Bart Sheehan

Donepezil and Memantine for Moderate-to-Severe Alzheimer's Disease

BACKGROUND Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimers disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. METHODS We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimers disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS. RESULTS Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone. CONCLUSIONS In patients with moderate or severe Alzheimers disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimers Society; Current Controlled Trials number, ISRCTN49545035.).

Assessment scales in dementia

Dementia involves progressive and often remorseless decline in cognition, function, behaviour and care needs. Assessment in dementia relies on collateral as well as patient-derived information. Many assessment scales have been developed over decades for use in dementia research and care. These scales are used to reduce uncertainty in decision making, for example in screening for cognitive impairment, making diagnoses of dementia and monitoring change. Ideal scales used in dementia should demonstrate face validity and concurrent validity against gold standard assessments, should be reliable, practical, and should rely on objective rather than subjective information. Assessment scales in the domains of cognition, function, behaviour, quality of life, depression in dementia, carer burden and overall dementia severity are reviewed in this article. The practical use of these scales in clinical practice and in research is discussed.

Determining the minimum clinically important differences for outcomes in the DOMINO trial

Although less likely to be reported in clinical trials than expressions of the statistical significance of differences in outcomes, whether or not a treatment has delivered a specified minimum clinically important difference (MCID) is also relevant to patients and their caregivers and doctors. Many dementia treatment randomised controlled trials (RCTs) have not reported MCIDs and, where they have been done, observed differences have not reached these.

Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: secondary and post-hoc analyses

BACKGROUND Findings from observational studies have suggested a delay in nursing home placement with dementia drug treatment, but findings from a previous randomised trial of patients with mild-to-moderate Alzheimers disease showed no effect. We investigated the effects of continuation or discontinuation of donepezil and starting of memantine on subsequent nursing home placement in patients with moderate-to-severe Alzheimers disease. METHODS In the randomised, double-blind, placebo-controlled Donepezil and Memantine in Moderate to Severe Alzheimers Disease (DOMINO-AD) trial, community-living patients with moderate-to-severe Alzheimers disease (who had been prescribed donepezil continuously for at least 3 months at a dose of 10 mg for at least the previous 6 weeks and had a score of between 5 and 13 on the Standardised Mini-Mental State Examination) were recruited from 15 secondary care memory centres in England and Scotland and randomly allocated to continue donepezil 10 mg per day without memantine, discontinue donepezil without memantine, discontinue donepezil and start memantine 20 mg per day, or continue donepezil 10 mg per day and start memantine 20 mg per day, for 52 weeks. After 52 weeks, choice of treatment was left to participants and their physicians. Place of residence was recorded during the first 52 weeks of the trial and then every 26 weeks for a further 3 years. A secondary outcome of the trial, reported in this study, was nursing home placement: an irreversible move from independent accommodation to a residential caring facility. Analyses restricted to risk of placement in the first year of follow-up after the patients had completed the double-blind phase of the trial were post-hoc. The DOMINO-AD trial is registered with the ISRCTN Registry, number ISRCTN49545035. FINDINGS Between Feb 11, 2008, and March 5, 2010, 73 (25%) patients were randomly assigned to continue donepezil without memantine, 73 (25%) to discontinue donepezil without memantine, 76 (26%) to discontinue donepezil and start memantine, and 73 (25%) to continue donepezil and start memantine. 162 (55%) patients underwent nursing home placement within 4 years of randomisation, with similar numbers for all groups (36 [49%] in patients who continued donepezil without memantine, 42 [58%] who discontinued donepezil without memantine, 41 [54%] who discontinued donepezil and started memantine, and 43 [59%] who continued donepezil and started memantine). We noted significant (p=0·010) heterogeneity of treatment effect over time, with significantly more nursing home placements in the combined donepezil discontinuation groups during the first year (hazard ratio 2·09 [95% CI 1·29-3·39]) than in the combined donepezil continuation groups, and no difference during the next 3 years (0·89 [0·58-1·35]). We noted no effect of patients starting memantine compared with not starting memantine during the first year (0·92 [0·58-1·45]) or the next 3 years (1·23 [0·81-1·87]). INTERPRETATION Withdrawal of donepezil in patients with moderate-to-severe Alzheimers disease increased the risk of nursing home placement during 12 months of treatment, but made no difference during the following 3 years of follow-up. Decisions to stop or continue donepezil treatment should be informed by potential risks of withdrawal, even if the perceived benefits of continued treatment are not clear. FUNDING Medical Research Council and UK Alzheimers Society.

Review: somatization in the elderly

Somatization is a common medical problem encountered at all levels of medical care. It is strongly associated with use of services and may be difficult to treat. Somatization in the elderly has been traditionally seen as a masked presentation of depression. Population studies have shown no consistent increase in somatization among the elderly, and the elderly may downplay physical symptoms. Among the elderly depressed, somatization is common and may be commoner if physical illness is also present. Psychological distress is usually acknowledged, not masked, in the elderly depressed. Neuroticism, as well as psychiatric illness, may be an important aetiological factor for somatization in the elderly. Treatment strategies must attend to underlying psychiatric disorders, but there is a need for studies of treatment of the phenomenon in the elderly. Copyright

Outdoor wayfinding in dementia

We aimed in this study to investigate (1) outdoor wayfinding performance of people with dementia; and (2) which features of the outdoor built environment are used in wayfinding by people with dementia. We observed 13 older subjects with confirmed dementia and 10 controls on outdoor walks.Two accompanying researchers recorded performance in wayfinding, built environment features and use of these features in wayfinding. Results showed that people with dementia performed worse on wayfinding, even in familiar areas, but that they attended to similar features of the built environment and made equal use of features such as signs in wayfinding. Research that investigates the built environment for people with dementia is feasible and may help guide planning policies likely to enhance independent community living for this group.

DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease - a multicentre RCT.

BackgroundAlzheimers disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil.MethodDOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization.DiscussionThere is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point.Trial registrationCurrent controlled trials ISRCTN49545035

Somatization among older primary care attenders.

BACKGROUND The importance of somatization among older primary care attenders is unclear. We aimed to establish the prevalence, persistence and associations of somatization among older primary care attenders, and the associations of frequent attendance. METHOD One hundred and forty primary care attenders over 65 years were rated twice, 10 months apart, on measures of somatization, psychiatric status, physical health and attendance. RESULTS The syndrome of GMS hypochondriacal neurosis had a prevalence of 5% but was transient. Somatized symptoms and attributions were persistent and associated with depression, physical illness and perceived poor social support. Frequent attenders (top third) had higher rates of depression, physical illness and somatic symptoms, and lower perceived support. CONCLUSION Somatization is common among older primary care attenders and has similar correlates to younger primary care somatizers. Psychological distress among older primary care attenders is associated with frequent attendance. Improved recognition should result in benefits to patients and services.

Screening for dementia in general hospital inpatients: a systematic review and meta-analysis of available instruments

OBJECTIVE Dementia is common and often undiagnosed. Improving rates of diagnosis has become a key part of current dementia guidelines. Older people admitted to hospital are a potential target population for screening for dementia. The objective was to report whether instruments advocated in screening for dementia had been validated in hospital inpatients and to make recommendations on evidence-based screening for dementia in this population. DESIGN a systematic review was performed by an initial electronic database search using three key search criteria. Studies were then selected in a systematic fashion using specific predetermined criteria. Pooled meta-analysis was performed. Inclusion criteria were studies where the study group were inpatients in general hospitals, including a clearly defined group of older people (60 or older), they used a recognised screening instrument compared with a reference standard, and included at least 10 cases of dementia. Demographic data as well as sensitivity and specificity were recorded from the selected studies. RESULTS in total nine studies describing validation of six discreet instruments satisfied all our criteria and we were able to perform meta-analysis with one instrument, the Abbreviated Mental Test Score (AMTS). With a cut-off of <7, pooled analysis of the AMTS showed a sensitivity of 81%, a specificity of 84% and an area under the curve (AUC) of 0.88. CONCLUSION a small number of instruments have been validated for screening for dementia in general hospital. Understanding strengths and weaknesses of currently available instruments allows informed decisions about screening in this setting.

Patient and proxy measurement of quality of life among general hospital in-patients with dementia

Background: We aimed to investigate quality of life ratings among people with varying severity of dementia and their carers, recruited in general hospital. Method: We recruited 109 people with dementia, and their proxies (carers), from psychiatric referrals of inpatients in two general hospitals in England. From patients, we gathered data on quality of life (QoL-AD and EQ5-D) and depressive symptoms, and from proxies we gathered data on patient quality of life (Proxy QoL-AD and EQ5-D), severity of dementia, activities of daily living, physical illness and depressive symptoms, and on carer stress. Results: Completion rates for both measures were progressively lower with increasing dementia severity. Patients rated their quality of life more highly than proxies on Qol-AD (patients = 32.2, CI = 30.7–33.7, proxies = 24.7, CI = 23.8–26.0, p < 0.001) and on EQ5D (patients = 0.71, CI = 0.64–0.77, proxies = 0.30, CI = 0.22–0.38, p < 0.001). For proxy EQ5D, impaired instrumental ADLs (p = 0.003) and more severe dementia (p = 0.019) were associated with ratings, while for proxy QoL-AD, only more severe dementia (p = 0.039) was associated with ratings. Lower patient EQ-5D scores were independently associated only with carer stress (p = 0.01). Lower patient QoL-AD scores were associated with patient depression (p = 0.001), impaired activities of daily living (p = 0.02) and proxy psychiatric symptoms (p = 0.002). Conclusions: Among patients with moderate to severe dementia in general hospital, proxy measures of quality of life are the only practical option. Patients and proxies appear to have very different concepts of quality of life in dementia.