Anne Corbett

Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial

BACKGROUND Parkinsons disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinsons disease. We aimed to assess safety and efficacy of pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population. METHODS In our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ≥40 years) with Parkinsons disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinsons disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01174004. FINDINGS Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a -5·79 decrease in SAPS-PD scores compared with -2·73 for placebo (difference -3·06, 95% CI -4·91 to -1·20; p=0·001; Cohens d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function. INTERPRETATION Pimavanserin may benefit patients with Parkinsons disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease. FUNDING ACADIA Pharmaceuticals.

Assessment and treatment of pain in people with dementia

Many elderly people experience pain and regularly take analgesic medication. Pain is also frequent in people with dementia, particularly those with severe disease. As no robust clinical guidelines are available for the treatment of pain in the context of dementia, the risk of inadequate treatment in individuals with this condition is high. Furthermore, our understanding of the aetiology of pain and the potential role of dementia-associated neuropathology in pain is limited. These issues are important in the clinical management of individuals with dementia, as untreated pain is a major contributor to reduced quality of life and disability, and can lead to increased behavioural and psychological symptoms. Assessment scales to identify pain in people with dementia have been highlighted in recent studies, but there is little evidence for consistency between these tools. Numerous studies have evaluated various approaches for the treatment of pain, including stepped-care protocols and/or administration of paracetamol and opioid medications. In this Review, we summarize the best-available evidence regarding the aetiology, assessment and treatment of pain in people with dementia. Further validation of assessment tools and large-scale trials of treatment approaches in people with dementia are needed to improve clinical guidance for the treatment of pain in these individuals.

Drug repositioning for Alzheimer's disease

Existing drugs for Alzheimers disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimers-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimers disease.

Pain management in patients with dementia

There are an estimated 35 million people with dementia across the world, of whom 50% experience regular pain. Despite this, current assessment and treatment of pain in this patient group are inadequate. In addition to the discomfort and distress caused by pain, it is frequently the underlying cause of behavioral symptoms, which can lead to inappropriate treatment with antipsychotic medications. Pain also contributes to further complications in treatment and care. This review explores four key perspectives of pain management in dementia and makes recommendations for practice and research. The first perspective discussed is the considerable uncertainty within the literature on the impact of dementia neuropathology on pain perception and processing in Alzheimer’s disease and other dementias, where white matter lesions and brain atrophy appear to influence the neurobiology of pain. The second perspective considers the assessment of pain in dementia. This is challenging, particularly because of the limited capacity of self-report by these individuals, which means that assessment relies in large part on observational methods. A number of tools are available but the psychometric quality and clinical utility of these are uncertain. The evidence for efficient treatment (the third perspective) with analgesics is also limited, with few statistically well-powered trials. The most promising evidence supports the use of stepped treatment approaches, and indicates the benefit of pain and behavioral interventions on both these important symptoms. The fourth perspective debates further difficulties in pain management due to the lack of sufficient training and education for health care professionals at all levels, where evidence-based guidance is urgently needed. To address the current inadequate management of pain in dementia, a comprehensive approach is needed. This would include an accurate, validated assessment tool that is sensitive to different types of pain and therapeutic effects, supported by better training and support for care staff across all settings.

Optimised anaesthesia to reduce post operative cognitive decline (POCD) in older patients undergoing elective surgery, a randomised controlled trial.

Background The study determined the one year incidence of post operative cognitive decline (POCD) and evaluated the effectiveness of an intra-operative anaesthetic intervention in reducing post-operative cognitive impairment in older adults (over 60 years of age) undergoing elective orthopaedic or abdominal surgery. Methods and Trial Design The design was a prospective cohort study with a nested randomised, controlled intervention trial, using intra-operative BiSpectral index and cerebral oxygen saturation monitoring to enable optimisation of anaesthesia depth and cerebral oxygen saturation in older adults undergoing surgery. Results In the 52 week prospective cohort study (192 surgical patients and 138 controls), mild (χ2 = 17.9 p<0.0001), moderate (χ2 = 7.8 p = 0.005) and severe (χ2 = 5.1 p = 0.02) POCD were all significantly higher after 52 weeks in the surgical patients than among the age matched controls. In the nested RCT, 81 patients were randomized, 73 contributing to the data analysis (34 intervention, 39 control). In the intervention group mild POCD was significantly reduced at 1, 12 and 52 weeks (Fisher’s Exact Test p = 0.018, χ2 = 5.1 p = 0.02 and χ2 = 5.9 p = 0.015), and moderate POCD was reduced at 1 and 52 weeks (χ2 = 4.4 p = 0·037 and χ2 = 5.4 p = 0.02). In addition there was significant improvement in reaction time at all time-points (Vigilance Reaction Time MWU Z =  −2.1 p = 0.03, MWU Z = −2.7 p = 0.004, MWU Z = −3.0 p = 0.005), in MMSE at one and 52 weeks (MWU Z = −2.9 p = 0.003, MWU Z = −3.3 p = 0.001), and in executive function at 12 and 52 weeks (Trail Making MWU Z = −2.4 p = .0.018, MWU Z = −2.4 p = 0.019). Conclusion POCD is common and persistent in older adults following surgery. The results of the nested RCT indicate the potential benefits of intra-operative monitoring of anaesthetic depth and cerebral oxygenation as a pragmatic intervention to reduce post-operative cognitive impairment. Trial Registration Controlled-Trials.com ISRCTN39503939

Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial

BACKGROUND Prevalence of Alzheimers disease in people with Downs syndrome is very high, and many such individuals who are older than 40 years have pathological changes characteristic of Alzheimers disease. Evidence to support treatment with Alzheimers drugs is inadequate, although memantine is beneficial in transgenic mice. We aimed to assess safety and efficacy of memantine on cognition and function in individuals with Downs syndrome. METHODS In our prospective randomised double-blind trial, we enrolled adults (>40 years) with karyotypic or clinically diagnosed Downs syndrome, with and without dementia, at four learning disability centres in the UK and Norway. We randomly allocated participants (1:1) to receive memantine or placebo for 52 weeks by use of a computer-generated sequence and a minimisation algorithm to ensure balanced allocation for five prognostic factors (sex, dementia, age group, total Downs syndrome attention, memory, and executive function scales [DAMES] score, and centre). The primary outcome was change in cognition and function, measured with DAMES scores and the adaptive behaviour scale (ABS) parts I and II. We analysed differences in DAMES and ABS scores between groups with analyses of covariance or quantile regression in all patients who completed the 52 week assessment and had available follow-up data. This study is registered, number ISRCTN47562898. FINDINGS We randomly allocated 88 patients to receive memantine (72 [82%] had DAMES data and 75 [85%] had ABS data at 52 weeks) and 85 to receive placebo (74 [87%] and 73 [86%]). Both groups declined in cognition and function but rates did not differ between groups for any outcomes. After adjustment for baseline score, there were non-significant differences between groups of -4·1 (95% CI -13·1 to 4·8) in DAMES scores, -8·5 (-20·1 to 3·1) in ABS I scores, and 2·0 (-7·2 to 11·3) in ABS II scores, all in favour of controls. 10 (11%) of 88 participants in the memantine group and six (7%) of 85 controls had serious adverse events (p=0·33). Five participants in the memantine group and four controls died from serious adverse events (p=0·77). INTERPRETATION There is a striking absence of evidence about pharmacological treatment of cognitive impairment and dementia in people older than 40 years with Downs syndrome. Despite promising indications, memantine is not an effective treatment. Therapies that are effective for Alzheimers disease are not necessarily effective in this group of patients. FUNDING Lundbeck.

Management of neuropsychiatric symptoms in people with dementia.

Neuropsychiatric symptoms are frequent and troublesome in people with dementia and present a major treatment challenge for clinicians. Most good practice guidelines suggest non-pharmacological treatments as the first-line therapy and there is emerging evidence, including randomized controlled trials, that a variety of psychological and training interventions, including social interaction and person-centred care training, are effective. There is evidence from meta-analyses that some atypical antipsychotic drugs, specifically risperidone and aripiprazole, confer benefit in the treatment of aggression in people with Alzheimer’s disease over a period of up to 12 weeks. However, these benefits have to be considered in the context of significant adverse events, including extrapyramidal symptoms, accelerated cognitive decline, stroke and death. In addition, the limited evidence available does not indicate ongoing treatment benefits over longer periods of therapy. The evidence is limited for other pharmacological treatment approaches, but the best evidence is probably for carbamazepine, memantine and citalopram. There is very limited evidence for any therapies in non-Alzheimer dementias.In conclusion, it is important in most situations to limit the use of antipsychotic medication to short-term treatment (up to 12 weeks) of severe neuropsychiatric symptoms to limit harm. Non-pharmacological therapies offer a viable and effective alternative in many situations. Adequately powered randomized controlled trials for the treatment of clinically significant agitation are urgently needed to explore alternative pharmacological therapies.

Management of agitation and aggression associated with Alzheimer's disease: controversies and possible solutions.

Purpose of review Behavioral and psychological symptoms of dementia (BPSD) are frequent among people with Alzheimers disease and other dementias, commonly confer risk to the person and others, and present a significant management challenge for clinicians. The purpose of this review is to describe the current state of knowledge regarding management of BPSD, with a particular focus on agitation. Recent findings There is increasing evidence to support the value of simple psychological interventions and staff-training programs as a first-line management strategy for agitation prior to pharmacotherapy. The most widely prescribed pharmacological treatments – atypical antipsychotics – have a modest but significant beneficial effect in the short-term treatment of aggression (over 6–12 weeks), but limited benefits in longer term therapy. In addition, there have been increasing concerns regarding the potential for serious adverse outcomes, including stroke and death. The potential pharmacological alternatives to atypical antipsychotics with the most encouraging preliminary evidence include memantine, carbamazepine and citalopram. Summary Large prospective, randomized, placebo-controlled trials are needed to establish the role of agents other than neuroleptics as clinical therapies for the treatment of BPSD and studies are urgently needed to evaluate BPSD treatments in non-Alzheimer dementias.

Atypical antipsychotics for the treatment of behavioral and psychological symptoms in dementia, with a particular focus on longer term outcomes and mortality

Importance of the field: Many people with Alzheimers disease (AD) and other dementias are prescribed atypical antipsychotics for behavioral and psychiatric symptoms such as aggression and psychosis. Recent evidence has highlighted safety concerns regarding antipsychotics in these individuals. Areas covered in this review: We summarize the evidence pertaining to efficacy and safety from short-term randomized controlled trials (up to 12 weeks), key findings from case-register studies and more detailed discussion of longer term outcome studies, including longer term mortality risk of antipsychotics in AD. What the reader will gain: The review aims to provide a balanced and up to date overview of the efficacy and safety concerns related to atypical antipsychotics in people with AD, in particular providing a detailed overview of mortality risk, and a personal interpretation of the implications and recommendations for the way forward. Take home message: Atypical antipsychotics confer modest benefits for short-term (up to 12 weeks) treatment of aggression and psychosis in AD. These benefits have to be balanced against the risk of serious adverse events including 1.5 – 1.8-fold increased mortality. The benefits are less clear-cut with longer term prescribing, but the mortality risk remains significantly elevated. Pharmacogenetics may provide an opportunity to more effectively focus prescribing in the future.

Pain assessment for people with dementia: a systematic review of systematic reviews of pain assessment tools

BackgroundThere is evidence of under-detection and poor management of pain in patients with dementia, in both long-term and acute care. Accurate assessment of pain in people with dementia is challenging and pain assessment tools have received considerable attention over the years, with an increasing number of tools made available. Systematic reviews on the evidence of their validity and utility mostly compare different sets of tools. This review of systematic reviews analyses and summarises evidence concerning the psychometric properties and clinical utility of pain assessment tools in adults with dementia or cognitive impairment.MethodsWe searched for systematic reviews of pain assessment tools providing evidence of reliability, validity and clinical utility. Two reviewers independently assessed each review and extracted data from them, with a third reviewer mediating when consensus was not reached. Analysis of the data was carried out collaboratively. The reviews were synthesised using a narrative synthesis approach.ResultsWe retrieved 441 potentially eligible reviews, 23 met the criteria for inclusion and 8 provided data for extraction. Each review evaluated between 8 and 13 tools, in aggregate providing evidence on a total of 28 tools. The quality of the reviews varied and the reporting often lacked sufficient methodological detail for quality assessment. The 28 tools appear to have been studied in a variety of settings and with varied types of patients. The reviews identified several methodological limitations across the original studies. The lack of a ‘gold standard’ significantly hinders the evaluation of tools’ validity. Most importantly, the samples were small providing limited evidence for use of any of the tools across settings or populations.ConclusionsThere are a considerable number of pain assessment tools available for use with the elderly cognitive impaired population. However there is limited evidence about their reliability, validity and clinical utility. On the basis of this review no one tool can be recommended given the existing evidence.