Clive Ballard

ICL, Londinium, England, United Kingdom

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Publications (264)1717.08 Total impact

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    ABSTRACT: Objective: This study evaluated the impact of antipsychotic review, social interaction, and exercise, in conjunction with person-centered care, on antipsychotic use, agitation, and depression in people with dementia living in nursing homes. Method: A cluster-randomized factorial controlled trial with two replications was conducted in people with dementia in 16 U.K. nursing homes. All homes received training in person-centered care. Eight homes were randomly assigned to antipsychotic review, to a social interaction intervention, and to an exercise intervention for 9 months, with most homes assigned to more than one intervention. The primary outcome measures were antipsychotic use, agitation, and depression. Secondary outcome measures were overall neuropsychiatric symptoms and mortality. Results: Antipsychotic review significantly reduced antipsychotic use by 50% (odds ratio 0.17, 95% confidence interval [CI] 0.05 to 0.60). Antipsychotic review plus the social interaction intervention significantly reduced mortality (odds ratio 0.26, 95% CI 0.13 to 0.51) compared with the group receiving neither. The group receiving antipsychotic review but not the social intervention showed significantly worse outcome in neuropsychiatric symptoms compared with the group receiving neither (score difference +7.37, 95% CI 1.53 to 13.22). This detrimental impact was mitigated by concurrent delivery of the social intervention (-0.44, CI -4.39 to 3.52). The exercise intervention significantly improved neuropsychiatric symptoms (-3.59, 95% CI -7.08 to -0.09) but not depression (-1.21, CI -4.35 to -1.93). None of the interventions had a significant impact specifically on agitation. Conclusions: While reductions in antipsychotic use can be achieved by using a "real world" intervention, this may not be of benefit to people with dementia in the current climate of more judicious prescribing unless nonpharmacological interventions such as social interaction or exercise are provided in parallel.
    American Journal of Psychiatry 11/2015; DOI:10.1176/appi.ajp.2015.15010130 · 12.30 Impact Factor
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    ABSTRACT: A common complication after stroke is development of cognitive impairment and dementia. However, effective strategies for reducing the risk of developing these problems remain undefined. Potential strategies include intensive lowering of blood pressure (BP) and/or lipids. This paper summarises the baseline characteristics, statistical analysis plan and feasibility of a randomised control trial of blood pressure and lipid lowering in patients post-stroke with the primary objective of reducing cognitive impairment and dementia. The Prevention Of Decline in Cognition After Stroke Trial (PODCAST) was a multi-centre prospective randomised open-label blinded-endpoint controlled partial-factorial internal pilot trial running in secondary and primary care. Participants without dementia were enrolled 3–7 months post ischaemic stroke or spontaneous intracerebral haemorrhage, and randomised to intensive versus guideline BP lowering (target systolic BP <125 mmHg versus <140 mmHg); patients with ischaemic stroke were also randomised to intensive or guideline lipid lowering (target LDL cholesterol <1.4 mmol/L versus <3 mmol/L). The primary outcome was the Addenbrooke’s Cognitive Examination-Revised; a key secondary outcome was to assess feasibility of performing a large trial of one or both interventions. Data are number (%) or mean (standard deviation). The trial was planned to last for 8 years with follow-up between 1 and 8 years. The plan for reporting the main results is included as Additional file 2. 83 patients (of a planned 600) were recruited from 19 UK sites between 7 October 2010 and 31 January 2014. Delays, due to difficulties in the provision of excess treatment costs and to complexity of follow-up, led to few centres taking part and a much lower recruitment rate than planned. Patient characteristics at baseline were: age 74 (SD 7) years, male 64 (77 %), index stroke ischaemic 77 (93 %), stroke onset to randomisation 4.5 [SD 1.3] months, Addenbrooke’s Cognitive Examination-Revised 86 (of 100, SD 8), Montreal Cognitive Assessment 24 (of 30, SD 3), BP 147/82 (SD 19/11) mmHg, total cholesterol 4.0 (SD 0.8) mmol/L and LDL cholesterol 2.0 (SD 0.7) mmol/L, modified Rankin Scale 1.1 (SD 0.8). Limited recruitment suggests that a large trial is not feasible using the current protocol. The effects of the interventions on BP, lipids, and cognition will be reported in the main publication. Trial registration ISRCTN85562386 registered on 23 September 2009
    Trials 11/2015; 16(1):509. DOI:10.1186/s13063-015-1033-2 · 1.73 Impact Factor

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    ABSTRACT: 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 Alzheimer's 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 Alzheimer's disease. Methods: In the randomised, double-blind, placebo-controlled Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial, community-living patients with moderate-to-severe Alzheimer's 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 Alzheimer's 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 Alzheimer's Society.
    The Lancet Neurology 10/2015; 14(12). DOI:10.1016/S1474-4422(15)00258-6 · 21.90 Impact Factor
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    ABSTRACT: Background: Nursing home patients have complex mental and physical health problems, disabilities and social needs, combined with widespread prescription of psychotropic drugs. Preservation of their quality of life is an important goal. This can only be achieved within nursing homes that offer competent clinical conditions of treatment and care. COmmunication, Systematic assessment and treatment of pain, Medication review, Occupational therapy, Safety (COSMOS) is an effectiveness-implementation hybrid trial that combines and implements organization of activities evidence-based interventions to improve staff competence and thereby the patients' quality of life, mental health and safety. The aim of this paper is to describe the development, content and implementation process of the COSMOS trial. Methods/design: COSMOS includes a 2-month pilot study with 128 participants distributed among nine Norwegian nursing homes, and a 4-month multicenter, cluster randomized effectiveness-implementation clinical hybrid trial with follow-up at month 9, including 571 patients from 67 nursing home units (one unit defined as one cluster). Clusters are randomized to COSMOS intervention or current best practice (control group). The intervention group will receive a 2-day education program including written guidelines, repeated theoretical and practical training (credited education of caregivers, physicians and nursing home managers), case discussions and role play. The 1-day midway evaluation, information and interviews of nursing staff and a telephone hotline all support the implementation process. Outcome measures include quality of life in late-stage dementia, neuropsychiatric symptoms, activities of daily living, pain, depression, sleep, medication, cost-utility analysis, hospital admission and mortality. Discussion: Despite complex medical and psychosocial challenges, nursing home patients are often treated by staff possessing low level skills, lacking education and in facilities with a high staff turnover. Implementation of a research-based multicomponent intervention may improve staff's knowledge and competence and consequently the quality of life of nursing home patients in general and people with dementia in particular. Trial registration: NCT02238652.
    Implementation Science 09/2015; 10(1):131. DOI:10.1186/s13012-015-0310-5 · 4.12 Impact Factor
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    ABSTRACT: To establish the mortality risk and adverse events associated with the use of atypical antipsychotic medications in people with Parkinson disease psychosis (PDP) in a clinically defined trial cohort. Post hoc analysis of data from a multicenter, open-label extension study of pimavanserin comparing people taking and not taking current antipsychotics. Primary and secondary care medical centers in the United States, Canada, Europe, and India. A total of 423 people with PDP enrolled in the extension study. Participants were between ages 30 and 80 years, and had an established diagnosis of idiopathic Parkinson disease and moderate to severe psychosis. Participants were categorized into 2 groups: those receiving concomitant antipsychotic medications ("concurrent APD") and those who did not take antipsychotic medications at any time during the study ("no APD"). Participants were receiving 40 mg pimavanserin daily in addition to concurrent antipsychotics and Parkinson disease medications. Safety assessments at 2 weeks; 1, 3, 6, 9, and 12 months; and every 6 months thereafter, including evaluation of adverse events (AEs), vital signs, weight, physical examinations, 12-lead electrocardiograms, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and the Unified Parkinson's Disease Rating Scale Parts II and III (UPDRS-II+III, activities of daily living and motor impairment, respectively). Differences between participants taking and not taking current antipsychotics were evaluated using incidence rate ratios (IRRs) with 95% confidence intervals (CIs). There was significant increase in the mortality rate for participants taking concurrent antipsychotics compared with the group not taking antipsychotic medications (IRR 4.20, 95% CI 2.13-7.96). Participants who received a concurrent antipsychotic were also significantly more likely to experience overall a serious AE (IRR 2.95, 95% CI 2.02-4.24), any antipsychotic-related event (IRR 1.66, 95% CI 1.18-2.29), cognition-related events (IRR 2.70, 95% CI 1.19-5.58), infections (IRR 1.97, 95% CI 1.17-3.16), and edema (IRR 2.61, 95% CI 1.09-5.59). The risk of falls, stroke, sedation, orthostatic hypotension, and thromboembolic events was also increased in these individuals but this was not significant. This study highlights a significant risk of mortality, and severe AEs in patients with Parkinson disease receiving atypical antipsychotics. This is similar to or greater than the risks seen in people with Alzheimer disease, although with a less clear-cut risk of stroke and a longer delay to increased mortality. Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
    Journal of the American Medical Directors Association 07/2015; 16(10). DOI:10.1016/j.jamda.2015.06.021 · 4.94 Impact Factor
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    ABSTRACT: The unfolded protein response (UPR) is a pro-survival defense mechanism induced during periods of endoplasmic reticulum stress, and it has recently emerged as an attractive therapeutic target across a number of neurodegenerative conditions, but has not yet been studied in synuclein disorders. The level of a key mediator of the UPR pathway, glucose regulated protein 78 (GRP78), also known as binding immunoglobulin protein (BiP), was measured in post-mortem brain tissue of patients with dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) in comparison to Alzheimer's disease (AD) and age matched controls using western blot. The UPR activation was further confirmed by immunohistochemical detection of GRP78/BiP and phosphorylated protein kinase RNA-like ER kinase (p-PERK). GRP78/BiP was increased to a greater extent in DLB and PDD patients compared to AD and control subjects in cingulate gyrus and parietal cortex. However, there were no changes in the prefrontal and temporal cortices. There was a significant positive correlation between GRP78/BiP level and α-synuclein pathology in the cingulate gyrus, while AD-type pathology showed an inverse correlation relationship in the parietal cortex. Overall, these results give emphasis to the role of UPR in Lewy body dementias, and suggest that Lewy body degeneration, in combination with AD-type pathologies, is associated with increased UPR activation to a greater extent than AD alone, possibly as a consequence of the increasing load of ER proteins. This work also highlights a novel opportunity to explore the UPR as a therapeutic target in synuclein diseases. This article is protected by copyright. All rights reserved.
    Neuropathology and Applied Neurobiology 07/2015; DOI:10.1111/nan.12260 · 3.93 Impact Factor
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    ABSTRACT: To contribute to an optimised training programme for care staff that supports the implementation of evidence-based psychosocial interventions in long-term care. Qualitative study that involved focus group discussions with 119 care home staff within 16 care homes in the UK. Part of wider clinical trial aimed at developing and evaluating an effective and practical psychosocial intervention and implementation approach for people with dementia in long-term care. Inductive thematic analysis was used to identify themes and interpret the data. The findings highlighted that successful training and support interventions must acknowledge and respond to 'whole home' issues. Three overarching themes emerged as influential: the importance of contextual factors such as staff morale, interpersonal relationships within the home, and experience and perceived value of the proposed intervention. Priority must be given to obtain the commitment of all staff, management and relatives to the training programme and ensure that expectations regarding interaction with residents, participation in activities and the reduction of medication are shared across the care home. Copyright © 2015 John Wiley & Sons, Ltd.
    International Journal of Geriatric Psychiatry 07/2015; DOI:10.1002/gps.4322 · 2.87 Impact Factor
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    ABSTRACT: Objectives This paper reports on the acceptability and effectiveness of the FITS into Practice Programme which was scaled up from an intervention that had proven significant results from an earlier cluster randomised controlled trial. Method An in depth ten-day education course in person-centred care was delivered over a three-month period and followed by 6 supervision sessions. Participants were care-home staff designated as Dementia Care Coaches (DCCs) responsible for implementing interventions in their home. The course and supervision was provided by educators called Dementia Practice Development Coaches (DPDCs). Effectiveness data included monitoring antipsychotic prescriptions, goal attainment, knowledge, attitude and implementation questionnaires. Qualitative data elucidated issues of implementation. Results Of the 100 DCCs recruited, 66 DCCs completed the programme. Pre-post questionnaires demonstrated increased knowledge and confidence and improved attitudes to dementia. 20.1% of residents were prescribed antipsychotics at baseline which reduced to 13.9% (30.5% reduction) with additional dose reductions being reported alongside improved personalised goal attainment. Crucial for FITS into Practice to succeed was the allocation and protection of time for the DCC to attend training and supervision and to carry out implementation tasks in addition to their existing job role. Evaluation data showed that this was a substantial barrier to implementation in a number of homes. Discussion and conclusions The FITS intervention can be delivered at scale and is a robust way of bringing about positive change. The evaluation informed revisions to the person specification for DCCs and DPDCs and factors to enable successful implementation.
    Aging and Mental Health 07/2015; In Press. DOI:10.1080/13607863.2015.1063102 · 1.75 Impact Factor
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    ABSTRACT: To produce a practice guideline that includes a set of detailed consensus principles regarding the prescription of antipsychotics (APs) amongst people with dementia living in care homes. We used a modified Delphi consensus procedure with three rounds, where we actively specified and optimized statements throughout the process, utilizing input from four focus groups, carried out in UK, Norway, and the Netherlands. This was done to identify relevant themes and a set of statement that experts agreed upon using the Research and Development/University of California at Los Angeles (RAND/UCLA) methodology. A total of 72 scientific and clinical experts and 14 consumer experts reached consensus upon 150 statements covering five themes: (1) General prescription stipulations, (2) assessments prior to prescription, (3) care and treatment plan, (4) discontinuation, and (5) long-term treatment. In this practice guideline, novel information was provided about detailed indication and thresholds of symptoms, risk factors, circumstances at which APs should be stopped or tapered, specific criteria for justifying long-term treatment, involvement of the multidisciplinary team, and family caregiver in the process of prescription. The practice guideline is based on formal consensus of clinicians and consumer experts and provides clinicians relevant practical information that is lacking in current guidelines.
    International Psychogeriatrics 06/2015; -1(11):1-11. DOI:10.1017/S1041610215000745 · 1.93 Impact Factor
  • Anne Corbett · Gareth Williams · Clive Ballard ·
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    ABSTRACT: Drug repositioning offers an innovative approach to drug discovery with great potential in the field of Alzheimer's Disease and dementia therapeutics. Investigation of licensed compounds enables processing through the drug discovery pipeline in a rapid and cost-effective manner. A growing body of evidence supports the translation of priority compounds to be taken forward to clinical trials, based on established and proposed mechanisms of action. A number of drugs have already entered clinical trial following repositioning, and novel technologies have been created to enable high-throughput screening. This review discusses the novel approaches that build on transcriptional signature profiling to support repositioning in AD, and the novel candidate drugs that are emerging from this exciting new technique.
    Frontiers in bioscience (Scholar edition) 06/2015; 7(1):184-188.
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    Nicola Ferreira · Adrian Owen · Anita Mohan · Anne Corbett · Clive Ballard ·
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    ABSTRACT: Objectives Emerging literature suggests that lifestyle factors may play an important role in reducing age-related cognitive decline. There have, however, been few studies investigating the role of cognitively stimulating leisure activities in maintaining cognitive health. This study sought to identify changes in cognitive performance with age and to investigate associations of cognitive performance with several key cognitively stimulating leisure activities. Method Over 65,000 participants provided demographic and lifestyle information and completed tests of grammatical reasoning, spatial working memory, verbal working memory and episodic memory. ResultsRegression analyses suggested that frequency of engaging in Sudoku or similar puzzles was significantly positively associated with grammatical reasoning, spatial working memory and episodic memory scores. Furthermore, for participants aged under 65years, frequency of playing non-cognitive training computer games was also positively associated with performance in the same cognitive domains. The results also suggest that grammatical reasoning and episodic memory are particularly vulnerable to age-related decline. Further investigation to determine the potential benefits of participating in Sudoku puzzles and non-cognitive computer games is indicated, particularly as they are associated with grammatical reasoning and episodic memory, cognitive domains found to be strongly associated with age-related cognitive decline. Conclusions Results of this study have implications for developing improved guidance for the public regarding the potential value of cognitively stimulating leisure activities. The results also suggest that grammatical reasoning and episodic memory should be targeted in developing appropriate outcome measures to assess efficacy of future interventions, and in developing cognitive training programmes to prevent or delay cognitive decline. Copyright (c) 2014 John Wiley & Sons, Ltd.
    International Journal of Geriatric Psychiatry 04/2015; 30(4). DOI:10.1002/gps.4155 · 2.87 Impact Factor
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    ABSTRACT: Neuropsychiatric symptoms in Alzheimer disease (AD) cause significant distress and present a complex clinical challenge for treatment. Pharmacological treatment options are limited to antipsychotics, which carry extensive safety issues. There is emerging evidence to support the potential benefits of memantine, currently licensed for moderate to severe AD, in the prophylaxis of neuropsychiatric symptoms. The MAIN-AD study is a double-blind randomized placebo-controlled withdrawal trial comparing memantine with antipsychotics for the treatment of neuropsychiatric symptoms over 24 weeks. A total of 199 people with probable AD living in care homes already receiving an antipsychotic were randomized to receive either memantine or to continue an antipsychotic. The primary outcomes were function (Bristol Activities of Daily Living Scale [BADLS]) and agitation (Cohen-Mansfield Agitation Inventory [CMAI]). Secondary outcomes were Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), and mortality. There was no significant difference between groups on the BADLS or CMAI. At 24 weeks, there was a nonsignificant adjusted difference in favor of memantine on the BADLS of 0.23 (95% CI -1.80-2.27; P = .82) and in favor of antipsychotic on the CMAI of 0.09 (95% CI -0.35-8.53; P = .07). Although there were no significant differences in total NPI, there were 5.01 (95% CI -1.68-11.70; P = .05) and 3.63 (95% CI -1.40-8.67; P = .16) point advantages favoring antipsychotics at weeks 12 and 24, respectively. In addition, in an exploratory analysis, individuals allocated to antipsychotics were significantly less likely to experience relapse of neuropsychiatric symptoms at all time points. The group receiving memantine had a nonsignificant 1.3-point advantage on the MMSE at 24 weeks. This study indicates no benefits for memantine in the long-term treatment and prophylaxis of clinically significant neuropsychiatric symptoms. The results did indicate some benefits for antipsychotic medications in reducing the relapse of neuropsychiatric symptoms, but this must be balanced against increased mortality risk. Copyright © 2014 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
    Journal of the American Medical Directors Association 12/2014; 16(4). DOI:10.1016/j.jamda.2014.11.002 · 4.94 Impact Factor
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    Vanessa Lawrence · James Pickett · Clive Ballard · Joanna Murray ·
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    ABSTRACT: Objective There is great interest in conducting clinical trials of disease-modifying therapies in the prodromal (early, pre-dementia), asymptomatic stages of Alzheimer's disease. Diagnostic biomarker tests offer a means of identifying prodromal patients, but it is unclear how potential participants feel about their use. Deciding whether to take part in a clinical trial is a complex process in which eligible participants must balance risks and discomforts against uncertain benefits. We sought to explore the views of potential participants through qualitative research methods. Methods Focus groups with people with early memory problems, current and former family carers explored attitudes towards participating in clinical trials in the prodromal stages of the disease, using an example of anti-amyloid antibody-therapy (immunotherapy), which are currently in development. ResultsDespite the complexities involved, almost all participants had a clear idea about whether they, personally, would like to take part. Many were highly motivated to obtain an unambiguous diagnosis, regardless of their desire to participate in a clinical trial. Participants expressed minimal concern regarding the risk of adverse events associated with immunotherapy, whereas certain tests and trial procedures provoked greater anxiety. People with memory problems were found to assess the study demands in relation to their own priorities and circumstances. Conclusions The priorities of patients might be different to clinicians and those who design and regulate clinical trials. Patient views can be used to inform the ethical debate around the disclosure of biomarker status, the design of clinical trials and the content of trial information. Copyright (c) 2013 John Wiley & Sons, Ltd.
    International Journal of Geriatric Psychiatry 12/2014; 29(1). DOI:10.1002/gps.3958 · 2.87 Impact Factor
  • Anne Corbett · Alistair Burns · Clive Ballard ·

    BMJ Clinical Research 11/2014; 349(nov03 1):g6420. DOI:10.1136/bmj.g6420 · 14.09 Impact Factor
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    Neurobiology of Aging 11/2014; 35(11):2661. DOI:10.1016/j.neurobiolaging.2014.06.016 · 5.01 Impact Factor
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    Neurobiology of Aging 11/2014; 35(11):2659. DOI:10.1016/j.neurobiolaging.2014.06.017 · 5.01 Impact Factor
  • Martin Broadstock · Clive Ballard · Anne Corbett ·
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    ABSTRACT: Parkinson's disease (PD) affects 10 million people worldwide. Half will develop psychosis, the majority experiencing hallucinations rather than delusions. Emergence of psychosis increases the likelihood of institutionalization and mortality. Where pharmacological treatment is warranted, options are limited. Most currently licensed atypical antipsychotics are ineffective or worsen motor symptoms in people with PD. This review of provides an overview of the current landscape of treatments and the opportunities in emerging research. Clozapine is the only licensed antipsychotic with proven efficacy, although the associated side effects limit its use. With recent advances in understanding the role of serotonin, rational drug design approaches have delivered a novel pharmacological treatment with recently proven efficacy in clinical trials of people with PD and psychosis. Pimavanserin represents an important addition to treatment.
    Expert Review of Clinical Pharmacology 10/2014; 7(6):1-8. DOI:10.1586/17512433.2014.966814 · 2.18 Impact Factor
  • Byron Creese · Anne Corbett · Emma Jones · Chris Fox · Clive Ballard ·
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    ABSTRACT: Introduction: There is evidence that neurofibrillary tangle (NFT) burden is associated with psychotic symptoms in Alzheimer disease (AD). However, it is not clear whether this association is direct or mediated through the increased cognitive impairment associated with NFTs. Methods: We sought to determine whether the extended MAPT haplotype was associated with the worsening of delusions and hallucinations in a combined cohort of 95 patients who participated in 2 clinical trials of treatment with memantine. Results: After controlling for baseline dementia severity, exposure to memantine, and antipsychotics, analysis shows that carriers of at least one H2 allele had a 5.4-fold (P = .03) increased risk of worsening hallucinations. There was some evidence of association with worsening delusions but only in analysis by allele. Conclusion: These results are the first to indicate that the H2 allele of the extended MAPT haplotype negatively affects the course of psychotic symptoms in AD independently of disease severity. It will be important for future research to examine MAPT transcription in people with AD with and without psychotic symptoms to understand the exact mechanisms underlying these findings.
    Journal of the American Medical Directors Association 10/2014; 15(12). DOI:10.1016/j.jamda.2014.08.011 · 4.94 Impact Factor

Publication Stats

8k Citations
1,717.08 Total Impact Points


  • 2005-2015
    • ICL
      Londinium, England, United Kingdom
  • 2004-2015
    • King's College London
      • • Wolfson Centre for Age-Related Diseases
      • • Institute of Psychiatry
      Londinium, England, United Kingdom
  • 2005-2014
    • Stavanger University Hospital
      • Department of Neurology
      Stavenger, Rogaland, Norway
  • 2008-2013
    • The Kings College
      Norway, Michigan, United States
  • 2005-2012
    • The Alzheimers Society
      Londinium, England, United Kingdom
  • 2011
    • The King's College
      Charlotte, North Carolina, United States
    • University of Antwerp
      Antwerpen, Flemish, Belgium
  • 1997-2007
    • Newcastle University
      • Institute for Ageing and Health
      Newcastle-on-Tyne, England, United Kingdom
  • 2006
    • University of Hull
      Kingston upon Hull, England, United Kingdom
  • 1996-2004
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
      • Department of Neurology
      Newcastle-on-Tyne, England, United Kingdom
  • 2001
    • Royal College of Psychiatrists
      Londinium, England, United Kingdom
    • Newcastle University Medicine Malaysia
      Bharu, Johor, Malaysia
  • 1998
    • Central Peninsula Hospital
      SXQ, Alaska, United States
  • 1995
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom
    • University of Birmingham
      Birmingham, England, United Kingdom