Treatment Of Agitation In Dementia Research Articles

S7: Updates on Electroconvulsive Therapy practice and research

Electroconvulsive Therapy (ECT) has evolved into a highly safe, effective, and well tolerated treatment for several severe psychiatric conditions and has become a necessary tool in the armamentarium of modern psychiatry. In this symposium we will review current state of the art clinical practices in Electroconvulsive Therapy (ECT) and new data on research.More specifically Dr. Charles Kellner will review the elements of optimal patient selection/preparation in the ECT consultation and review clinical decision-making during a course of ECT (including electrode placement, stimulus dosing and other technical procedural details.)Dr Raphael Braga will review the evidence for the use of ECT as an augmentation to antipsychotic medications strategy for the treatment of patients with schizophrenia who are resistant to medications, including clozapine.Dr. Brent Forester will discuss the rationale and evidence base for the safety and efficacy of ECT for the treatment of Agitation in Dementia. Agitation is the most common neuropsychiatric symptom of dementia, accounts for about 12% of the total health and social care costs (approximately $31billion/year). It is implicated in a vicious cycle of negative events including deterioration of family and professional relationships, increased risk of death, and increased caregiver burden, which is a significant predictor for institutionalization or death of patients with dementia. His presentation will highlight the existing evidence base and method of ECT delivery to target symptoms of severe agitation, and review an ongoing multi-site NIA funded clinical trial of ECT for severe agitation in dementia.Dr Søren Dinesen Østergaard will discuss the suicide risk in patients receiving ECT which, despite the well-established anti-suicidal effect of ECT, remains high due to the severity of their underlying illness. He will present data quantifying and identifying risk factors for suicide among patients receiving ECT using data from nationwide Danish registers on 11,780 patients.Dr. Georgios Petrides is the organizer and will moderate this symposium

Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders.

Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6 (5-HT6) receptor has been an area of substantial research. 5-HT6 receptor is a G-protein-coupled receptor mediating its effects through diverse signaling pathways. Exceptional features of the receptors fueling drug discovery efforts include unique localization and specific distribution in the brain regions having a role in learning, memory, mood, and behavior, and the affinity of several clinically used psychotropic agents. Although non-clinical data suggest that both agonist and antagonist may have similar behavioral effects, most of the agents that entered clinical evaluation were antagonists. Schizophrenia was the initial target; more recently, cognitive deficits associated with Alzheimer's disease (AD) or other neurological disorders has been the target for clinically evaluated 5-HT6 receptor antagonists. Several 5-HT6 receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing. The observations from both non-clinical and clinical studies suggest that 5-HT6 receptor antagonists may have a role in the management of neuropsychiatric symptoms in dementia. Masupirdine, a selective 5-HT6 receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT6 receptor antagonists in the treatment of agitation in dementia of the Alzheimer's type.

A reflection on the use of Antidepressants to manage agitation in dementia

IntroductionAgitated behaviors is a common neuropsychiatric symptom (NPS) in dementia, defined as inappropriate verbal, vocal, or motor activity that is not thought to be caused by an unmet need. It is frequently reported as a major problem, that impairs the quality of life for the elderly themselves and for caregivers. There has been increasing interest in the use of sedative antidepressants to treat NPS due to concerns over the safety and efficacy of antipsychotics in this setting.ObjectivesWe aim to review clinical evidence of alternatives to antipsychoticst to manage agitation in dementia.MethodsWe conduct a non-systematic review of recent evidence on dementia and agitation, using PubMed/Medline database.ResultsAlthough non-pharmacological interventions are the first-line treatment for agitation, it is a legitimate target for therapeutic intervention and according to previous guidelines, antipsychotic are among the most used drugs, albeit restricted because of side-effects. A substitution strategy to avoid antipsychotic prescription was highly considered, however there is limited evidence to support the use of antidepressants as a safe and effective alternative for agitation in dementia. Studies compare Mirtazapine, Selective serotonin reuptake inhibitors (SSRIs) and Trazodone and a reduced benefit in mortality is observed. However, citalopram was more effective were more likely outpatients for moderately agitation and Mirtazapine reveals being potentially harmful, in different studies.ConclusionsMoving forward, a greater understanding of NPS neurobiology, will help to clarify the efficacy of Antedepressants for the treatment of agitation in dementia. Benefits an also the patient and caregiver preference should be kept in mind.DisclosureNo significant relationships.

The Rationale and Design of Behavioral Interventions for Management of Agitation in Dementia in a Multi-Site Clinical Trial.

Agitation and aggression are common in patients with Alzheimer's disease and related dementias and pose a significant burden on patients, caregivers, and the healthcare systems. Guidelines recommend personalized behavioral interventions as the first-line treatment; however, these interventions are often underutilized. The Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study (ClinicalTrials.gov Identifier # NCT0367220) is a multisite randomized controlled trial comparing an Integrated Care Pathway, that includes a sequential pharmacological algorithm and structured behavioral interventions, with treatment-as-usual to treat agitation in dementia in long-term care and inpatient settings. To describe the rationale and design of structured behavioral interventions in the StaN study. Structured behavioral interventions are designed and implemented based on the following considerations: 1) personalization, 2) evidence base, 3) dose and duration, 4) measurement-based care, and 5) environmental factors and feasibility. The process to design behavioral interventions for each individual starts with a comprehensive assessment, followed by personalized, evidence-based interventions delivered in a standardized manner with ongoing monitoring of global clinical status. Measurement-based care is used to tailor the interventions and integrate them with pharmacotherapy. Individualized behavioral interventions in patients with dementia may be challenging to design and implement. Here we describe a process to design and implement individualized and structured behavioral interventions in the context of a multisite trial in long-term care and inpatient settings. This process can inform the design of behavioral interventions in future trials and in clinical settings for the treatment of agitation in dementia.

Mirtazapine for agitation in dementia: moving forward

Alzheimer's disease is a progressive and fatal neurodegenerative disorder with a worldwide prevalence estimated at 25–37 million. 1 WHOFact sheets: dementia. 2020. https://www.who.int/news-room/fact-sheets/detail/dementia Google Scholar Although Alzheimer's disease is clinically characterised by cognitive impairments and functional deficits, agitation is a particularly common symptom 2 Zhao QF Tan L Wang HF et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease: systematic review and meta-analysis. J Affect Disord. 2016; 190: 264-271 Crossref PubMed Scopus (299) Google Scholar and associated with excess disability, increased institutionalisation, and diminished quality of life. 3 Antonsdottir IM Smith J Keltz M Porsteinsson AP Advancements in the treatment of agitation in Alzheimer's disease. Expert Opin Pharmacother. 2015; 16: 1649-1656 Crossref PubMed Scopus (23) Google Scholar There is an urgent and unmet need for efficacious treatments for agitation. Over the past decade, efforts have included trials using citalopram, 4 Porsteinsson AP Drye LT Pollock BG et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014; 311: 682-691 Crossref PubMed Scopus (302) Google Scholar dextromethorphan, 5 Cummings JL Lyketsos CG Peskind ER et al. Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia: a randomized clinical trial. JAMA. 2015; 314: 1242-1254 Crossref PubMed Scopus (101) Google Scholar brexpiprazole, 6 Grossberg GT Kohegyi E Mergel V et al. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer's dementia: two 12-week, randomized, double-blind, placebo-controlled trials. Am J Geriatr Psychiatry. 2020; 28: 383-400 Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar and nabilone. 7 Herrmann N Ruthirakuhan M Gallagher D et al. Randomized placebo-controlled trial of nabilone for agitation in Alzheimer's disease. Am J Geriatr Psychiatry. 2019; 27: 1161-1173 Summary Full Text Full Text PDF PubMed Scopus (35) Google Scholar Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trialThis trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia. Full-Text PDF Open Access

Essential oils for agitation in dementia [rELOAD]: A pragmatic, cluster-randomized, placebo-controlled, pilot feasibility trial

BackgroundClinical guidelines recommend non-pharmacological interventions as the first line of treatment for agitation in dementia. One intervention that shows some promise as a treatment for agitation is essential oils. The objective of this study was to provide preliminary evidence of the effectiveness and feasibility of using topically-administered, individualized essential oil preparations for the alleviation of agitation in persons with dementia. MethodsWe conducted a 10-week pragmatic, cluster-randomized, placebo-controlled, pilot feasibility trial to compare the effectiveness of topically-administered, individualized essential oil preparations to control (placebo) preparations. Outcomes included frequency and severity of agitation, quality of life, frequency of antipsychotic medication use and physical restraint, incidence of adverse events, and trial feasibility. Participants with dementia and clinically significant agitation were recruited from five residential aged-care facilities across regional South Australia. ResultsThirty-eight participants were randomized from five sites. Accounting for random effects, we found statistically significant differences between the intervention and control groups in Pittsburgh Agitation Scale (PAS) aberrant vocalization sub score, Cohen Mansfield Agitation Inventory (CMAI) verbally agitated sub score and CMAI total score at week 4, but not at weeks 8 (post-intervention) or 10 (follow-up). No significant time-group interactions were observed for other PAS/CMAI scores or sub scores, quality of life - Alzheimer's disease total score, or frequency of physical restraint or as-needed antipsychotic medication. No adverse events were reported in any group. ConclusionsThe study findings highlight some promising effects of topically-administered, individualized essential oil preparations for agitation in dementia, and indicate that a large multi-center, cluster-randomized controlled trial of this treatment is feasible. Trial registrationAustralian New Zealand Clinical Trial Registry [ACTRN12617001159347].

Behavioural and psychological symptoms of dementia: a new framework for holistic understanding and non-pharmacological management

SUMMARYThe National Institute for Health and Care Excellence (NICE) informs us that the first-line treatments for behavioural and psychological symptoms of dementia (BPSD) are non-pharmacological. Although psychotropics used to be the main strategy in the management of behaviours that challenge, there has been an increase in the use of biopsychosocial formulations since 2010, and there are now over a dozen to choose from. However, many are overly focused on obtaining information about the agitation, and less specific about providing details of the actions required to manage the behaviours. The NICE guidelines too fail to provide specific guidance on which non-pharmacological approaches to use. This article argues for giving equal weight to both the collection of meaningful information and the development of ‘informed actions’, because it is the actions that lead to change. The article outlines a management programme providing a framework for the assessment, formulation and treatment of agitation in dementia. The work draws on theory, evidence-based practice and practice-based evidence to provide a model with sufficient structure and flexibility to be useful for clinicians across a range of settings and professional groups.

Dextromethorphan for the treatment of agitation in dementia: A pilot study

AbstractBackgroundAgitation is highly prevalent in patients with dementia and off‐label use of antipsychotic agents for agitation is common. But antipsychotic agents are clearly associated with increased adverse effects. A recent study found dextromethorphan (DXM) and low dose quinidine may be effective for the management of agitation in patients with Alzheimer disease (AD).MethodsThis is an open‐label, 10‐week study. Eligible dementia patients (AD or VaD) were enrolled. These patients received DXM 60 mg/day from Day 1 through Day 7. If the symptoms of agitation were not reduced, the dose might be gradually increased to 240 mg/day. The primary endpoint was score change in agitation domain of the Neuropsychiatric Inventory (NPI), and secondary endpoints include change on NPI total score and subscores, CGI, and MMSE.ResultsA total of 16 patients were recruited. The mean (SD) of age was 79.3 (9.9) years, with male to female ratio 1:1. The mean (SD) of MMSE was 9.7 (9.7). At baseline, CGI‐Severity for agitation was 4 to 6 (mean=4.9), The mean and SD of behavioral disturbances were: 8.4 (3.5) for NPI agitation score, 8.1 (4.3) for NPI irritability score, 7.6 (4.8) for NPI aberrant motor behavior, and 58.8 (33.7) for NPI total score. At the endpoint, the mean dose of DXM was 150 mg/day. There was a significant decrease of the score of behavioral disturbance: 3.8 (3.0) for NPI agitation score (p<0.001), 4.2 (3.9) for NPI irritability score (p<0.001), 2.3 (3.9) for NPI aberrant motor behavior (p<0.036), and 24.4 (19.6) for NPI total score (p<0.001). The CGI‐I on agitation revealed 69% (n=11) with much/very much improved, 25% (n=4) minimal improved, and 6% (n=1) minimally worse. There were some mild to moderate adverse effects reported, including malaise, anemia, drowsiness, skin itching, and increased appetite. No severe adverse effects were found.ConclusionsThe results of this preliminary study suggest DXM 60‐240 mg/day seem quite efficacious for the treatment of agitation in dementia and without severe adverse reactions. It may be suitable for short‐term use for control of agitation in elderly dementia patients.

Developing an ontology for representing the domain knowledge specific to non-pharmacological treatment for agitation in dementia.

IntroductionA large volume of clinical care data has been generated for managing agitation in dementia. However, the valuable information in these data has not been used effectively to generate insights for improving the quality of care. Application of artificial intelligence technologies offers us enormous opportunities to reuse these data. For health data science to achieve this, this study focuses on using ontology to coding clinical knowledge for non‐pharmacological treatment of agitation in a machine‐readable format.MethodsThe resultant ontology—Dementia‐Related Agitation Non‐Pharmacological Treatment Ontology (DRANPTO)—was developed using a method adopted from the NeOn methodology.ResultsDRANPTO consisted of 569 concepts and 48 object properties. It meets the standards for biomedical ontology.DiscussionDRANPTO is the first comprehensive semantic representation of non‐pharmacological management for agitation in dementia in the long‐term care setting. As a knowledge base, it will play a vital role to facilitate the development of intelligent systems for managing agitation in dementia.

A preclinical screen to evaluate pharmacotherapies for the treatment of agitation in dementia.

Agitation associated with dementia is frequently reported clinically but has received little attention in preclinical models of dementia. The current study used a 7PA2 CM intracerebroventricular injection model of Alzheimer's disease (AD) to assess acute memory impairment, and a bilateral intrahippocampal (IH) injection model of AD (aggregated Aβ1-42 injections) and a bilateral IH injection model of dementia with Lewy bodies (aggregated NAC61-95 injections) to assess chronic memory impairment in the rat. An alternating-lever cyclic-ratio schedule of operant responding was used for data collection, where incorrect lever perseverations measured executive function (memory) and running response rates (RRR) measured behavioral output (agitation). The results indicate that bilateral IH injections of Aβ1-42 and bilateral IH injections of NAC61-95 decreased memory function and increased RRRs, whereas intracerebroventricular injections of 7PA2 CM decreased memory function but did not increase RRRs. These findings show that using the aggregated peptide IH injection models of dementia to induce chronic neurotoxicity, memory decline was accompanied by elevated behavioral output. This demonstrates that IH peptide injection models of dementia provide a preclinical screen for pharmacological interventions used in the treatment of increased behavioral output (agitation), which also establish detrimental side effects on memory.

AVP-786 for the treatment of agitation in dementia of the Alzheimer’s type

ABSTRACTIntroduction: Agitation is common and distressing in patients with Alzheimer-type dementia, but safe, effective treatments remain elusive. Psychological treatments are first-line options, but they have limited efficacy. Off-label psychotropic medications are frequently used, but they also have limited effectiveness, and their use may have harmful side effects, including death.Areas covered: This review discusses the history leading to the conception of AVP-786 (deuterated (d6)-dextromethorphan/quinidine), its pharmacokinetic and pharmacodynamic profiles and safety issues, together with an overview of recent clinical trials. Data were found in the medical literature, in US and EU clinical trial registries and in information provided by the manufacturer.Expert opinion: AVP-786 is one of six investigational compounds in recent phase III clinical development for agitation in Alzheimer disease (AD). Quinidine and deuteration appear to prolong dextromethorphan’s plasma half-life and facilitate brain penetration. The FDA granted fast-track designation to AVP-786 and allowed use of data generated on dextromethorphan-quinidine (AVP-923, Nuedexta®) for regulatory filings. AVP-923 reduced agitation in AD and was well tolerated in a phase II RCT that included more than 200 patients. A phase III clinical development program of AVP-786 for AD agitation was recently initiated. This program is expected to start generating results in July 2018.

Non-Pharmacologic Interventions for Treatment of Agitation in Dementia in Nursing Home Residents

Non-Pharmacologic Interventions for Treatment of Agitation in Dementia in Nursing Home Residents

Off-Label Use of Antipsychotic Medications in the Department of Veterans Affairs Health Care System

This study aimed to determine the prevalence of prescribing antipsychotics to adults without schizophrenia or bipolar disorder and to identify factors associated with such off-label use. Patients with at least one prescription for an antipsychotic medication from the Department of Veterans Affairs (VA) during fiscal year (FY) 2007 were identified in national VA administrative databases. Rates of off-label antipsychotic use were determined along with average doses. Multivariate logistic regression models identified sociodemographic and clinical characteristics associated with off-label use. Of the 279,778 individuals in FY 2007 who received an antipsychotic medication, 168,442 (60.2%) had no record of a diagnosis for which these drugs are approved. The most common mental illness diagnoses among patients given prescriptions for antipsychotics off label were posttraumatic stress disorder (PTSD, 41.8%), minor depression (39.5%), major depression (23.4%), and anxiety disorder (20.0%). Among VA patients with mental illness other than schizophrenia or bipolar disorder, the proportion who received prescriptions for antipsychotic medications ranged from a low of 9.1% among patients with adjustment reaction; to about 20% for those with depression, dementia, or PTSD; and to a high of 40.7% among patients with other psychoses. Doses were low, with over half of patients who received off-label quetiapine, risperidone, or first-generation antipsychotics receiving doses below those recommended for schizophrenia. In logistic regression models, patients diagnosed as having other psychosis or dementia had the highest odds of receiving an antipsychotic medication off label. Off-label use of antipsychotic medications was common. Given that these drugs are expensive, have potentially severe side effects, and have limited evidence supporting their effectiveness for off-label usage, they should be used with greater caution.

ECT Treatment for Two Cases of Dementia-Related Pathological Yelling

ECT Treatment for Two Cases of Dementia-Related Pathological Yelling

ECT Treatment for Two Cases of Dementia-Related Pathological Yelling

ECT Treatment for Two Cases of Dementia-Related Pathological Yelling

With Precautions, Psychiatrists Need Not Shun off-Label Prescribing

With Precautions, Psychiatrists Need Not Shun off-Label Prescribing

Divalproex Sodium in Nursing Home Residents With Possible or Probable Alzheimer Disease Complicated by Agitation: A Randomized, Controlled Trial

<h3>Objective</h3> Three placebo-controlled clinical trials have suggested the benefit of valproate for treatment of agitation associated with dementia; one was used as the basis for this multicenter trial, conducted by the Alzheimer's Disease (AD) Cooperative Study. It addresses the efficacy, safety, and tolerability of divalproex sodium for the treatment of agitation associated with dementia. <h3>Methods</h3> This was a randomized, double-blind, placebo-controlled clinical trial in 153 nursing home residents with probable or possible AD complicated by agitation; 110 (72%) completed the trial. Participants were randomized to treatment with divalproex sodium at a target dose of 750 mg/day (N = 75) or placebo (N = 78) for 6 weeks. The primary outcome measure was change from baseline on the Brief Psychiatric Rating Scale (BPRS) Agitation factor. Secondary outcomes included total BPRS, Clinical Global Impression of Change, Cohen-Mansfield Agitation Inventory score, and measures of safety and tolerability. <h3>Results</h3> Compliance averaged 88%. Participants receiving divalproex achieved a mean dose of 800 mg/day. Change in mean BPRS Agitation factor scores did not differ between patients treated with divalproex and placebo, nor did secondary behavioral measures. Measures of safety and tolerability did not reveal clinically important drug/placebo differences. <h3>Conclusions</h3> This multicenter trial showed no benefit of divalproex sodium for treatment for agitation in dementia at a mean dose of 800 mg/day over 6 weeks. The results do not support findings from previous trials indicating possible benefit.

Divalproex Sodium in Nursing Home Residents With Possible or Probable Alzheimer Disease Complicated by Agitation: A Randomized, Controlled Trial

Three placebo-controlled clinical trials have suggested the benefit of valproate for treatment of agitation associated with dementia; one was used as the basis for this multicenter trial, conducted by the Alzheimer's Disease (AD) Cooperative Study. It addresses the efficacy, safety, and tolerability of divalproex sodium for the treatment of agitation associated with dementia. This was a randomized, double-blind, placebo-controlled clinical trial in 153 nursing home residents with probable or possible AD complicated by agitation; 110 (72%) completed the trial. Participants were randomized to treatment with divalproex sodium at a target dose of 750 mg/day (N = 75) or placebo (N = 78) for 6 weeks. The primary outcome measure was change from baseline on the Brief Psychiatric Rating Scale (BPRS) Agitation factor. Secondary outcomes included total BPRS, Clinical Global Impression of Change, Cohen-Mansfield Agitation Inventory score, and measures of safety and tolerability. Compliance averaged 88%. Participants receiving divalproex achieved a mean dose of 800 mg/day. Change in mean BPRS Agitation factor scores did not differ between patients treated with divalproex and placebo, nor did secondary behavioral measures. Measures of safety and tolerability did not reveal clinically important drug/placebo differences. This multicenter trial showed no benefit of divalproex sodium for treatment for agitation in dementia at a mean dose of 800 mg/day over 6 weeks. The results do not support findings from previous trials indicating possible benefit.

Regulación respecto a síntomas psicológicos y conductuales de la demencia en Eslovenia: guías de actuación

Behavioural and psychological symptoms of dementia (BPSD) are very common among patients with dementia. They are often associated with the indiscriminate prescription of psychotropic medication, especially benzodiazepines and antipsychotics. Therefore, over the last decade, awareness arose world-wide that more rigorous guidelines are necessary pertaining to the prescription and monitoring of medication. The clinical practice of the use of psychotropic drugs for the treatment of agitation in dementia in Slovenia is not always the best. Therefore a suggestion was made that guidelines are needed. The guidelines drawn-up in December 2001 are presented here.

Agitated Symptom Response to Divalproex Following Acute Brain Injury

Agitated Symptom Response to Divalproex Following Acute Brain Injury