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Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial.
Banerjee, S, High, J, Stirling, S, Shepstone, L, Swart, AM, Telling, T, Henderson, C, Ballard, C, Bentham, P, Burns, A, et al
Lancet (London, England). 2021;(10310):1487-1497
Abstract
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.
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Visual hallucinations in neurological and ophthalmological disease: pathophysiology and management.
O'Brien, J, Taylor, JP, Ballard, C, Barker, RA, Bradley, C, Burns, A, Collerton, D, Dave, S, Dudley, R, Francis, P, et al
Journal of neurology, neurosurgery, and psychiatry. 2020;(5):512-519
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Abstract
Visual hallucinations are common in older people and are especially associated with ophthalmological and neurological disorders, including dementia and Parkinson's disease. Uncertainties remain whether there is a single underlying mechanism for visual hallucinations or they have different disease-dependent causes. However, irrespective of mechanism, visual hallucinations are difficult to treat. The National Institute for Health Research (NIHR) funded a research programme to investigate visual hallucinations in the key and high burden areas of eye disease, dementia and Parkinson's disease, culminating in a workshop to develop a unified framework for their clinical management. Here we summarise the evidence base, current practice and consensus guidelines that emerged from the workshop.Irrespective of clinical condition, case ascertainment strategies are required to overcome reporting stigma. Once hallucinations are identified, physical, cognitive and ophthalmological health should be reviewed, with education and self-help techniques provided. Not all hallucinations require intervention but for those that are clinically significant, current evidence supports pharmacological modification of cholinergic, GABAergic, serotonergic or dopaminergic systems, or reduction of cortical excitability. A broad treatment perspective is needed, including carer support. Despite their frequency and clinical significance, there is a paucity of randomised, placebo-controlled clinical trial evidence where the primary outcome is an improvement in visual hallucinations. Key areas for future research include the development of valid and reliable assessment tools for use in mechanistic studies and clinical trials, transdiagnostic studies of shared and distinct mechanisms and when and how to treat visual hallucinations.
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Deep and Frequent Phenotyping study protocol: an observational study in prodromal Alzheimer's disease.
Koychev, I, Lawson, J, Chessell, T, Mackay, C, Gunn, R, Sahakian, B, Rowe, JB, Thomas, AJ, Rochester, L, Chan, D, et al
BMJ open. 2019;(3):e024498
Abstract
INTRODUCTION Recent failures of potential novel therapeutics for Alzheimer's disease (AD) have prompted a drive towards clinical studies in prodromal or preclinical states. However, carrying out clinical trials in early disease stages is extremely challenging-a key reason being the unfeasibility of using classical outcome measures of dementia trials (eg, conversion to dementia) and the lack of validated surrogate measures so early in the disease process. The Deep and Frequent Phenotyping (DFP) study aims to resolve this issue by identifying a set of markers acting as indicators of disease progression in the prodromal phase of disease that could be used as indicative outcome measures in proof-of-concept trials. METHODS AND ANALYSIS The DFP study is a repeated measures observational study where participants will be recruited through existing parent cohorts, research interested lists/databases, advertisements and memory clinics. Repeated measures of both established (cognition, positron emission tomography (PET) imaging or cerebrospinal fluid (CSF) markers of pathology, structural MRI markers of neurodegeneration) and experimental modalities (functional MRI, magnetoencephalography and/or electroencephalography, gait measurement, ophthalmological and continuous smartphone-based cognitive and other assessments together with experimental CSF, blood, tear and saliva biomarkers) will be performed. We will be recruiting male and female participants aged >60 years with prodromal AD, defined as absence of dementia but with evidence of cognitive impairment together with AD pathology as assessed using PET imaging or CSF biomarkers. Control participants without evidence of AD pathology will be included at a 1:4 ratio. ETHICS AND DISSEMINATION The study gained favourable ethical opinion from the South Central-Oxford B NHS Research Ethics Committee (REC reference 17/SC/0315; approved on 18 August 2017; amendment 13 February 2018). Data will be shared with the scientific community no more than 1 year following completion of study and data assembly.
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"Psychogeritechnology" in Japan: Exemplars from a super-aged society.
Leroi, I, Watanabe, K, Hird, N, Sugihara, T
International journal of geriatric psychiatry. 2018;(12):1533-1540
Abstract
BACKGROUND The burgeoning field of gerontechnology, which is the interdisciplinary field of applying technology to ageing issues, has focused primarily on "active ageing" and maintaining independence for older adults. To date, there has been less focus on people who develop dementia. Here, we argue for the field of gerontechnology to have a greater emphasis on clinical applications for dementia. This can be captured under the rubric of "psychogeritechnology," a term we have coined to describe the range of technology approaches to the prevention, prediction, screening, assessment, diagnosis, management, and monitoring of people at risk of, or living with, dementia. AIM: Using Japan as the world's leading "super-aged' nation as a paradigm, the purpose of this paper is to provide a narrative review of the use of innovative technology for the diagnosis, management and support of people at risk of, or living with, dementia. METHODS By following the "life course" of dementia, we will use clinical exemplars and case studies of psychogeritechnological applications from a Japanese context, specific to each stage of dementia, from the preclinical to the advanced stage. In the preclinical stage, the focus will be on prevention and early detection of degenerative cognitive-functional trajectories. In the early-stage of dementia, we will outline examples of screening, assessment, diagnosis, and clinical monitoring, as well as the use of technology to support independent living and autonomy. In the moderate stage, examples of safety monitoring systems, and assistive technology to foster independence, quality of life will be outlined. Finally, in the advanced stage of dementia, our focus will be on assistive technology in the care home setting, and the need to foster secure and efficient communication among care providers. We will discuss these applications in terms of the evolution of the "technological roadmap" for dementia, and the need for a theoretical underpinning for the field, a meaningful and flexible evaluation framework, and consideration of the "wider perspective" including safety-critical issues, ethical issues, and the relation to policy and health economics. CONCLUSIONS Japan, as a rapidly ageing society, is on the forefront of developing technology to support people with dementia. The new field of psychogeritechnology must harness the potential of such developments, while furthering the methodology to implement and evaluate the changes.
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A pilot randomized controlled trial of sleep therapy in Parkinson's disease: effect on patients and caregivers.
Leroi, I, Baker, P, Kehoe, P, Daniel, E, Byrne, EJ
International journal of geriatric psychiatry. 2010;(10):1073-9
Abstract
OBJECTIVE By means of a controlled trial, to investigate the efficacy, tolerability and feasibility of a multi-component sleep therapy intervention versus basic sleep hygiene education in PD patients with sleep disturbances and their live-in carers. METHODS Patient-carer dyads were randomised to either of the two interventions. Quantitative measures of sleep, psychiatric and overall functioning were administered at baseline and two weeks after the intervention to patients and carers. RESULTS Sleep disturbances in the PD patients improved significantly in both the groups. Between group comparisons in both carers and patients revealed no significant differences on any outcome measures. The intervention was found to be well tolerated, feasible and could easily be translated into the clinical setting. CONCLUSIONS This pilot study makes the case for further, more rigorous study of pragmatic, non-pharmacological interventions for sleep disturbances in PD.
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Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial.
Aarsland, D, Ballard, C, Walker, Z, Bostrom, F, Alves, G, Kossakowski, K, Leroi, I, Pozo-Rodriguez, F, Minthon, L, Londos, E
The Lancet. Neurology. 2009;(7):613-8
Abstract
BACKGROUND Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are common forms of dementia that substantially affect quality of life. Currently, the only treatment licensed for PDD is rivastigmine, and there are no licensed treatments for DLB. We aimed to test the safety and efficacy of the N-methyl D-aspartate (NMDA) receptor antagonist memantine in patients with PDD or DLB. METHODS We did a parallel-group, 24-week, randomised controlled study of memantine (20 mg per day) versus placebo at four psychiatric and neurological outpatient clinics in Norway, Sweden, and the UK during 2005-08. Patients were included if they fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease (PD) and developed dementia according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM IV) criteria at least 1 year after the onset of motor symptoms (PDD) or met the revised consensus operationalised criteria for DLB. Patients were assigned to a computer-generated randomisation list. All physicians who had contact with patients were masked to treatment allocation. The primary outcome measure was clinical global impression of change (CGIC), which ranged from 1 to 7 points, and a low score means a better outcome. Analysis was by intention to treat based on the last observation carried forward. This trial is registered, number ISRCTN89624516. FINDINGS 72 patients with PDD or DLB were randomly assigned and started treatment: 34 with memantine and 38 with placebo. 56 (78%) completed the study. All withdrawals were owing to adverse events, but the proportion of withdrawals was similar in both groups. At week 24 the patients in the memantine group had better CGIC scores than those taking placebo (mean difference 0.7, 95% CI 0.04-1.39; p=0.03). With the exception of improved speed on attentional tasks in the memantine group (a quick test of cognition [AQT] form: difference 12.4, 95% CI 6.0-30.9; p=0.004), there were no significant differences between the groups in secondary outcome measures. INTERPRETATION Patients with DLB or PDD might benefit from treatment with memantine, which was well tolerated. Large-scale studies are now required to confirm our preliminary findings. FUNDING The Western Norway Regional Health Authority; H Lundbeck A/S.
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Randomized controlled trial of memantine in dementia associated with Parkinson's disease.
Leroi, I, Overshott, R, Byrne, EJ, Daniel, E, Burns, A
Movement disorders : official journal of the Movement Disorder Society. 2009;(8):1217-21
Abstract
The objective of this study is to investigate the safety and tolerability of memantine, a glutamatergic modulator, in patients suffering from dementia associated with Parkinson's disease (PDD), an increasingly common complication of PD. This was a 22-week trial of 25 participants with a DSM-IV diagnosis of PDD who were randomized to either placebo or 20 mg/day of memantine. Memantine was well tolerated by participants at 20 mg/day dosing. No participant was withdrawn due to memantine-related adverse events. Six weeks after drug withdrawal, a significantly greater proportion (P = 0.04) of memantine-treated participants deteriorated globally compared with those treated with placebo. These findings suggest that continued treatment with memantine may be needed to maintain global level of functioning over time. Based on the findings of this pilot study, memantine is safe and very well-tolerated in PDD.
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Non-dopaminergic treatment of cognitive impairment and dementia in Parkinson's disease: a review.
Leroi, I, Collins, D, Marsh, L
Journal of the neurological sciences. 2006;(1-2):104-14
Abstract
OBJECTIVE To review the clinical management of cognitive impairment and dementia related to Parkinson's disease (PD), with emphasis on pharmacologic intervention strategies such as cholinesterase inhibitors. DATA SOURCES A MEDLINE, EMBASE, PsychINFO, and Cochrane Collaboration search of English language literature from 1970 to 2004 was performed to identify reviews, studies, case reports, and letters pertaining to the treatment of cognitive impairment in PD. The bibliographies of selected articles were reviewed for additional references. STUDY SELECTION Human studies or case reports in adults with PD describing the use of drug and other therapies for the treatment of cognitive impairment in PD. DATA EXTRACTION Studies were reviewed for study design, number of subjects, outcome measures, dosage, side-effects, particularly, worsening of PD motor symptoms. CONCLUSION The strongest evidence for the pharmacological treatment of cognitive impairment and dementia in PD supports the use of cholinesterase inhibitors. Evidence for the efficacy and safety of other agents in PD dementia is either insufficient or inconclusive, but offers intriguing clues for potential future treatments. No reports from the Cochrane Collaboration were found.