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The American Journal of Geriatric... Apr 2020To assess the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To assess the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD).
DESIGN
Two 12-week, randomized, double-blind, placebo-controlled, parallel-arm studies (NCT01862640; NCT01922258).
SETTING
Study 1: 81 sites in 7 countries. Study 2: 62 sites in 9 countries.
PARTICIPANTS
Patients with AAD (Study 1: 433 randomized; Study 2: 270 randomized) in a care facility or community-based setting. Stable Alzheimer disease medications were permitted.
INTERVENTION
Study 1 (fixed dose): brexpiprazole 2 mg/day, brexpiprazole 1 mg/day, or placebo (1:1:1) for 12 weeks. Study 2 (flexible dose): brexpiprazole 0.5-2 mg/day or placebo (1:1) for 12 weeks.
MEASUREMENTS
Cohen-Mansfield Agitation Inventory (CMAI) (Total score range: 29-203; higher scores indicate more frequent agitated behaviors), and Clinical Global Impression - Severity of illness (CGI-S) as related to agitation. Safety was also assessed.
RESULTS
In Study 1, brexpiprazole 2 mg/day demonstrated statistically significantly greater improvement in CMAI Total score from baseline to Week 12 than placebo (adjusted mean difference, -3.77; confidence limits, -7.38, -0.17; t = -2.06; p = 0.040; MMRM). Brexpiprazole 1 mg/day did not show meaningful separation from placebo (0.23; -3.40, 3.86; t = 0.12; p = 0.90; MMRM). In Study 2, brexpiprazole 0.5-2 mg/day did not achieve statistical superiority over placebo (-2.34; -5.49, 0.82; t = -1.46; p = 0.15; MMRM). However, a benefit was observed in post hoc analyses among patients titrated to the maximum brexpiprazole dose of 2 mg/day compared with similarly titrated placebo patients (-5.06; -8.99, -1.13; t = -2.54; p = 0.012; MMRM). On the CGI-S, a greater numerical improvement than placebo was demonstrated for brexpiprazole 2 mg/day in Study 1 (-0.16; -0.39, 0.06; t = -1.42; nominal p = 0.16; MMRM), and a greater improvement for brexpiprazole 0.5-2 mg/day in Study 2 (-0.31; -0.55, -0.06; t = -2.42; nominal p = 0.016; MMRM). In Study 1, treatment-emergent adverse events (TEAEs) with incidence ≥5% among patients receiving brexpiprazole 2 mg/day were headache (9.3% versus 8.1% with placebo), insomnia (5.7% versus 4.4%), dizziness (5.7% versus 3.0%), and urinary tract infection (5.0% versus 1.5%). In Study 2, TEAEs with incidence ≥5% among patients receiving brexpiprazole 0.5-2 mg/day were headache (7.6% versus 12.4% with placebo) and somnolence (6.1% versus 3.6%). In both studies, the majority of TEAEs were mild or moderate in severity.
CONCLUSIONS
Brexpiprazole 2 mg/day has the potential to be efficacious, safe, and well tolerated in the treatment of AAD.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Female; Headache; Humans; Internationality; Male; Middle Aged; Psychiatric Status Rating Scales; Psychomotor Agitation; Quinolones; Sleep Initiation and Maintenance Disorders; Thiophenes; Treatment Outcome
PubMed: 31708380
DOI: 10.1016/j.jagp.2019.09.009 -
Korean Journal of Anesthesiology Dec 2020Emergence agitation (EA), also referred to as emergence delirium, can have clinically significant consequences. The mechanism of EA remains unclear. The proposed risk... (Review)
Review
Emergence agitation (EA), also referred to as emergence delirium, can have clinically significant consequences. The mechanism of EA remains unclear. The proposed risk factors of EA include age, male sex, type of surgery, emergency operation, use of inhalational anesthetics with low blood-gas partition coefficients, long duration of surgery, anticholinergics, premedication with benzodiazepines, voiding urgency, postoperative pain, and the presence of invasive devices. If preoperative or intraoperative objective monitoring could predict the occurrence of agitation during emergence, this would help to reduce its adverse consequences. Several tools are available for assessing EA. However, there are no standardized clinical research practice guidelines and its incidence varies considerably with the assessment tool or definition used. Total intravenous anesthesia, propofol, μ-opioid agonists, N-methyl-D-aspartate receptor antagonists, nefopam, α2-adrenoreceptor agonists, regional analgesia, multimodal analgesia, parent-present induction, and preoperative education for surgery may help in preventing of EA. However, it is difficult to identify patients at high risk and apply preventive measures in various clinical situations. The risk factors and outcomes of preventive strategies vary with the methodologies of studies and patients assessed.This review discusses important outcomes of research on EA and directions for future research.
Topics: Adult; Anesthesia Recovery Period; Anesthetics, Inhalation; Child; Child, Preschool; Emergence Delirium; Humans; Male; Psychomotor Agitation; Sevoflurane
PubMed: 32209961
DOI: 10.4097/kja.20097 -
The Cochrane Database of Systematic... Aug 2020Medications licensed for the treatment of dementia have limited efficacy against cognitive impairment or against the distressed behaviours (behavioural and psychological... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Medications licensed for the treatment of dementia have limited efficacy against cognitive impairment or against the distressed behaviours (behavioural and psychological symptoms, or behaviour that challenges) which are also often the most distressing aspect of the disorder for caregivers. Complementary therapies, including aromatherapy, are attractive to patients, practitioners and families, because they are perceived as being unlikely to cause adverse effects. Therefore there is interest in whether aromatherapy might offer a safe means of alleviating distressed behaviours in dementia.
OBJECTIVES
To assess the efficacy and safety of aromatherapy for people with dementia.
SEARCH METHODS
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 5 May 2020 using the terms: aromatherapy, lemon, lavender, rose, aroma, alternative therapies, complementary therapies, essential oils. In addition, we searched MEDLINE, Embase, PsycINFO (all via Ovid SP), Web of Science Core Collection (via Thompson Web of Science), LILACS (via BIREME), CENTRAL (via the Cochrane Library), ClinicalTrials.gov and the World Health Organization (WHO) trials portal (ICTRP) on 5 May 2020.
SELECTION CRITERIA
We included randomised controlled trials which compared fragrance from plants in an intervention defined as aromatherapy for people with dementia with placebo aromatherapy or with treatment as usual. All doses, frequencies and fragrances of aromatherapy were considered. Participants in the included studies had a diagnosis of dementia of any subtype and severity.
DATA COLLECTION AND ANALYSIS
Two reviewers independently selected studies for inclusion, extracted data and assessed risk of bias in included studies, involving other authors to reach consensus decisions where necessary. We did not perform any meta-analyses because of heterogeneity between studies, but presented a narrative synthesis of results from the included trials. Because of the heterogeneity of analysis methods and inadequate or absent reporting of data from some trials, we used statistical significance (P ≤ or > 0.5) as a summary metric when synthesising results across studies. As far as possible, we used GRADE methods to assess our confidence in the results of the trials, downgrading for risk of bias and imprecision.
MAIN RESULTS
We included 13 studies with 708 participants. All participants had dementia and in the 12 trials which described the setting, all were resident in institutional care facilities. Nine trials recruited participants because they had significant agitation or other behavioural and psychological symptoms in dementia (BPSD) at baseline. The fragrances used were lavender (eight studies); lemon balm (four studies); lavender and lemon balm, lavender and orange, and cedar extracts (one study each). For six trials, assessment of risk of bias and extraction of results was hampered by poor reporting. Four of the other seven trials were at low risk of bias in all domains, but all were small (range 18 to 186 participants; median 66), reducing our confidence in the results. Our primary outcomes were agitation, overall behavioural and psychological symptoms, and adverse effects. Ten trials assessed agitation using various scales. Among the five trials for which our confidence in the results was moderate or low, four trials reported no significant effect on agitation and one trial reported a significant benefit of aromatherapy. The other five trials either reported no useable data or our confidence in the results was very low. Eight trials assessed overall BPSD using the Neuropsychiatric Inventory and we had moderate or low confidence in the results of five of them. Of these, four reported significant benefit from aromatherapy and one reported no significant effect. Adverse events were poorly reported or not reported at all in most trials. No more than two trials assessed each of our secondary outcomes of quality of life, mood, sleep, activities of daily living, caregiver burden. We did not find evidence of benefit on these outcomes. Three trials assessed cognition: one did not report any data and the other two trials reported no significant effect of aromatherapy on cognition. Our confidence in the results of these studies was low.
AUTHORS' CONCLUSIONS
We have not found any convincing evidence that aromatherapy (or exposure to fragrant plant oils) is beneficial for people with dementia although there are many limitations to the data. Conduct or reporting problems in half of the included studies meant that they could not contribute to the conclusions. Results from the other studies were inconsistent. Harms were very poorly reported in the included studies. In order for clear conclusions to be drawn, better design and reporting and consistency of outcome measurement in future trials would be needed.
Topics: Aromatherapy; Behavioral Symptoms; Bias; Dementia; Humans; Oils, Volatile; Psychomotor Agitation; Randomized Controlled Trials as Topic
PubMed: 32813272
DOI: 10.1002/14651858.CD003150.pub3 -
International Journal of Environmental... Apr 2021The early and correct assessment of psychomotor agitation (PMA) is essential to ensure prompt intervention by healthcare professionals to improve the patient's... (Review)
Review
The early and correct assessment of psychomotor agitation (PMA) is essential to ensure prompt intervention by healthcare professionals to improve the patient's condition, protect healthcare staff, and facilitate future management. Proper training for recognizing and managing agitation in all care settings is desirable to improve patient outcomes. The best approach is one that is ethical, non-invasive, and respectful of the patient's dignity. When deemed necessary, pharmacological interventions must be administered rapidly and avoid producing an excessive state of sedation, except in cases of severe and imminent danger to the patient or others. The purpose of this brief review is to raise awareness about best practices for the management of PMA in emergency care situations and consider the role of new pharmacological interventions in patients with agitation associated with bipolar disorder or schizophrenia.
Topics: Antipsychotic Agents; Bipolar Disorder; Humans; Loxapine; Psychomotor Agitation; Schizophrenia
PubMed: 33924111
DOI: 10.3390/ijerph18084368 -
CNS Spectrums Apr 2022Accurate diagnosis and appropriate treatment of tardive dyskinesia (TD) are imperative, as its symptoms can be highly disruptive to both patients and their caregivers.... (Review)
Review
Accurate diagnosis and appropriate treatment of tardive dyskinesia (TD) are imperative, as its symptoms can be highly disruptive to both patients and their caregivers. Misdiagnosis can lead to incorrect interventions with suboptimal or even deleterious results. To aid in the identification and differentiation of TD in the psychiatric practice setting, we review its clinical features and movement phenomenology, as well as those of other antipsychotic-induced movement disorders, with accompanying links to illustrative videos. Exposure to dopamine receptor blocking agents (DRBAs) such as antipsychotics or antiemetics is associated with a spectrum of movement disorders including TD. The differential diagnosis of TD is based on history of DRBA exposure, recent discontinuation or dose reduction of a DRBA, and movement phenomenology. Common diagnostic challenges are the abnormal behaviors and dyskinesias associated with advanced age or chronic mental illness, and other movement disorders associated with DRBA therapy, such as akathisia, parkinsonian tremor, and tremor related to use of mood stabilizing agents (eg, lithium, divalproex). Duration of exposure may help rule out acute drug-induced syndromes such as acute dystonia or acute/subacute akathisia. Another important consideration is the potential for TD to present together with other drug-induced movement disorders (eg, parkinsonism, parkinsonian tremor, and postural tremor from mood stabilizers) in the same patient, which can complicate both diagnosis and management. After documentation of the phenomenology, severity, and distribution of TD movements, treatment options should be reviewed with the patient and caregivers.
Topics: Antipsychotic Agents; Humans; Movement Disorders; Psychomotor Agitation; Tardive Dyskinesia; Tremor
PubMed: 33213556
DOI: 10.1017/S109285292000200X -
Expert Opinion on Pharmacotherapy Apr 2023Neuropsychiatric symptoms (NPS) in Alzheimer's Disease (AD) are associated with negative outcomes for patients and their care partners. Agitation is a common and...
INTRODUCTION
Neuropsychiatric symptoms (NPS) in Alzheimer's Disease (AD) are associated with negative outcomes for patients and their care partners. Agitation is a common and distressing NPS, without safe and effective treatments. Nonpharmacological interventions are first line treatment, but not effective or appropriate for every patient. Current pharmacological treatments of agitation in AD include off-label use of antipsychotics, sedative/hypnotics, anxiolytics, mood-stabilizing anticonvulsants, acetylcholinesterase inhibitors, NMDA receptor antagonists, and antidepressants. Despite prevalent use, efficacy and safety concerns remain.
AREAS COVERED
Better understanding of neurobiological mechanisms of agitation have fueled recent clinical trials. This article is an update to our 2017 review. Comprehensive search of ClinicalTrials.gov was completed from January 2017 to February 2023 using the search terms "Alzheimer's Disease" and "Agitation". Subsequent scoping review was completed in PubMed and Google Scholar. Several agents were identified, including: brexpiprazole, cannabinoids, dexmedetomidine, dextromethorphan, escitalopram, masupirdine, and prazosin.
EXPERT OPINION
Clinical trials utilize both novel and repurposed agents for agitation in AD. With increasing understanding of the neurobiological mechanisms that fuel development of agitation in AD, use of enahanced trial design and conduct, advanced statistical approaches, and accelerated pathways for regulatory approval, we advance closer to safe and efficacious treatment options for agitation in AD.
Topics: Humans; Acetylcholinesterase; Alzheimer Disease; Antidepressive Agents; Antipsychotic Agents; Psychomotor Agitation; Treatment Outcome
PubMed: 36958727
DOI: 10.1080/14656566.2023.2195539 -
Annals of Emergency Medicine Feb 2020Agitation and delirium are common reasons for older adults to seek care in the emergency department (ED). Providing care for this population in the ED setting can be... (Review)
Review
Agitation and delirium are common reasons for older adults to seek care in the emergency department (ED). Providing care for this population in the ED setting can be challenging for emergency physicians. There are several knowledge translation gaps in how to best screen older adults for these conditions and how to manage them. A working group of subject-matter experts convened to develop an easy-to-use, point-of-care tool to assist emergency physicians in the care of these patients. The tool is designed to serve as a resource to address the knowledge translation and implementation gaps that exist in the field. The purpose of this article is present and explain the Assess, Diagnose, Evaluate, Prevent, and Treat tool. Participants were identified with expertise in emergency medicine, geriatric emergency medicine, geriatrics, and psychiatry. Background literature reviews were performed before the in-person meeting in key areas: delirium, dementia, and agitation in older adults. Participants worked electronically before and after an in-person meeting to finalize development of the tool in 2017. Subsequent work was performed electronically in the following months and additional expert review sought. EDs are an important point of care for older adults. Behavioral changes in older adults can be a manifestation of underlying medical problems, mental health concerns, medication adverse effects, substance abuse, or dementia. Five core principles were identified by the group that can help ensure adequate and thorough care for older adults with agitation or delirium: assess, diagnose, evaluate, prevent, and treat. This article provides background for and explains the importance of these principles related to the care of older adults with agitation. It is important for emergency physicians to recognize the spectrum of underlying causes of behavioral changes and have the tools to screen older adults for those causes, and methods to treat the underlying causes and ameliorate their symptoms.
Topics: Aged; Aged, 80 and over; Delirium; Delivery of Health Care; Dementia; Diagnostic and Statistical Manual of Mental Disorders; Emergency Service, Hospital; Geriatric Assessment; Guidelines as Topic; Humans; Psychomotor Agitation
PubMed: 31563402
DOI: 10.1016/j.annemergmed.2019.07.023 -
The Journal of Head Trauma...To systematically review the available literature on the pharmacological management of agitation and/or aggression in patients with traumatic brain injury (TBI),...
OBJECTIVE
To systematically review the available literature on the pharmacological management of agitation and/or aggression in patients with traumatic brain injury (TBI), synthesize the available data, and provide guidelines.
DESIGN
Systematic review of systematic reviews.
MAIN MEASURES
A literature review of the following websites was performed looking for systematic reviews on the treatment of agitation and/or aggression among patients with TBI: PubMed, CINAHL, DynaMed, Health Business Elite, and EBSCO (Psychology and behavioral sciences collection). Two researchers independently assessed articles for meeting inclusion/exclusion criteria. Data were extracted on year of publication, reviewed databases, dates of coverage, search limitations, pharmacological agents of interest, and a list of all controlled studies included. The included controlled studies were then examined to determine potential reasons for any difference in recommendations.
RESULTS
The literature review led to 187 citations and 67 unique publications after removing the duplicates. Following review of the title/abstracts and full texts, a total of 11 systematic reviews were included. The systematic reviews evaluated the evidence for safety and efficacy of the following medications: amantadine, amphetamines, methylphenidate, antiepileptics, atypical and typical antipsychotics, benzodiazepines, β-blockers, and sertraline.
CONCLUSIONS
On the basis of the results of this literature review, the authors recommend avoiding benzodiazepines and haloperidol for treating agitation and/or aggression in the context of TBI. Atypical antipsychotics (olanzapine in particular) can be considered as practical alternatives for the as-needed management of agitation and/or aggression in lieu of benzodiazepines and haloperidol. Amantadine, β-blockers (propranolol and pindolol), antiepileptics, and methylphenidate can be considered for scheduled treatment of agitation and/or aggression in patients with TBI.
Topics: Aggression; Antipsychotic Agents; Brain Injuries, Traumatic; Humans; Psychomotor Agitation; Systematic Reviews as Topic
PubMed: 33656478
DOI: 10.1097/HTR.0000000000000656 -
European Neuropsychopharmacology : the... Jul 2023Antipsychotic-induced akathisia is severely distressing. We aimed to investigate relationships between antipsychotic doses and akathisia risk. We searched for randomised... (Meta-Analysis)
Meta-Analysis
Antipsychotic-induced akathisia is severely distressing. We aimed to investigate relationships between antipsychotic doses and akathisia risk. We searched for randomised controlled trials that investigated monotherapy of 17 antipsychotics in adults with acute schizophrenia until 06 March 2022. The primary outcome was the number of participants with akathisia, which was analysed with odds ratios (ORs). We applied one-stage random-effects dose-response meta-analyses using restricted cubic splines to model the dose-response relationships. We included 98 studies (343 dose arms, 34,225 participants), most of which were short-term and had low-to-moderate risk of bias. We obtained data on all antipsychotics except clozapine and zotepine. In patients with acute exacerbations of chronic schizophrenia, from moderate to high certainty of evidence, our analysis showed that sertindole and quetiapine carried negligible risks for akathisia across examined doses (flat curves), while most of the other antipsychotics had their risks increase initially with increasing doses and then either plateaued (hyperbolic curves) or continued to rise (monotonic curves), with maximum ORs ranging from 1.76 with 95% Confidence Intervals [1.24, 2.52] for risperidone at 5.4 mg/day to OR 11.92 [5.18, 27.43] for lurasidone at 240 mg/day. We found limited or no data on akathisia risk in patients with predominant negative symptoms, first-episode schizophrenia, or elderly patients. In conclusion, liability of akathisia varies between antipsychotics and is dose-related. The dose-response curves for akathisia in most antipsychotics are either monotonic or hyperbolic, indicating that higher doses carry a greater or equal risk compared to lower doses.
Topics: Humans; Adult; Aged; Antipsychotic Agents; Schizophrenia; Psychomotor Agitation; Risperidone; Quetiapine Fumarate
PubMed: 37075639
DOI: 10.1016/j.euroneuro.2023.03.015 -
Annals of Palliative Medicine Apr 2022Dexmedetomidine is a potent adrenergic alpha-2 receptor agonist. It was first approved for sedation for mechanically ventilated patients. Being a sedative medication... (Review)
Review
BACKGROUND AND OBJECTIVE
Dexmedetomidine is a potent adrenergic alpha-2 receptor agonist. It was first approved for sedation for mechanically ventilated patients. Being a sedative medication that is not associated with respiratory depression and holding analgesic properties fosters the interest for this drug in the palliative care field. The primary objectives of this review were to identify the key indications for the real-world use of dexmedetomidine in palliative care and other disciplines.
METHODS
A narrative review after extensive PubMed search was performed from 1950 to present on October 21st 2021. The language of the publications was restricted to English, German, French and Italian.
KEY CONTENT AND FINDINGS
(I) Current dexmedetomidine use. There is a growing body of evidence that dexmedetomidine may reduce the incidence and severity of delirium, reduce opioid-consumption and postoperative nausea in intensive care settings. It is also used to facilitate withdrawal from different substances (alcohol, opioids, heroin). Concerning safety aspects of the drug, some studies reported an increased rate of serious cardiovascular events in patients with pre-existing heart conditions due to bradycardia and arterial hypo- and hypertension. Since the drug has a main hepatic metabolism, dose reduction is mandatory in patients with hepatic impairment. (II) Dexmedetomidine and palliative care. There have been sporadic case reports about the successful use of dexmedetomidine in palliative care. Indications for symptom control included sedation for hyperactive delirium, cancer pain, opioid-induced-hyperalgesia, dystonia, cough, vomiting, shivering and dyspnea. It is mainly applied via the intravenous (i.v.), subcutaneous, but also nasal and, buccal routes. Admixture ("syringe-driver") studies showed that dexmedetomidine is compatible with morphine, hydromorphone, hyoscine and haloperidol. In 2021, a first prospective cohort study became available. Here, the authors reported promising result for dexmedetomidine use in hyperactive terminal delirium for reducing delirium intensity and agitation. Especially the unique "conscious sedation" or "awake sedation" that allows patients to arouse easily under sedation and report comfort or distress was discussed by the authors.
CONCLUSIONS
In this review, we present the main findings for dexmedetomidine from palliative care settings and other disciplines. The potential benefits and criticalities of the drug are discussed and practical recommendations for its use are provided.
Topics: Analgesics, Opioid; Delirium; Dexmedetomidine; Humans; Palliative Care; Prospective Studies; Psychomotor Agitation
PubMed: 35400162
DOI: 10.21037/apm-21-1989