A pragmatic, multicentre, double-blind, placebo-controlled randomised trial to assess the safety, clinical and cost-effectiveness of mirtazapine and carbamazepine in people with Alzheimer's disease and agitated behaviours: the HTA-SYMBAD trial.

Background: Agitation is common and impacts negatively on people with dementia and carers. Non-drug patient-centred care is first-line treatment, but we need other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics. Objectives: To assess clinical and cost-effectiveness and safety of mirtazapine and carbamazepine in treating agitation in dementia. Design: Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine over 12 weeks (carbamazepine arm discontinued). Setting: Twenty-six UK secondary care centres. Participants: Eligibility: probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, Cohen-Mansfield Agitation Inventory score ≥ 45. Interventions: Mirtazapine (target 45 mg), carbamazepine (target 300 mg) and placebo. Outcome measures: Primary: Cohen-Mansfield Agitation Inventory score 12 weeks post randomisation. Main economic outcome evaluation: incremental cost per six-point difference in Cohen-Mansfield Agitation Inventory score at 12 weeks, from health and social care system perspective. Data from participants and informants at baseline, 6 and 12 weeks. Long-term follow-up Cohen-Mansfield Agitation Inventory data collected by telephone from informants at 6 and 12 months. Randomisation and blinding: Participants allocated 1 : 1 : 1 ratio (to discontinuation of the carbamazepine arm, 1 : 1 thereafter) to receive placebo or carbamazepine or mirtazapine, with treatment as usual. Random allocation was block stratified by centre and residence type with random block lengths of three or six (after discontinuation of carbamazepine, two or four). Double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, trial management team and research workers who did assessments were masked to group allocation. Results: Two hundred and forty-four participants recruited and randomised (102 mirtazapine, 102 placebo, 40 carbamazepine). The carbamazepine arm was discontinued due to slow overall recruitment; carbamazepine/placebo analyses are therefore statistically underpowered and not detailed in the abstract. Mean difference placebo-mirtazapine (-1.74, 95% confidence interval -7.17 to 3.69; p = 0.53). Harms: The number of controls with adverse events (65/102, 64%) was similar to the mirtazapine group (67/102, 66%). However, there were more deaths in the mirtazapine group (n = 7) by week 16 than in the control group (n = 1). Post hoc analysis suggests this was of marginal statistical significance (p = 0.065); this difference did not persist at 6- and 12-month assessments. At 12 weeks, the costs of unpaid care by the dyadic carer were significantly higher in the mirtazapine than placebo group [difference: £1120 (95% confidence interval £56 to £2184)]. In the cost-effectiveness analyses, mean raw and adjusted outcome scores and costs of the complete cases samples showed no differences between groups. Limitations: Our study has four important potential limitations: (1) we dropped the proposed carbamazepine group; (2) the trial was not powered to investigate a mortality difference between the groups; (3) recruitment beyond February 2020, was constrained by the COVID-19 pandemic; and (4) generalisability is limited by recruitment of participants from old-age psychiatry services and care homes. Conclusions: The data suggest mirtazapine is not clinically or cost-effective (compared to placebo) for agitation in dementia. There is little reason to recommend mirtazapine for people with dementia with agitation. Future work: Effective and cost-effective management strategies for agitation in dementia are needed where non-pharmacological approaches are unsuccessful. Study registration: This trial is registered as ISRCTN17411897/NCT03031184. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 23. See the NIHR Journals Library website for further project information.

It is common for people with Alzheimer's disease to experience agitation, for example feeling restless or unsettled. If left untreated, agitation can lead to poorer quality of life and increased hospitalisation and strain for family carers. Often these symptoms are treated with medications that are usually used to manage psychosis (antipsychotic drugs), but such medication has limited effectiveness and can cause serious adverse effects to patients, including risk of increased death. Two medications that are already commonly prescribed for other health issues, mirtazapine (an antidepressant) and carbamazepine (a drug used to treat epilepsy), had been identified as a possible alternative way of treating agitation in Alzheimer's disease that might not have the harms associated with antipsychotic medication. In this study, we compared the effects of giving mirtazapine or carbamazepine with a dummy drug (placebo) in people with Alzheimer's disease who were experiencing agitation. The results of the study showed that neither medication was any more effective than the placebo in reducing agitation over 12 weeks in terms of improving symptoms, or in economic terms. Mirtazapine may lead to additional carer costs as compared to placebo. The study findings are stronger for mirtazapine than carbamazepine because the carbamazepine arm was stopped when it had recruited less than half the numbers needed. That was done because the study was not recruiting quickly enough to support both the mirtazapine and the carbamazepine arms. The findings from this study show that mirtazapine should not be recommended to treat agitation in Alzheimer's disease. More work is needed to formulate effective ways and to test new drug and non-drug treatments for agitation in dementia.

Cost-effectiveness of mirtazapine for agitated behaviors in dementia: findings from a randomized controlled trial.

OBJECTIVES: To examine the costs and cost-effectiveness of mirtazapine compared to placebo over 12-week follow-up. DESIGN: Economic evaluation in a double-blind randomized controlled trial of mirtazapine vs. placebo. SETTING: Community settings and care homes in 26 UK centers. PARTICIPANTS: People with probable or possible Alzheimer's disease and agitation. MEASUREMENTS: Primary outcome included incremental cost of participants' health and social care per 6-point difference in CMAI score at 12 weeks. Secondary cost-utility analyses examined participants' and unpaid carers' gain in quality-adjusted life years (derived from EQ-5D-5L, DEMQOL-Proxy-U, and DEMQOL-U) from the health and social care and societal perspectives. RESULTS: One hundred and two participants were allocated to each group; 81 mirtazapine and 90 placebo participants completed a 12-week assessment (87 and 95, respectively, completed a 6-week assessment). Mirtazapine and placebo groups did not differ on mean CMAI scores or health and social care costs over the study period, before or after adjustment for center and living arrangement (independent living/care home). On the primary outcome, neither mirtazapine nor placebo could be considered a cost-effective strategy with a high level of confidence. Groups did not differ in terms of participant self- or proxy-rated or carer self-rated quality of life scores, health and social care or societal costs, before or after adjustment. CONCLUSIONS: On cost-effectiveness grounds, the use of mirtazapine cannot be recommended for agitated behaviors in people living with dementia. Effective and cost-effective medications for agitation in dementia remain to be identified in cases where non-pharmacological strategies for managing agitation have been unsuccessful.

A cohort study of the impact of COVID-19 on the quality of life of people newly diagnosed with dementia and their family carers.

Introduction: COVID-19 has impacted people with dementia and their family carers, yet little is known about effects on overall quality of life. Methods: In a UK cohort study, pre- and post-pandemic data were collected from 114 carers and 93 recently diagnosed people with dementia. Latent growth curve modeling examined change in quality of life. Results: Carers reported significant decline in quality of life, although no change was demonstrated by people with dementia. In multivariable analyses, higher levels of cognitive impairment, deprivation, study site, and lower number of memory clinic contacts were associated with greater decline in carer quality of life. Discussion: Maintaining life quality for people with dementia during the pandemic appears to have come at the expense of their family carers. This inequity has fallen hardest on those caring for people with more severe dementia, in deprived areas, and with least support from memory services. These effects may be prevented or reversed by post-diagnostic care.

Assessment of autonomic symptoms may assist with early identification of mild cognitive impairment with Lewy bodies.

OBJECTIVES: Autonomic symptoms are a common feature of the synucleinopathies, and may be a distinguishing feature of prodromal Lewy body disease. We aimed to assess whether the cognitive prodrome of dementia with Lewy bodies, mild cognitive impairment (MCI) with Lewy bodies (MCI-LB), would have more severe reported autonomic symptoms than cognitively healthy older adults, with MCI due to Alzheimer's disease (MCI-AD) also included for comparison. We also aimed to assess the utility of an autonomic symptom scale in differentiating MCI-LB from MCI-AD. METHODS: Ninety-three individuals with MCI and 33 healthy controls were assessed with the Composite Autonomic Symptom Score 31-item scale (COMPASS). Mild cognitive impairment patients also underwent detailed clinical assessment and differential classification of MCI-AD or MCI-LB according to current consensus criteria. Differences in overall COMPASS score and individual symptom sub-scales were assessed, controlling for age. RESULTS: Age-adjusted severity of overall autonomic symptomatology was greater in MCI-LB (Ratio = 2.01, 95% CI: 1.37-2.96), with higher orthostatic intolerance and urinary symptom severity than controls, and greater risk of gastrointestinal and secretomotor symptoms. MCI-AD did not have significantly higher autonomic symptom severity than controls overall. A cut-off of 4/5 on the COMPASS was sensitive to MCI-LB (92%) but not specific to this (42% specificity vs. MCI-AD and 52% vs. healthy controls). CONCLUSIONS: Mild cognitive impairment with Lewy bodies had greater autonomic symptom severity than normal ageing and MCI-AD, but such autonomic symptoms are not a specific finding. The COMPASS-31 may therefore have value as a sensitive screening test for early-stage Lewy body disease.

Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia. METHODS: This parallel-group, double-blind, placebo-controlled trial-the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)-was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897. FINDINGS: Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference -1·74, 95% CI -7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065). INTERPRETATION: This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

Improving productivity, costs and environmental impact in International Eye Health Services: using the 'Eyefficiency' cataract surgical services auditing tool to assess the value of cataract surgical services.

OBJECTIVE: Though one of the most common surgeries, there is limited information on variability of practices in cataract surgeries. 'Eyefficiency' is a cataract surgical services auditing tool to help global units improve their surgical productivity and reduce their costs, waste generation and carbon footprint. The aim of the present research is to identify variability and efficiency opportunities in cataract surgical practices globally. METHODS AND ANALYSIS: 9 global cataract surgical facilities used the Eyefficiency tool to collect facility-level data (staffing, pathway steps, costs of supplies and energy use), and live time-and-motion data. A point person from each site gathered and reported data on 1 week or 30 consecutive cataract surgeries. Environmental life cycle assessment and descriptive statistics were used to quantify productivity, costs and carbon footprint. The main outcomes were estimates of productivity, costs, greenhouse gas emissions, and solid waste generation per-case at each site. RESULTS: Nine participating sites recorded 475 cataract extractions (a mix of phacoemulsification and manual small incision). Cases per hour ranged from 1.7 to 4.48 at single-bed sites and 1.47 to 4.25 at dual-bed sites. Average per-case expenditures ranged between £31.55 and £399.34, with a majority of costs attributable to medical equipment and supplies. Average solid waste ranged between 0.19 kg and 4.27 kg per phacoemulsification, and greenhouse gases ranged from 41 kg carbon dioxide equivalents (CO2e) to 130 kg CO2e per phacoemulsification. CONCLUSION: Results demonstrate the global diversity of cataract surgical services and non-clinical metrics. Eyefficiency supports local decision-making for resource efficiency and could help identify regional or global best practices for optimising productivity, costs and environmental impact of cataract surgery.

The Impact of Environment on Gait Assessment: Considerations from Real-World Gait Analysis in Dementia Subtypes.

Laboratory-based gait assessments are indicative of clinical outcomes (e.g., disease identification). Real-world gait may be more sensitive to clinical outcomes, as impairments may be exaggerated in complex environments. This study aims to investigate how different environments (e.g., lab, real world) impact gait. Different walking bout lengths in the real world will be considered proxy measures of context. Data collected in different dementia disease subtypes will be analysed as disease-specific gait impairments are reported between these groups. Thirty-two people with cognitive impairment due to Alzheimer's disease (AD), 28 due to dementia with Lewy bodies (DLB) and 25 controls were recruited. Participants wore a tri-axial accelerometer for six 10 m walks in lab settings, and continuously for seven days in the real world. Fourteen gait characteristics across five domains were measured (i.e., pace, variability, rhythm, asymmetry, postural control). In the lab, the DLB group showed greater step length variability (p = 0.008) compared to AD. Both subtypes demonstrated significant gait impairments (p < 0.01) compared to controls. In the real world, only very short walking bouts (<10 s) demonstrated different gait impairments between subtypes. The context where walking occurs impacts signatures of gait impairment in dementia subtypes. To develop real-world gait assessment as a clinical tool, algorithms and metrics must accommodate for changes in context.

DETERMinants of quality of life, care and costs, and consequences of INequalities in people with Dementia and their carers (DETERMIND): A protocol paper.

OBJECTIVES: DETERMIND (DETERMinants of quality of life, care and costs, and consequences of INequalities in people with Dementia and their carers) is designed to address fundamental, and, as yet unanswered questions about inequalities, outcomes and costs following diagnosis with dementia. These answers are needed to improve the quality of care and equity of access to care, and therefore the quality of life, of people with dementia and their carers. METHOD: DETERMIND is a programme of research consisting of seven complementary workstreams (WS) exploring various components that may result in unequal dementia care: WS1: Recruitment and follow-up of the DETERMIND cohort-900 people with dementia and their carers from three geographically and socially diverse sites within six months following diagnosis, and follow them up for three years. WS2: Investigation of the extent of inequalities in access to dementia care. WS3: Relationship between use and costs of services and outcomes. WS4: Experiences of self-funders of care. WS5: Decision-making processes for people with dementia and carers. WS6: Effect of diagnostic stage and services on outcomes. WS7: Theory of Change informed strategy and actions for applying the research findings. OUTCOMES: During the life of the programme, analysing baseline results and then follow-up of the DETERMIND cohort over 3 years, we will establish evidence on current services and practice. DETERMIND will deliver novel, detailed data on inequalities in dementia care and what drives positive and negative outcomes and costs for people with dementia and carers, and identify factors that help or hinder living well with dementia.

Neighborhood stress and autonomic nervous system activity during sleep.

Study Objectives: Stressful neighborhood environments are known to adversely affect health and contribute to health disparities but underlying mechanisms are not well understood. Healthy sleep can provide a respite from sustained sympathetic nervous system (SNS) activity. Our objective was to evaluate relationships between neighborhood stress and nocturnal and daytime SNS and parasympathetic nervous system (PNS) activity. Methods: Eighty-five urban-residing African Americans (56.5% female; mean age of 23.0) participated. Evaluation included surveys of neighborhood stress and sleep-related vigilance, and continuous electrocardiogram (ECG) and actigraphic recording in participants' homes from which heart rate variability (HRV) analysis for low frequency/high frequency (LF/HF) ratio and normalized high frequency (nHF), as indicators of SNS and PNS activity, respectively, and total sleep time (TST), and wake after sleep onset were derived. Results: All significant relationships with HRV measures were from the sleep period. Neighborhood disorder correlated negatively with nHF (r = -.24, p = .035). There were also significant correlations of HRV indices with sleep duration and sleep fears. Among females, LF/HF correlated with exposure to violence, r = .39, p = .008, and nHF with census tract rates for violent crime (r = -.35, p = .035). In a stepwise regression, TST accounted for the variance contributed by violent crime to nHF in the female participants. Conclusions: Further investigation of relationships between neighborhood environments and SNS/PNS balance during sleep and their consequences, and strategies for mitigating such effects would have implications for health disparities.

Feasibility of a staff training and support programme to improve pain assessment and management in people with dementia living in care homes.

OBJECTIVES: The objective of this study was to establish the feasibility and initial effectiveness of training and support intervention for care staff to improve pain management in people with dementia living in care homes (PAIN-Dem). METHODS: PAIN-Dem training was delivered to care staff from three care homes in South London, followed by intervention support and resources to encourage improved pain management by staff over 4 weeks. Feasibility was assessed through fidelity to intervention materials and qualitative approaches. Focus group discussions with staff explored the use of the PAIN-Dem intervention, and interviews were held with six residents and family carers. Pain was assessed in all residents at baseline, 3 and 4 weeks, and goal attainment scaling was assessed at 4 weeks. RESULTS: Delivery of training was a key driver for success and feasibility of the PAIN-Dem intervention. Improvements in pain management behaviour and staff confidence were seen in homes where training was delivered in a care home setting across the care team with good manager buy-in. Family involvement in pain management was highlighted as an area for improvement. Goal attainment in residents was significantly improved across the cohort, although no significant change in pain was seen. CONCLUSIONS: This study shows good initial feasibility of the PAIN-Dem intervention and provides valuable insight into training and support paradigms that deliver successful learning and behaviour change. There is a need for a larger trial of PAIN-Dem to establish its impact on resident pain and quantifiable staff behaviour measures. Copyright © 2017 John Wiley & Sons, Ltd.

Development of assessment toolkits for improving the diagnosis of the Lewy body dementias: feasibility study within the DIAMOND Lewy study.

OBJECTIVE: The Lewy body dementias (LBD, dementia with Lewy bodies and Parkinson's disease dementia) are the second most common cause of neurodegenerative dementia but remain under-recognised, with long delays from initial assessment to diagnosis. Whilst validated instruments have been developed for key symptoms, there is no brief instrument for overall diagnostic assessment suitable for routine practice. We here report the development of such assessment toolkits. METHODS: We developed the LBD assessment toolkits in three stages. First, we conducted a systematic search for brief validated assessments for key symptoms and combined these into draft instruments. Second, we obtained feedback on acceptability and feasibility through two rounds of interviews with our patient and public involvement group. This led to modification of the toolkits. Finally, we piloted the toolkits in a feasibility study in routine dementia and Parkinson's disease services to produce final instruments suitable for routine clinical practice. RESULTS: Eleven clinicians, working in both dementia/memory assessment and Parkinson's disease/movement disorder services, consented to pilot the assessment toolkits and provide feedback on their feasibility. Clinicians worked in routine health service (not academic) settings and piloted the draft toolkits by integrating them into their regular clinical assessments. Feedback obtained informally, by written comments and through qualitative interviews led to modifications and production of final acceptable versions. CONCLUSIONS: We were able to address an important need, the under-diagnosis of LBD, by developing toolkits for improving the recognition and diagnosis of the LBD, which were acceptable to clinicians working in routine dementia and Parkinson's disease services. © 2016 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons, Ltd.

Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: association with cognitive impairment.

The loss of zinc transporter 3 (ZnT3) has been implicated in age-related cognitive decline in mice, and the protein has been associated with plaques. We investigated the levels of ZnT3 and postsynaptic density protein 95 (PSD95), a marker of the postsynaptic terminal, in people with Parkinson's disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer's disease (AD, n = 16), and controls (n = 24), using semiquantitative western blotting and immunohistochemistry in 3 cortical regions. Standardized cognitive assessments during life and semiquantitative scoring of amyloid ß (Aß), tau, and α-synuclein at postmortem were used to investigate the relationship between ZnT3 and PSD95, cognition and pathology. Associations were observed between ZnT3 and PSD95 levels in prefrontal cortex and cognitive impairment (p = 0.001 and p = 0.002, respectively) and between ZnT3 levels in the parietal cortex and cognitive impairment (p = 0.036). Associations were also seen between ZnT3 levels in cingulate cortex and severity of Aß (p = 0.003) and tau (p = 0.011) pathologies. DLB and PDD were characterized by significant reductions of PSD95 (p < 0.05) and ZnT3 (p < 0.001) in prefrontal cortex compared with controls and AD. PSD95 levels in the parietal cortex were found to be decreased in AD cases compared with controls (p = 0.02) and PDD (p = 0.005). This study has identified Zn(2+) modulation as a possible novel target for the treatment of cognitive impairment in DLB and PDD and the potential for synaptic proteins to be used as a biomarker for the differentiation of DLB and PDD from AD.

Cost-effectiveness analyses for mirtazapine and sertraline in dementia: randomised controlled trial.

BACKGROUND: Depression is a common and costly comorbidity in dementia. There are very few data on the cost-effectiveness of antidepressants for depression in dementia and their effects on carer outcomes. AIMS: To evaluate the cost-effectiveness of sertraline and mirtazapine compared with placebo for depression in dementia. METHOD: A pragmatic, multicentre, randomised placebo-controlled trial with a parallel cost-effectiveness analysis (trial registration: ISRCTN88882979 and EudraCT 2006-000105-38). The primary cost-effectiveness analysis compared differences in treatment costs for patients receiving sertraline, mirtazapine or placebo with differences in effectiveness measured by the primary outcome, total Cornell Scale for Depression in Dementia (CSDD) score, over two time periods: 0-13 weeks and 0-39 weeks. The secondary evaluation was a cost-utility analysis using quality-adjusted life years (QALYs) computed from the Euro-Qual (EQ-5D) and societal weights over those same periods. RESULTS: There were 339 participants randomised and 326 with costs data (111 placebo, 107 sertraline, 108 mirtazapine). For the primary outcome, decrease in depression, mirtazapine and sertraline were not cost-effective compared with placebo. However, examining secondary outcomes, the time spent by unpaid carers caring for participants in the mirtazapine group was almost half that for patients receiving placebo (6.74 v. 12.27 hours per week) or sertraline (6.74 v. 12.32 hours per week). Informal care costs over 39 weeks were £1510 and £1522 less for the mirtazapine group compared with placebo and sertraline respectively. CONCLUSIONS: In terms of reducing depression, mirtazapine and sertraline were not cost-effective for treating depression in dementia. However, mirtazapine does appear likely to have been cost-effective if costing includes the impact on unpaid carers and with quality of life included in the outcome. Unpaid (family) carer costs were lower with mirtazapine than sertraline or placebo. This may have been mediated via the putative ability of mirtazapine to ameliorate sleep disturbances and anxiety. Given the priority and the potential value of supporting family carers of people with dementia, further research is warranted to investigate the potential of mirtazapine to help with behavioural and psychological symptoms in dementia and in supporting carers.

Assessment of cognitive fluctuation in dementia: a systematic review of the literature.

OBJECTIVE: Cognitive fluctuations (CF) are defined as spontaneous alterations in cognition, attention and arousal. They are a recognised feature of the dementias, especially dementia with Lewy bodies (DLB) and Parkinson's disease dementia. However, the accurate identification and assessment of CF presents a major clinical difficulty, with the operationalisation of the term 'cognitive fluctuation' remaining elusive, despite several attempts to identify, quantify and assess the phenomenon. No published reviews of CF in dementia exist despite this being an important clinical phenomenon and a core diagnostic feature of DLB. METHODS: We systematically explored the literature and measures available for the definition, assessment and quantification of CF in the dementias. RESULTS: We identified only three psychometric measures, which have been developed for the identification and assessment of CF, and these have not been adequately tested as yet for reliability and validity. DISCUSSION AND CONCLUSIONS: We conclude that further research is warranted into the assessment of CF, and this is timely given the increasing recognition of the clinical importance of CF as a dementia symptom, particularly in the Lewy body dementias.

Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial.

BACKGROUND: Depression is common in dementia but the evidence base for appropriate drug treatment is sparse and equivocal. We aimed to assess efficacy and safety of two of the most commonly prescribed drugs, sertraline and mirtazapine, compared with placebo. METHODS: We undertook the parallel-group, double-blind, placebo-controlled, Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) trial in participants from old-age psychiatry services in nine centres in England. Participants were eligible if they had probable or possible Alzheimer's disease, depression (lasting ≥4 weeks), and a Cornell scale for depression in dementia (CSDD) score of 8 or more. Participants were ineligible if they were clinically critical (eg, suicide risk), contraindicated to study drugs, on antidepressants, in another trial, or had no carer. The clinical trials unit at King's College London (UK) randomly allocated participants with a computer-generated block randomisation sequence, stratified by centre, with varying block sizes, in a 1:1:1 ratio to receive sertraline (target dose 150 mg per day), mirtazapine (45 mg), or placebo (control group), all with standard care. The primary outcome was reduction in depression (CSDD score) at 13 weeks (outcomes to 39 weeks were also assessed), assessed with a mixed linear-regression model adjusted for baseline CSDD, time, and treatment centre. This study is registered, number ISRCTN88882979 and EudraCT 2006-000105-38. FINDINGS: Decreases in depression scores at 13 weeks did not differ between 111 controls and 107 participants allocated to receive sertraline (mean difference 1·17, 95% CI -0·23 to 2·58; p=0·10) or mirtazapine (0·01, -1·37 to 1·38; p=0·99), or between participants in the mirtazapine and sertraline groups (1·16, -0·25 to 2·57; p=0·11); these findings persisted to 39 weeks. Fewer controls had adverse reactions (29 of 111 [26%]) than did participants in the sertraline group (46 of 107, 43%; p=0·010) or mirtazapine group (44 of 108, 41%; p=0·031), and fewer serious adverse events rated as severe (p=0·003). Five patients in every group died by week 39. INTERPRETATION: Because of the absence of benefit compared with placebo and increased risk of adverse events, the present practice of use of these antidepressants, with usual care, for first-line treatment of depression in Alzheimer's disease should be reconsidered. FUNDING: UK National Institute of Health Research HTA Programme.

Sleep in dementia and caregiving--assessment and treatment implications: a review.

BACKGROUND: The increasing prevalence of dementia will precipitate a significant burden in terms of the costs of caring for people with dementia over the next 30 years; sleep disturbances in dementia are an important factor contributing to this burden. METHODS: We reviewed sleep disturbances in people with dementia and their carers and describe the various diagnostic, assessment and treatment strategies available to physicians in the management of this clinically significant problem. RESULTS: Sleep disturbances in people with dementia and their carers (i) are highly prevalent; (ii) impact significantly on quality of life of both people with dementia and their carers; (iii) increase the rate of cognitive decline; and (iv) accelerate the breakdown of community-based care. The training of physicians in the assessment and treatment of sleep disturbances in dementia and caregiving is scant despite a wide range of assessment strategies and treatment approaches, which comprise both pharmacological (including hypnotic/sedative medications) and non-pharmacological approaches (including: environmental; psychobehavioral; exercise and activity; and multi-component interventions). Specific diagnostic criteria for sleep disturbances in people with dementia and their carers remain lacking despite established criteria for general insomnia. Further to this, proposed changes to diagnostic criteria for DSM-V do not include a specific focus for the diagnosis and management of sleep disturbances in people with dementia or their carers. CONCLUSIONS: This review suggests that the improved training of physicians to meet the needs of these vulnerable groups of older people is a priority, especially in the context of a rapidly increasing demand for accurate, early diagnosis and efficient management of sleep disturbance in these groups.