Agitation In Alzheimer's Disease Research Articles

Pilot trial of Dronabinol adjunctive treatment of agitation in Alzheimer’s disease (THC‐AD)

AbstractBackgroundAgitation in Alzheimer’s Disease (Agit‐AD) is a common and troubling neuropsychiatric syndrome which adds significantly to disability and caregiver stress. Behavioral interventions lack consistent efficacy and there are no FDA‐approved medications. Neurobiological mechanisms that contribute to Agit‐AD include brain atrophy, degradation of neurotransmission, neuroinflammation, disrupted circadian rhythms, comorbidities and frailty. Agit‐AD is a major source of disease progression, patient disability, financial burden, and caregiver stress. Dronabinol is a synthetic cannabinoid (tetrahydrocannabinol, THC). Cannabinoids may improve Agit‐AD by providing protection against neuroinflammation and excitotoxicity, regulating neurotransmitters, improving comorbidities, stabilizing circadian rhythms, and increasing cerebral blood flow.MethodTHC‐AD is a three‐week placebo‐controlled, double‐blind, RCT of dronabinol (10 mg QD) in 80 patients with severe Agit‐AD. Twice daily administration maximizes daytime coverage for agitation and minimizes sundowning. Inclusionary criteria include a diagnosis of AD, severe agitation, and being 60‐95 years old, while exclusionary criteria include serious or unstable medical illness, seizure disorder, delirium, current use of lithium, and inability to swallow a pill. Primary outcomes include a change in the Pittsburgh Agitation Scale and NPI‐C Agitation/Aggression subscales.ResultWe have enrolled 58 out of targeted 80 participants (Table 1: mean age 77.8 years, 65.5% female, 87.9% Caucasian, mean education 13.8 years, 45.6% family history). On average, study participants are very cognitively impaired (Table 2: mean baseline MMSE of 8.1), very agitated (mean NPI‐C Agitation 14.6, mean NPI‐C Aggression 6.3) and in reasonable overall health (Figure 1: General Medical Health Rating, 12.1% “excellent,” 51.7% “good” and 34.5% "fair”). Recorded AEs have been tolerable (Figure 2). Due to the COVID‐19 pandemic, we expanded our inpatient trial to include outpatient enrollments and implemented hybrid visits with telemedicine to limit in‐person interactions. We also added a supplemental study to evaluate the effects of the pandemic on caregiver stress and burden. We are collaborating with additional clinical sites, increasing dementia bed capacity, and deploying recruitment strategies for outpatients, including referrals from providers and other research trials, social media ads, and virtual community outreach.ConclusionSafe and effective interventions for severe agitation are greatly needed. This pilot trial will help to examine the safety and efficacy of dronabinol for Agit‐AD.

Efficacy, Safety and Tolerability of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial

Efficacy, Safety and Tolerability of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial

Anesthetic-loaded nanodroplets with focused ultrasound reduces agitation in Alzheimer's mice.

Alzheimer's disease (AD) is often associated with neuropsychiatric symptoms, including agitation and aggressive behavior. These symptoms increase with disease severity, ranging from 10% in mild cognitive impairment to 50% in patients with moderate-to-severe AD, pose a great risk for self-injury and injury to caregivers, result in high rates of institutionalization and great suffering for patients and families. Current pharmacological therapies have limited efficacy and a high potential for severe side effects. Thus, there is a growing need to develop novel therapeutics tailored to safely and effectively reduce agitation and aggressive behavior in AD. Here, we investigate for the first time the use of focused ultrasound combined with anesthetic-loaded nanodroplets (nanoFUS) targeting the amygdala (key structure in the neurocircuitry of agitation) as a novel minimally invasive tool to modulate local neural activity and reduce agitation and aggressive behavior in the TgCRND8 AD transgenic mice. Male and female animals were tested in the resident-intruder (i.e., aggressive behavior) and open-field tests (i.e., motor agitation) for baseline measures, followed by treatment with active- or sham-nanoFUS. Behavioral testing was then repeated after treatment. Active-nanoFUS neuromodulation reduced aggressive behavior and agitation in male mice, as compared to sham-treated controls. Treatment with active-nanoFUS increased the time male mice spent in social-non-aggressive behaviors. Our results show that neuromodulation with active-nanoFUS may be a potential therapeutic tool for the treatment of neuropsychiatric symptoms, with special focus on agitation and aggressive behaviors. Further studies are necessary to establish cellular, molecular and long-term behavioral changes following treatment with nanoFUS.

Efficacy, Safety and Tolerability of Brexpiprazole for the Treatment of Agitation in Alzheimer’s Dementia: A 12‐Week, Randomized, Double‐Blind, Placebo‐Controlled Trial

AbstractBackgroundAgitation is a prevalent clinical manifestation of Alzheimer’s dementia, and is one of the most stressful aspects of care in patients affected by the disease. However, currently, there are no FDA‐approved pharmacological treatments for agitation in this patient population. Following two prior clinical trials of brexpiprazole in this patient population, the aim of this study was to confirm the efficacy, safety and tolerability of brexpiprazole in patients with agitation in Alzheimer’s dementia.MethodsThis was a 12‐week, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐arm study (NCT03548584). Eligible patients were aged 55–90 years, in a care facility or community‐based setting, had a diagnosis of probable Alzheimer’s disease, and met criteria for agitation as defined by the International Psychogeriatric Association (IPA). Patients were randomized 2:1 to brexpiprazole or placebo; within the brexpiprazole arm, patients were further randomized 1:2 to fixed‐dose 2 mg/day or 3 mg/day. Stable background medications for the treatment of Alzheimer’s disease were permitted. The primary endpoint was change from baseline to Week 12 in Cohen–Mansfield Agitation Inventory (CMAI) Total score. The key secondary endpoint was change from baseline to Week 12 in Clinical Global Impression − Severity of illness (CGI‐S) score, as related to agitation. Safety was also assessed.ResultsA total of 345 patients were randomized to brexpiprazole or placebo. On the primary endpoint, the mean change from baseline to Week 12 in CMAI Total score was statistically significantly greater in the brexpiprazole group (2 mg/day or 3 mg/day) versus the placebo group (p = 0.0026). Statistically significant separation between the brexpiprazole and placebo groups was also observed on the key secondary endpoint of change from baseline to Week 12 in CGI‐S score (p = 0.0055). Aside from headache (6.6%), no other treatment‐emergent adverse events occurred with an incidence ≥5% in the brexpiprazole group.ConclusionIn this Phase 3 study of patients with agitation in Alzheimer’s dementia, treatment with brexpiprazole was associated with a statistically significantly greater reduction in agitation, and improvement in clinical global impression of agitation, compared with placebo, supporting the findings of two prior clinical trials. Brexpiprazole was generally well tolerated, and no new safety signals were observed.

Innovative Framework to Assess the Costs of Untreated Agitation in Alzheimer’s Disease (AAD)

AbstractBackgroundIn the past decade, researchers and advocates have taken steps towards quantifying the full costs of Alzheimer’s disease and related dementias. However, our current understanding of these costs does not fully consider the behavioral symptoms of dementia, notably agitation. Agitation in Alzheimer’s disease contributes to negative social and financial outcomes for people with the condition, their care partners, and health systems. When left untreated, the negative impact of these outcomes is exacerbated, yet the scale of this impact is unknown. A review of the literature shows that there are no frameworks to help assess the true costs of agitation calling for a need for further research and assessment.MethodWe created a Markov model that investigates each stage of Alzheimer’s disease with agitation. The model utilizes five transition states with six‐month cycles. This framework assesses direct and indirect costs of disease. Direct costs include professional caregiving, non‐pharmacological intervention, nursing home costs, healthcare professional consultations, and hospitalizations. Indirect costs of disease evaluated include loss of income and value of unpaid caregiving. To establish the difference in cost to understand true costs of untreated disease, this model will allow us to compare outcomes associated with intervention with that of no intervention, from which one can derive an Incremental Cost‐Effectiveness Ratio (ICER). Additionally, we used quality‐adjusted life years to measure disease burden and health outcomes. Finally, we utilized a deterministic and probabilistic sensitivity analysis to assess the robustness of this model.ResultResults will describe a finalized Markov model with which one can assess the costs of untreated agitation in Alzheimer’s. This discussion will include perspectives and feedback from key opinion leaders in Alzheimer’s research, care, and economics from across the worldConclusionAgitation has severe consequences on individuals, families, and health systems. Oftentimes one of the first symptoms of Alzheimer’s or dementia, agitation can increase the caregiving responsibilities, trigger placement into nursing homes, and cause severe emotional and physical toll on care partners. We cannot understand the full costs of dementia or AD until we account for untreated agitation vis‐à‐vis a multi‐symptom assessment. This framework is the first step in evaluating the costs of agitation.

Involvement of inflammation in the medial temporal region in the development of agitation in Alzheimer's disease: an in vivo positron emission tomography study.

The evaluation of 11 C-DPA-713 binding using positron emission tomography for quantifying the translocator protein can be a sensitive approach in determining the level of glial activation induced by neuroinflammation. Herein, we aimed to investigate the relationship between regional 11 C-DPA713-binding potential (BPND ) and neuropsychiatric symptoms (NPS) in amyloid-positive Alzheimer's disease (AD) patients. Fifteen AD patients were enrolled in this study. Correlations were evaluated between the 11 C-DPA713-BPND and Neuropsychiatric Inventory Questionnaire (NPI-Q) scores, including scores in its four domains: agitation, psychosis, affective, and apathy. 11 C-DPA713-BPND values were compared between groups with and without the neuropsychiatric symptoms for which a relationship was observed in the abovementioned correlation analysis. A positive correlation was found between the severity of agitation and 11 C-DPA713-BPND in the Braak 1-3 area, including the amygdala, hippocampal and parahippocampal regions, and lingual and fusiform areas. An increase in the 11 C-DPA713-BPND was observed in AD patients with agitation. We did not find any significant effects of possible confounding factors, such as age, duration of illness, education, gender, Mini-Mental State Examination score, cerebrospinal fluid amyloid β 42/40 ratio, and apolipoprotein E4 positivity, on either the 11 C-DPA713-BPND or agitation score. Neuroinflammation in the medial temporal region and its neighbouring area was shown to be associated with the development of agitation symptoms in AD patients. Our findings extend those of previous studies showing an association between some NPS and inflammation, suggesting that immunologically based interventions for agitation can serve as an alternative treatment for dementia.

Risks and benefits of current and novel drugs to treat agitation in Alzheimer’s disease

ABSTRACT Introduction At present, no pharmacological interventions have been approved for the treatment of agitation in Alzheimer’s disease (AD), an important neuropsychiatric symptom that has been linked to increased mortality and greater caregiver burden. Antipsychotics offer some benefit, but increase the risk of adverse events such as falls, extrapyramidal symptoms, stroke, and mortality. Over the past 10 years, several new and repurposed medications have shown promise for treating AD-associated agitation. Areas covered We review the risks and benefits of emerging therapies for agitation in AD, which include newer atypical antipsychotics, selective serotonin reuptake inhibitors, cannabinoids, and dextromethorphan combination products. Other drugs such as mirtazapine, prazosin, and lithium are also discussed. Clinicaltrials.gov, PubMed/MEDLINE, EMBASE and Cochrane Central databases were searched for relevant studies from 1 January 2012 to 1 May 2022. Expert opinion At the present time, there are no pharmacological interventions for the treatment of agitation in AD whose benefits clearly outweigh their potential safety concerns. Therefore, management of agitation in AD should primarily be based on non-pharmacological approaches. When medications are considered necessary, they should only be initiated with the caregiver’s appreciation of their risks and benefits and with careful and ongoing assessment of their safety.

Targeting Neuroplasticity for the Management of Pain and Agitation in Alzheimer’s Disease via Bergamot Nanotherapy

Alzheimer’s disease (AD) accounts for 50–70% of cases of dementia worldwide and is a social burden to the affected population. Although several pathogenetic hypotheses have been proposed, evidence favoring the role of aberrant neuroplasticity in the development of the neuropsychiatric symptoms associated with dementia is increasing. Specifically, agitation is resistant to treatment and affects the quality of life, also because of the lack of safe and effective treatment for AD. Alterations in pain processing due to plastic modifications occur during aging and neurodegeneration. Up to 80% of AD patients have chronic pain due to age-related comorbidities that are misdiagnosed and remain unattended due to a lack of self-reporting because of communication hindrance, which also contributes to the development of agitation. Here, we reported a strategy to target altered neuroplasticity for treating pain and agitation by applying bergamot essential oil with evidence for in-vivo analgesic effects on neuropathic and inflammatory pain preclinical models. Bergamot was engineered in a nanotechnology delivery system, NanoBEO, which provides the opportunity to investigate its efficacy in the NCT04321889 randomized, double-blind, placebo-controlled clinical trial BRAINAID. This trial can provide a rational basis for safe and effective treatment to alleviate agitation and pain, thus improving the quality of life of people suffering from AD.

Antipsychotic treatment patterns in Alzheimer’s disease patients with agitation: a cohort study using the UK clinical practice research datalink

Objectives There is a lack of robust epidemiological evidence on antipsychotic (AP) use in patients with agitation in Alzheimer’s disease (AD). Authors studied AP use in patients with AD and agitation and compared their use with patients with other or no neuropsychiatric symptoms (NPS). Methods A retrospective cohort study in the UK Clinical Practice Research Datalink, included patients with AD between January 1st, 2015, and December 31st, 2017. AP use was compared between patients with agitation, other types of NPS and no NPS. Results There were 24,464 patients with AD, median follow-up of 1.1 years (interquartile range [IQR] 0.5–2.1), and median age 83 years (78–88). A larger percentage of patients with agitation (n = 2432) were prescribed APs (38.2%) than other NPS (n = 13,076, 20.4%) and no NPS (n = 11,816, 12.2%). Compared to patients with no NPS, adjusted hazard ratios for AP use were 3.45 (95% CI 2.86–4.17) for patients with agitation and 1.31 (95% CI 1.19–1.44) for patients with other NPS. Among users of APs, the treatment discontinuation rate at six months was 44.8% in patients with agitation (other NPS 57.1%; no NPS 63.5%). Conclusions Patients with AD and agitation were frequently prescribed APs and for long periods in routine clinical practice in the UK. The high real-life usage of APs suggests that physicians prefer using APs for the treatment of agitation despite recommendations against their long-term use. These data support a need for AP therapies that better address known safety concerns with currently used APs to treat agitation in elderly patients with AD.

Emerging Perspectives in the Management of Agitation in Alzheimer's Disease and Patients with Dementia

While Alzheimer's disease, the most common cause of dementia, is perhaps best characterized by cognitive decline, more than 90% of patients exhibit behavioural and psychological symptoms of dementia. Agitation in patients with dementia is often difficult to manage, and is associated with increased morbidity and mortality in patients and a heightened caregiver burden. Thus, effective management of dementia-related agitation (DRA) is vital. Care should first be taken to consider and address causes of agitation and aggression, after which non-pharmacological interventions should be employed. If non-pharmacological measures are unsuccessful in reducing DRA then medications should be considered, although none are approved by the Food and Drug Administration for this indication. Electroconvulsive therapy may be a promising option for patients with treatment-refractory DRA, although more studies are needed. While there are several drugs in the pipeline for DRA treatment, results from robust randomized clinical trials are necessary before they can be administered to patients. Thus, clinicians should employ current strategies to manage DRA to ensure holistic care for patients with Alzheimer's disease.

Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer's disease (THC‐AD)

AbstractBackgroundAlthough agitation in Alzheimer’s Disease (Agit‐AD) is a common and troubling neuropsychiatric syndrome, behavioral interventions lack consistent efficacy and there are no FDA‐approved medications. Neurobiological mechanisms that contribute to Agit‐AD include brain atrophy, degradation of neurotransmission, neuroinflammation, disrupted circadian rhythms, comorbidities and frailty. Agit‐AD is a major source of disease progression, patient disability, financial burden, and caregiver stress. Dronabinol is synthetic tetrahydrocannabinol (THC, one of the predominant biochemical constituents of cannabis). Cannabinoids may improve Agit‐AD by providing protection against neuroinflammation and excitotoxicity, regulating neurotransmitters, improving comorbidities, stabilizing circadian rhythms, and increasing cerebral blood flow.MethodTHC‐AD is a three‐week placebo‐controlled, double‐blind, RCT of dronabinol (10 mg QD) in 80 patients with severe Agit‐AD. Twice daily administration maximizes daytime coverage for agitation and minimizes sundowning. Inclusionary criteria include a diagnosis of AD, severe agitation, and being 60‐95 years old, while exclusionary criteria include serious or unstable medical illness, seizure disorder, delirium, current use of lithium, and inability to swallow a pill. Primary outcomes include a change in the Pittsburgh Agitation Scale and NPI‐C Agitation/Aggression subscales.ResultWe have enrolled 37 out of 80 participants (Table 1: mean age 78.2 years, 78.4% female, 83.8% Caucasian, mean education 13.2 years, 48.6% family history). Study participants are significantly cognitively impaired (Table 2: mean baseline MMSE of 7.1), agitated (mean NPI‐C Agitation 14.8, mean NPI‐C Aggression 6.4) and in reasonable overall health (Figure 1: General Medical Health Rating, 10.8% “excellent,” 48.6% "good" and 40.5% "fair”). Recorded AEs have been tolerable (Figure 2). Due to the COVID‐19 pandemic, we expanded our inpatient trial to include outpatient enrollments and implemented hybrid visits with telemedicine to limit in‐person interactions. To bolster our recruitment, we are collaborating with additional clinical sites, increasing dementia bed capacity, and deploying recruitment strategies for outpatients, including referrals from providers and other research trials, social media ads, and virtual community outreach. Updated results will be presented at AAIC (estimated 6‐10 additional participants).ConclusionSafe and effective interventions for severe agitation are greatly needed. This pilot trial will help to examine the safety and efficacy of dronabinol for Agit‐AD.

Application of the IPA definition of agitation in cognitive disorders in clinical trials

AbstractBackgroundIn 2015, the IPA published provisional criteria for Agitation in Cognitive Disorders. The criteria have since been extensively applied in clinical research and clinical trials. We review the impact of these criteria and the implications of their common use.MethodThe IPA criteria for Agitation in Cognitive Disorders were developed through an extensive process involving multiple stakeholders with two membership surveys, an in‐person meeting of international experts, and an iterative process of criteria and manuscript development. We reviewed the application of the IPA criteria in clinical trials since 2015 through interrogation of the clinicaltrials.gov registry.ResultsThere have been 21 clinical trials for agitation in Alzheimer’s diseases conducted since 2015, out of those, IPA criteria have been used as inclusion criteria in 11 trials, the other 10 trials did not identify the IPA criteria as the explicit entry criteria. There is trend for trials planned more recently to use the criteria (6 of 9 trials registered since 2018). The criteria have been used in clinical trials with agents of a variety of mechanisms of action: 7 different mechanisms are represented in the trials using the criteria.ConclusionsThe 2015 IPA provisional criteria for Agitation in Cognitive Disorder are widely used. They have been implemented as inclusion criteria in a majority of agitation trials conducted since their introduction. A variety of pharmacologic mechanisms are represented in the trials using the criteria; the criteria facilitated comparing efficacy across multiple agents. The convergent and concurrent validity demonstrated for the criteria support removal of “provisional” from the criteria.

Low‐dose lithium treatment of behavioral complications in Alzheimer’s disease: Lit‐AD randomized clinical trial

AbstractBackgroundTo evaluate low‐dose lithium treatment of agitation in Alzheimer’s disease (AD).MethodIn a four‐site trial, patients with AD and agitation/aggression on the Neuropsychiatric Inventory (NPI) were randomized, double‐blind, to lithium carbonate 150‐600 mg daily or placebo for 12 weeks. Primary efficacy outcome was change in NPI agitation/aggression; secondary efficacy outcome was treatment response defined by 30% reduction in NPI combined score for agitation/aggression plus psychosis and a Clinical Global Impression (CGI) score of much or very much improved. Somatic, cognitive, metabolic, and neurological side effects were assessed.ResultFifty‐eight of 77 patients (75.3%) completed the trial. In linear mixed effects model analyses, lithium did not differ from placebo in agitation/aggression change scores. Proportion of responders was 31.6% on lithium and 17.9% on placebo (χ2=1.26, p=0.26). Moderate or marked improvement on global CGI change, which incorporated behavior, cognition, and function, was greater on lithium (10/38=36.8%) than placebo (0/39=0%, Fisher’s exact test p<0.001). In exploratory analyses, improvement on lithium was greater than placebo on NPI delusions and irritability/lability (p’s<0.05). Lithium showed greater reduction than placebo in patients with high Young Mania Rating Scale scores (β=5.06; 95%CI, 1.18 to 8.94, p=0.01). Oral dose and serum lithium levels demonstrated similar associations with efficacy outcomes. Lithium did not differ significantly from placebo on any safety outcome.ConclusionLow dose lithium was not efficacious in treating agitation but was associated with global clinical improvement and excellent safety. A larger trial may be warranted with precision pharmacological targeting of likely lithium‐responsive behavioral symptoms that overlap with mania.

Caring for behavioral symptoms of dementia (CBD): A new investigation into cannabidiol for the treatment of anxiety and agitation in Alzheimer’s dementia

AbstractBackgroundAnxiety and agitation symptoms affect 25‐70% of the dementia population, though there are no FDA‐approved medications that treat the behavioral symptoms of AD. Thus, the need for developing safe and efficacious treatments for anxiety and agitation in AD is dire. One potential treatment is cannabidiol (CBD), the major non‐intoxicating constituent of cannabis sativa, a variety of the cannabis plant that contains <0.3% delta9‐tetrahydrocannabinol (THC), the main intoxicating constituent in cannabis, by weight. The present open‐label clinical trial seeks to address this gap in knowledge by assessing the efficacy and tolerability of a high‐CBD/low‐THC sublingual solution as a treatment for anxiety and agitation in older adults with Alzheimer’s disease.MethodAn 8‐week open‐label clinical trial of an industrial hemp‐derived high‐CBD/low‐THC sublingual solution. This includes 12 research participants with AD and symptoms of anxiety with or without agitation. Our primary efficacy outcome measures include the anxiety domain of the Neuropsychiatric Inventory‐Clinician Version (NPI‐C) and the Generalized Anxiety Disorder‐7 Item Scale (GAD‐7). Our secondary safety outcome measures include monitoring for serious adverse events and medication side effects, cognitive decline estimates from the Mini Mental Status Exam (MMSE), and the emergence of possible delirium from the Confusion Assessment Method (CAM). Scores on the NPI‐C, the Cohen‐Mansfield Agitation Inventory (CMAI), and caregiver burden estimates from the Zarit Caregiver Burden Interview will be included as additional exploratory measures.ResultsWe hypothesize that twice daily treatment with a high‐CBD/low‐THC solution in older adults with AD for 8 weeks will be associated with a statistically significant reduction in anxiety and agitation symptoms compared to baseline, as measured by our efficacy outcome measurements. We predict that the solution will be well‐tolerated by the study population, as measured by our safety outcome measurements.ConclusionWith no current FDA‐approved treatments for these behavioral symptoms, patients with AD risk ineffective therapies or mortality‐associated antipsychotic treatments to address their NPS. Treating anxiety and agitation in these patients not only alleviates their symptoms but could also reduce caregiver burden and lengthen the time to institutionalization. CBD is a promising anxiolytic treatment that could advance our available treatment options for anxiety and agitation in AD.

Музична терапія в лікуванні хвороби Альцгеймера

Стаття являє собою огляд досліджень, присвячених застосуванню музичної терапії у комплексному лікуванні хвороби Альцгеймера. Аналізуються результати наукових досліджень, опублікованих за останні 5 років у журналах, що індексуються у науково-дослідних базах Scopus, Web of Science, MedLine та PubMed. Аналіз свідчить, що музична терапія позитивно впливає на когнітивні функції пацієнтів із деменцією завдяки здатності стимулювати нейропластичність мозку і холінергічну активність вегетативної нервової системи, посилювати кровообіг головного мозку, ослабляти стрес і патологічні адренергічні впливи. Музична терапія є ефективним та безпечним методом покращення пам’яті, ослаблення депресії, тривоги та ажитації в осіб з хворобою Альцгеймера. Широке використання методу у практичній діяльності неврологічної служби буде сприяти підвищенню ефективності лікування хвороби Альцгеймера.

Study rationale and baseline data for pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer's dementia (THC-AD).

Agitation is a common complication of Alzheimer's dementia (Agit-AD) associated with substantial morbidity, high healthcare service utilization, and adverse emotional and physical impact on care partners. There are currently no FDA-approved pharmacological treatments for Agit-AD. We present the study design and baseline data for an ongoing multisite, three-week, double-blind, placebo-controlled, randomized clinical trial of dronabinol (synthetic tetrahydrocannabinol [THC]), titrated to a dose of 10 mg daily, in 80 participants to examine the safety and efficacy of dronabinol as an adjunctive treatment for Agit-AD. Preliminary findings for 44 participants enrolled thus far show a predominately female, white sample with advanced cognitive impairment (Mini Mental Status Examination mean 7.8) and agitation (Neuropsychiatric Inventory-Clinician Agitation subscale mean 14.1). Adjustments to study design in light of the COVID-19 pandemic are described. Findings from this study will provide guidance for the clinical utility of dronabinol for Agit-AD. ClinicalTrials.gov Identifier: NCT02792257.

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

532 - “Mapping the Lived Experiences: The Dyad Journey of People with Agitation in Alzheimer’s and Their Care Partners”

AbstractA substantial amount of analysis has been dedicated to understanding the individual journeys of the “patient” and the “caregiver” in Alzheimer’s disease. This work has provided valuable insights, but a few priorities remain:how is the lived experience journey in Alzheimer’s shaped by the complexities of agitation and other behavioral aspects of the disease;how can insights from “social listening” analysis structure our understanding of these journeys;how can we understand the dyad journey of the person with Alzheimer’s and the care partner as well as the interactions therein, particularly through the lens of agitation.This project, “Mapping the Lived Experiences” recasts the Alzheimer’s journey to better reflect these priorities. We offer a visual interpretation of the journey with the rationale and proof points that underpin it.“Mapping the Lived Experiences” prioritizes agitation and other behavioral aspects of Alzheimer’s as pivotal, enduring challenges on the disease journey. We frame the journey into two overarching phases: “the first loss,” which accounts for the more widely recognized symptoms of the disease, such as memory loss and declining cognitive function; and “the second loss,” which is characterized by agitation and behavioral aspects of the disease. We structure the journey around “milestone moments” – moments when both the person with Alzheimer’s and the care partner recognize that the disease has taken a major progression.The “milestones” moment framework reflects an interpretive framework developed through an ongoing “social listening” research project. This social listening research allows analysis of the online conversation as it is happening in social channels and discussion boards, and it provides a poignant counterpoint to quantitative market research insofar as it illuminates the unfiltered, unmitigated experiences as articulated by the people who are learning in real-time to manage and live with Alzheimer’s. From social listening insights and analysis, our research posits that journeys – for both the person with Alzheimer’s and the care partner – are not linear, straight-line trajectories, but jagged, fragmented paths marked by “milestone moments” that shape thinking, understanding, and behavior.“Mapping the Lived Experiences” offers a dyad visualization and articulations, as it fuses the journeys of the person with lived experience and the care partner together in the same visual space. This approach reveals how, over time, these journey relate, inform, and ultimately depart from one another. This dyad offers new insights into both the lived experience and care partner journeys.

Deuterated dextromethorphan/quinidine for agitation in Alzheimer's disease.

Deuterated dextromethorphan/quinidine for agitation in Alzheimer's disease.

Agitation in Alzheimer's disease: Novel outcome measures reflecting the International Psychogeriatric Association (IPA) agitation criteria.

IntroductionThe 2017 European Union‐North American Clinical Trials in Alzheimer's Disease Task Force recommended development of clinician‐rated primary outcome measures for Alzheimer's disease (AD) agitation trials, incorporating International Psychogeriatric Association (IPA) criteria.MethodsIn a modified Delphi process, Cohen‐Mansfield Agitation Inventory (CMAI) and Neuropsychiatric Inventory‐Clinician (NPI‐C) items were mapped to IPA agitation domains generating novel instruments, CMAI‐IPA and NPI‐C‐IPA. Validation in the Agitation and Aggression AD Cohort (A3C) assessed minimal clinically important differences (MCIDs), change sensitivity, and predictive validity.ResultsMCID was –17 (odds ratio [OR] = 14.9, 95% confidence interval [CI] = 6.8–32.6) for CMAI; –5 (OR = 9.3, 95% CI = 4.0–21.2) for CMAI‐IPA; –3 (OR = 11.9, 95% CI = 4.1–34.8) for NPI‐C‐A+A; and –5 (OR = 7.8, 95% CI = 3.4–17.9) for NPI‐C‐IPA at 3 months. Areas under the curve suggested no scale better predicted global clinician ratings. Sensitivity to change for all measures was high.ConclusionInternal consistency and reliability analyses demonstrated better accuracy for the NPI‐C‐IPA than for the CMAI‐IPA and can be used for agitation clinical trial inclusion, and for response to intervention.