|
1
|
Abbott V, Housden BE, Houldsworth A. Could immunotherapy and regulatory T cells be used therapeutically to slow the progression of Alzheimer's disease? Brain Commun 2025; 7:fcaf092. [PMID: 40078868 PMCID: PMC11896979 DOI: 10.1093/braincomms/fcaf092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 11/25/2024] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
Alzheimer's disease and other cognitive impairments are a growing problem in the healthcare world with the ageing population. There are currently no effective treatments available; however, it has been suggested that targeting neuroinflammation may be a successful approach in slowing the progression of neurodegeneration. Reducing the destructive hyperinflammatory pathology to maintain homeostasis in neural tissue is a promising option to consider. This review explores the mechanisms behind neuroinflammation and the effectiveness of immunotherapy in slowing the progression of cognitive decline in patients with Alzheimer's disease. The key components of neuroinflammation in Alzheimer's disease researched are microglia, astrocytes, cytokines and CD8+ effector T cells. The role of oxidative stress on modulating regulatory T cells and some of the limitations of regulatory T cell-based therapies are also explored. Increasing regulatory T cells can decrease activation of microglia, proinflammatory cytokines and astrocytes; however, it can also increase levels of inflammatory cytokines. There is a complex network of regulatory T cell interactions that reduce Alzheimer's disease pathology, which is not fully understood. Exploring the current literature, further research into the use of immunotherapy in Alzheimer's disease is vital to determine the potential of these techniques; however, there is sufficient evidence to suggest that increasing regulatory T cells count does prevent Alzheimer's disease symptoms and pathology in patients with Alzheimer's disease. Some exciting innovative therapies are muted to explore in the future. The function of regulatory T cells in the presence of reactive oxygen species and oxidative stress should be investigated further in patients with neurogenerative disorders to ascertain if combination therapies could reduce oxidative stress while also enhancing regulatory T cells function. Could methods of immunotherapy infuse exogenous functional Tregs or enhance the immune environment in favour of endogenous regulatory T cells differentiation, thus reducing neuroinflammation in neurodegenerative pathology, inhibiting the progression of Alzheimer's disease?
Collapse
Affiliation(s)
- Victoria Abbott
- Neuroscience, Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter EX2 4TH, UK
| | - Benjamin E Housden
- Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter EX2 4TH, UK
- Living Systems Institute, University of Exeter, Exeter EX4 4QD, UK
| | - Annwyne Houldsworth
- Neuroscience, Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter EX2 4TH, UK
- Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter EX2 4TH, UK
| |
Collapse
|
|
2
|
Calvin-Dunn KN, Mcneela A, Leisgang Osse A, Bhasin G, Ridenour M, Kinney JW, Hyman JM. Electrophysiological insights into Alzheimer's disease: A review of human and animal studies. Neurosci Biobehav Rev 2025; 169:105987. [PMID: 39732222 DOI: 10.1016/j.neubiorev.2024.105987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 11/16/2024] [Accepted: 12/17/2024] [Indexed: 12/30/2024]
Abstract
This review highlights the crucial role of neuroelectrophysiology in illuminating the mechanisms underlying Alzheimer's disease (AD) pathogenesis and progression, emphasizing its potential to inform the development of effective treatments. Electrophysiological techniques provide unparalleled precision in exploring the intricate networks affected by AD, offering insights into the synaptic dysfunction, network alterations, and oscillatory abnormalities that characterize the disease. We discuss a range of electrophysiological methods, from non-invasive clinical techniques like electroencephalography and magnetoencephalography to invasive recordings in animal models. By drawing on findings from these studies, we demonstrate how electrophysiological research has deepened our understanding of AD-related network disruptions, paving the way for targeted therapeutic interventions. Moreover, we underscore the potential of electrophysiological modalities to play a pivotal role in evaluating treatment efficacy. Integrating electrophysiological data with clinical neuroimaging and longitudinal studies holds promise for a more comprehensive understanding of AD, enabling early detection and the development of personalized treatment strategies. This expanded research landscape offers new avenues for unraveling the complexities of AD and advancing therapeutic approaches.
Collapse
Affiliation(s)
- Kirsten N Calvin-Dunn
- Interdisciplinary Neuroscience Program, University of Nevada, Las Vegas, United States; Cleveland Clinic Lou Ruvo Center for Brain Health, United States.
| | - Adam Mcneela
- Interdisciplinary Neuroscience Program, University of Nevada, Las Vegas, United States
| | - A Leisgang Osse
- Interdisciplinary Neuroscience Program, University of Nevada, Las Vegas, United States; Department of Brain Health, University of Nevada, Las Vegas, United States
| | - G Bhasin
- Interdisciplinary Neuroscience Program, University of Nevada, Las Vegas, United States; Department of Psychology, University of Nevada, Las Vegas, United States
| | - M Ridenour
- Department of Psychology, University of Nevada, Las Vegas, United States
| | - J W Kinney
- Interdisciplinary Neuroscience Program, University of Nevada, Las Vegas, United States; Department of Brain Health, University of Nevada, Las Vegas, United States
| | - J M Hyman
- Interdisciplinary Neuroscience Program, University of Nevada, Las Vegas, United States; Department of Psychology, University of Nevada, Las Vegas, United States
| |
Collapse
|
|
3
|
Vora N, Patel P, Marsool MDM, Marsool ADM, Sunasra R, Ladani P, Pati S, Khoont D, Prajjwal P, Ranjan R. Atypical Alzheimer's dementia: Addressing the subtypes, epidemiology, atypical presentations, diagnostic biomarkers, and treatment updates. Dis Mon 2025:101863. [PMID: 39894694 DOI: 10.1016/j.disamonth.2025.101863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Alzheimer's disease is a progressive neurodegenerative disorder that primarily affects the elderly population; and is characterized by the gradual loss of memory, cognition, and ability to carry out daily activities. However, a growing body of research indicates that there exists a subtype of Alzheimer's disease known as Atypical Alzheimer's disease. Atypical Alzheimer's disease is a rare form of dementia that differs from the typical presentation of Alzheimer's disease, such as variations in the age of onset, distribution of brain pathology, and clinical symptoms. The patients affected have a younger age of onset and have predominantly visual, language, executive function, motor, and behavioral dysfunction. The diagnosis requires a comprehensive neurological evaluation with specific attention to cognitive and behavioral changes while ruling out other potential causes of dementia. Emerging biomarkers including CSF profiles, amyloid and tau PET imaging, and advanced neuroimaging techniques offer promising avenues for improving diagnostic accuracy and understanding disease mechanisms. In this article, we focus on atypical presentations seen in the posterior cortical variant, frontal variant, progressive aphasic variant, corticobasal syndrome and look at the specific biomarkers used in the diagnosis of each variant along with focusing on the treatment of the disease. We also aim to provide an understanding of Atypical Alzheimer's disease, its clinical features, the biomarkers helping in diagnosing the disease, the current treatment guidelines, and the current scientific advancements in the field.
Collapse
Affiliation(s)
- Neel Vora
- M.B.B.S., Internal Medicine, B. J. Medical College, Ahmedabad, India.
| | - Parth Patel
- M.B.B.S., Internal Medicine, Pramukhswami Medical College, Karamsad, India
| | | | | | - Rayyan Sunasra
- M.B.B.S., Hinduhriday Samrat Balasaheb Thackeray Medical College, Mumbai, India
| | - Parva Ladani
- M.B.B.S., Internal Medicine, Seth G.S. Medical College, Mumbai, India
| | - Shefali Pati
- Medical Student, St George's University, School of Medicine, Grenada
| | - Dhruvi Khoont
- M.B.B.S., Internal Medicine, Narendra Modi Medical College, Ahmedabad, India
| | | | - Raunak Ranjan
- M.B.B.S., Neurology, Bharati Vidyapeeth Medical College, Pune, India
| |
Collapse
|
|
4
|
Lee HH, Chinnameyyappan A, Feldman OJ, Marotta G, Survilla K, Lanctôt KL. Behavioral and Psychological Symptoms (BPSD) in Alzheimer's Disease (AD): Development and Treatment. Curr Top Behav Neurosci 2025; 69:245-273. [PMID: 39853561 DOI: 10.1007/7854_2024_566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2025]
Abstract
Behavioral and psychological symptoms of dementia (BPSD), such as agitation, apathy, and psychosis, are highly prevalent and have a significant impact on patients and their care partners. The neurobiology of BPSD involves a complex interplay of structural brain changes and alterations in the neurotransmitter system. Various genetic and plasma biomarkers have also been studied. Research in BPSD has been limited by heterogeneity in the diagnostic criteria and assessment tools. As such, there have been ongoing efforts to develop a gold-standard assessment tool and diagnostic criteria. Current practice guidelines recommend nonpharmacological therapies as first-line treatments. Pharmacological options are often used when there is an insufficient response to nonpharmacological strategies, but there can be serious adverse effects with existing pharmacological agents. This has resulted in growing efforts to develop novel therapeutics with more favorable tolerability profiles, with some showing promising results. Other biological therapies, such as neurostimulation, have also demonstrated positive results. As our understanding of BPSD evolves, ongoing research efforts in treatment of BPSD are warranted in order to enhance the quality of life for patients and their care partners.
Collapse
Affiliation(s)
- Hyewon H Lee
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.
| | | | - Oriel J Feldman
- Neuropsychopharmacology Research Group, Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
| | - Giovanni Marotta
- Neuropsychopharmacology Research Group, Sunnybrook Research Institute, Toronto, ON, Canada
- Division of Geriatric Medicine, University of Toronto, Toronto, ON, Canada
| | - Kate Survilla
- Neuropsychopharmacology Research Group, Sunnybrook Research Institute, Toronto, ON, Canada
| | - Krista L Lanctôt
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Neuropsychopharmacology Research Group, Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
- Bernick Chair in Geriatric Psychopharmacology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| |
Collapse
|
|
5
|
Murphy KS, Golden JC, Tampi RR. Dexmedetomidine for agitation in dementia: Current data and future direction. J Am Geriatr Soc 2024. [PMID: 39295447 DOI: 10.1111/jgs.19196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 08/27/2024] [Indexed: 09/21/2024]
Abstract
BACKGROUND The incidence and prevalence of dementia, and thus dementia-related behavioral and psychological symptoms, are increasing significantly. Currently, there are limited safe and efficacious options for treating these symptoms. Dexmedetomidine has been used for agitation related to delirium and showed significant benefit in prior studies. This raises the question whether dexmedetomidine could also provide a safe and effective treatment for BPSD, including agitation related to dementia. METHODS Our team searched PubMed, Cochrane Database, and Ovid with the terms dexmedetomidine and dementia. Only studies published in English language journals, or with official English language translations, and human studies were included. All reports of dexmedetomidine for dementia were included regardless of study type. RESULTS No completed studies on dexmedetomidine for agitation in dementia were identified. The TRANQUILITY study is in progress, although results are yet to be published. CONCLUSION Dexmedetomidine has shown benefit for hospital delirium and for agitation in schizophrenia and bipolar disorder. However, there are no completed studies published on dexmedetomidine for agitation in dementia. Controlled studies with larger sample sizes are needed to assess the efficacy, safety, and the best route of administration for this drug in managing BPSD including agitation.
Collapse
Affiliation(s)
- Kayla S Murphy
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Julia C Golden
- Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Rajesh R Tampi
- Department of Psychiatry, Creighton University, Omaha, Nebraska, USA
| |
Collapse
|
|
6
|
Waite LM. New and emerging drug therapies for Alzheimer disease. Aust Prescr 2024; 47:75-79. [PMID: 38962384 PMCID: PMC11216914 DOI: 10.18773/austprescr.2024.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/05/2024] Open
Abstract
Established drug therapies for Alzheimer disease (cholinesterase inhibitors and memantine) do not modify the disease course and provide only modest clinical benefit. Biomarker measures of amyloid, tau and neurodegeneration have been integral to Alzheimer disease clinical trials for biologic drugs, for patient selection and efficacy monitoring. At the time of writing, two monoclonal antibodies targeting the amyloid-beta protein (aducanumab and lecanemab) have been approved in the USA, and two agents (lecanemab and donanemab) are under evaluation by the Therapeutic Goods Administration in Australia. Clinical trials have demonstrated that monoclonal antibodies are effective at removing amyloid from the brain in people with early Alzheimer disease. Cognitive benefits are statistically significant, but do not achieve the minimal clinically important difference. Amyloid-related imaging abnormalities of vasogenic oedema and microhaemorrhages occur more frequently on treatment; although these are usually asymptomatic or transient, in some people they are serious or fatal. Targeting amyloid as a unimodal strategy is unlikely to be sufficient and future therapies may need to be multimodal, targeting multiple pathogenic pathways. The burden of dementia is greatest in the older population where mixed dementia pathology dominates; the relationship between biomarkers, clinical phenotype and pathology attenuates; and frailty and comorbidity impact cognition. This creates challenges in identifying effective therapies for the group where dementia is most prevalent.
Collapse
|
|
7
|
Madar P, Nagalapur P, Chaudhari S, Sharma D, Koparde A, Buchade R, Kshirsagar S, Uttekar P, Jadhav S, Chaudhari P. The Unveiling of Therapeutic Targets for Alzheimer's Disease: An Integrative Review. Curr Top Med Chem 2024; 24:850-868. [PMID: 38424435 DOI: 10.2174/0115680266282492240220101049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 02/02/2024] [Accepted: 02/08/2024] [Indexed: 03/02/2024]
Abstract
Alzheimer's disease (AD) is characterized by a complex pathological landscape, necessitating a comprehensive treatment approach. This concise review paper delves into the idea of addressing multiple mechanisms in AD, summarizing the latest research findings on pathogenesis, risk factors, diagnostics, and therapeutic strategies. The etiology of AD is multifaceted, involving genetic, environmental, and lifestyle factors. The primary feature is the accumulation of amyloid-- beta and tau proteins, leading to neuroinflammation, synaptic dysfunction, oxidative stress, and neuronal loss. Conventional single-target therapies have shown limited effectiveness, prompting a shift toward simultaneously addressing multiple disease-related processes. Recent advancements in AD research underscore the potential of multifaceted therapies. This review explores strategies targeting both tau aggregation and amyloid-beta, along with interventions to alleviate neuroinflammation, enhance synaptic function, and reduce oxidative stress. In conclusion, the review emphasizes the growing importance of addressing various pathways in AD treatment. A holistic approach that targets different aspects of the disease holds promise for developing effective treatments and improving the quality of life for Alzheimer's patients and their caregivers.
Collapse
Affiliation(s)
- Pratiksha Madar
- Department of Pharmaceutical Chemistry, Modern College of Pharmacy, Savitribai Phule Pune University, Pune, India
| | - Pooja Nagalapur
- Department of Pharmaceutical Chemistry, Modern College of Pharmacy, Savitribai Phule Pune University, Pune, India
| | - Somdatta Chaudhari
- Department of Pharmaceutical Chemistry, Modern College of Pharmacy, Savitribai Phule Pune University, Pune, India
| | - Devesh Sharma
- Department of Biotechnology, National JALMA Institute for Leprosy & Other Mycobacterial Diseases, Agra, India
| | - Akshada Koparde
- Department of Pharmaceutical Chemistry, Krishna Foundation's Jaywant Institute of Pharmacy, Malkapur, Karad, India
| | - Rahul Buchade
- Department of Pharmaceutical Chemistry, Indira College of Pharmacy, Tathwade, Pune, India
| | - Sandip Kshirsagar
- Department of Pharmaceutical Chemistry, Dr. D Y Patil College of Pharmacy, Pune, India
| | - Pravin Uttekar
- Department of Pharmacuetics, Savitribai Phule Pune University, Pune, India
| | - Shailaja Jadhav
- Department of Pharmaceutical Chemistry, Modern College of Pharmacy, Savitribai Phule Pune University, Pune, India
| | - Praveen Chaudhari
- Department of Pharmaceutical Chemistry, Modern College of Pharmacy, Savitribai Phule Pune University, Pune, India
| |
Collapse
|
|
8
|
Mackiewicz J, Lisek M, Boczek T. Targeting CaN/NFAT in Alzheimer's brain degeneration. Front Immunol 2023; 14:1281882. [PMID: 38077352 PMCID: PMC10701682 DOI: 10.3389/fimmu.2023.1281882] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 11/06/2023] [Indexed: 12/18/2023] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of cognitive functions. While the exact causes of this debilitating disorder remain elusive, numerous investigations have characterized its two core pathologies: the presence of β-amyloid plaques and tau tangles. Additionally, multiple studies of postmortem brain tissue, as well as results from AD preclinical models, have consistently demonstrated the presence of a sustained inflammatory response. As the persistent immune response is associated with neurodegeneration, it became clear that it may also exacerbate other AD pathologies, providing a link between the initial deposition of β-amyloid plaques and the later development of neurofibrillary tangles. Initially discovered in T cells, the nuclear factor of activated T-cells (NFAT) is one of the main transcription factors driving the expression of inflammatory genes and thus regulating immune responses. NFAT-dependent production of inflammatory mediators is controlled by Ca2+-dependent protein phosphatase calcineurin (CaN), which dephosphorylates NFAT and promotes its transcriptional activity. A substantial body of evidence has demonstrated that aberrant CaN/NFAT signaling is linked to several pathologies observed in AD, including neuronal apoptosis, synaptic deficits, and glia activation. In view of this, the role of NFAT isoforms in AD has been linked to disease progression at different stages, some of which are paralleled to diminished cognitive status. The use of classical inhibitors of CaN/NFAT signaling, such as tacrolimus or cyclosporine, or adeno-associated viruses to specifically inhibit astrocytic NFAT activation, has alleviated some symptoms of AD by diminishing β-amyloid neurotoxicity and neuroinflammation. In this article, we discuss the recent findings related to the contribution of CaN/NFAT signaling to the progression of AD and highlight the possible benefits of targeting this pathway in AD treatment.
Collapse
Affiliation(s)
| | | | - Tomasz Boczek
- Department of Molecular Neurochemistry, Medical University of Lodz, Lodz, Poland
| |
Collapse
|
|
9
|
Banerjee S, Farina N, Henderson C, High J, Stirling S, Shepstone L, Fountain J, Ballard C, Bentham P, Burns A, Fox C, Francis P, Howard R, Knapp M, Leroi I, Livingston G, Nilforooshan R, Nurock S, O'Brien J, Price A, Thomas AJ, Swart AM, Telling T, Tabet N. 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. Health Technol Assess 2023; 27:1-108. [PMID: 37929672 PMCID: PMC10641860 DOI: 10.3310/vpdt7105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2023] Open
Abstract
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.
Collapse
Affiliation(s)
- Sube Banerjee
- Faculty of Health, University of Plymouth, Plymouth, UK
| | - Nicolas Farina
- Faculty of Health, University of Plymouth, Plymouth, UK
- Centre for Dementia Studies, Brighton and Sussex Medical School, University of Sussex, Brighton and Hove, UK
| | - Catherine Henderson
- Care Policy and Evaluation Centre, London School of Economics and Political Science, London, UK
| | - Juliet High
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, Norfolk, UK
| | - Susan Stirling
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, Norfolk, UK
| | - Lee Shepstone
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, Norfolk, UK
| | - Julia Fountain
- Coordinator for Service User and Carer Involvement in Research, Sussex Partnership NHS Foundation Trust, Brighton and Hove, UK
| | - Clive Ballard
- College of Medicine and Health, University of Exeter, Exeter, UK
| | - Peter Bentham
- Birmingham and Solihull Mental Health Foundation NHS Trust, Birmingham, UK
| | - Alistair Burns
- Department of Psychiatry, University of Manchester, Manchester, UK
| | - Chris Fox
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, Norfolk, UK
| | - Paul Francis
- College of Medicine and Health, University of Exeter, Exeter, UK
| | - Robert Howard
- Division of Psychiatry, University College London, London, UK
| | - Martin Knapp
- Care Policy and Evaluation Centre, London School of Economics and Political Science, London, UK
| | - Iracema Leroi
- Department of Psychiatry, Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland
| | - Gill Livingston
- Division of Psychiatry, University College London, London, UK
| | - Ramin Nilforooshan
- Research and Development, Surrey and Borders Partnership NHS Foundation Trust, Leatherhead, UK
| | - Shirley Nurock
- Former Carer, Alzheimer's Society Research Network, London, UK
| | - John O'Brien
- Department of Psychiatry, University of Cambridge School of Medicine, Cambridge, UK
| | - Annabel Price
- Cambridgeshire and Peterborough Foundation Trust, Cambridge, UK
| | - Alan J Thomas
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Ann Marie Swart
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, Norfolk, UK
| | - Tanya Telling
- Joint Clinical Research Office, University of Sussex, Brighton, UK
| | - Naji Tabet
- Centre for Dementia Studies, Brighton and Sussex Medical School, University of Sussex, Brighton and Hove, UK
| |
Collapse
|
|
10
|
Ting YY, Tien Y, Huang HP. Effects of aromatherapy on agitation in patients with dementia in the community: A quasi-experimental study. Geriatr Nurs 2023; 51:422-428. [PMID: 37148590 DOI: 10.1016/j.gerinurse.2023.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/12/2023] [Accepted: 04/14/2023] [Indexed: 05/08/2023]
Abstract
The behavioral and psychological symptoms of dementia (BPSD) are experienced by up to 90% of patients with dementia throughout dementia. This study aims to investigate the effect of aromatherapy on agitation in patients with dementia in the community. This prospective cohort study was conducted at a single day-care center for patients with dementia located in northern Taiwan with 2-week and 4-week follow-ups, comparing the severity of agitation between 3 measure points as the primary outcome. The aromatherapy was performed over 5 consecutive days for 4 weeks. Throughout the four-week observation were analyzed by GEE. Significant differences were found in the Chinese version of Cohen-Mansfield Agitation Inventory (CCMAI) total agitation score (ß=-3.622, p=0.037) and physically non-aggressive behavior subscale (ß=-4.005, p=0.004) between aromatherapy group and control group. The severity of dementia-related agitation, especially the severity of physically non-aggressive behavior in demented patients, could be significantly reduced by a four-week intervention of aromatherapy.
Collapse
Affiliation(s)
- Yi-Yun Ting
- Graduate Institute of Gerontology and Health Care Management, Chang Gung University of Science and Technology, Taoyuan City, Taiwan
| | - Yun Tien
- Deparement of Psychiatry, Taoyuan Psychiatric Center, Taoyuan City, Taiwan
| | - Hsiang-Ping Huang
- Department of Nursing, Chang Gung University of Science and Technology, Taoyuan City, Taiwan.
| |
Collapse
|
|
11
|
Guo C, Wang T, Zhang D, Ge X, Li J. Plasminogen decreases Aβ42 and Tau deposition, and shows multi-beneficial effects on Alzheimer's disease in mice and humans. Biochem Biophys Res Commun 2023; 654:102-111. [PMID: 36905760 DOI: 10.1016/j.bbrc.2023.02.078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/08/2023] [Accepted: 02/26/2023] [Indexed: 03/06/2023]
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disorder in the world. The aggregation of both amyloid beta (Aβ) peptides extracellularly and Tau proteins intracellularly plays key roles in the pathological consequences of AD, which lead to cholinergic neurodegeneration and eventually death. Currently, there are no effective methods to stop the progression of AD. Using ex vivo, in vivo and clinical approaches, we investigated the functional effects of plasminogen on the widely used FAD, Aβ42 oligomer or Tau intracranial injection-induced AD mouse model and explored its therapeutic effects on patients with AD. The results show that intravenously injected plasminogen rapidly crosses the blood‒brain barrier (BBB); increases plasmin activity in the brain; colocalizes with and effectively promotes the clearance of Aβ42 peptide and Tau protein deposits ex vivo and in vivo; increases the choline acetyltransferase (ChAT) level and decreases the acetylcholinesterase (AChE) activity; and improves the memory functions. Clinically, when GMP-level plasminogen was administered to 6 AD patients for 1-2 weeks, their average scores on the Minimum Mental State Examination (MMSE), which is a standard scoring system used to measure the memory loss and cognitive deficits, were extremely significantly improved by 4.2 ± 2.23 points, e.g., an average increase from 15.5 ± 8.22 before treatment to 19.7 ± 7.09 after treatment. The preclinical study and pilot clinical study suggest that plasminogen is effective in treating AD and may be a promising drug candidate.
Collapse
Affiliation(s)
- Chunying Guo
- Department of Applied Research, Talengen Institute of Life Sciences, Shenzhen, PR China; Department of Applied Research, Ruijian Xingze Biomedical Co. Ltd, Dongguan, PR China
| | - Ting Wang
- Department of Applied Research, Talengen Institute of Life Sciences, Shenzhen, PR China; Department of Applied Research, Ruijian Xingze Biomedical Co. Ltd, Dongguan, PR China
| | - Dongmei Zhang
- Beijing Chang'an Chinese and Western Integrated Medicine Hospital, Beijing, PR China
| | - Xiaojing Ge
- Department of Applied Research, Talengen Institute of Life Sciences, Shenzhen, PR China; Department of Applied Research, Ruijian Xingze Biomedical Co. Ltd, Dongguan, PR China
| | - Jinan Li
- Department of Applied Research, Talengen Institute of Life Sciences, Shenzhen, PR China; Department of Applied Research, Ruijian Xingze Biomedical Co. Ltd, Dongguan, PR China.
| |
Collapse
|
|
12
|
Chen K, Li H, Yang L, Jiang Y, Wang Q, Zhang J, He J. Comparative efficacy and safety of antidepressant therapy for the agitation of dementia: A systematic review and network meta-analysis. Front Aging Neurosci 2023; 15:1103039. [PMID: 36936502 PMCID: PMC10020338 DOI: 10.3389/fnagi.2023.1103039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 02/13/2023] [Indexed: 03/06/2023] Open
Abstract
Background Dementia is a clinical syndrome commonly seen in the elderly individuals. With the prevalence of dementia, the incidence of neuropsychiatric symptoms in dementia patients is increasing annually. Agitation, as one of the neuropsychiatric symptoms, has a serious impact on the quality of life of patients with dementia. Several antidepressant drugs have been shown to be effective for treating agitated behavior symptoms in patients with dementia, but there are no direct comparisons among those drugs. Therefore, we carried out a network meta-analysis (NMA) to examine the efficacy and safety of those antidepressant drugs. Methods We searched eight databases (PubMed, Cochrane Library, Web of Science, Embase, Wanfang Database, China National Knowledge Infrastructure, VIP Database and China biomedical literature service) from their inception to 6 November 2022. Randomized controlled trials (RCTs) reporting the efficacy and safety of antidepressant drugs in treating agitated behavior symptoms in patients with dementia were included in our analysis. The quality assessment was carried out by two researchers individually and the analysis was based on the frequency method. Results Twelve articles with 1,146 participants were included in our analysis. Based on the outcome of the agitation score, treatment with citalopram (standardized mean difference, SMD = -0.44, 95% confidence interval, 95% CI = -0.72 to -0.16) showed significant benefits over the placebo group. Treatment with trazodone (odds ratio, OR = 4.58, 95% CI = 1.12-18.69) was associated with a higher risk of total adverse events compared with a placebo treatment. Conclusion Among the antidepressant drugs included in this study, treatment with citalopram was probably the only optimal intervention, when considering the improvement from baseline to the end of the intervention, and there was not a statistically significant difference in safety when compared with a placebo treatment. Systematic review registration https://www.crd.york.ac.uk/prospero/#recordDetails, identifier: PROSPERO, CRD42022320932.
Collapse
Affiliation(s)
- Kaili Chen
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Haiqi Li
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Le Yang
- Department of Endocrinology, Jilin Province People's Hospital, Changchun, China
| | - Yan Jiang
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Qiaoli Wang
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jiao Zhang
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jinting He
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
- *Correspondence: Jinting He
| |
Collapse
|
|
13
|
Miller A, Desai A, Roley LT, Goodwin RL, Nathaniel AI, Nathaniel TI. The role of ethnicity, biological sex, and psychotropic agents in early and late onset Alzheimer's disease. Front Aging Neurosci 2022; 14:1052330. [PMID: 36620767 PMCID: PMC9815502 DOI: 10.3389/fnagi.2022.1052330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
Objective This study investigates differences in pharmacological and demographic factors among male and female patients with Late-onset Alzheimer's disease (LOAD) and Early-onset Alzheimer's disease (EOAD). Method Data are from 10,126 AD patients, 9,290 were diagnosed with LOAD, while 836 were diagnosed with EOAD. Data were collected from the Prisma Health Upstate Alzheimer's patients' registry between 2016 and 2021. The logistic regression analysis was used to assess the association between pharmacological and demographic factors in males and females with LOAD and EOAD. Results In the adjusted analysis for males, patients that were administered memantine [odd ratio (OR) = 1.588, 95% CI, 1.175-2.145, p = 0.003], and buspirone [OR = 1.971, 95% CI, 1.221-3.183, p = 0.006] were more likely to be associated with EOAD, while increasing age [OR = 0.816, 95% CI, 0.799-0.834, p < 0.001] was associated with LOAD. Female patients with a history of alcohol (ETOH) use were more likely to be associated with EOAD while increasing age [OR = 0.845, 95% CI, 0.834-0.857, p < 0.001], treatment with memantine [OR = 0.774, 95% CI, 0.627-0.956, p = 0.017], African Americans [OR = 0.621, 95% CI, 0.462-0.835, p = 0.002] and tobacco use [OR = 0.529, 95% CI, 0.424-0.660, p < 0.001] were associated with LOAD. Conclusion Our findings identified specific demographic and pharmacological factors associated with males and females with LOAD and EOAD. These findings suggest the need to develop strategies to eliminate disparity in the care of LOAD or EOAD patients.
Collapse
Affiliation(s)
- Alyssa Miller
- Department of Biology, North Greenville University, Tigerville, SC, United States
| | - Ashna Desai
- Department of Biology, University of South Carolina, Columbia, SC, United States
| | | | - Richard L. Goodwin
- School of Medicine Greenville, University of South Carolina, Greenville, SC, United States
| | | | - Thomas I. Nathaniel
- School of Medicine Greenville, University of South Carolina, Greenville, SC, United States,*Correspondence: Thomas I. Nathaniel,
| |
Collapse
|
|
14
|
Henderson C, Knapp M, Stirling S, Shepstone L, High J, Ballard C, Bentham P, Burns A, Farina N, Fox C, Fountain J, Francis P, Howard R, Leroi I, Livingston G, Nilforooshan R, Nurock S, O'Brien JT, Price A, Swart AM, Tabet N, Telling T, Thomas AJ, Banerjee S. Cost-effectiveness of mirtazapine for agitated behaviors in dementia: findings from a randomized controlled trial. Int Psychogeriatr 2022; 34:905-917. [PMID: 35852256 DOI: 10.1017/s1041610222000436] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
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.
Collapse
Affiliation(s)
- Catherine Henderson
- Care Policy and Evaluation Centre, London School of Economics and Political Science, London, UK
| | - Martin Knapp
- Care Policy and Evaluation Centre, London School of Economics and Political Science, London, UK
| | - Susan Stirling
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Lee Shepstone
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Juliet High
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Clive Ballard
- College of Medicine and Health, University of Exeter, Exeter, UK
| | - Peter Bentham
- Birmingham and Solihull Mental Health Foundation NHS Trust, Birmingham, UK
| | | | - Nicolas Farina
- Centre for Dementia Studies, Brighton and Sussex Medical School, University of Sussex, Brighton, UK
| | - Chris Fox
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Julia Fountain
- Research & Development Department, Sussex Partnership NHS Foundation Trust, Sussex Education Centre, Hove, UK
| | - Paul Francis
- College of Medicine and Health, University of Exeter, Exeter, UK
| | - Robert Howard
- Division of Psychiatry, University College London, London, UK
| | - Iracema Leroi
- Department of Psychiatry, Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland
| | - Gill Livingston
- Division of Psychiatry, University College London, London, UK
| | | | | | - John T O'Brien
- Department of Psychiatry, University of Cambridge School of Medicine, Cambridge, UK
| | - Annabel Price
- Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK
| | - Ann Marie Swart
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Naji Tabet
- Centre for Dementia Studies, Brighton and Sussex Medical School, University of Sussex, Brighton, UK
| | - Tanya Telling
- Joint Clinical Research Office, University of Sussex, Brighton, UK
| | - Alan J Thomas
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Sube Banerjee
- Faculty of Health, University of Plymouth, Plymouth, UK
| |
Collapse
|
|
15
|
Agüera-Ortiz L, Babulal GM, Bruneau MA, Creese B, D'Antonio F, Fischer CE, Gatchel JR, Ismail Z, Kumar S, McGeown WJ, Mortby ME, Nuñez NA, de Oliveira FF, Pereiro AX, Ravona-Springer R, Rouse HJ, Wang H, Lanctôt KL. Psychosis as a Treatment Target in Dementia: A Roadmap for Designing Interventions. J Alzheimers Dis 2022; 88:1203-1228. [PMID: 35786651 PMCID: PMC9484097 DOI: 10.3233/jad-215483] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials.
Collapse
Affiliation(s)
- Luis Agüera-Ortiz
- Department of Psychiatry, Instituto de Investigación Sanitaria (imas12), Hospital Universitario 12 de Octubre, & Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Instituto de Salud Carlos III, Madrid, Spain
| | - Ganesh M Babulal
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.,Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.,Department of Psychology, Faculty of Humanities, University of Johannesburg, South Africa
| | - Marie-Andrée Bruneau
- Department of Psychiatry and Addictology, Faculty of Medicine, University of Montreal, Quebec, Canada.,Geriatric Institute of Montreal Research Center, Montreal, Quebec, Canada
| | - Byron Creese
- Medical School, College of Medicine and Health, University of Exeter, UK
| | | | - Corinne E Fischer
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.,University of Toronto, Department of Psychiatry, Toronto, Ontario, Canada
| | - Jennifer R Gatchel
- Harvard Medical School; Massachusetts General Hospital, Boston MA, USA.,McLean Hospital, Belmont MA, USA
| | - Zahinoor Ismail
- Hotchkiss Brain Institute & O'Brien Institute for Public Health, University of Calgary, Calgary, Canada
| | - Sanjeev Kumar
- Adult Neurodevelopmental and Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.,Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - William J McGeown
- School of Psychological Sciences and Health, University of Strathclyde, Glasgow, UK
| | - Moyra E Mortby
- School of Psychology, University of New South Wales, Sydney, Australia & Neuroscience Research Australia, Sydney, Australia
| | - Nicolas A Nuñez
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA
| | - Fabricio F de Oliveira
- Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Arturo X Pereiro
- Facultade de Psicoloxía, Universidade de Santiago de Compostela, Spain
| | - Ramit Ravona-Springer
- Sheba Medical Center, Tel Hashomer, Israel & Sackler School of Medicine, Tel Aviv University, Israel
| | - Hillary J Rouse
- School of Aging Studies, University of South Florida, Tampa, FL, USA.,SiteRx, New York, NY, USA
| | - Huali Wang
- Dementia Care and Research Center, Peking University Institute of Mental Health; National & Clinical Research Center for Mental Disorders, Beijing, China
| | - Krista L Lanctôt
- Hurvitz Brain Sciences Program, Sunnybrook Research Institute and Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
16
|
Bartsch CJ, Nordman JC. Promises and Pitfalls of NMDA Receptor Antagonists in Treating Violent Aggression. Front Behav Neurosci 2022; 16:938044. [PMID: 35801096 PMCID: PMC9253591 DOI: 10.3389/fnbeh.2022.938044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 05/25/2022] [Indexed: 11/24/2022] Open
Abstract
Treatment options for chronically aggressive individuals remain limited despite recent medical advances. Traditional pharmacological agents used to treat aggression, such as atypical antipsychotics, have limited efficacy and are often replete with dangerous side effects. The non-competitive NMDAR antagonists ketamine and memantine are promising alternatives, but their effects appear to be highly dependent on dosage, context, and personal experience. Importantly, these drugs can increase aggression when combined with substances of abuse or during periods of heightened stress. This is likely due to mechanistic differences operating at specific synapses under different contexts. Previous findings from our lab and others have shown that early life stress, substance abuse, and attack experience promote aggression through NMDAR-dependent synaptic plasticity within aggression-related brain circuits. Ketamine and memantine affect these types of aggression in opposite ways. This has led us to propose that ketamine and memantine oppositely affect aggression brought on by early life stress, substance abuse, or attack experience through opposite effects on NMDAR-dependent synaptic plasticity. This would account for the persistent effects of these drugs on aggression and suggest they could be leveraged as a more long-lasting treatment option. However, a more thorough examination of the effects of ketamine and memantine on cellular and synaptic function will be necessary for responsible administration. Additionally, because the effects of ketamine and memantine are highly dependent on prior drug use, traumatic stress, or a history of aggressive behavior, we propose a more thorough medical evaluation and psychiatric assessment will be necessary to avoid possible adverse interactions with these drugs.
Collapse
Affiliation(s)
- Caitlyn J. Bartsch
- Department of Physiology, University of Southern Illinois Carbondale, Carbondale, IL, United States
| | - Jacob C. Nordman
- Department of Physiology, University of Southern Illinois School of Medicine, Carbondale, IL, United States
- *Correspondence: Jacob C. Nordman
| |
Collapse
|
|
17
|
Bhoopatiraju S, Grossberg G. Emerging Perspectives in the Management of Agitation in Alzheimer's Disease and Patients with Dementia. Neurology 2022. [DOI: 10.17925/usn.2022.18.1.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
While Alzheimer's disease, the most common cause of dementia, is perhaps best characterized by cognitive decline, more than 90% of patients exhibit behavioural and psychological symptoms of dementia. Agitation in patients with dementia is often difficult to manage, and is associated with increased morbidity and mortality in patients and a heightened caregiver burden. Thus, effective management of dementia-related agitation (DRA) is vital. Care should first be taken to consider and address causes of agitation and aggression, after which non-pharmacological interventions should be employed. If non-pharmacological measures are unsuccessful in reducing DRA then medications should be considered, although none are approved by the Food and Drug Administration for this indication. Electroconvulsive therapy may be a promising option for patients with treatment-refractory DRA, although more studies are needed. While there are several drugs in the pipeline for DRA treatment, results from robust randomized clinical trials are necessary before they can be administered to patients. Thus, clinicians should employ current strategies to manage DRA to ensure holistic care for patients with Alzheimer's disease.
Collapse
|
|
18
|
Tseng PT, Zeng BY, Chen YW, Yang CP, Su KP, Chen TY, Wu YC, Tu YK, Lin PY, Carvalho AF, Stubbs B, Matsuoka YJ, Li DJ, Liang CS, Hsu CW, Sun CK, Cheng YS, Yeh PY, Shiue YL. The Dose and Duration-dependent Association between Melatonin Treatment and Overall Cognition in Alzheimer's Dementia: A Network Meta- Analysis of Randomized Placebo-Controlled Trials. Curr Neuropharmacol 2022; 20:1816-1833. [PMID: 35450525 PMCID: PMC9886806 DOI: 10.2174/1570159x20666220420122322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 02/18/2022] [Accepted: 04/14/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND While Alzheimer's dementia (AD) has a prevalence as high as 3-32% and is associated with cognitive dysfunction and the risk of institutionalization, no efficacious and acceptable treatments can modify the course of cognitive decline in AD. Potential benefits of exogenous melatonin for cognition have been divergent across trials. OBJECTIVE The current network meta-analysis (NMA) was conducted under the frequentist model to evaluate the potential beneficial effects of exogenous melatonin supplementation on overall cognitive function in participants with AD in comparison to other FDA-approved medications (donepezil, galantamine, rivastigmine, memantine, and Namzaric). METHODS The primary outcome was the changes in the cognitive function [measured by mini-mental state examination (MMSE)] after treatment in patients with Alzheimer's dementia. The secondary outcomes were changes in the quality of life, behavioral disturbance, and acceptability (i.e., drop-out due to any reason and rate of any adverse event reported). RESULTS The current NMA of 50 randomized placebo-controlled trials (RCTs) revealed the medium-term lowdose melatonin to be associated with the highest post-treatment MMSE (mean difference = 1.48 in MMSE score, 95% confidence intervals [95% CIs] = 0.51 to 2.46) and quality of life (standardized mean difference = -0.64, 95% CIs = -1.13 to -0.15) among all of the investigated medications in the participants with AD. Finally, all of the investigated exogenous melatonin supplements were associated with similar acceptability as was the placebo. CONCLUSION The current NMA provides evidence for the potential benefits of exogenous melatonin supplementation, especially medium-term low-dose melatonin, in participants with AD.
Collapse
Affiliation(s)
- Ping-Tao Tseng
- Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
- Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan; Clinical Psychology Center, Asia University Hospital, Taichung, Taiwan
| | - Bing-Yan Zeng
- Department of Internal Medicine, E-DA Dachang Hospital, Kaohsiung, Taiwan
| | - Yen-Wen Chen
- Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung, Taiwan
| | - Chun-Pai Yang
- Department of Neurology, Kuang Tien General Hospital, Taichung, Taiwan
- Department of Nutrition, Huangkuang University, Taichung, Taiwan
| | - Kuan-Pin Su
- Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
- An-Nan Hospital, China Medical University, Tainan, Taiwan
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
| | - Tien-Yu Chen
- Department of Psychiatry, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei112, Taiwan
| | - Yi-Cheng Wu
- Department of Sports Medicine, Landseed International Hospital, Taoyuan, Taiwan
| | - Yu-Kang Tu
- Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
| | - Pao-Yen Lin
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Andre F. Carvalho
- Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia
| | - Brendon Stubbs
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
- Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, UK
- Faculty of Health, Social Care Medicine and Education, Anglia Ruskin University, Chelmsford, UK
| | - Yutaka J. Matsuoka
- Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan
- Former Division Chief of Health Care Research, National Cancer Center, Japan
| | - Dian-Jeng Li
- Department of Addiction Science, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung City, Taiwan
| | - Chih-Sung Liang
- Department of Psychiatry, Beitou Branch, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Wei Hsu
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheuk-Kwan Sun
- Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students
| | - Yu-Shian Cheng
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
- Department of Psychiatry, Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai’s Home, Taiwan
| | - Pin-Yang Yeh
- Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan; Clinical Psychology Center, Asia University Hospital, Taichung, Taiwan
| | - Yow-Ling Shiue
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| |
Collapse
|
|
19
|
Heilman KM, Nadeau SE. Emotional and Neuropsychiatric Disorders Associated with Alzheimer's Disease. Neurotherapeutics 2022; 19:99-116. [PMID: 35013934 PMCID: PMC9130428 DOI: 10.1007/s13311-021-01172-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2021] [Indexed: 01/03/2023] Open
Abstract
Alzheimer's disease is associated with impairments in emotional communication including comprehension and production of facial emotional expressions, comprehension of affective prosody, and alexithymia. It is also associated with disorders of emotional experience including mood disorders (depression and anxiety), agitation/aggression, and psychosis. Agitation/aggression and psychosis are particularly disruptive, are associated with earlier institutionalization, and pose a major challenge to institutional management. Treatment of disorders of emotional experience has been primarily pharmacologic (reviewed here in detail) and has relied heavily on antipsychotic medications despite the small effect sizes demonstrated in a large number of randomized controlled trials and the prevalence of serious side effects associated with these drugs. Recent studies suggest that treatment with pimavanserin, an antipsychotic without activity at dopamine receptors, may represent an important advance for treatment of psychotic manifestations, even as the drug appears to pose significant risk. Dextromethorphan/quinidine may represent an important advance in the treatment of agitation/aggression. There is also compelling evidence that sleep disorders, which are common among patients with Alzheimer's disease and are readily treatable, may potentiate psychotic manifestations and agitation/aggression, but further studies are needed.
Collapse
Affiliation(s)
- Kenneth M Heilman
- Geriatric Research, Education, and Clinical Center, Malcom Randall VA Medical Center, 1601 SW Archer Road, Gainesville, FL, 32608-1197, USA
- The Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Road, Gainesville, FL, 32608-1197, USA
- Malcom Randall VA Medical Center and the Department of Neurology, University of Florida College of Medicine, Gainesville, FL, USA
| | - Stephen E Nadeau
- Research Service, Malcom Randall VA Medical Center, 1601 SW Archer Road, Gainesville, FL, 32608-1197, USA.
- The Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Road, Gainesville, FL, 32608-1197, USA.
- Malcom Randall VA Medical Center and the Department of Neurology, University of Florida College of Medicine, Gainesville, FL, USA.
| |
Collapse
|
|
20
|
Banerjee S, High J, Stirling S, Shepstone L, Swart AM, Telling T, Henderson C, Ballard C, Bentham P, Burns A, Farina N, Fox C, Francis P, Howard R, Knapp M, Leroi I, Livingston G, Nilforooshan R, Nurock S, O'Brien J, Price A, Thomas AJ, Tabet N. Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial. Lancet 2021; 398:1487-1497. [PMID: 34688369 PMCID: PMC8546216 DOI: 10.1016/s0140-6736(21)01210-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/03/2021] [Accepted: 05/14/2021] [Indexed: 12/11/2022]
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.
Collapse
Affiliation(s)
- Sube Banerjee
- Faculty of Health, University of Plymouth, Plymouth, UK.
| | - Juliet High
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK
| | - Susan Stirling
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK
| | - Lee Shepstone
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK
| | - Ann Marie Swart
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK
| | - Tanya Telling
- Joint Clinical Research Office, University of Sussex, Brighton, UK
| | - Catherine Henderson
- Care Policy and Evaluation Centre, London School of Economics and Political Science, London, UK
| | - Clive Ballard
- College of Medicine and Health, University of Exeter, Exeter, UK
| | - Peter Bentham
- Birmingham and Solihull Mental Health Foundation NHS Trust, Birmingham, UK
| | | | - Nicolas Farina
- Centre for Dementia Studies, Brighton and Sussex Medical School, University of Sussex, Brighton, UK
| | - Chris Fox
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK
| | - Paul Francis
- College of Medicine and Health, University of Exeter, Exeter, UK
| | - Robert Howard
- Division of Psychiatry, University College London, London, UK
| | - Martin Knapp
- Care Policy and Evaluation Centre, London School of Economics and Political Science, London, UK
| | - Iracema Leroi
- Department of Psychiatry, Global Brain Health Institute, Trinity College, Dublin, Ireland
| | - Gill Livingston
- Division of Psychiatry, University College London, London, UK
| | | | - Shirley Nurock
- Former Carer, Alzheimer's Society Research Network, University of Cambridge School of Medicine, Cambridge, UK
| | - John O'Brien
- Department of Psychiatry, University of Cambridge School of Medicine, Cambridge, UK
| | - Annabel Price
- Cambridgeshire and Peterborough Foundation Trust, Cambridge, UK
| | - Alan J Thomas
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Naji Tabet
- Centre for Dementia Studies, Brighton and Sussex Medical School, University of Sussex, Brighton, UK
| |
Collapse
|
|
21
|
Lu ZK, Xiong X, Wang X, Wu J. Gender Disparities in Anti-dementia Medication Use among Older Adults: Health Equity Considerations and Management of Alzheimer's Disease and Related Dementias. Front Pharmacol 2021; 12:706762. [PMID: 34512340 PMCID: PMC8424001 DOI: 10.3389/fphar.2021.706762] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 08/13/2021] [Indexed: 11/13/2022] Open
Abstract
Objective: The prevalence of Alzheimer's disease and related dementias (ADRD) in women is higher than men. However, the knowledge of gender disparity in ADRD treatment is limited. Therefore, this study aimed to determine the gender disparities in the receipt of anti-dementia medications among Medicare beneficiaries with ADRD in the U.S. Methods: We used data from the Medicare Current Beneficiary Survey 2016. Anti-dementia medications included cholinesterase inhibitors (ChEIs; including rivastigmine, donepezil, and galantamine) and N-methyl-D-aspartate (NMDA) receptor antagonists (including memantine). Descriptive analysis and multivariate logistic regression models were implemented to determine the possible gender disparities in the receipt of anti-dementia medications. Subgroup analyses were conducted to identify gender disparities among beneficiaries with Alzheimer's disease (AD) and those with only AD-related dementias. Results: Descriptive analyses showed there were statistically significant differences in age, marital status, and Charlson comorbidities index (CCI) between Medicare beneficiaries who received and who did not receive anti-dementia medications. After controlling for covariates, we found that female Medicare beneficiaries with ADRD were 1.7 times more likely to receive anti-dementia medications compared to their male counterparts (odds ratio [OR]: 1.71; 95% confidence interval [CI]: 1.19-2.45). Specifically, among Medicare beneficiaries with AD, females were 1.2 times more likely to receive anti-dementia medications (Odds Radio: 1.20; 95% confidence interval: 0.58-2.47), and among the Medicare beneficiaries with only AD-related dementias, females were 1.9 times more likely to receive anti-dementia medications (OR: 1.90; 95% CI: 1.23-2.95). Conclusion: Healthcare providers should be aware of gender disparities in receiving anti-dementia medications among patients with ADRD, and the need to plan programs of care to support both women and men. Future approaches to finding barriers of prescribing, receiving and, adhering to anti-dementia medications by gender should include differences in longevity, biology, cognition, social roles, and environment.
Collapse
Affiliation(s)
- Z. Kevin Lu
- Department of Clinical Pharmacy and Outcomes Sciences, University of South Carolina, Columbia, SC, United States
| | - Xiaomo Xiong
- Department of Clinical Pharmacy and Outcomes Sciences, University of South Carolina, Columbia, SC, United States
| | - Xinyuan Wang
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Jun Wu
- Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, Clinton, SC, United States
| |
Collapse
|
|
22
|
Carrarini C, Russo M, Dono F, Barbone F, Rispoli MG, Ferri L, Di Pietro M, Digiovanni A, Ajdinaj P, Speranza R, Granzotto A, Frazzini V, Thomas A, Pilotto A, Padovani A, Onofrj M, Sensi SL, Bonanni L. Agitation and Dementia: Prevention and Treatment Strategies in Acute and Chronic Conditions. Front Neurol 2021; 12:644317. [PMID: 33935943 PMCID: PMC8085397 DOI: 10.3389/fneur.2021.644317] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 03/12/2021] [Indexed: 01/11/2023] Open
Abstract
Agitation is a behavioral syndrome characterized by increased, often undirected, motor activity, restlessness, aggressiveness, and emotional distress. According to several observations, agitation prevalence ranges from 30 to 50% in Alzheimer's disease, 30% in dementia with Lewy bodies, 40% in frontotemporal dementia, and 40% in vascular dementia (VaD). With an overall prevalence of about 30%, agitation is the third most common neuropsychiatric symptoms (NPS) in dementia, after apathy and depression, and it is even more frequent (80%) in residents of nursing homes. The pathophysiological mechanism underlying agitation is represented by a frontal lobe dysfunction, mostly involving the anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC), respectively, meaningful in selecting the salient stimuli and subsequent decision-making and behavioral reactions. Furthermore, increased sensitivity to noradrenergic signaling has been observed, possibly due to a frontal lobe up-regulation of adrenergic receptors, as a reaction to the depletion of noradrenergic neurons within the locus coeruleus (LC). Indeed, LC neurons mainly project toward the OFC and ACC. These observations may explain the abnormal reactivity to weak stimuli and the global arousal found in many patients who have dementia. Furthermore, agitation can be precipitated by several factors, e.g., the sunset or low lighted environments as in the sundown syndrome, hospitalization, the admission to nursing residencies, or changes in pharmacological regimens. In recent days, the global pandemic has increased agitation incidence among dementia patients and generated higher distress levels in patients and caregivers. Hence, given the increasing presence of this condition and its related burden on society and the health system, the present point of view aims at providing an extensive guide to facilitate the identification, prevention, and management of acute and chronic agitation in dementia patients.
Collapse
Affiliation(s)
- Claudia Carrarini
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Mirella Russo
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Fedele Dono
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Filomena Barbone
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Marianna G Rispoli
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Laura Ferri
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Martina Di Pietro
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Anna Digiovanni
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Paola Ajdinaj
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Rino Speranza
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Alberto Granzotto
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.,Behavioral Neurology and Molecular Neurology Units, Center for Advanced Studies and Technology-CAST, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.,Institute for Mind Impairments and Neurological Disorders-iMIND, University of California, Irvine, Irvine, CA, United States
| | - Valerio Frazzini
- Behavioral Neurology and Molecular Neurology Units, Center for Advanced Studies and Technology-CAST, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.,Institut du Cerveau et de la Moelle épinière, ICM, INSERM UMRS 1127, CNRS UMR 7225, Pitié Salpêtrière Hospital, Paris, France.,AP-HP, GH Pitie-Salpêtrière-Charles Foix, Epilepsy Unit and Neurophysiology Department, Paris, France
| | - Astrid Thomas
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Andrea Pilotto
- Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.,Parkinson's Disease Rehabilitation Centre, FERB ONLUS-S. Isidoro Hospital, Trescore Balneario, Italy
| | - Alessandro Padovani
- Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Marco Onofrj
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.,Behavioral Neurology and Molecular Neurology Units, Center for Advanced Studies and Technology-CAST, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Stefano L Sensi
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.,Behavioral Neurology and Molecular Neurology Units, Center for Advanced Studies and Technology-CAST, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Laura Bonanni
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.,Behavioral Neurology and Molecular Neurology Units, Center for Advanced Studies and Technology-CAST, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| |
Collapse
|
|
23
|
Parsons C, Lim WY, Loy C, McGuinness B, Passmore P, Ward SA, Hughes C. Withdrawal or continuation of cholinesterase inhibitors or memantine or both, in people with dementia. Cochrane Database Syst Rev 2021; 2:CD009081. [PMID: 35608903 PMCID: PMC8094886 DOI: 10.1002/14651858.cd009081.pub2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
BACKGROUND Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment. OBJECTIVES To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes. SEARCH METHODS We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. SELECTION CRITERIA We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs. DATA COLLECTION AND ANALYSIS Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to 2 months after randomisation), medium term (3-11 months) and long term (12 months or more). We assessed the overall certainty of the evidence for each outcome using GRADE methods. MAIN RESULTS We included six trials investigating cholinesterase inhibitor withdrawal, and one trial investigating withdrawal of either donepezil or memantine. No trials assessed withdrawal of memantine only. Drugs were withdrawn abruptly in five trials and stepwise in two trials. All participants had dementia due to Alzheimer's disease, with severities ranging from mild to very severe, and were taking cholinesterase inhibitors without known adverse effects at baseline. The included trials randomised 759 participants to treatment groups relevant to this review. Study duration ranged from 6 weeks to 12 months. There were too few included studies to allow planned subgroup analyses. We considered some studies to be at unclear or high risk of selection, performance, detection, attrition or reporting bias. Compared to continuing cholinesterase inhibitors, discontinuing treatment may be associated with worse cognitive function in the short term (standardised mean difference (SMD) -0.42, 95% confidence interval (CI) -0.64 to -0.21; 4 studies; low certainty), but the effect in the medium term is very uncertain (SMD -0.40, 95% CI -0.87 to 0.07; 3 studies; very low certainty). In a sensitivity analysis omitting data from a study which only included participants who had shown a relatively poor prior response to donepezil, inconsistency was reduced and we found that cognitive function may be worse in the discontinuation group in the medium term (SMD -0.62; 95% CI -0.94 to -0.31). Data from one longer-term study suggest that discontinuing a cholinesterase inhibitor is probably associated with worse cognitive function at 12 months (mean difference (MD) -2.09 Standardised Mini-Mental State Examination (SMMSE) points, 95% CI -3.43 to -0.75; moderate certainty). Discontinuation may make little or no difference to functional status in the short term (SMD -0.25, 95% CI -0.54 to 0.04; 2 studies; low certainty), and its effect in the medium term is uncertain (SMD -0.38, 95% CI -0.74 to -0.01; 2 studies; very low certainty). After 12 months, discontinuing a cholinesterase inhibitor probably results in greater functional impairment than continuing treatment (MD -3.38 Bristol Activities of Daily Living Scale (BADLS) points, 95% CI -6.67 to -0.10; one study; moderate certainty). Discontinuation may be associated with a worsening of neuropsychiatric symptoms over the short term and medium term, although we cannot exclude a minimal effect (SMD - 0.48, 95% CI -0.82 to -0.13; 2 studies; low certainty; and SMD -0.27, 95% CI -0.47 to -0.08; 3 studies; low certainty, respectively). Data from one study suggest that discontinuing a cholinesterase inhibitor may result in little to no change in neuropsychiatric status at 12 months (MD -0.87 Neuropsychiatric Inventory (NPI) points; 95% CI -8.42 to 6.68; moderate certainty). We found no clear evidence of an effect of discontinuation on dropout due to lack of medication efficacy or deterioration in overall medical condition (odds ratio (OR) 1.53, 95% CI 0.84 to 2.76; 4 studies; low certainty), on number of adverse events (OR 0.85, 95% CI 0.57 to 1.27; 4 studies; low certainty) or serious adverse events (OR 0.80, 95% CI 0.46 to 1.39; 4 studies; low certainty), and on mortality (OR 0.75, 95% CI 0.36 to 1.55; 5 studies; low certainty). Institutionalisation was reported in one trial, but it was not possible to extract data for the groups relevant to this review. AUTHORS' CONCLUSIONS This review suggests that discontinuing cholinesterase inhibitors may result in worse cognitive, neuropsychiatric and functional status than continuing treatment, although this is supported by limited evidence, almost all of low or very low certainty. As all participants had dementia due to Alzheimer's disease, our findings are not transferable to other dementia types. We were unable to determine whether the effects of discontinuing cholinesterase inhibitors differed with baseline dementia severity. There is currently no evidence to guide decisions about discontinuing memantine. There is a need for further well-designed RCTs, across a range of dementia severities and settings. We are aware of two ongoing registered trials. In making decisions about discontinuing these drugs, clinicians should exercise caution, considering the evidence from existing trials along with other factors important to patients and their carers.
Collapse
Affiliation(s)
- Carole Parsons
- School of Pharmacy, Queen's University Belfast, Belfast, UK
| | - Wei Yin Lim
- Centre for Clinical Epidemiology, Institute for Clinical Research, National Institutes of Health, Ministry of Health Malaysia, Shah Alam, Malaysia
| | - Clement Loy
- Brain and Mind Centre and Sydney School of Public Health, Faculty of Medicine, University of Sydney, Sydney, Australia
| | | | - Peter Passmore
- Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - Stephanie A Ward
- Monash Aging Research Center, The Kingston Centre, Cheltenham, Australia
| | - Carmel Hughes
- School of Pharmacy, Queen's University Belfast, Belfast, UK
| |
Collapse
|
|
24
|
Richardson K, Savva GM, Boyd PJ, Aldus C, Maidment I, Pakpahan E, Loke YK, Arthur A, Steel N, Ballard C, Howard R, Fox C. Non-benzodiazepine hypnotic use for sleep disturbance in people aged over 55 years living with dementia: a series of cohort studies. Health Technol Assess 2021; 25:1-202. [PMID: 33410736 PMCID: PMC7812417 DOI: 10.3310/hta25010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Sleep disturbance affects around 60% of people living with dementia and can negatively affect their quality of life and that of their carers. Hypnotic Z-drugs (zolpidem, zopiclone and zaleplon) are commonly used to treat insomnia, but their safety and efficacy have not been evaluated for people living with dementia. OBJECTIVES To estimate the benefits and harms of Z-drugs in people living with dementia with sleep disturbance. DESIGN A series of observational cohort studies using existing data from (1) primary care linked to hospital admission data and (2) clinical cohort studies of people living with dementia. DATA SOURCES Primary care study - Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality data. Clinical cohort studies - the Resource Use and Disease Course in Dementia - Nursing Homes (REDIC) study, National Alzheimer's Coordinating Centre (NACC) clinical data set and the Improving Well-being and Health for People with Dementia (WHELD) in nursing homes randomised controlled trial. SETTING Primary care study - 371 primary care practices in England. Clinical cohort studies - 47 nursing homes in Norway, 34 Alzheimer's disease centres in the USA and 69 care homes in England. PARTICIPANTS Primary care study - NHS England primary care patients diagnosed with dementia and aged > 55 years, with sleep disturbance or prescribed Z-drugs or low-dose tricyclic antidepressants, followed over 2 years. Clinical cohort studies - people living with dementia consenting to participate, followed over 3 years, 12 years and 9 months, for REDIC, NACC and WHELD, respectively. INTERVENTIONS The primary exposure was prescription or use of Z-drugs. Secondary exposures included prescription or use of benzodiazepines, low-dose tricyclic antidepressants and antipsychotics. MAIN OUTCOME MEASURES Falls, fractures, infection, stroke, venous thromboembolism, mortality, cognitive function and quality of life. There were insufficient data to investigate sleep disturbance. RESULTS The primary care study and combined clinical cohort studies included 6809 and 18,659 people living with dementia, with 3089 and 914 taking Z-drugs, respectively. New Z-drug use was associated with a greater risk of fractures (hazard ratio 1.40, 95% confidence interval 1.01 to 1.94), with risk increasing with greater cumulative dose (p = 0.002). The hazard ratio for Z-drug use and hip fracture was 1.59 (95% confidence interval 1.00 to 2.53) and for mortality was 1.34 (95% confidence interval 1.10 to 1.64). No excess risks of falls, infections, stroke or venous thromboembolism were detected. Z-drug use also did not have an impact on cognition, neuropsychiatric symptoms, disability or quality of life. LIMITATIONS Primary care study - possible residual confounding because of difficulties in identifying patients with sleep disturbance and by dementia severity. Clinical cohort studies - the small numbers of people living with dementia taking Z-drugs and outcomes not necessarily being measured before Z-drug initiation restricted analyses. CONCLUSIONS We observed a dose-dependent increase in fracture risk, but no other harms, with Z-drug use in dementia. However, multiple outcomes were examined, increasing the risk of false-positive findings. The mortality association was unlikely to be causal. Further research is needed to confirm the increased fracture risk. Decisions to prescribe Z-drugs may need to consider the risk of fractures, balanced against the impact of improved sleep for people living with dementia and that of their carers. Our findings suggest that when Z-drugs are prescribed, falls prevention strategies may be needed, and that the prescription should be regularly reviewed. FUTURE WORK More research is needed on safe and effective management strategies for sleep disturbance in people living with dementia. STUDY REGISTRATION This study is registered as European Union electronic Register of Post-Authorisation Studies (EU PAS) 18006. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 1. See the NIHR Journals Library website for further project information.
Collapse
Affiliation(s)
| | - George M Savva
- School of Health Sciences, University of East Anglia, Norwich, UK
- Quadram Institute, Norwich, UK
| | - Penelope J Boyd
- School of Health Sciences, University of East Anglia, Norwich, UK
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Clare Aldus
- School of Health Sciences, University of East Anglia, Norwich, UK
| | - Ian Maidment
- School of Life and Health Sciences, Aston University, Birmingham, UK
| | - Eduwin Pakpahan
- Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
| | - Yoon K Loke
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Antony Arthur
- School of Health Sciences, University of East Anglia, Norwich, UK
| | - Nicholas Steel
- Norwich Medical School, University of East Anglia, Norwich, UK
| | | | - Robert Howard
- Division of Psychiatry, University College London, London, UK
| | - Chris Fox
- Norwich Medical School, University of East Anglia, Norwich, UK
| |
Collapse
|
|
25
|
Cummings JL, Tong G, Ballard C. Treatment Combinations for Alzheimer's Disease: Current and Future Pharmacotherapy Options. J Alzheimers Dis 2020; 67:779-794. [PMID: 30689575 PMCID: PMC6398562 DOI: 10.3233/jad-180766] [Citation(s) in RCA: 318] [Impact Index Per Article: 63.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Although Alzheimer’s disease (AD) is the world’s leading cause of dementia and the population of patients with AD continues to grow, no new therapies have been approved in more than a decade. Many clinical trials of single-agent therapies have failed to affect disease progression or symptoms compared with placebo. The complex pathophysiology of AD may necessitate combination treatments rather than monotherapy. The goal of this narrative literature review is to describe types of combination therapy, review the current clinical evidence for combination therapy regimens (both symptomatic and disease-modifying) in the treatment of AD, describe innovative clinical trial study designs that may be effective in testing combination therapy, and discuss the regulatory and drug development landscape for combination therapy. Successful combination therapies in other complex disorders, such as human immunodeficiency virus, may provide useful examples of a potential path forward for AD treatment.
Collapse
Affiliation(s)
| | | | - Clive Ballard
- University of Exeter Medical School, St Luke's Campus, Exeter, UK
| |
Collapse
|
|
26
|
Gerlach LB, Kales HC. Managing Behavioral and Psychological Symptoms of Dementia. Clin Geriatr Med 2020; 36:315-327. [DOI: 10.1016/j.cger.2019.11.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
|
|
27
|
Maidment ID, Barton G, Campbell N, Shaw R, Seare N, Fox C, Iliffe S, Randle E, Hilton A, Brown G, Barnes N, Wilcock J, Gillespie S, Damery S. MEDREV (pharmacy-health psychology intervention in people living with dementia with behaviour that challenges): the feasibility of measuring clinical outcomes and costs of the intervention. BMC Health Serv Res 2020; 20:157. [PMID: 32122341 PMCID: PMC7053151 DOI: 10.1186/s12913-020-5014-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 02/20/2020] [Indexed: 12/19/2022] Open
Abstract
Background People living with dementia in care homes frequently exhibit “behaviour that challenges”. Anti-psychotics are used to treat such behaviour, but are associated with significant morbidity. This study researched the feasibility of conducting a trial of a full clinical medication review for care home residents with behaviour that challenges, combined with staff training. This paper focusses on the feasibility of measuring clinical outcomes and intervention costs. Methods People living with moderate to severe dementia, receiving psychotropics for behaviour that challenges, in care homes were recruited for a medication review by a specialist pharmacist. Care home and primary care staff received training on the management of challenging behaviour. Data were collected at 8 weeks, and 3 and 6 months. Measures were Neuropsychiatric Inventory-Nursing Home version (NPI-NH), cognition (sMMSE), quality of life (EQ-5D-5 L/DEMQoL) and costs (Client Services Receipt Inventory). Response rates, for clinical, quality of life and health economic measures, including the levels of resource-use associated with the medication review and other non-intervention costs were calculated. Results Twenty-nine of 34 participants recruited received a medication review. It was feasible to measure the effects of the complex intervention on the management of behaviour that challenges with the NPI-NH. There was valid NPI-NH data at each time point (response rate = 100%). The sMMSE response rate was 18.2%. Levels of resource-use associated with the medication review were estimated for all 29 participants who received a medication review. Good response levels were achieved for other non-intervention costs (100% completion rate), and the EQ-5D-5 L and DEMQoL (≥88% at each of the time points where data was collected). Conclusions It is feasible to measure the clinical and cost effectiveness of a complex intervention for behaviour that challenges using the NPI-NH and quality of life measures. Trial registration ISRCTN58330068. Retrospectively registered, 15 October 2017.
Collapse
Affiliation(s)
- Ian D Maidment
- School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.
| | - Garry Barton
- Norwich Clinical Trials Unit, University of East Anglia, Earlham Road, Norwich, Norfolk, NR4 7TJ, UK
| | - Niyah Campbell
- School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK
| | - Rachel Shaw
- School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK
| | - Nichola Seare
- Aston Health Research Innovation Cluster, Aston University, Birmingham, B4 7ET, UK
| | - Chris Fox
- Norwich Medical School, University of East Anglia, Earlham Road, Norwich, Norfolk, NR4 7TJ, UK
| | - Steve Iliffe
- Research Department of Primary Care & Population Health, University College London, Royal Free Campus, Rowland Hill St, London, NW3 2PF, UK
| | - Emma Randle
- Birmingham and Solihull Mental Health NHS Foundation Trust, Research and Innovation Department, The Barberry, 25 Vincent Drive, Birmingham, B15 2FG, UK
| | - Andrea Hilton
- Faculty of Health Sciences, University of Hull, Hull, HU6 7RX, UK
| | - Graeme Brown
- Birmingham and Solihull Mental Health NHS Foundation Trust, Unit 1, B1, 50 Summer Hill Road, Birmingham, B1 3RB, UK
| | - Nigel Barnes
- Birmingham and Solihull Mental Health NHS Foundation Trust, Unit 1, B1, 50 Summer Hill Road, Birmingham, B1 3RB, UK
| | - Jane Wilcock
- Research Department of Primary Care & Population Health, University College London, Royal Free Campus, Rowland Hill St, London, NW3 2PF, UK
| | - Sarah Gillespie
- Department of Clinical Healthcare, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane Campus, Headington, Oxford, OX3 0FL, UK
| | - Sarah Damery
- Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| |
Collapse
|
|
28
|
Phan SV, Osae S, Morgan JC, Inyang M, Fagan SC. Neuropsychiatric Symptoms in Dementia: Considerations for Pharmacotherapy in the USA. Drugs R D 2019; 19:93-115. [PMID: 31098864 PMCID: PMC6544588 DOI: 10.1007/s40268-019-0272-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Dementia affects all domains of cognition. The relentless progression of the disease after diagnosis is associated with a 98% incidence of neuropsychiatric symptoms (NPS) at some point in the disease, including depression, psychosis, agitation, aggression, apathy, sleep disturbances, and disinhibition. These symptoms can be severe and lead to excess morbidity and mortality. The purpose of this article was to describe current literature on the medication management of NPS of dementia and highlight approaches to and concerns about the pharmacological treatment of NPS in the USA. Guidelines and expert opinion favor nonpharmacologic management of NPS as first-line management. Unfortunately, lack of adequate caregiver training and a high failure rate eventually result in the use of psychotropic agents in patients with dementia. Various psychotropic medications have been studied, although how they should be used in the management of NPS remains unclear. A systematic approach to evaluation, treatment, and monitoring, along with careful documentation and evidenced-based agent and dose selection, is likely to reduce risk and improve patient outcomes. Considerations should be given to the NPS presentation, including type, frequency, and severity, when weighing the risks and benefits of initiating, continuing, or discontinuing psychotropic management. Use of antidepressants, sedative/hypnotics, antipsychotics, and antiepileptic agents should include a clear and documented analysis of risk and benefit in a given patient with dementia.
Collapse
Affiliation(s)
- Stephanie V Phan
- Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia, Southwest Georgia Clinical Campus, Albany, GA, USA.
| | - Sharmon Osae
- Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia, Southwest Georgia Clinical Campus, Albany, GA, USA
| | - John C Morgan
- Memory Disorders Program, Department of Neurology, Augusta University, Augusta, GA, USA
| | - Mfon Inyang
- Phoebe Putney Memorial Hospital, Albany, GA, USA
| | - Susan C Fagan
- Memory Disorders Program, Department of Neurology, Augusta University, Augusta, GA, USA.,Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia, Augusta, GA, USA.,Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, USA
| |
Collapse
|
|
29
|
Abstract
PURPOSE OF REVIEW The goal of the current review is to provide an update on the management of agitation in persons with dementia with a focus on pharmacological management of persons with Alzheimer's disease. RECENT FINDINGS As consistently effective and safe pharmacologic interventions are still lacking, identifying and addressing medical and environmental precipitants remain a priority. Acetylcholinesterase inhibitors and memantine should be initiated to enhance cognition, and if present, management of insomnia or sundowning with trazodone is indicated. If agitation persists, treatment with citalopram can be initiated with attention paid to potential prolongation of the QT interval. Treatment with low doses of atypical antipsychotics such as risperidone or quetiapine can be effective after appropriate consideration of and disclosure of potential adverse effects. In light of the lack of consistently effective treatments for agitation in dementia, there have been renewed efforts to define the condition and improve the design of trials of medications to treat it. Considering the heterogeneity of patients and their comorbidities as well as the specific nature of their "agitation", there is no "one-size fits all" approach to agitation in AD. However, many options exist that can be prudently pursued for this common problem in this delicate population.
Collapse
Affiliation(s)
- John M Ringman
- Helene and Lou Galen Professor of Clinical Neurology, Department of Neurology, Center for Health Professions, Keck School of Medicine at USC, 1540 Alcazar Street, Suite 209F, Los Angeles, CA, 90033, USA.
| | - Lon Schneider
- Keck School of Medicine of USC, 1540 Alcazar St, #216, Los Angeles, CA, 90089, USA
| |
Collapse
|
|
30
|
Makino M, Takahashi-Ito K, Murasawa H, Pawlak A, Kashimoto Y, Kitano Y. Memantine ameliorates learning and memory disturbance and the behavioral and psychological symptoms of dementia in thiamine-deficient mice. Pharmacol Biochem Behav 2019; 183:6-13. [PMID: 31175916 DOI: 10.1016/j.pbb.2019.05.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 05/22/2019] [Accepted: 05/23/2019] [Indexed: 11/25/2022]
Abstract
Several studies have reported on the beneficial effects of memantine on behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer's disease. However, the effects of memantine on BPSD-like behaviors in animals have not been well addressed. Here, the effects of memantine on memory disturbance and BPSD-like behaviors were evaluated in thiamine-deficient (TD) mice. Memantine (3 and 10 mg/kg, b.i.d.) was orally administered to ddY mice fed a TD diet for 22 days. During the treatment period, the forced swimming test, elevated plus-maze test, passive avoidance test, and locomotor activity test were performed. Neurotransmitter levels in the brain were analyzed after the treatment period. Daily oral administration of memantine ameliorated the memory disturbances, anxiety-like behavior, and depression-like behavior observed in TD mice. Memantine did not have a significant effect on monoamine levels, but increased glutamate levels in the hippocampus in TD mice. These results suggest that memantine prevents or suppresses the progression of BPSD-like behaviors that develop due to TD. This effect may be mediated in part by the enhancement of glutamatergic neuron activity in the hippocampus.
Collapse
Affiliation(s)
- Mitsuhiro Makino
- Specialty Medicine Research Laboratories II, R&D Division, Daiichi-Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
| | - Kaori Takahashi-Ito
- Specialty Medicine Research Laboratories I, R&D Division, Daiichi-Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Hiroyasu Murasawa
- Department of Pharmacology, Nihon Bioresearch Inc., 6-104 Majima, Fukuju-cho, Hashima, Gifu 501-6251, Japan
| | - Akiko Pawlak
- Department of Pharmacology, Nihon Bioresearch Inc., 6-104 Majima, Fukuju-cho, Hashima, Gifu 501-6251, Japan
| | - Yoshinori Kashimoto
- Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan
| | - Yutaka Kitano
- Specialty Medicine Research Laboratories I, R&D Division, Daiichi-Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| |
Collapse
|
|
31
|
Li DD, Zhang YH, Zhang W, Zhao P. Meta-Analysis of Randomized Controlled Trials on the Efficacy and Safety of Donepezil, Galantamine, Rivastigmine, and Memantine for the Treatment of Alzheimer's Disease. Front Neurosci 2019; 13:472. [PMID: 31156366 PMCID: PMC6529534 DOI: 10.3389/fnins.2019.00472] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 04/26/2019] [Indexed: 01/02/2023] Open
Abstract
To study the impact of donepezil, rivastigmine, galantamine, and memantine on cognitive, functional, behavioral, global changes and adverse effects in patients with mild, moderate and severe Alzheimer’s disease (AD), we screened the literature published before September 2017 in the Pubmed, Embase, Cochrane library and Web of Science Electronic databases according to the inclusion criteria. Thirty-six studies were finally determined from 1560 preliminary screened articles. The AD Assessment Scale-cognitive Subscale (ADAS-cog), AD Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), and Clinician’s Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+) were used as valid endpoints. Of the 36 trials included, meta-analyses of these placebo-control trials showed that there were significant differences between the donepezil, rivastigmine and placebo groups using ADAS-cog, ADCS-ADL, and CIBIC+. Meta-analyses of these placebo-controlled trials showed that there were significant differences between the galantamine and placebo groups using ADAS-cog, ADCS-ADL, NPI, and CIBIC+. These observations suggest that memantine is beneficial for stabilizing or slowing the decline in ADAS-cog and ADCS-ADL19 changes in AD patients. However, there was no significant effect according to the ADCS-ADL23, NPI, and CIBIC+ tests, which indicated that memantine treatment has no significant effect on these cognitive aspects of AD patients. Different effects of donepezil, rivastigmine, galantamine, or memantine on AD were found in this study. According to the results, we conclude that galantamine is effective in treating all aspects of AD and is the first choice for the treatment of AD. However, due to limited data, we should consider additional data to obtain more stable results.
Collapse
Affiliation(s)
- Dan-Dan Li
- College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Ya-Hong Zhang
- College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Wei Zhang
- Department of Hepatobiliary Surgery, General Hospital of Northern Theater Command, Shenyang, China
| | - Pu Zhao
- College of Life and Health Sciences, Northeastern University, Shenyang, China
| |
Collapse
|
|
32
|
Livingston G, Barber J, Marston L, Stringer A, Panca M, Hunter R, Cooper C, Laybourne A, La Frenais F, Reeves S, Manela M, Lambe K, Banerjee S, Rapaport P. Clinical and cost-effectiveness of the Managing Agitation and Raising Quality of Life (MARQUE) intervention for agitation in people with dementia in care homes: a single-blind, cluster-randomised controlled trial. Lancet Psychiatry 2019; 6:293-304. [PMID: 30872010 DOI: 10.1016/s2215-0366(19)30045-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 01/18/2019] [Accepted: 01/19/2019] [Indexed: 01/29/2023]
Abstract
BACKGROUND Many people with dementia living in care homes have distressing and costly agitation symptoms. Interventions should be efficacious, scalable, and feasible. METHODS We did a parallel-group, cluster-randomised controlled trial in 20 care homes across England. Care homes were eligible if they had 17 residents or more with dementia, agreed to mandatory training for all eligible staff and the implementation of plans, and more than 60% of eligible staff agreed to participate. Staff were eligible if they worked during the day providing face-to-face care for residents with dementia. Residents were eligible if they had a known dementia diagnosis or scored positive on screening with the Noticeable Problems Checklist. A statistician independent of the study randomised care homes (1:1) to the Managing Agitation and Raising Quality of Life (MARQUE) intervention or treatment as usual (TAU) using computer-generated randomisation in blocks of two, stratified by type of home (residential or nursing). Care home staff were not masked to the intervention but were asked not to inform assessors. Residents with dementia, family carers, outcome assessors, statisticians, and health economists were masked to allocation until the data were analysed. MARQUE is an evidence-based manualised intervention, delivered by supervised graduate psychologists to staff in six interactive sessions. The primary outcome was agitation score at 8 months, measured using the Cohen-Mansfield Agitation Inventory (CMAI). Analysis of the primary outcome was done in the modified intention-to-treat population, which included all randomly assigned residents for whom CMAI data was available at 8 months. Mortality was assessed in all randomly assigned residents. This study is registered with the ISRCTN registry, number ISRCTN96745365. FINDINGS Between June 14, 2016, and July 4, 2017, we randomised ten care homes (189 residents) to the MARQUE intervention and ten care homes (215 residents) to TAU. At 8 months, primary outcome data were available for 155 residents in the MARQUE group and 163 residents in the TAU group. At 8 months, no significant differences in mean CMAI scores were identified between the MARQUE and TAU groups (adjusted difference -0·40 [95% CI -3·89 to 3·09; p=0·8226]). In the intervention care homes, 84% of all eligible staff completed all sessions. The mean difference in cost between the MARQUE and TAU groups was £204 (-215 to 623; p=0·320) and mean difference in quality-adjusted life-years was 0·015 (95% CI -0·004 to 0·034; p=0·127). At 8 months, 27 (14%) of 189 residents in the MARQUE group and 41 (19%) of 215 residents in the TAU group had died. The prescription of antipsychotic drugs was not significantly different between the MARQUE group and the TAU group (odds ratio 0·66; 95% CI 0·26 to 1·69, p=0·3880). INTERPRETATION The MARQUE intervention was not efficacious for agitation although feasible and cost-effective in terms of quality of life. Addressing agitation in care homes might require resourcing for delivery by professional staff of a more intensive intervention, implementing social and activity times, and a longer time to implement change. FUNDING UK Economic and Social Research Council and the National Institute of Health Research.
Collapse
Affiliation(s)
- Gill Livingston
- Division of Psychiatry, University College London, London, UK; Camden and Islington NHS Foundation Trust, St Pancras Hospital, London, UK.
| | - Julie Barber
- UCL Statistical Science and PRIMENT Clinical Trials Unit, University College London, London, UK
| | - Louise Marston
- Department of Primary Care and Population Health, Faculty of Population Health Sciences, University College London, London, UK
| | | | - Monica Panca
- Department of Primary Care and Population Health, Faculty of Population Health Sciences, University College London, London, UK
| | - Rachael Hunter
- Department of Primary Care and Population Health, Faculty of Population Health Sciences, University College London, London, UK
| | - Claudia Cooper
- Division of Psychiatry, University College London, London, UK; Camden and Islington NHS Foundation Trust, St Pancras Hospital, London, UK
| | - Anne Laybourne
- Division of Psychiatry, University College London, London, UK
| | | | - Suzanne Reeves
- Division of Psychiatry, University College London, London, UK; Camden and Islington NHS Foundation Trust, St Pancras Hospital, London, UK
| | - Monica Manela
- Division of Psychiatry, University College London, London, UK
| | - Katie Lambe
- Division of Psychiatry, University College London, London, UK
| | - Sube Banerjee
- Centre for Dementia Studies, Brighton and Sussex Medical School and Sussex Partnership, NHS Foundation Trust, Brighton, UK
| | - Penny Rapaport
- Division of Psychiatry, University College London, London, UK
| |
Collapse
|
|
33
|
McShane R, Westby MJ, Roberts E, Minakaran N, Schneider L, Farrimond LE, Maayan N, Ware J, Debarros J. Memantine for dementia. Cochrane Database Syst Rev 2019; 3:CD003154. [PMID: 30891742 PMCID: PMC6425228 DOI: 10.1002/14651858.cd003154.pub6] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Memantine is a moderate affinity uncompetitive antagonist of glutamate NMDA receptors. It is licensed for use in moderate and severe Alzheimer's disease (AD); in the USA, it is also widely used off-label for mild AD. OBJECTIVES To determine efficacy and safety of memantine for people with dementia. To assess whether memantine adds benefit for people already taking cholinesterase inhibitors (ChEIs). SEARCH METHODS We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register of trials (http://www.medicine.ox.ac.uk/alois/) up to 25 March 2018. We examined clinical trials registries, press releases and posters of memantine manufacturers; and the web sites of the FDA, EMEA and NICE. We contacted authors and companies for missing information. SELECTION CRITERIA Double-blind, parallel group, placebo-controlled, randomised trials of memantine in people with dementia. DATA COLLECTION AND ANALYSIS We pooled and analysed data from four clinical domains across different aetiologies and severities of dementia and for AD with agitation. We assessed the impact of study duration, severity and concomitant use of ChEIs. Consequently, we restricted analyses to the licensed dose (20 mg/day or 28 mg extended release) and data at six to seven months duration of follow-up, and analysed separately results for mild and moderate-to-severe AD.We transformed results for efficacy outcomes into the difference in points on particular outcome scales. MAIN RESULTS Across all types of dementia, data were available from almost 10,000 participants in 44 included trials, most of which were at low or unclear risk of bias. For nearly half the studies, relevant data were obtained from unpublished sources. The majority of trials (29 in 7885 participants) were conducted in people with AD.1. Moderate-to-severe AD (with or without concomitant ChEIs). High-certainty evidence from up to 14 studies in around 3700 participants consistently shows a small clinical benefit for memantine versus placebo: clinical global rating (CGR): 0.21 CIBIC+ points (95% confidence interval (CI) 0.14 to 0.30); cognitive function (CF): 3.11 Severe Impairment Battery (SIB) points (95% CI 2.42 to 3.92); performance on activities of daily living (ADL): 1.09 ADL19 points (95% CI 0.62 to 1.64); and behaviour and mood (BM): 1.84 Neuropsychiatric Inventory (NPI) points (95% CI 1.05 to 2.76). There may be no difference in the number of people discontinuing memantine compared to placebo: risk ratio (RR) 0.93 (95% CI 0.83 to 1.04) corresponding to 13 fewer people per 1000 (95% CI 31 fewer to 7 more). Although there is moderate-certainty evidence that fewer people taking memantine experience agitation as an adverse event: RR 0.81 (95% CI 0.66 to 0.99) (25 fewer people per 1000, 95% CI 1 to 44 fewer), there is also moderate-certainty evidence, from three additional studies, suggesting that memantine is not beneficial as a treatment for agitation (e.g. Cohen Mansfield Agitation Inventory: clinical benefit of 0.50 CMAI points, 95% CI -3.71 to 4.71) .The presence of concomitant ChEI does not impact on the difference between memantine and placebo, with the possible exceptions of the BM outcome (larger effect in people taking ChEIs) and the CF outcome (smaller effect).2. Mild AD (Mini Mental State Examination (MMSE) 20 to 23): mainly moderate-certainty evidence based on post-hoc subgroups from up to four studies in around 600 participants suggests there is probably no difference between memantine and placebo for CF: 0.21 ADAS-Cog points (95% CI -0.95 to 1.38); performance on ADL: -0.07 ADL 23 points (95% CI -1.80 to 1.66); and BM: -0.29 NPI points (95% CI -2.16 to 1.58). There is less certainty in the CGR evidence, which also suggests there may be no difference: 0.09 CIBIC+ points (95% CI -0.12 to 0.30). Memantine (compared with placebo) may increase the numbers of people discontinuing treatment because of adverse events (RR 2.12, 95% CI 1.03 to 4.39).3. Mild-to-moderate vascular dementia. Moderate- and low-certainty evidence from two studies in around 750 participants indicates there is probably a small clinical benefit for CF: 2.15 ADAS-Cog points (95% CI 1.05 to 3.25); there may be a small clinical benefit for BM: 0.47 NOSGER disturbing behaviour points (95% CI 0.07 to 0.87); there is probably no difference in CGR: 0.03 CIBIC+ points (95% CI -0.28 to 0.34); and there may be no difference in ADL: 0.11 NOSGER II self-care subscale points (95% CI -0.35 to 0.54) or in the numbers of people discontinuing treatment: RR 1.05 (95% CI 0.83 to 1.34).There is limited, mainly low- or very low-certainty efficacy evidence for other types of dementia (Parkinson's disease and dementia Lewy bodies (for which CGR may show a small clinical benefit; four studies in 319 people); frontotemporal dementia (two studies in 133 people); and AIDS-related Dementia Complex (one study in 140 people)).There is high-certainty evidence showing no difference between memantine and placebo in the proportion experiencing at least one adverse event: RR 1.03 (95% CI 1.00 to 1.06); the RR does not differ between aetiologies or severities of dementia. Combining available data from all trials, there is moderate-certainty evidence that memantine is 1.6 times more likely than placebo to result in dizziness (6.1% versus 3.9%), low-certainty evidence of a 1.3-fold increased risk of headache (5.5% versus 4.3%), but high-certainty evidence of no difference in falls. AUTHORS' CONCLUSIONS We found important differences in the efficacy of memantine in mild AD compared to that in moderate-to-severe AD. There is a small clinical benefit of memantine in people with moderate-to-severe AD, which occurs irrespective of whether they are also taking a ChEI, but no benefit in people with mild AD.Clinical heterogeneity in AD makes it unlikely that any single drug will have a large effect size, and means that the optimal drug treatment may involve multiple drugs, each having an effect size that may be less than the minimum clinically important difference.A definitive long-duration trial in mild AD is needed to establish whether starting memantine earlier would be beneficial over the long term and safe: at present the evidence is against this, despite it being common practice. A long-duration trial in moderate-to-severe AD is needed to establish whether the benefit persists beyond six months.
Collapse
Affiliation(s)
- Rupert McShane
- University of OxfordRadcliffe Department of MedicineJohn Radcliffe HospitalLevel 4, Main Hospital, Room 4401COxfordOxfordshireUKOX3 9DU
| | - Maggie J Westby
- University of Manchester, Manchester Academic Health Science CentreDivision of Nursing, Midwifery and Social Work, School of Health Sciences, Faculty of Biology, Medicine and HealthJean McFarlane BuildingOxford RoadManchesterUKM13 9PL
| | - Emmert Roberts
- King's College LondonDepartment of Psychological Medicine and National Addiction CentreWeston Education CentreLondonLondonUKSE5 9RJ
| | - Neda Minakaran
- Moorfields Eye Hospital NHS Foundation TrustDepartment of Ophthalmology162 City RoadLondonUKEC1V 2PD
| | - Lon Schneider
- Keck School of Medicine of the University of Southern California1540 Alcazar Street, CHP 216Los AngelesCAUSA90033
| | - Lucy E Farrimond
- Oxford University Hospitals NHS Foundation TrustNeurosciences DepartmentJohn Radcliffe HospitalOxfordUKOX3 9DU
| | - Nicola Maayan
- CochraneCochrane ResponseSt Albans House57‐59 HaymarketLondonUKSW1Y 4QX
| | - Jennifer Ware
- University of OxfordCochrane Dementia and Cognitive Improvement GroupOxfordUKOX3 9DU
| | - Jean Debarros
- University of OxfordNuffield Department of Clinical Neurosciences (NDCN)Level 6, West Wing, John Radcliffe HospitalOxfordUKOX3 9DU
| | | |
Collapse
|
|
34
|
Liu J, Chang L, Song Y, Li H, Wu Y. The Role of NMDA Receptors in Alzheimer's Disease. Front Neurosci 2019; 13:43. [PMID: 30800052 PMCID: PMC6375899 DOI: 10.3389/fnins.2019.00043] [Citation(s) in RCA: 281] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 01/16/2019] [Indexed: 12/13/2022] Open
Abstract
In Alzheimer’s disease (AD), early synaptic dysfunction is associated with the increased oligomeric amyloid-beta peptide, which causes NMDAR-dependent synaptic depression and spine elimination. Memantine, low-affinity NMDAR channel blocker, has been used in the treatment of moderate to severe AD. However, clear evidence is still deficient in demonstrating the underlying mechanisms and a relationship between NMDARs dysfunction and AD. This review focuses on not only changes in expression of different NMDAR subunits, but also some unconventional modes of NMDAR action.
Collapse
Affiliation(s)
- Jinping Liu
- School of Medicine, Tsinghua University, Beijing, China
| | - Lirong Chang
- Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
| | - Yizhi Song
- Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
| | - Hui Li
- Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
| | - Yan Wu
- Department of Anatomy, Ministry of Science and Technology Laboratory of Brain Disorders, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
| |
Collapse
|
|
35
|
Ballard C, Banister C, Khan Z, Cummings J, Demos G, Coate B, Youakim JM, Owen R, Stankovic S. Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer's disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study. Lancet Neurol 2019; 17:213-222. [PMID: 29452684 DOI: 10.1016/s1474-4422(18)30039-5] [Citation(s) in RCA: 119] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Revised: 12/19/2017] [Accepted: 12/19/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Pimavanserin is a selective 5-HT2A receptor inverse agonist and antagonist approved in the USA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. No safe or effective pharmacological treatment is approved for psychosis in patients with Alzheimer's disease. Therefore, we aimed to evaluate the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer's disease psychosis. METHODS We did a phase 2, randomised, double-blind, placebo-controlled, single-centre (with multiple affiliated nursing home sites across the UK) study. We included participants of either sex who were aged 50 years or older with possible or probable Alzheimer's disease and psychotic symptoms including visual or auditory hallucinations, delusions, or both. Participants were randomly assigned (1:1) to 12 weeks of oral treatment with either pimavanserin (two 17 mg tablets daily) or placebo, with use of permuted block sizes of four and stratified by baseline Mini-Mental State Examination (MMSE) total score (<6 or ≥6) and Neuropsychiatric Inventory-Nursing Home version (NPI-NH) psychosis score (<12 or ≥12). Participants, caregivers, the study sponsor, and study personnel at the clinic site were masked to treatment assignment. The primary endpoint was mean change from baseline to week 6 in the NPI-NH psychosis score for pimavanserin versus placebo in the modified intention-to-treat population. Sustained benefit and safety of pimavanserin were assessed through week 12. This study is registered at ClinicalTrials.gov, number NCT02035553. FINDINGS Between Jan 16, 2014, and Oct 27, 2016, 345 participants across 133 nursing homes were screened, of whom 181 were randomly assigned treatment (n=90 pimavanserin and n=91 placebo). 178 participants were included in the modified intention-to-treat population. Mean total baseline NPI-NH psychosis scores were 9·5 (SD 4·8) for the pimavanserin group and 10·0 (5·6) for the placebo group. Mean change in the NPI-NH psychosis score at week 6 was -3·76 points (SE 0·65) for pimavanserin and -1·93 points (0·63) for placebo (mean difference -1·84 [95% CI -3·64 to -0·04], Cohen's d=-0·32; p=0·045). By week 12, no significant advantage for pimavanserin versus placebo was observed for the overall study population (treatment difference -0·51 [95% CI -2·23 to 1·21]; p=0·561). Common adverse events were falls (21 [23%] of 90 participants in the pimavanserin group vs 21 [23%] of 91 in the placebo group), urinary tract infections (20 [22%] vs 25 [28%]), and agitation (19 [21%] vs 13 [14%]). Eight (9%) participants on pimavanserin and 11 (12%) on placebo discontinued treatment because of adverse events. No detrimental effect was observed on cognition or motor function in either group. INTERPRETATION Pimavanserin showed efficacy in patients with Alzheimer's disease psychosis at the primary endpoint (week 6) with an acceptable tolerability profile and without negative effect on cognition. Further follow-up to week 12 did not show significant advantage for pimavanserin versus placebo. FUNDING ACADIA Pharmaceuticals.
Collapse
Affiliation(s)
- Clive Ballard
- Institute of Health Research, University of Exeter Medical School, Exeter, UK.
| | - Carol Banister
- Wolfson Centre for Age-related Diseases, King's College London, London, UK
| | - Zunera Khan
- Wolfson Centre for Age-related Diseases, King's College London, London, UK
| | - Jeffrey Cummings
- Department Center for Brain Health, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA
| | | | | | | | | | | | | |
Collapse
|
|
36
|
Zhang N, Lv Y, Li H, Chen J, Li Y, Yin F, Li L, Zheng Q. Quantifying placebo responses in clinical evaluation of neuropsychiatric symptoms in Alzheimer's disease. Eur J Clin Pharmacol 2019; 75:497-509. [PMID: 30612155 DOI: 10.1007/s00228-018-02620-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 12/26/2018] [Indexed: 12/23/2022]
Abstract
PURPOSE This study aimed to establish a non-linear mixed effects model to quantitatively analyze the placebo responses of neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD). METHODS A comprehensive literature search was conducted in public databases. Placebo-controlled randomized AD clinical trials using the neuropsychiatric inventory (NPI) score as the primary or secondary outcome were included. Non-linear mixed effects model was used to describe the time course of the placebo responses of NPS in AD clinical trials. Potential affecting factors were tested as covariates. RESULTS A total of 32 clinical studies (involving 3942 subjects) were included in model-based analysis. We found that the maximal placebo responses of NPS were reached at week 4 approximately, after which rebound effects appeared. The baseline NPI score had a significant impact on the placebo responses. Higher baseline NPI score tended to cause greater reductions in NPI score at week 8 and a smaller degree of rebound. For AD patients whose normalized baseline NPI score was 10 points and 30 points, the reduction in normalized NPI score at week 8 was estimated to be 0.83 and 7.43 points, respectively; and the rebound rate after week 8 was estimated to be 0.1 points/week and 0.08 points/week, respectively. CONCLUSIONS The duration of 4 weeks is sufficient to determine the drug efficacy for assessing NPS in AD clinical trials. The baseline NPI score was a key factor associated with placebo responses of NPS, which should be considered when designing future clinical trials and conducting comparisons across trials.
Collapse
Affiliation(s)
- Ningyuan Zhang
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No. 1200 Cailun Road, Shanghai, 201203, China
| | - Yinghua Lv
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No. 1200 Cailun Road, Shanghai, 201203, China
| | - Huafang Li
- Shanghai Mental Health Center, Shanghai, China
| | - Junchao Chen
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No. 1200 Cailun Road, Shanghai, 201203, China
| | - Yunfei Li
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No. 1200 Cailun Road, Shanghai, 201203, China
| | - Fang Yin
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No. 1200 Cailun Road, Shanghai, 201203, China
| | - Lujin Li
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No. 1200 Cailun Road, Shanghai, 201203, China.
| | - Qingshan Zheng
- Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, No. 1200 Cailun Road, Shanghai, 201203, China.
| |
Collapse
|
|
37
|
Deardorff WJ, Grossberg GT. Behavioral and psychological symptoms in Alzheimer's dementia and vascular dementia. HANDBOOK OF CLINICAL NEUROLOGY 2019; 165:5-32. [PMID: 31727229 DOI: 10.1016/b978-0-444-64012-3.00002-2] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent and represent a significant burden for patients and their caregivers. Early recognition and management of these symptoms is crucial as they are associated with increased risk of institutionalization, impairments in daily functioning, reduced quality of life, and more rapid progression to severe dementia. This chapter will discuss the pathophysiology, proposed diagnostic criteria, clinical features, and management of BPSD, including apathy, depression, agitation/aggression, psychosis, and sleep disturbances. Apathy and depression are the most common overall, and apathy is associated with high symptom severity likely because of its greater persistence. Symptoms such as agitation, aggression, hallucinations, and delusions may be especially distressing and dangerous to patients and caregivers. Nonpharmacologic management should be considered first-line therapy in most cases due to the modest and inconsistent evidence base for pharmacologic agents and greater risk of harm. However, the judicious use of pharmacologic agents may be warranted when symptoms are dangerous and/or severely distressing.
Collapse
Affiliation(s)
- William James Deardorff
- Department of Psychiatry and Behavioral Neuroscience, St. Louis University School of Medicine, St Louis, MO, United States
| | - George T Grossberg
- Department of Psychiatry and Behavioral Neuroscience, St. Louis University School of Medicine, St Louis, MO, United States.
| |
Collapse
|
|
38
|
Knight R, Khondoker M, Magill N, Stewart R, Landau S. A Systematic Review and Meta-Analysis of the Effectiveness of Acetylcholinesterase Inhibitors and Memantine in Treating the Cognitive Symptoms of Dementia. Dement Geriatr Cogn Disord 2018; 45:131-151. [PMID: 29734182 DOI: 10.1159/000486546] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 12/29/2017] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Acetylcholinesterase inhibitors (AChEIs) and memantine are commonly used in the management of dementia. In routine clinical practice, dementia is often monitored via the Mini-Mental State Examination (MMSE). We conducted a systematic review and meta-analysis of the effects of these drugs on MMSE scores. SUMMARY Eighty trials were identified. Pooled effect estimates were in favour of both AChEIs and memantine at 6 months. Meta-regression indicated that dementia subtype was a moderator of AChEI treatment effect, with the effect of treatment versus control twice as high for patients with Parkinson disease dementia/ dementia with Lewy bodies (2.11 MMSE points at 6 months) as for patients with Alzheimer disease/vascular dementia (0.91 MMSE points at 6 months). Key Messages: AChEIs demonstrate a modest effect versus control on MMSE scores which is moderated by dementia subtype. For memantine the effect is smaller.
Collapse
Affiliation(s)
- Ruth Knight
- Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Mizanur Khondoker
- Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | - Nicholas Magill
- Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Robert Stewart
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.,South London and Maudsley NHS Foundation Trust, London, United Kingdom
| | - Sabine Landau
- Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| |
Collapse
|
|
39
|
Liang J, Li J, Jia R, Wang Y, Wu R, Zhang H, Hang L, Xu Y. Identification of the optimal cognitive drugs among Alzheimer's disease: a Bayesian meta-analytic review. Clin Interv Aging 2018; 13:2061-2073. [PMID: 30425461 PMCID: PMC6201988 DOI: 10.2147/cia.s184968] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
PURPOSE The increasing prevalence of Alzheimer's disease (AD) demands more effective drugs, which are still unclear. The aim of this study is to compare the effectiveness of six drugs, such as donepezil, rivastigmine, galantamine, memantine, huperzine-A, and tacrine, in senior AD patients and identify the most effective one to improve patients' cognitive function. METHODS A system of search strategies was used to identify relevant studies including randomized controlled trials and clinical controlled trials evaluating the efficacy of six drugs in patients with AD. We updated relevant studies that were published before March 2018 as full-text articles. Using Bayesian network meta-analysis (NMA), we ranked cognitive ability objectively based on Mini-Mental State Examination (MMSE). Pairwise and NMAs were sequentially performed for the efficacy of drugs compared to each drug or control group through the trials included. RESULTS Among the 35 trials included, no obvious heterogeneity (I 2=0.0%, P=0.583) was revealed according to the pooled data for cognition in NMA and the mean difference (MD) of memantine (MD=1.7, 95% CI: 0.73, 2.8) showed that the memantine was significantly efficacious in the treatment group in terms of MMSE. Followed by galantamine, huperzine-A, rivastigmine, tacrine, and donepezil. CONCLUSION As the first NMA comparing the major drugs in market for AD, our study suggests that memantine might have a more significant benefit on cognition than other five drugs available.
Collapse
Affiliation(s)
- Jinghong Liang
- Department of Child Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China,
| | - Jiayu Li
- Department of Child Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China,
| | - Ruixia Jia
- Department of Child Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China,
| | - Yingquan Wang
- Department of Child Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China,
| | - Rongkun Wu
- Department of Child Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China,
| | - Hongbo Zhang
- Department of Child Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China,
| | - Lei Hang
- Department of Child Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China,
| | - Yong Xu
- Department of Child Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China,
| |
Collapse
|
|
40
|
Kongpakwattana K, Sawangjit R, Tawankanjanachot I, Bell JS, Hilmer SN, Chaiyakunapruk N. Pharmacological treatments for alleviating agitation in dementia: a systematic review and network meta-analysis. Br J Clin Pharmacol 2018; 84:1445-1456. [PMID: 29637593 PMCID: PMC6005613 DOI: 10.1111/bcp.13604] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 03/28/2018] [Accepted: 03/28/2018] [Indexed: 12/18/2022] Open
Abstract
AIMS To determine the most efficacious and acceptable treatments of agitation in dementia. METHODS MEDLINE, EMBASE, PsycINFO, CENTRAL and clinicaltrials.gov were searched up to 7 February 2017. Two independent reviewers selected randomized controlled trials (RCTs) of treatments to alleviate agitation in people with all-types dementia. Data were extracted using standardized forms and study quality was assessed using the revised Cochrane Risk of Bias Tool for RCTs. Data were pooled using meta-analysis. The primary outcome, efficacy, was 8-week response rates defined as a 50% reduction in baseline agitation score. The secondary outcome was treatment acceptability defined as treatment continuation for 8 weeks. RESULTS Thirty-six RCTs comprising 5585 participants (30.9% male; mean ± standard deviation age, 81.8 ± 4.9 years) were included. Dextromethorphan/quinidine [odds ratio (OR) 3.04; 95% confidence interval (CI), 1.63-5.66], risperidone (OR 1.96; 95% CI, 1.49-2.59) and selective serotonin reuptake inhibitors as a class (OR 1.61; 95% CI, 1.02-2.53) were found to be significantly more efficacious than placebo. Haloperidol appeared less efficacious than nearly all comparators. Most treatments had noninferior treatment continuation compared to placebo, except oxcarbazepine, which was inferior. Findings were supported by subgroup and sensitivity analyses. CONCLUSIONS Risperidone, serotonin reuptake inhibitors as a class and dextromethorphan/quinidine demonstrated evidence of efficacy for agitation in dementia, although findings for dextromethorphan/quinidine were based on a single RCT. Our findings do not support prescribing haloperidol due to lack of efficacy, or oxcarbazepine due to lack of acceptability. The decision to prescribe should be based on comprehensive consideration of the benefits and risks, including those not evaluated in this meta-analysis.
Collapse
Affiliation(s)
| | - Ratree Sawangjit
- Clinical Trials and Evidence Base Syntheses Research Unit (CTEBs RU), Department of Clinical Pharmacy, Faculty of PharmacyMahasarakham UniversityMahasarakhamThailand
| | - Itthipol Tawankanjanachot
- Department of Psychiatry, King Chulalongkorn Memorial Hospital, Faculty of MedicineChulalongkorn UniversityBangkokThailand
| | - J. Simon Bell
- Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical SciencesMonash UniversityAustralia
| | - Sarah N. Hilmer
- Kolling Institute of Medical ResearchRoyal North Shore Hospital and University of SydneySt LeonardsNSWAustralia
| | - Nathorn Chaiyakunapruk
- School of PharmacyMonash University MalaysiaSelangorMalaysia
- Center of Pharmaceutical Outcomes Research (CPOR), Department of Pharmacy Practice, Faculty of Pharmaceutical SciencesNaresuan UniversityPhitsanulokThailand
- Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well‐being Cluster, Global Asia in the 21st Century (GA21) PlatformMonash University MalaysiaBandar SunwaySelangorMalaysia
- School of PharmacyUniversity of WisconsinMadisonUSA
| |
Collapse
|
|
41
|
Rapaport P, Livingston G, Hamilton O, Turner R, Stringer A, Robertson S, Cooper C. How do care home staff understand, manage and respond to agitation in people with dementia? A qualitative study. BMJ Open 2018; 8:e022260. [PMID: 29961036 PMCID: PMC6042579 DOI: 10.1136/bmjopen-2018-022260] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVES Little is known about how care home staff understand and respond to distress in residents living with dementia labelled as agitation. The aim of this study was to describe how care home staff understand and respond to agitation and the factors that determine how it is managed. DESIGN We conducted a qualitative thematic analysis. SETTING We recruited staff from six care homes in South East England including residential and nursing homes of differing sizes run by both the private and charity sector and located in urban and rural areas. PARTICIPANTS We interviewed 25 care home staff using purposive sampling to include staff of either sex, differing age, ethnicity, nationality and with different roles and experience. RESULTS We identified four overarching themes: (1) behaviours expressing unmet need; (2) staff emotional responses to agitation; (3) understanding the individual helps and (4) constraints on staff responses. Staff struggled with the paradox of trying to connect with the personhood of residents while seeing the person as separate to and, therefore, not responsible for their behaviours. Staff often felt powerless, frightened and overwhelmed, and their responses were constrained by care home structures, processes and a culture of fear and scrutiny. CONCLUSIONS Responding to agitation expressed by residents was not a linear process and staff faced tensions and dilemmas in deciding how to respond, especially when initial strategies were unsuccessful or when attempts to respond to residents' needs were inhibited by structural and procedural constraints in the care home. Future trials of psychosocial interventions should support staff to identify and respond to residents' unmet needs and include how staff can look after themselves.
Collapse
Affiliation(s)
- Penny Rapaport
- UCL Department of Old Age Psychiatry, Division of Psychiatry, University College London, London, UK
- North Thames CLAHRC, London, UK
| | - Gill Livingston
- UCL Department of Old Age Psychiatry, Division of Psychiatry, University College London, London, UK
| | - Olivia Hamilton
- UCL Department of Old Age Psychiatry, Division of Psychiatry, University College London, London, UK
| | - Rebecca Turner
- UCL Department of Old Age Psychiatry, Division of Psychiatry, University College London, London, UK
| | - Aisling Stringer
- UCL Department of Old Age Psychiatry, Division of Psychiatry, University College London, London, UK
| | - Sarah Robertson
- UCL Department of Old Age Psychiatry, Division of Psychiatry, University College London, London, UK
- North Thames CLAHRC, London, UK
| | - Claudia Cooper
- UCL Department of Old Age Psychiatry, Division of Psychiatry, University College London, London, UK
| |
Collapse
|
|
42
|
Jennings AA, Foley T, Walsh KA, Coffey A, Browne JP, Bradley CP. General practitioners' knowledge, attitudes, and experiences of managing behavioural and psychological symptoms of dementia: A mixed-methods systematic review. Int J Geriatr Psychiatry 2018; 33:1163-1176. [PMID: 29900592 PMCID: PMC6099359 DOI: 10.1002/gps.4918] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 04/03/2018] [Indexed: 01/08/2023]
Abstract
OBJECTIVES To synthesise the existing published literature on general practitioners (GP)'s knowledge, attitudes, and experiences of managing behavioural and psychological symptoms of dementia (BPSD) with a view to informing future interventions. METHODS We conducted a systematic review and synthesis of quantitative and qualitative studies that explored GPs' experiences of managing BPSD (PROSPERO protocol registration CRD42017054916). Seven electronic databases were searched from inception to October 2017. Each stage of the review process involved at least 2 authors working independently. The meta-ethnographic approach was used to synthesise the findings of the included studies while preserving the context of the primary data. The Confidence in the Evidence from Reviews of Qualitative research (CERQual) was used to assess the confidence in our individual review findings. RESULTS Of the 1638 articles identified, 76 full texts were reviewed and 11 were included. Three main concepts specific to GPs' experiences of managing BPSD emerged: unmet primary care resource needs, justification of antipsychotic prescribing, and the pivotal role of families. A "line of argument" was drawn, which described how in the context of resource limitations a therapeutic void was created. This resulted in GPs being over reliant on antipsychotics and family caregivers. These factors appeared to culminate in a reactive response to BPSD whereby behaviours and symptoms could escalate until a crisis point was reached. CONCLUSION This systematic review offers new insights into GPs' perspectives on the management of BPSD and will help to inform the design and development of interventions to support GPs managing BPSD.
Collapse
Affiliation(s)
- Aisling A. Jennings
- Department of General Practice, School of MedicineUniversity College CorkCorkIreland
| | - Tony Foley
- Department of General Practice, School of MedicineUniversity College CorkCorkIreland
| | - Kieran A. Walsh
- School of Public HealthUniversity College CorkCorkIreland
- Pharmaceutical Care Research Group, School of PharmacyUniversity College CorkCorkIreland
- Centre for Gerontology and Rehabilitation, School of MedicineUniversity College CorkCorkIreland
| | - Alice Coffey
- Department of Nursing and MidwiferyUniversity of LimerickLimerickIreland
| | - John P. Browne
- School of Public HealthUniversity College CorkCorkIreland
| | - Colin P. Bradley
- Department of General Practice, School of MedicineUniversity College CorkCorkIreland
| |
Collapse
|
|
43
|
Creese B, Da Silva MV, Johar I, Ballard C. The modern role of antipsychotics for the treatment of agitation and psychosis in Alzheimer's disease. Expert Rev Neurother 2018; 18:461-467. [PMID: 29764230 DOI: 10.1080/14737175.2018.1476140] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Antipsychotics have long been the mainstay of treatment for agitation and psychosis in Alzheimer's disease. Despite their current use successive studies have shown that they only confer a modest benefit which must be balanced against their well-established serious side effects (extrapyramidal symptoms, stroke, accelerated cognitive decline and mortality). Areas covered: This review outlines the current guidance on antipsychotic usage and the evidence of their continued usage against a backdrop of emerging pharmacological treatments and an increasing emphasis on the importance of non-pharmacological interventions. Expert commentary: The current justification for antipsychotic use in the context of the changing landscape of prescribing and provide a view on the most promising alternative candidates to this class of drug are appraised.
Collapse
Affiliation(s)
- Byron Creese
- a University of Exeter Medical School , University of Exeter , UK
| | | | - Iskandar Johar
- b Department of Old Age Psychiatry , Institute of Psychiatry, Psychology and Neuroscience, King's College London , UK
| | - Clive Ballard
- a University of Exeter Medical School , University of Exeter , UK
| |
Collapse
|
|
44
|
Kishi T, Matsunaga S, Oya K, Nomura I, Ikuta T, Iwata N. Memantine for Alzheimer's Disease: An Updated Systematic Review and Meta-analysis. J Alzheimers Dis 2018; 60:401-425. [PMID: 28922160 DOI: 10.3233/jad-170424] [Citation(s) in RCA: 156] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND The clinical benefit of memantine for Alzheimer's disease (AD) remains inconclusive. OBJECTIVE We performed an updated systematic review and meta-analysis of the efficacy/safety of memantine in AD. METHODS We included randomized trials of memantine for AD patients. Cognitive function scores (CF), behavioral disturbances scores (BD), and all-cause discontinuation were used as primary measures. Effect size based on a random-effects model was evaluated in the meta-analyses. RESULTS Thirty studies (n = 7,567; memantine versus placebo: N = 11, n = 3,298; memantine + cholinesterase inhibitors (M+ChEIs) versus ChEIs: N = 17, n = 4,175) were identified. Memantine showed a significant improvement in CF [standardized mean difference (SMD) = -0.24, 95% confidence intervals (95% CIs) = -0.34, -0.15, p < 0.00001, I2 = 35% ] and BD (SMD = -0.16, 95% CIs = -0.29, -0.04, p = 0.01, I2 = 52%) compared with placebo. In the sensitivity analysis including only patients with moderate-severe AD, memantine was superior to the placebo in reducing BD without considerable heterogeneity (SMD = -0.20, 95% CIs = -0.34, -0.07, p = 0.003, I2 = 36%). Compared with ChEIs, M+ChEIs showed a greater reduction in BD (SMD = -0.20, 95% CIs = -0.36, -0.03, p = 0.02, I2 = 77%) and a trend of CF improvement (SMD = -0.11, 95% CIs = -0.22, 0.01, p = 0.06, I2 = 56%). However, in the sensitivity analysis of double-blind, placebo-controlled studies only, M+ChEIs showed a significant reduction in BD compared with ChEIs without considerable heterogeneity (SMD = -0.11, 95% CIs = -0.21, -0.01, p = 0.04, I2 = 40%). When performing the sensitivity analysis of donepezil studies only, M+ChEIs was superior to ChEIs in improving CF without considerable heterogeneity (SMD = -0.18, 95% CIs = -0.31, -0.05, p = 0.006, I2 = 49%). No differences were detected in all-cause discontinuation between the groups. CONCLUSIONS The meta-analyses suggest the credible efficacy and safety of memantine in treating AD when used alone or in combination with ChEIs.
Collapse
Affiliation(s)
- Taro Kishi
- Department of Psychiatry, Fujita Health University School of Medicine, Kutsukake-cho, Toyoake, Aichi, Japan
| | - Shinji Matsunaga
- Department of Psychiatry, Fujita Health University School of Medicine, Kutsukake-cho, Toyoake, Aichi, Japan
| | - Kazuto Oya
- Department of Psychiatry, Fujita Health University School of Medicine, Kutsukake-cho, Toyoake, Aichi, Japan
| | - Ikuo Nomura
- Department of Psychiatry, Fujita Health University School of Medicine, Kutsukake-cho, Toyoake, Aichi, Japan
| | - Toshikazu Ikuta
- Department of Communication Sciences and Disorders, School of Applied Sciences, University of Mississippi, University MS, USA
| | - Nakao Iwata
- Department of Psychiatry, Fujita Health University School of Medicine, Kutsukake-cho, Toyoake, Aichi, Japan
| |
Collapse
|
|
45
|
Azuar C, Levy R. Behavioral disorders: The ‘blind spot’ of neurology and psychiatry. Rev Neurol (Paris) 2018; 174:182-189. [DOI: 10.1016/j.neurol.2018.02.083] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 02/16/2018] [Accepted: 02/20/2018] [Indexed: 11/25/2022]
|
|
46
|
Zambrano P, Suwalsky M, Jemiola-Rzeminska M, Strzalka K. Studies on the interaction of NMDA receptor antagonist memantine with cell membranes: A mini-review. Chem Biol Interact 2018; 283:47-50. [DOI: 10.1016/j.cbi.2018.01.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 01/15/2018] [Accepted: 01/26/2018] [Indexed: 01/08/2023]
|
|
47
|
Abstract
Behavioral and psychological symptoms of dementia (BPSD) are universally experienced by people with dementia throughout the course of the illness and cause a significant negative impact on quality of life for patients and caregivers. Nonpharmacologic treatments have been recommended as first-line treatment of BPSD by multiple professional organizations and should target patients with dementia factors, caregiver factors, and environmental factors. Psychotropic medications are often prescribed off-label without significant evidence to support their use. The Describe, Investigate, Create, Evaluate approach can provide a structured method to investigate and treat BPSD with flexibility to use in multiple treatment settings.
Collapse
Affiliation(s)
- Lauren B Gerlach
- Program for Positive Aging, Department of Psychiatry, University of Michigan, 4250 Plymouth Road, Ann Arbor, MI 48109, USA.
| | - Helen C Kales
- Program for Positive Aging, Department of Psychiatry, University of Michigan, 4250 Plymouth Road, Ann Arbor, MI 48109, USA; Center for Clinical Management Research, VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI 48105, USA
| |
Collapse
|
|
48
|
Tewari D, Stankiewicz AM, Mocan A, Sah AN, Tzvetkov NT, Huminiecki L, Horbańczuk JO, Atanasov AG. Ethnopharmacological Approaches for Dementia Therapy and Significance of Natural Products and Herbal Drugs. Front Aging Neurosci 2018; 10:3. [PMID: 29483867 PMCID: PMC5816049 DOI: 10.3389/fnagi.2018.00003] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Accepted: 01/08/2018] [Indexed: 12/21/2022] Open
Abstract
Dementia is a clinical syndrome wherein gradual decline of mental and cognitive capabilities of an afflicted person takes place. Dementia is associated with various risk factors and conditions such as insufficient cerebral blood supply, toxin exposure, mitochondrial dysfunction, oxidative damage, and often coexisting with some neurodegenerative disorders such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). Although there are well-established (semi-)synthetic drugs currently used for the management of AD and AD-associated dementia, most of them have several adverse effects. Thus, traditional medicine provides various plant-derived lead molecules that may be useful for further medical research. Herein we review the worldwide use of ethnomedicinal plants in dementia treatment. We have explored a number of recognized databases by using keywords and phrases such as “dementia”, “Alzheimer's,” “traditional medicine,” “ethnopharmacology,” “ethnobotany,” “herbs,” “medicinal plants” or other relevant terms, and summarized 90 medicinal plants that are traditionally used to treat dementia. Moreover, we highlight five medicinal plants or plant genera of prime importance and discuss the physiological effects, as well as the mechanism of action of their major bioactive compounds. Furthermore, the link between mitochondrial dysfunction and dementia is also discussed. We conclude that several drugs of plant origin may serve as promising therapeutics for the treatment of dementia, however, pivotal evidence for their therapeutic efficacy in advanced clinical studies is still lacking.
Collapse
Affiliation(s)
- Devesh Tewari
- Department of Pharmaceutical Sciences, Faculty of Technology, Kumaun University, Nainital, India
| | - Adrian M Stankiewicz
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, Poland
| | - Andrei Mocan
- Department of Pharmaceutical Botany, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,ICHAT and Institute for Life Sciences, University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania
| | - Archana N Sah
- Department of Pharmaceutical Sciences, Faculty of Technology, Kumaun University, Nainital, India
| | - Nikolay T Tzvetkov
- Department of Molecular Biology and Biochemical Pharmacology, Institute of Molecular Biology Roumen Tsanev, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Lukasz Huminiecki
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, Poland
| | - Jarosław O Horbańczuk
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, Poland
| | - Atanas G Atanasov
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, Poland.,Department of Pharmacognosy, University of Vienna, Vienna, Austria
| |
Collapse
|
|
49
|
|
|
50
|
Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, Ballard C, Banerjee S, Burns A, Cohen-Mansfield J, Cooper C, Fox N, Gitlin LN, Howard R, Kales HC, Larson EB, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N. Dementia prevention, intervention, and care. Lancet 2017; 390:2673-2734. [PMID: 28735855 DOI: 10.1016/s0140-6736(17)31363-6] [Citation(s) in RCA: 3737] [Impact Index Per Article: 467.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 01/20/2017] [Accepted: 01/25/2017] [Indexed: 12/15/2022]
Affiliation(s)
- Gill Livingston
- Division of Psychiatry, University College London, London, UK; Camden and Islington NHS Foundation Trust, London, UK.
| | | | - Vasiliki Orgeta
- Division of Psychiatry, University College London, London, UK
| | - Sergi G Costafreda
- Division of Psychiatry, University College London, London, UK; Camden and Islington NHS Foundation Trust, London, UK
| | - Jonathan Huntley
- Division of Psychiatry, University College London, London, UK; Department of Old Age Psychiatry, King's College London, London, UK
| | - David Ames
- National Ageing Research Institute, Parkville, VIC, Australia; Academic Unit for Psychiatry of Old Age, University of Melbourne, Kew, VIC, Australia
| | | | - Sube Banerjee
- Centre for Dementia Studies, Brighton and Sussex Medical School, University of Sussex, Brighton, UK
| | - Alistair Burns
- Centre for Dementia Studies, University of Manchester, Manchester, UK
| | - Jiska Cohen-Mansfield
- Department of Health Promotion, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Heczeg Institute on Aging, Tel Aviv University, Tel Aviv, Israel; Minerva Center for Interdisciplinary Study of End of Life, Tel Aviv University, Tel Aviv, Israel
| | - Claudia Cooper
- Division of Psychiatry, University College London, London, UK; Camden and Islington NHS Foundation Trust, London, UK
| | - Nick Fox
- Dementia Research Centre, University College London, Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK
| | - Laura N Gitlin
- Center for Innovative Care in Aging, Johns Hopkins University, Baltimore, MD, USA
| | - Robert Howard
- Division of Psychiatry, University College London, London, UK; Camden and Islington NHS Foundation Trust, London, UK
| | - Helen C Kales
- Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA; VA Center for Clinical Management Research, Ann Arbor, MI, USA
| | - Eric B Larson
- Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA
| | - Karen Ritchie
- Inserm, Unit 1061, Neuropsychiatry: Epidemiological and Clinical Research, La Colombière Hospital, University of Montpellier, Montpellier, France; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Kenneth Rockwood
- Centre for the Health Care of Elderly People, Geriatric Medicine Dalhousie University, Halifax, NS, Canada
| | - Elizabeth L Sampson
- Marie Curie Palliative Care Research Department, Division of Psychiatry, University College London, London, UK
| | - Quincy Samus
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins Bayview, Johns Hopkins University, Baltimore, MD, USA
| | - Lon S Schneider
- Department of Neurology and Department of Psychiatry and the Behavioural Sciences, Keck School of Medicine, Leonard Davis School of Gerontology of the University of Southern California, Los Angeles, CA, USA
| | - Geir Selbæk
- Norwegian National Advisory Unit on Aging and Health, Vestfold Health Trust, Tønsberg, Norway; Institute of Health and Society, Faculty of Medicine, University of Oslo, Oslo, Norway; Centre for Old Age Psychiatric Research, Innlandet Hospital Trust, Ottestad, Norway
| | - Linda Teri
- Department Psychosocial and Community Health, School of Nursing, University of Washington, Seattle, WA, USA
| | - Naaheed Mukadam
- Division of Psychiatry, University College London, London, UK
| |
Collapse
|