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Sayadnasiri M, Darvishskandari S, Latifian M, Shariful Islam SM. The Effect of Adding Mirtazapine to Quetiapine on Reducing Agitation in Patients with Alzheimer's Disease. J Alzheimers Dis Rep 2024; 8:143-150. [PMID: 38312532 PMCID: PMC10836607 DOI: 10.3233/adr-230123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 12/18/2023] [Indexed: 02/06/2024] Open
Abstract
Background Alzheimer's disease (AD) is one of the most debilitating diseases in old age, associated with cognitive decline and behavioral symptoms. Objective This study aimed to investigate the effect of adding mirtazapine to quetiapine in reducing agitation among patients with AD. Methods Thirty-seven elderly patients (18 cases and 19 controls) with AD, diagnosed according to National Institute on Aging and Alzheimer's Association (NIA-AA) criteria, were enrolled at Nezam-Mafi Clinic. Inclusion criteria comprised a minimum of two years post-diagnosis, a Cohen-Mansfield Agitation and Aggression Questionnaire (CMAI) score above 45, and treatment with 100-150 mg of quetiapine. Patients were randomly assigned to receive mirtazapine (15 mg at night, increased to 30 mg at night after two weeks) or a placebo. Cognitive changes were assessed at weeks 0 and 6 using the Mini-Mental State Examination instrument. Furthermore, symptoms of agitation and aggression were evaluated using the CMAI questionnaire at weeks 4 and 6. Results In this study, the mean duration of AD in the control group was 4.68 years, and in the case group, it was 5.05 years. Although the total agitation score showed no significant change at the end of the study compared to the control group, the rate of physical non-aggressive behavior showed a significant decrease (p < 0.05). Conclusions According to this study, adding mirtazapine to the antipsychotic drug regimen may not be an effective treatment for agitation in AD patients.
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Affiliation(s)
- Mohammad Sayadnasiri
- Department of Psychiatry, Psychosis Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Sahar Darvishskandari
- Department of Psychiatry, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Maryam Latifian
- Substance Abuse and Dependence Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
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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.
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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
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Lalani E, Menon R, Mufti MA, Kumfa C, Raji M. Mirtazapine: A One-Stop Strategy for Treatment of Opioid Withdrawal Symptoms. Cureus 2023; 15:e43821. [PMID: 37736438 PMCID: PMC10509332 DOI: 10.7759/cureus.43821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2023] [Indexed: 09/23/2023] Open
Abstract
Public health efforts to reduce the opioid overdose epidemic and treat opioid use disorder (OUD) have met with challenges associated with current non-standardized approaches to managing opioid withdrawal symptoms, such as itching, jitteriness, anxiety, depression, craving, vomiting, diarrhea, insomnia, and anorexia. These symptoms pose substantial obstacles to the safe initiation of medications for OUD, maintenance of long-term sobriety, and prevention of relapse. In clinical practice, multiple medications (polypharmacy) are prescribed to manage these withdrawal symptoms, including ondansetron and promethazine for vomiting and nausea, loperamide and Lomotil for diarrhea, hydroxyzine and doxepin for pruritus, benzodiazepines, the Z-drugs, and melatonin for insomnia, and benzos, tricyclic antidepressants (TCAs), and various serotonergic agents for anxiety. This polypharmacy is associated with an increased risk of adverse drug-drug interactions and adverse drug events, increased medical costs, and increased odds of medication non-adherence and relapse. We propose an alternative single medication, mirtazapine, a noradrenergic and specific serotonergic receptor antagonist, that can be used for myriad symptoms of opioid withdrawal. Case series, clinical studies, and clinical trials have shown mirtazapine to be effective for treating nausea and vomiting resulting from multiple etiologies, including hyperemesis gravidarum and chemotherapy-induced emesis. Other evidence supports the salutary effects of mirtazapine on itching and craving. Research findings support mirtazapine's beneficial effects on diarrhea and anxiety, a consequence of its modulating effects on serotonergic receptors mediating mood and gastrointestinal symptoms. There is also evidence supporting its efficacy as a potent and non-addictive sleep aid, which presents itself as a solution for insomnia associated with opioid withdrawal. The current review presents evidence from extant literature supporting mirtazapine as a one-drug strategy to treat the variety of symptoms of opioid withdrawal. This one-drug strategy has much potential to decrease polypharmacy, adverse drug events, relapse, and healthcare cost and increase the likelihood of prolonged sobriety and better quality of life for people living with OUD.
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Affiliation(s)
- Elisha Lalani
- Department of Internal Medicine, Division of General Medicine, University of Texas Medical Branch, Galveston, USA
| | - Raakhi Menon
- Department of Internal Medicine, Division of General Medicine, University of Texas Medical Branch, Galveston, USA
| | - Mariam A Mufti
- Department of Internal Medicine, Division of Geriatrics & Palliative Medicine, University of Texas Medical Branch, Galveston, USA
| | - Cecil Kumfa
- Department of Internal Medicine, Division of Geriatrics & Palliative Medicine, University of Texas Medical Branch, Galveston, USA
| | - Mukaila Raji
- Department of Internal Medicine, Division of Geriatrics & Palliative Medicine, University of Texas Medical Branch, Galveston, USA
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Kratzer A, Scheel-Barteit J, Altona J, Wolf-Ostermann K, Graessel E, Donath C. Agitation and aggression in people living with dementia and mild cognitive impairment in shared-housing arrangements - validation of a German version of the Cohen-Mansfield Agitation Inventory-Short Form (CMAI-SF). Health Qual Life Outcomes 2023; 21:51. [PMID: 37248478 DOI: 10.1186/s12955-023-02132-y] [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: 12/27/2022] [Accepted: 05/17/2023] [Indexed: 05/31/2023] Open
Abstract
BACKGROUND The Cohen-Mansfield Agitation Inventory-Short Form (CMAI-SF) is a 14-item scale for assessing agitation and aggression, derived from the original 29-item CMAI, and completed by a proxy. Because the CMAI-SF has not yet been validated in German language, the aim of this study is to explore its construct validity. METHODS Baseline data from a cluster-randomized trial to evaluate a non-pharmacological complex intervention for people living with dementia (PlwD) and mild cognitive impairment (MCI) were analyzed. The study sample consisted of 97 shared-housing arrangements (SHAs) in Germany, comprising N = 341 residents with mild to severe dementia and MCI. Trained nursing staff collected data by proxy-rating the CMAI-SF, Neuropsychiatric Inventory-Nursing Home Version (NPI-NH), and QUALIDEM. They also conducted the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). RESULTS In an exploratory factor analysis, three factors emerged: "aggressive behavior", "verbally agitated behavior", and "physically non-aggressive behavior". The CMAI-SF total score showed good internal consistency (α = .85), and the factors themselves showed adequate internal consistency (α = .75/.76/.73). The CMAI-SF showed convergent validity with the NPI-NH agitation item (r = .66) and the NPI-NH "agitation & restless behavior" factor (r = .82). Discriminant validity was confirmed by a low (r = .28) correlation with the NPI-NH apathy item. Quality of life decreased significantly with agitation, as the CMAI-SF showed a moderate negative correlation with the QUALIDEM total score (r = -.35). CONCLUSIONS The 14-item CMAI-SF is a time-efficient, reliable, and valid assessment instrument. Three factors emerged that were similar to those already found in nursing home samples for the original CMAI and the CMAI-SF and in day care samples for the CMAI-SF. The findings provide preliminary evidence that the CMAI-SF can be used instead of the CMAI to reduce time, costs, and burden in future trials. TRIAL REGISTRATION The DemWG study from which data were used to draft this manuscript was prospectively registered on 16 July 2019 at ISRCTN registry (ISRCTN89825211).
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Affiliation(s)
- André Kratzer
- Center for Health Services Research in Medicine, Department of Psychiatry and Psychotherapy, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054, Erlangen, Germany.
| | - Jennifer Scheel-Barteit
- Institute of General Practice, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Universitätsstr. 29, D-91054, Erlangen, Germany
| | - Janissa Altona
- Institute for Public Health and Nursing Science (IPP), University of Bremen, Grazer Str. 4, D-28359, Bremen, Germany
| | - Karin Wolf-Ostermann
- Institute for Public Health and Nursing Science (IPP), University of Bremen, Grazer Str. 4, D-28359, Bremen, Germany
- Health Sciences Bremen, Bremen, Germany
| | - Elmar Graessel
- Center for Health Services Research in Medicine, Department of Psychiatry and Psychotherapy, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054, Erlangen, Germany
| | - Carolin Donath
- Center for Health Services Research in Medicine, Department of Psychiatry and Psychotherapy, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054, Erlangen, Germany
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Mercan D, Heneka MT. The Contribution of the Locus Coeruleus-Noradrenaline System Degeneration during the Progression of Alzheimer's Disease. BIOLOGY 2022; 11:1822. [PMID: 36552331 PMCID: PMC9775634 DOI: 10.3390/biology11121822] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/07/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022]
Abstract
Alzheimer's disease (AD), which is characterized by extracellular accumulation of amyloid-beta peptide and intracellular aggregation of hyperphosphorylated tau, is the most common form of dementia. Memory loss, cognitive decline and disorientation are the ultimate consequences of neuronal death, synapse loss and neuroinflammation in AD. In general, there are many brain regions affected but neuronal loss in the locus coeruleus (LC) is one of the earliest indicators of neurodegeneration in AD. Since the LC is the main source of noradrenaline (NA) in the brain, degeneration of the LC in AD leads to decreased NA levels, causing increased neuroinflammation, enhanced amyloid and tau burden, decreased phagocytosis and impairment in cognition and long-term synaptic plasticity. In this review, we summarized current findings on the locus coeruleus-noradrenaline system and consequences of its dysfunction which is now recognized as an important contributor to AD progression.
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Affiliation(s)
- Dilek Mercan
- German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
| | - Michael Thomas Heneka
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4365 Esch-sur-Alzette, Luxembourg
- Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Lanctôt KL, Herrmann N. Mirtazapine for agitation in dementia: moving forward. Lancet 2021; 398:1462-1463. [PMID: 34688357 DOI: 10.1016/s0140-6736(21)01421-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 06/15/2021] [Indexed: 11/24/2022]
Affiliation(s)
- Krista L Lanctôt
- Sunnybrook Research Institute, University of Toronto, Toronto M4N 3M5, ON, Canada.
| | - Nathan Herrmann
- Merchavim Medical Center for Brain and Mental Health, Be'er Yaacov, Israel
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Roland JP, Bliwise DL. Impact of Pharmacotherapy on Insomnia in Patients with Alzheimer's Disease. Drugs Aging 2021; 38:951-966. [PMID: 34569029 PMCID: PMC8593056 DOI: 10.1007/s40266-021-00891-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2021] [Indexed: 02/03/2023]
Abstract
Insomnia is a pervasive sleep disorder affecting numerous patients across diverse demographical populations and comorbid disease states. Contributing factors are often a complex interaction of biological, psychological, and social components, requiring a multifaceted approach in terms of both diagnosis and management. In the setting of Alzheimer’s disease, insomnia is an even more complicated issue, with a higher overall prevalence than in the general population, greater complexity of contributing etiologies, and differences in diagnosis (at times based on caregiver observation of sleep disruption rather than subjective complaints by the individual with the disorder), and requiring more discretion in terms of treatment, particularly in regard to adverse effect profile concerns. There also is growing evidence of the bidirectional nature of sleep disruption and Alzheimer’s disease, with insomnia potentially contributing to disease progression, making the condition even more paramount to address. The objective of this review was to provide the clinician with an overview of treatment strategies that may have value in the treatment of disturbed sleep in Alzheimer’s disease. Nonpharmacological approaches to treatment should be exhausted foremost; however, pharmacotherapy may be needed in certain clinical scenarios, which can be a challenge for clinicians given the paucity of evidence and guidelines for treatment in the subpopulation of Alzheimer’s disease. Agents such as sedating antidepressants, melatonin, and site-specific γ-aminobutyric acid agonists are often employed based on historical usage but are not necessarily supported by high-quality trials. Newer agents such as dual orexin receptor antagonists have demonstrated some promise but still need further evaluation.
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Affiliation(s)
- Joshua P Roland
- Department of Pulmonology, Critical Care, and Sleep Medicine, David Geffen School of Medicine at UCLA, UCLA, 700 W. 7th Street, Suite S270-D, Los Angeles, CA, 90017, USA.
| | - Donald L Bliwise
- Department of Neurology, Emory University School of Medicine, Emory University, Atlanta, GA, USA
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Correia AS, Vale N. Antidepressants in Alzheimer's Disease: A Focus on the Role of Mirtazapine. Pharmaceuticals (Basel) 2021; 14:ph14090930. [PMID: 34577630 PMCID: PMC8467729 DOI: 10.3390/ph14090930] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/07/2021] [Accepted: 09/14/2021] [Indexed: 12/21/2022] Open
Abstract
Mirtazapine belongs to the category of antidepressants clinically used mainly in major depressive disorder but also used in obsessive-compulsive disorders, generalized anxiety, and sleep disturbances. This drug acts mainly by antagonizing the adrenergic α2, and the serotonergic 5-HT2 and 5-HT3 receptors. Neuropsychiatric symptoms, such as depression and agitation, are strongly associated with Alzheimer’s disease, reducing the life quality of these patients. Thus, it is crucial to control depression in Alzheimer’s patients. For this purpose, drugs such as mirtazapine are important in the control of anxiety, agitation, and other depressive symptoms in these patients. Indeed, despite some contradictory studies, evidence supports the role of mirtazapine in this regard. In this review, we will focus on depression in Alzheimer’s disease, highlighting the role of mirtazapine in this context.
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Affiliation(s)
- Ana Salomé Correia
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Nuno Vale
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Correspondence:
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Pottegård A, Lundby C, Jarbøl DE, Larsen SP, Hoppe BC, Hoffmann H, Thompson W. Use of sedating medications around nursing home admission in Denmark. Pharmacoepidemiol Drug Saf 2021; 30:1560-1565. [PMID: 34382278 DOI: 10.1002/pds.5341] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 07/13/2021] [Accepted: 08/09/2021] [Indexed: 11/06/2022]
Abstract
PURPOSE To examine use of sedating medications around the time of nursing home admission in Denmark. METHODS We conducted a register-based drug utilization study, describing patterns of commonly used medications with sedative effects leading up to and after nursing home admission using data from 94 Danish nursing homes between 2015 and 2017. RESULTS We identified 5179 residents (median age 84 years, 63% female) and described monthly incidence and total use of benzodiazepines (BZDs), Z drugs, mirtazapine/mianserin, quetiapine, promethazine, and melatonin. The proportion of unique users of sedating medications was similar before and after admission (42% before vs. 40% after) despite an increase in total use after admission. The overall incidence of sedating medications peaked in the 6 months before and 6 months after admission (peaking at 4.6 per 100 person-months 1 month after admission). The most commonly initiated medications were mirtazapine/mianserin, followed by BZDs and Z drugs. Total use of sedating medications increased leading up to admission (peaking at 1001 defined daily doses per 100 residents per month 1 month after admission) and decreased gradually after admission. CONCLUSIONS Sedative medication initiation increases sharply leading up to admission in Danish nursing homes. Mirtazapine/mianserin is a commonly used agent in nursing homes, despite limited evidence on benefits and harms. Efforts to promote rational use of these medications in nursing homes remain warranted.
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Affiliation(s)
- Anton Pottegård
- Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark.,Hospital Pharmacy Funen, Odense University Hospital, Odense, Denmark.,Odense Deprescribing Initiative (ODIN), Odense, Denmark
| | - Carina Lundby
- Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark.,Hospital Pharmacy Funen, Odense University Hospital, Odense, Denmark.,Odense Deprescribing Initiative (ODIN), Odense, Denmark.,Research Unit of General Practice, Department of Public Health, University of Southern Denmark, Odense, Denmark
| | - Dorte Ejg Jarbøl
- Research Unit of General Practice, Department of Public Health, University of Southern Denmark, Odense, Denmark
| | | | | | | | - Wade Thompson
- Hospital Pharmacy Funen, Odense University Hospital, Odense, Denmark.,Odense Deprescribing Initiative (ODIN), Odense, Denmark.,Research Unit of General Practice, Department of Public Health, University of Southern Denmark, Odense, Denmark
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Fabbretti E, Antognolli G, Tongiorgi E. Amyloid-β Impairs Dendritic Trafficking of Golgi-Like Organelles in the Early Phase Preceding Neurite Atrophy: Rescue by Mirtazapine. Front Mol Neurosci 2021; 14:661728. [PMID: 34149353 PMCID: PMC8209480 DOI: 10.3389/fnmol.2021.661728] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 04/30/2021] [Indexed: 12/20/2022] Open
Abstract
Neurite atrophy with loss of neuronal polarity is a pathological hallmark of Alzheimer's disease (AD) and other neurological disorders. While there is substantial agreement that disruption of intracellular vesicle trafficking is associated with axonal pathology in AD, comparatively less is known regarding its role in dendritic atrophy. This is a significant gap of knowledge because, unlike axons, dendrites are endowed with the complete endomembrane system comprising endoplasmic reticulum (ER), ER-Golgi intermediate compartment (ERGIC), Golgi apparatus, post-Golgi vesicles, and a recycling-degradative route. In this study, using live-imaging of pGOLT-expressing vesicles, indicative of Golgi outposts and satellites, we investigate how amyloid-β (Aβ) oligomers affect the trafficking of Golgi-like organelles in the different dendritic compartments of cultured rat hippocampal neurons. We found that short-term (4 h) treatment with Aβ led to a decrease in anterograde trafficking of Golgi vesicles in dendrites of both resting and stimulated (with 50 mM KCl) neurons. We also characterized the ability of mirtazapine, a noradrenergic and specific serotonergic tetracyclic antidepressant (NaSSA), to rescue Golgi dynamics in dendrites. Mirtazapine treatment (10 μM) increased the number and both anterograde and retrograde motility, reducing the percentage of static Golgi vesicles. Finally, mirtazapine reverted the neurite atrophy induced by 24 h treatment with Aβ oligomers, suggesting that this drug is able to counteract the effects of Aβ by improving the dendritic trafficking of Golgi-related vesicles.
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Affiliation(s)
- Elsa Fabbretti
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | | | - Enrico Tongiorgi
- Department of Life Sciences, University of Trieste, Trieste, Italy
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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.
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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
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Aftab A, Lam JA, Liu F, Ghosh A, Sajatovic M. Recent developments in geriatric psychopharmacology. Expert Rev Clin Pharmacol 2021; 14:341-355. [PMID: 33499693 DOI: 10.1080/17512433.2021.1882848] [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: 10/22/2022]
Abstract
INTRODUCTION There is a tremendous growing need to address the burden of geriatric psychiatric disorders. Recent developments relevant to geriatric psychiatry have focused on Alzheimer's disease (AD), severe/refractory depression, and cancer/end of life care. AREAS COVERED This is a non-systematic, narrative review (databases and websites for search: PubMed, Google Scholar, Medscape, ClinicalTrials.gov; focusing on the last 6 years), and covers developments in disease-modifying therapies for AD, diagnostic radiotracers for AD, medications for neuropsychiatric symptoms of dementia, ketamine/esketamine, psychedelics, and cannabinoids. EXPERT OPINION The focus of on-going trials of anti-amyloid agents has been on individuals with very early stage AD; several agents are under phase 3 investigation, and aducanumab is under FDA review. Amyloid and tau PET scans have been approved by the FDA to assist in the diagnoses of AD. Promising pharmaceuticals for neuropsychiatric symptoms of dementia include pimavanserin, brexpiprazole, escitalopram, dextromethorphan/quinidine, and lithium. Esketamine, although approved for treatment-resistant depression in general adults, failed to demonstrate efficacy in elderly patients in a phase 3 trial. There is preliminary evidence for benefit of psychedelic-assisted psychotherapy in end-of-life and cancer-related depression/anxiety. Evidence for the use of cannabinoids is currently lacking.
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Affiliation(s)
- Awais Aftab
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Jeffrey A Lam
- Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - Fred Liu
- Departments of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | - Anjan Ghosh
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Martha Sajatovic
- Departments of Psychiatry and Neurology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
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13
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Oliveira LDF, Camargos EF, Martini LLL, Machado FV, Novaes MRCG. Use of psychotropic agents to treat agitation and aggression in Brazilian patients with Alzheimer's disease: A naturalistic and multicenter study. Psychiatry Res 2021; 295:113591. [PMID: 33271491 DOI: 10.1016/j.psychres.2020.113591] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 11/22/2020] [Indexed: 02/07/2023]
Abstract
We assessed psychotropic prescribing patterns in the clinical treatment of agitation and aggressive behavior in patients with Alzheimer's disease (AD) treated at specialist outpatient clinics in the Federal District of Brazil. This was a naturalistic, observational, multicenter study of a convenience sample of patients with AD (according to DSM-5) who had behavioral symptoms of aggression and/or agitation at outpatient visits, as assessed by the Neuropsychiatric Inventory (NPI), and required pharmacologic intervention. Participants were recruited in 2018-2019 from 11 AD treatment centers. Sociodemographic and clinical data were collected during routine visits. The sample consisted of 369 older adults with a mean age of 82.3 (SD, 7.7) years. The medications most commonly used in patients with behavioral disorders were antidepressants (79.1%), antipsychotics (70.2%), benzodiazepines (10.6%), and mood stabilizers (9.5%). Quetiapine was the most frequently prescribed antipsychotic medication (48.5%), at a mean dose of 57.4 (SD, 40.7) mg. Citalopram was the most widely used antidepressant medication (32.0%), at a mean daily dose of 24.1 (SD, 8.1) mg. In this sample, two or more pharmacologic agents were frequently used together to control aggression and agitation. Benzodiazepine was not frequently used.
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Affiliation(s)
- Larissa de Freitas Oliveira
- Secretaria de Estado de Saúde do Distrito Federal, Geriatra(Staff geriatrician, Federal District Department of Health), Brasília, DF, Brazil.
| | - Einstein Francisco Camargos
- Hospital Universitário de Brasília, Geriatra(Staff geriatrician, University Hospital of Brasilia), Brasília, DF, Brazil
| | | | - Flávio Vieira Machado
- Programa de pós-graduação em Ciências Médicas, UnB, Psiquiatra(Psychiatrist, Graduate program in Medical Sciences), UnB, Brasília, DF, Brazil
| | - Maria Rita Carvalho Garbi Novaes
- Fundação de Ensino e Pesquisa em Ciências da Saúde, Farmacêutica(Pharmacist, Health Sciences Teaching and Research Foundation), Brasília, DF, Brazil
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14
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Marcinkowska M, Śniecikowska J, Fajkis N, Paśko P, Franczyk W, Kołaczkowski M. Management of Dementia-Related Psychosis, Agitation and Aggression: A Review of the Pharmacology and Clinical Effects of Potential Drug Candidates. CNS Drugs 2020; 34:243-268. [PMID: 32052375 PMCID: PMC7048860 DOI: 10.1007/s40263-020-00707-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Along with cognitive decline, 90% of patients with dementia experience behavioral and psychological symptoms of dementia, such as psychosis, aggression, agitation, and depression. Atypical antipsychotics are commonly prescribed off-label to manage certain symptoms, despite warnings from the regulatory agencies regarding the increased risk of mortality associated with their use in elderly patients. Moreover, these compounds display a limited clinical efficacy, mostly owing to the fact that they were developed to treat schizophrenia, a disease characterized by neurobiological deficits. Thus, to improve clinical efficacy, it has been suggested that patients with dementia should be treated with exclusively designed and developed drugs that interact with pharmacologically relevant targets. Within this context, numerous studies have suggested druggable targets that might achieve therapeutically acceptable pharmacological profiles. Based on this, several different drug candidates have been proposed that are being investigated in clinical trials for behavioral and psychological symptoms of dementia. We highlight the recent advances toward the development of therapeutic agents for dementia-related psychosis and agitation/aggression and discuss the relationship between the relevant biological targets and their etiology. In addition, we review the compounds that are in the early stage of development (discovery or preclinical phase) and those that are currently being investigated in clinical trials for dementia-related psychosis and agitation/aggression. We also discuss the mechanism of action of these compounds and their pharmacological utility in patients with dementia.
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Affiliation(s)
- Monika Marcinkowska
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688, Poland.
| | - Joanna Śniecikowska
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688 Poland ,Adamed Pharma S.A., Czosnow, Poland
| | - Nikola Fajkis
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688 Poland
| | - Paweł Paśko
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688 Poland
| | - Weronika Franczyk
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688 Poland
| | - Marcin Kołaczkowski
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Kraków, 30-688 Poland ,Adamed Pharma S.A., Czosnow, Poland
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15
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Kern DM, Cepeda MS, Lovestone S, Seabrook GR. Aiding the discovery of new treatments for dementia by uncovering unknown benefits of existing medications. ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS 2019; 5:862-870. [PMID: 31872043 PMCID: PMC6909196 DOI: 10.1016/j.trci.2019.07.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Introduction There is a significant need for disease-modifying therapies to treat and prevent dementia, including Alzheimer's disease. Availability of real-world observational information and new analytic techniques to analyze large volumes of data can provide a path to aid drug discovery. Methods Using a self-controlled study design, we examined the association between 2181 medications and incidence of dementia across four US insurance claims databases. Medications associated with ≥50% reduction in risk of dementia in ≥2 databases were examined. Results A total of 117,015,066 individuals were included in the analysis. Seventeen medications met our threshold criteria for a potential protective effect on dementia and fell into five classes: catecholamine modulators, anticonvulsants, antibiotics/antivirals, anticoagulants, and a miscellaneous group. Discussion The biological pathways of the medications identified in this analysis may be targets for further research and may aid in discovering novel therapeutic approaches to treat dementia. These data show association not causality.
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Affiliation(s)
- David M Kern
- Janssen Research & Development, Epidemiology, Titusville, NJ, USA
| | - M Soledad Cepeda
- Janssen Research & Development, Epidemiology, Titusville, NJ, USA
| | - Simon Lovestone
- Janssen Research & Development, Neuroscience, Beerse, Belgium
| | - Guy R Seabrook
- Johnson & Johnson, Scientific Innovation, South San Francisco, CA, USA
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16
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Keszycki RM, Fisher DW, Dong H. The Hyperactivity-Impulsivity-Irritiability-Disinhibition-Aggression-Agitation Domain in Alzheimer's Disease: Current Management and Future Directions. Front Pharmacol 2019; 10:1109. [PMID: 31611794 PMCID: PMC6777414 DOI: 10.3389/fphar.2019.01109] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 08/29/2019] [Indexed: 12/14/2022] Open
Abstract
Behavioral and psychological symptoms of dementia (BPSD) afflict the vast majority of patients with dementia, especially those with Alzheimer's disease (AD). In clinical settings, patients with BPSD most often do not present with just one symptom. Rather, clusters of symptoms commonly co-occur and can, thus, be grouped into behavioral domains that may ultimately be the result of disruptions in overarching neural circuits. One major BPSD domain routinely identified across patients with AD is the hyperactivity-impulsivity-irritiability-disinhibition-aggression-agitation (HIDA) domain. The HIDA domain represents one of the most difficult sets of symptoms to manage in AD and accounts for much of the burden for caregivers and hospital staff. Although many studies recommend non-pharmacological treatments for HIDA domain symptoms as first-line, they demonstrate little consensus as to what these treatments should be and are often difficult to implement clinically. Certain symptoms within the HIDA domain also do not respond adequately to these treatments, putting patients at risk and necessitating adjunct pharmacological intervention. In this review, we summarize the current literature regarding non-pharmacological and pharmacological interventions for the HIDA domain and provide suggestions for improving treatment. As epigenetic changes due to both aging and AD cause dysfunction in drug-targeted receptors, we propose that HIDA domain treatments could be enhanced by adjunct strategies that modify these epigenetic alterations and, thus, increase efficacy and reduce side effects. To improve the implementation of non-pharmacological approaches in clinical settings, we suggest that issues regarding inadequate resources and guidance for implementation should be addressed. Finally, we propose that increased monitoring of symptom and treatment progression via novel sensor technology and the "DICE" (describe, investigate, create, and evaluate) approach may enhance both pharmacological and non-pharmacological interventions for the HIDA domain.
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Affiliation(s)
- Rachel M. Keszycki
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Daniel W. Fisher
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Department of Psychiatry and Behavioral Sciences, University of Washington Medical Center, Seattle, WA, United States
| | - Hongxin Dong
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
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17
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Current Agents in Development for Treating Behavioral and Psychological Symptoms Associated with Dementia. Drugs Aging 2019; 36:589-605. [PMID: 30957198 DOI: 10.1007/s40266-019-00668-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Behavioral and psychological symptoms associated with dementia are highly prevalent and are associated with an increased risk of institutionalization and mortality. Current pharmacological treatments for these symptoms include cholinesterase inhibitors, antipsychotics, and selective serotonin reuptake inhibitors. When used for treating behavioral and psychological symptoms associated with dementia, they are associated with limited efficacy and/or serious adverse events. As such, there has been extensive research into novel agents with varying mechanisms of action targeting behavioral and psychological symptoms associated with dementia. In this article, we present the results of a comprehensive literature search and review that evaluates current agents that have completed or are currently in clinical trials for treating behavioral and psychological symptoms associated with dementia as a primary outcome. We highlight novel agents from miscellaneous drug classes, such as dextromethorphan/quinidine, bupropion/dextromethorphan, lumateperone, deudextromethorphan/quinidine, methylphenidate and scyllo-inositol, and drugs from various therapeutic classes (including atypical antipsychotics, selective serotonin reuptake inhibitors, and cannabinoids) that have demonstrated promising results and were generally well tolerated. Future research with large appropriately powered studies using validated outcome measures for behavioral and psychological symptoms associated with dementia should be conducted to further establish the clinical utility of these agents.
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18
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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.
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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
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Masopust J, Protopopová D, Vališ M, Pavelek Z, Klímová B. Treatment of behavioral and psychological symptoms of dementias with psychopharmaceuticals: a review. Neuropsychiatr Dis Treat 2018; 14:1211-1220. [PMID: 29785112 PMCID: PMC5953267 DOI: 10.2147/ndt.s163842] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Behavioral and psychological symptoms represent common complications in patients with different types of dementia. Predominantly, they comprise psychosis, agitation and mood disorders, disinhibited behavior, impairment of the sleep and wakefulness rhythm, wandering, perseveration, pathological collecting, or shouting. Their appearance is related to more rapid progression of the disease, earlier institutionalization, use of physical restraints, and higher risk of mortality. Consequently, appearance of behavioral and psychological symptoms of dementia leads to higher costs of care provided and greater distress for caregivers. Clinical guidelines recommend nonpharmacological approaches as the first choice in the treatment of behavioral and psychological symptoms. Pharmacological therapy should be initiated only if the symptoms were not the result of somatic causes, did not respond to nonpharmacological interventions, or were not caused by the prior medication. Acetylcholinesterase inhibitors, memantine, antipsychotic drugs, antidepressants, mood stabilizers, and benzodiazepines are used. This review summarizes the current findings about the efficacy and safety of the treatment of the neuropsychiatric symptoms in dementias with psychopharmaceuticals. Recommendations for treatment with antipsychotics for this indication are described in detail as this drug group is prescribed most often and, at the same time, is related to the highest risk of adverse effects and increased mortality.
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Affiliation(s)
- Jiří Masopust
- Department of Psychiatry, Charles University in Prague, Prague, Czech Republic.,Faculty of Medicine in Hradec Kralove and University Hospital, Hradec Kralove, Czech Republic.,Department of Neurology, Charles University in Prague, Prague, Czech Republic.,National Institute of Mental Health, Klecany, Czech Republic
| | | | - Martin Vališ
- Faculty of Medicine in Hradec Kralove and University Hospital, Hradec Kralove, Czech Republic.,Department of Neurology, Charles University in Prague, Prague, Czech Republic
| | - Zbyšek Pavelek
- Faculty of Medicine in Hradec Kralove and University Hospital, Hradec Kralove, Czech Republic.,Department of Neurology, Charles University in Prague, Prague, Czech Republic
| | - Blanka Klímová
- Department of Applied Linguistics, University of Hradec Kralove, Hradec Kralove, Czech Republic
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20
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Ijaopo EO. Dementia-related agitation: a review of non-pharmacological interventions and analysis of risks and benefits of pharmacotherapy. Transl Psychiatry 2017; 7:e1250. [PMID: 29087372 PMCID: PMC5682601 DOI: 10.1038/tp.2017.199] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 07/07/2017] [Accepted: 07/14/2017] [Indexed: 12/24/2022] Open
Abstract
Unsurprisingly, the subject of dementia has been a rising matter of public health concerns as people now live longer. World Alzheimer Report 2015, estimate that about 46.8 million people worldwide have dementia. These numbers are projected to almost double every 20 years, reaching 74.7 million in 2030 and 131.5 million in 2050. The modality for treating agitation and other behavioral symptoms in dementia patients has been a challenge. Many years on, there has been no FDA-approved pharmacotherapy in treating dementia-related agitation. This review discusses the current knowledge of non-pharmacological interventions, and analyzes the risks and benefits of pharmacotherapy in the management of dementia-related agitation, as well as providing an anecdotal of the author's clinical experience. This article aims to provide opportunity for increase awareness for clinicians, particularly those with no specialty training in geriatrics medicine but see dementia patients with agitation and other behavioral symptoms from time to time. Likewise, it hopefully will benefit the readers of medical journals to update their existing knowledge on matters relating to the management of dementia-related agitation.
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Affiliation(s)
- E O Ijaopo
- Department of Medicine, Royal Wolverhampton NHS Trust, New Cross Hospital, Wolverhampton, West Midlands, UK
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21
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Evidence and decision algorithm for the withdrawal of antipsychotic treatment in the elderly with dementia and neuropsychiatric symptoms. Eur J Clin Pharmacol 2017; 73:1389-1398. [PMID: 28780696 DOI: 10.1007/s00228-017-2314-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 07/26/2017] [Indexed: 11/26/2022]
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22
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Scoralick FM, Louzada LL, Quintas JL, Naves JOS, Camargos EF, Nóbrega OT. Mirtazapine does not improve sleep disorders in Alzheimer's disease: results from a double-blind, placebo-controlled pilot study. Psychogeriatrics 2017; 17:89-96. [PMID: 26818096 DOI: 10.1111/psyg.12191] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 11/27/2015] [Accepted: 12/30/2015] [Indexed: 11/29/2022]
Abstract
AIM The aim of this study was to test the efficacy and safety of mirtazapine in the treatment of sleep disorders in patients with Alzheimer's disease by means of a randomized, double-blind, placebo-controlled trial. Measurements were obtained for 7 days before intervention (baseline) and for 2 weeks after the onset of treatment. METHODS Alzheimer's disease patients with sleep disorders (n = 24) received 15-mg mirtazapine (n = 8) or placebo (n = 16) once daily at 2100 hours for 2 weeks. Patients were evaluated with actigraphy and structured scales before and after intervention. Historical control was employed. RESULTS Treatment with mirtazapine or placebo had no effect on cognitive and functional status as assessed by the Mini-Mental State Examination and the Katz scale, respectively. There were no differences between groups in the frequency or severity of the adverse events reported. Compared with the placebo group, mirtazapine users showed increased daytime sleepiness but no improvement in the duration or efficiency of nocturnal sleep after treatment. CONCLUSIONS This study showed no significant therapeutic effects of 15-mg mirtazapine in community-dwelling Alzheimer's disease patients with sleep disorders. Instead, this study found evidence of worsening of daytime sleep patterns.
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Affiliation(s)
- Francisca M Scoralick
- Department of Clinical Medicine, Geriatric Medical Center, Brasilia University Hospital, University of Brasilia, Brasília, Brazil.,Graduate Program in Health Sciences, University of Brasília, Brasília, Brazil
| | - Luciana L Louzada
- Department of Clinical Medicine, Geriatric Medical Center, Brasilia University Hospital, University of Brasilia, Brasília, Brazil
| | - Juliana L Quintas
- Department of Clinical Medicine, Geriatric Medical Center, Brasilia University Hospital, University of Brasilia, Brasília, Brazil
| | - Janeth O S Naves
- Graduate Program in Health Sciences, University of Brasília, Brasília, Brazil
| | - Einstein F Camargos
- Department of Clinical Medicine, Geriatric Medical Center, Brasilia University Hospital, University of Brasilia, Brasília, Brazil.,Graduate Program in Medical Sciences, University of Brasilia, Brasília, Brazil
| | - Otávio T Nóbrega
- Graduate Program in Medical Sciences, University of Brasilia, Brasília, Brazil.,Graduate Program in Health Sciences, University of Brasília, Brasília, Brazil
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Wang F, Feng TY, Yang S, Preter M, Zhou JN, Wang XP. Drug Therapy for Behavioral and Psychological Symptoms of Dementia. Curr Neuropharmacol 2016; 14:307-13. [PMID: 26644152 PMCID: PMC4876586 DOI: 10.2174/1570159x14666151208114232] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Revised: 07/16/2015] [Accepted: 10/09/2015] [Indexed: 01/14/2023] Open
Abstract
Dementia, which can be induced by diverse factors, is a clinical syndrome characterized by the decline of cognitive function. Behavioral and psychological symptoms of dementia (BPSD) include depression, agitation, and aggression. Dementia causes a heavy burden on patients and their caregivers. Patients with BPSD should be assessed comprehensively by practitioners and offered appropriate non-pharmacologic and pharmacologic therapy. Non-pharmacologic therapy has been recommended as the basal treatment for BPSD; however, pharmacologic therapy is required under many situations. Medications, including antipsychotic agents, antidepressants, sedative and hypnotic agents, mood stabilizers, cholinesterase inhibitors, and amantadine, are extensively used in clinical practice. We have reviewed the progression of pharmacologic therapy for BPSD.
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Affiliation(s)
| | | | | | | | | | - Xiao-Ping Wang
- Department of Neurology, Shanghai First People's Hospital, Shanghai Jiao-Tong University, China, 200080.
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Trends in Psychotropic Dispensing Among Older Adults with Dementia Living in Long-Term Care Facilities: 2004-2013. Am J Geriatr Psychiatry 2015; 23:1259-1269. [PMID: 26525997 DOI: 10.1016/j.jagp.2015.07.001] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 06/30/2015] [Accepted: 07/07/2015] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Guidelines worldwide have cautioned against the use of antipsychotics as first-line agents to treat neuropsychiatric symptoms of dementia. We aimed to investigate the changes over time in the dispensing of antipsychotics and other psychotropics among older adults with dementia living in long-term care facilities. METHODS We used drug claims data from Ontario, Canada, to calculate quarterly rates of prescription dispensing of six psychotropic drug classes among all elderly (≥65 years of age) long-term care residents with dementia from January 1, 2004, to March 31, 2013. Psychotropic drugs were classified into the following categories: atypical and conventional antipsychotics, non-sedative and sedative antidepressants, anti-epileptics, and benzodiazepines. We used time-series analysis to assess trends over time. RESULTS The study sample increased by 21% over the 10-year study period, from 49,251 patients to 59,785 patients. The majority of patients (within the range of 75%-79%) were dispensed at least one psychotropic medication. At the beginning of the study period atypical antipsychotics (38%) were the most frequently dispensed psychotropic, followed by benzodiazepines (28%), non-sedative antidepressants (27%), sedative antidepressants (17%), anti-epileptics (7%), and conventional antipsychotics (3%). Dispensing of anti-epileptics (2% increase) and conventional antipsychotics (1% decrease) displayed modest changes over time, but we observed more pronounced changes in dispensing of benzodiazepines (11% decrease) and atypical antipsychotics (4% decrease). Concurrently, we observed a substantial growth in the dispensing of both sedative (15% increase) and non-sedative (9% increase) antidepressants. The proportion of patients dispensed two or more psychotropic drug classes increased from 42% in 2004 to 50% in 2013. CONCLUSIONS Utilization patterns of psychotropic drugs in institutionalized patients with dementia have changed over the past decade. Although their use declined slightly over the study period, atypical antipsychotics continue to be used at a high rate. A decline in the use of benzodiazepines along with an increased use of sedative and non-sedative antidepressants suggests that the latter class of drugs is being substituted for the former in the management of neuropsychiatric symptoms. Psychotropic polypharmacy continues to be highly prevalent in these patient samples.
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Casey DA. Pharmacotherapy of neuropsychiatric symptoms of dementia. P & T : A PEER-REVIEWED JOURNAL FOR FORMULARY MANAGEMENT 2015; 40:284-287. [PMID: 25859124 PMCID: PMC4378522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Approximately 5 million Americans have dementia, and many receive psychiatric medications. Management of such patients is complex and controversial, and it has become apparent that all potential pharmacological therapies present risks.
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Madhusoodanan S, Ting MB. Pharmacological management of behavioral symptoms associated with dementia. World J Psychiatry 2014; 4:72-9. [PMID: 25540722 PMCID: PMC4274589 DOI: 10.5498/wjp.v4.i4.72] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Revised: 10/29/2014] [Accepted: 11/07/2014] [Indexed: 02/05/2023] Open
Abstract
Dementia is a clinical syndrome with features of neurocognitive decline. Subtypes of dementia include Alzheimer's, frontotemporal, Parkinson's, Lewy body disease, and vascular type. Dementia is associated with a variety of neuropsychiatric symptoms that may include agitation, psychosis, depression, and apathy. These symptoms can lead to dangerousness to self or others and are the main source for caregiver burnout. Treatment of these symptoms consists of nonpharmacological and pharmacological interventions. However, there are no Food and Drug Administration-approved medications for the treatment of behavioral and psychological symptoms of dementia. Pharmacological interventions are used off-label. This article reviews the current evidence supporting or negating the use of psychotropic medications along with safety concerns, monitoring, regulations, and recommendations.
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Buterbaugh WM, Jamrose T, Lazzara J, Honaker L, Thomas CJ. Review of antidepressants in the treatment of behavioral and psychiatric symptoms in dementia (BPSD). Ment Health Clin 2014. [DOI: 10.9740/mhc.n204508] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Behavioral disturbances are commonplace among patients with dementia. Management of these symptoms has proved difficult.1,2 Currently, there are no FDA approved pharmacologic treatments for the treatment of BPSD.3 Traditionally, atypical antipsychotics have been used to treat behavioral disturbances despite modest efficacy and undesirable adverse effects.34,5 Because of the increase in mortality, there is a continued push to reduce antipsychotic utilization in this population.9,10 Thus, many clinicians are using alternative agents such as antidepressants and mood stabilizers to help treat BPSD, while avoiding using antipsychotics. The goal of this review is to review, analyze, and discuss the current literature available on the use of antidepressants to treat BPSD.
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Alam A, Voronovich Z, Carley JA. A review of therapeutic uses of mirtazapine in psychiatric and medical conditions. Prim Care Companion CNS Disord 2013; 15:13r01525. [PMID: 24511451 DOI: 10.4088/pcc.13r01525] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 07/09/2013] [Indexed: 10/26/2022] Open
Abstract
OBJECTIVE To review the literature examining the use of mirtazapine with an emphasis on its therapeutic benefits for psychiatric patients with comorbid medical conditions. DATA SOURCES MEDLINE, PsycINFO, Global Health, and AGRICOLA were searched using the terms mirtazapine OR Remeron. Limits were English language, human, year 1980-2012, treatment and prevention, and therapy. STUDY SELECTION Two hundred ninety-three articles were identified. DATA EXTRACTION Identified articles were reviewed with a focus on indications and therapeutic benefits in patients with medical comorbidities. RESULTS Mirtazapine is an effective antidepressant with unique mechanisms of action. It is characterized by a relatively rapid onset of action, high response and remission rates, a favorable side-effect profile, and several unique therapeutic benefits over other antidepressants. Mirtazapine has also shown promise in treating some medical disorders, including neurologic conditions, and ameliorating some of the associated debilitating symptoms of weight loss, insomnia, and postoperative nausea and vomiting. CONCLUSIONS Mirtazapine offers clinicians multiple therapeutic advantages especially when treating patients with comorbid medical illness.
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Affiliation(s)
- Abdulkader Alam
- Departments of Psychiatry and Medicine (Dr Alam), University of Pittsburgh School of Medicine (Ms Voronovich), Pittsburgh, Pennsylvania; and University of Alabama School of Medicine, Birmingham (Dr Carley)
| | - Zoya Voronovich
- Departments of Psychiatry and Medicine (Dr Alam), University of Pittsburgh School of Medicine (Ms Voronovich), Pittsburgh, Pennsylvania; and University of Alabama School of Medicine, Birmingham (Dr Carley)
| | - Joseph A Carley
- Departments of Psychiatry and Medicine (Dr Alam), University of Pittsburgh School of Medicine (Ms Voronovich), Pittsburgh, Pennsylvania; and University of Alabama School of Medicine, Birmingham (Dr Carley)
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Banerjee S, Hellier J, Romeo R, Dewey M, Knapp M, Ballard C, Baldwin R, Bentham P, Fox C, Holmes C, Katona C, Lawton C, Lindesay J, Livingston G, McCrae N, Moniz-Cook E, Murray J, Nurock S, Orrell M, O'Brien J, Poppe M, Thomas A, Walwyn R, Wilson K, Burns A. Study of the use of antidepressants for depression in dementia: the HTA-SADD trial--a multicentre, randomised, double-blind, placebo-controlled trial of the clinical effectiveness and cost-effectiveness of sertraline and mirtazapine. Health Technol Assess 2013; 17:1-166. [PMID: 23438937 DOI: 10.3310/hta17070] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE Depression is common in dementia, causing considerable distress and other negative impacts. Treating it is a clinical priority, but the evidence base is sparse and equivocal. This trial aimed to determine clinical effectiveness of sertraline and mirtazapine in reducing depression 13 weeks post randomisation compared with placebo. DESIGN Multicentre, parallel-group, double-blind placebo-controlled randomised controlled trial of the clinical effectiveness of sertraline and mirtazapine with 13- and 39-week follow-up. SETTING Nine English old-age psychiatry services. PARTICIPANTS A pragmatic trial. Eligibility: probable or possible Alzheimer's disease (AD), depression (4+ weeks) and Cornell Scale for Depression in Dementia (CSDD) score of 8+. EXCLUSIONS clinically too critical (e.g. suicide risk); contraindication to medication; taking antidepressants; in another trial; and having no carer. INTERVENTIONS (1) Sertraline; (2) mirtazapine; and (3) placebo, all with normal care. Target doses: 150 mg of sertraline or 45 mg of mirtazapine daily. MAIN OUTCOME MEASURES OUTCOME CSDD score. Randomisation: Allocated 1 : 1 : 1 through Trials Unit, independently of trial team. Stratified block randomisation by centre, with randomly varying block sizes; computer-generated randomisation. Blinding: Double blind: medication and placebo identical for each antidepressant. Referring clinicians, research workers, participants and pharmacies were blind. Statisticians blind until analyses completed. RESULTS Numbers randomised: 326 participants randomised (111 placebo, 107 sertraline and 108 mirtazapine). OUTCOME Differences in CSDD at 13 weeks from an adjusted linear-mixed model: mean difference (95% CI) placebo-sertraline 1.17 (-0.23 to 2.78; p = 0.102); placebo-mirtazapine 0.01 (-1.37 to 1.38; p = 0.991); and mirtazapine-sertraline 1.16 (-0.27 to 2.60; p = 0.112). HARMS Placebo group had fewer adverse reactions (29/111, 26%) than sertraline (46/107, 43%) or mirtazapine (44/108, 41%; p = 0.017); 39-week mortality equal, five deaths in each group. CONCLUSIONS This is a trial with negative findings but important clinical implications. The data suggest that the antidepressants tested, given with normal care, are not clinically effective (compared with placebo) for clinically significant depression in AD. This implies a need to change current practice of antidepressants being the first-line treatment of depression in AD. From the data generated we formulated the following recommendations for future work. (1) The secondary analyses presented here suggest that there would be value in carrying out a placebo-controlled trial of the clinical effectiveness and cost-effectiveness of mirtazapine in the management of Behavioural and Psychological Symptoms of Dementia. (2) A conclusion from this study is that it remains both ethical and essential for trials of new medication for depression in dementia to have a placebo arm. (3) Further research is required to evaluate the impact that treatments for depression in people with dementia can have on their carers not only in terms of any impacts on their quality of life, but also the time they spend care-giving. (4) There is a need for research into alternative biological and psychological therapies for depression in dementia. These could include evaluations of new classes of antidepressants (such as venlafaxine) or antidementia medication (e.g. cholinesterase inhibitors). (5) Research is needed to investigate the natural history of depression in dementia in the community when patients are not referred to secondary care services. (6) Further work is needed to investigate the cost modelling results in this rich data set, investigating carer burden and possible moderators to the treatment effects. (7) There is scope for reanalysis of the primary outcome in terms of carer and participant CSDD results.
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Affiliation(s)
- S Banerjee
- Brighton and Sussex Medical School, BSMS Teaching Building, University of Sussex, Brighton, UK
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Seitz DP, Adunuri N, Gill SS, Gruneir A, Herrmann N, Rochon P. Antidepressants for agitation and psychosis in dementia. Cochrane Database Syst Rev 2011:CD008191. [PMID: 21328305 DOI: 10.1002/14651858.cd008191.pub2] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Agitation and psychosis are common among older adults with dementia and are challenging to manage. At the present time, little is known about the efficacy and safety of antidepressant medications when used to treat these symptoms. OBJECTIVES To assess the safety and efficacy of antidepressants in treating psychosis and agitation in older adults with Alzheimer's disease, vascular, or mixed dementia. SEARCH STRATEGY We searched the Cochrane Dementia and Cognitive Improvement Group's Specialized Register which included Cochrane Central Register of Controlled Trials (The Cochrane Library 2009, Issue 3), MEDLINE (January 1950 to October 2009), EMBASE (1980 - October 2009), CINAHL (all dates - October 2009) and PsycINFO (1806 to October 2009). SELECTION CRITERIA Randomized, controlled trials of antidepressants (selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, trazodone, and other antidepressants), compared to either placebo or comparator medications (typical or atypical antipsychotics, anticonvulsants, benzodiazepines, cholinesterase inhibitors, memantine or other medications) for treatment of agitation or psychosis in older adults with dementia. DATA COLLECTION AND ANALYSIS Two authors independently assessed trial quality and extracted trial data. We collected information on efficacy as measured by dementia neuropsychiatric symptom rating scales and adverse effects. Study authors were contacted for additional information. MAIN RESULTS Nine trials including a total of 692 individuals were included in the review. Five studies compared SSRIs to placebo and two studies were combined in a meta-analysis for the outcome of change in Cohen-Mansfield Agitation Inventory (CMAI) scores. There was a significant difference between antidepressants and placebo on measures of agitation as reported on the change in CMAI total score (mean difference (MD), -0.89, 95% CI, -1.22 to -0.57) although the results were heavily weighted by one large study. There were no significant differences in change in behavioral symptoms of dementia for SSRIs compared to placebo in the one study that reported on changes in the Neuropsychiatric Inventory and Behavioral Pathology in Dementia scales. One study comparing citalopram to placebo found a significant difference in NPS as measured on the Neurobehavioral Rating Scale (NBRS) after controlling for baseline severity NBRS score although the unadjusted mean difference was not statistically significant (MD - 7.70, 95% CI: -16.57 to 1.17). There was no difference in the rates of trial withdrawals due to adverse events for SSRIs compared to placebo for four studies reporting this outcome (relative risk (RR), 1.07, 95% CI: 0.55 to 2.11) or in the number of trial withdrawals due to any cause in the three studies reporting this outcome (RR, 0.91, 95% CI, 0.65 to 1.26). One study compared the SSRI citalopram to the atypical antipsychotic risperidone and found no difference in NBRS scores, trial withdrawals due to any cause or trial withdrawals due to adverse events although the rates of adverse events as measured on the UKU side effect scale total score were lower for citalopram (MD -2.82, 95% CI: -4.94 to -0.70). Three studies compared SSRIs to typical antipsychotics. In meta-analysis of two studies there was no statistically significant differences in changes in CMAI total scores (MD, 4.66, 95% CI: -3.58 to 12.90). There was also no difference in trial withdrawals due to any cause or due to adverse events for SSRIs compared to typical antipsychotics. One study of trazodone compared to placebo did not find any significant difference in change in CMAI total scores (MD, 5.18, 95% CI, -2.86 to 13.22) or trial withdrawals due to any cause (RR, 1.06, 95% CI, 0.54 to 2.09). Two studies comparing trazodone to haloperidol also failed to detect any difference in change in CMAI total scores (MD, 3.28, 95% CI, -3.28 to 9.85) or trial withdrawals due to any cause (RR, 0.79, 95% CI, 0.43 to 1.46). AUTHORS' CONCLUSIONS Currently there are relatively few studies of antidepressants for the treatment of agitation and psychosis in dementia. The SSRIs sertraline and citalopram were associated with a reduction in symptoms of agitation when compared to placebo in two studies. Both SSRIs and trazodone appear to be tolerated reasonably well when compared to placebo, typical antipsychotics and atypical antipsychotics. Future studies involving more subjects are required to determine if SSRIs, trazodone, or other antidepressants are safe and effective treatments for agitation and psychosis in dementia.
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Affiliation(s)
- Dallas P Seitz
- Department of Psychiatry, Queen's University, 752 King Street West, Kingston, Ontario, Canada, K7L 4X3
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