptoms of depression/psychosis • Clearer reporting, using a checklist tool, for example, PRISMA • Clearer and more specific recommendations for future research, for example, PICOS if applicable Recommendations for original research on BPS: • Prospective longitudinal studies • Large sample size • Standardised instruments for BPS • Wide age range, including oldest old • Improved comparability of results; report study characteristics clearly Republic of Ireland. 3 Cambridgeshire and Peterborough NHS Foundation Trust, Box 311, Fulbourn Hospital, Cambridge CB21 5EF, UK.