Brexpiprazole for Agitation Associated With Dementia Due to Alzheimer's Disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by progressive cognitive and functional decline. Nearly all patients with AD develop neuropsychiatric symptoms (NPSs). Agitation is one of the most distressing and challenging NPS. Brexpiprazole is an oral antipsychotic and is the first approved pharmacologic agent in the United States for the treatment of agitation associated with dementia due to AD. Its effect is thought to be from its partial serotonin 5-HT1A and dopamine D2 receptor agonist activity and serotonin 5-HT2A receptor antagonism. Brexpiprazole is a maintenance medication, and it should not be used "as needed" or as a "PRN" treatment for breakthrough agitation. Brexpiprazole is a major substrate of CYP2D6 and CYP3A4. Dose adjustments may be required for drug interactions or impaired renal or hepatic function. Clinical trials found brexpiprazole 2 to 3 mg/d demonstrated significant improvements in agitation, with brexpiprazole showing an approximate 5-point greater reduction on change in the Cohen-Mansfield Agitation Inventory total score at week 12 from baseline compared with placebo. Brexpiprazole is generally well tolerated and safe, and common adverse reactions when used for this indication include dizziness, headaches, insomnia, nasopharyngitis, somnolence, and urinary tract infections. Like other antipsychotics used for agitation in AD, brexpiprazole is associated with higher mortality rates compared with placebo. In a long-term care setting, there are several considerations for its use. Benefits include an oral agent that is well tolerated and clinical data showing statistically significant effects on agitation. However, brexpiprazole has not been studied in head-to-head clinical trials against other antipsychotics, and there are differing opinions if the agitation score reductions translate to a clinically meaningful difference. The approval of brexpiprazole signals favorably for upcoming agents for this indication, including escitalopram and dextromethorphan-bupropion. Both escitalopram and dextromethorphan-bupropion are currently undergoing clinical trials.

Review of valiltramiprosate (ALZ-801) for the treatment of Alzheimer's disease: a novel small molecule with disease modifying potential.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, functional impairments, and neuropsychiatric symptoms. Valiltramiprosate is a tramiprosate prodrug being investigated as a novel treatment for AD. AREAS COVERED: The online databases PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms 'ALZ-801' or 'valiltramiprosate.' Alzheon press releases were reviewed for emerging clinical information. Valiltramiprosate is an oral, well-tolerated synthetic valine-conjugate prodrug of tramiprosate. Valiltramiprosate's active metabolite include tramiprosate and 3-sulfopropanoic acid. Proposed mechanism of action is multiligand binding to Aß42 which stabilizes amyloid monomers to prevent peptide aggregation and oligomerization. Pharmacokinetic studies show 52% oral bioavailability, rapid absorption, approximately 40% brain-drug exposure, and near complete renal clearance. Compared to tramiprosate, valiltramiprosate extends plasma tramiprosate half-life and improves interindividual pharmacokinetic variability. Interim analyses from valiltramiprosate's phase II biomarker trial show: (1) significant reductions in plasma p-tau181 and related AD fluid biomarkers; (2) brain structure preservation and reduced hippocampal atrophy by MRI; and (3) improvements on cognitive assessments at multiple timepoints. Its phase III clinical trial in ApoE ε4 homozygotes is near completion. EXPERT OPINION: Valiltramiprosate's clinical trial data show early indications of efficacy with potential disease modifying effect in AD.

Use of Human-Centered Design Methodology to Develop a Digital Toolkit to Optimize Heart Failure Guideline-Directed Medical Therapy.

BACKGROUND: Guideline-directed medical therapies (GDMTs) improve quality of life and health outcomes for patients with heart failure (HF). However, GDMT utilization is suboptimal among patients with HF. OBJECTIVE: The aims of this study were to engage key stakeholders in semistructured, virtual human-centered design sessions to identify challenges in GDMT optimization posthospitalization and inform the development of a digital toolkit aimed at optimizing HF GDMTs. METHODS: For the human-centered design sessions, we recruited (a) clinicians who care for patients with HF across 3 hospital systems, (b) patients with HF with reduced ejection fraction (ejection fraction ≤ 40%) discharged from the hospital within 30 days of enrollment, and (c) caregivers. All participants were 18 years or older, English speaking, with Internet access. RESULTS: A total of 10 clinicians (median age, 37 years [interquartile range, 35-41], 12 years [interquartile range, 10-14] of experience caring for patients with HF, 80% women, 50% White, 50% nurse practitioners) and three patients and one caregiver (median age 57 years [IQR: 53-60], 75% men, 50% Black, 75% married) were included. Five themes emerged from the clinician sessions on challenges to GDMT optimization (eg, barriers to patient buy-in). Six themes on challenges (eg, managing medications), 4 themes on motivators (eg, regaining independence), and 3 themes on facilitators (eg, social support) to HF management arose from the patient and caregiver sessions. CONCLUSIONS: The clinician, patient, and caregiver insights identified through human-centered design will inform a digital toolkit aimed at optimizing HF GDMTs, including a patient-facing smartphone application and clinician dashboard. This digital toolkit will be evaluated in a multicenter, clinical trial.

24 h Rest/Activity Rhythms in Older Adults with Memory Impairment: Associations with Cognitive Performance and Depressive Symptomatology.

Little is known about links of circadian rhythm alterations with neuropsychiatric symptoms and cognition in memory impaired older adults. Associations of actigraphic rest/activity rhythms (RAR) with depressive symptoms and cognition are examined using function-on-scalar regression (FOSR). Forty-four older adults with memory impairment (mean: 76.84 ± 8.15 years; 40.9% female) completed 6.37 ± 0.93 days of actigraphy, the Beck depression inventory-II (BDI-II), mini-mental state examination (MMSE) and consortium to establish a registry for Alzheimer's disease (CERAD) delayed word recall. FOSR models with BDI-II, MMSE, or CERAD as individual predictors adjusted for demographics (Models A1-A3) and all three predictors and demographics (Model B). In Model B, higher BDI-II scores are associated with greater activity from 12:00-11:50 a.m., 2:10-5:50 p.m., 8:40-9:40 p.m., 11:20-12:00 a.m., higher CERAD scores with greater activity from 9:20-10:00 p.m., and higher MMSE scores with greater activity from 5:50-10:50 a.m. and 12:40-5:00 p.m. Greater depressive symptomatology is associated with greater activity in midafternoon, evening, and overnight into midday; better delayed recall with greater late evening activity; and higher global cognitive performance with greater morning and afternoon activity (Model B). Time-of-day specific RAR alterations may affect mood and cognitive performance in this population.

A 2023 update on the advancements in the treatment of agitation in Alzheimer's disease.

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.

Moral Injury and Moral Resilience in Health Care Workers during COVID-19 Pandemic.

Background: The 2019 coronavirus (COVID-19) pandemic placed unprecedented strains on the U.S. health care system, putting health care workers (HCWs) at increased risk for experiencing moral injury (MI). Moral resilience (MR), the ability to preserve or restore integrity, has been proposed as a resource to mitigate the detrimental effects of MI among HCWs. Objectives: The objectives of this study were to investigate the prevalence of MI among HCWs, to identify the relationship among factors that predict MI, and to determine whether MR can act as buffer against it. Design: Web-based exploratory survey. Setting/Subjects: HCWs from a research network in the U.S. mid-Atlantic region. Measurements: Survey items included: our outcome, Moral Injury Symptoms Scale-Health Professional (MISS-HP), and predictors including demographics, items derived from the Rushton Moral Resilience Scale (RMRS), and ethical concerns index (ECI). Results: Sixty-five percent of 595 respondents provided COVID-19 care. The overall prevalence of clinically significant MI in HCWs was 32.4%; nurses reporting the highest occurrence. Higher scores on each of the ECI items were significantly positively associated with higher MI symptoms (p < 0.05). MI among HCWs was significantly related to the following: MR score, ECI score, religious affiliation, and having ≥20 years in their profession. MR was a moderator of the effect of years of experience on MI. Conclusions: HCWs are experiencing MI during the pandemic. MR offers a promising individual resource to buffer the detrimental impact of MI. Further research is needed to understand how to cultivate MR, reduce ECI, and understand other systems level factors to prevent MI symptoms in U.S. HCWs.

Temporospatial components of brain ERPs as biomarkers for Alzheimer's disease.

INTRODUCTION: Developing biomarkers that distinguish individuals with Alzheimer's disease (AD) from those with normal cognition remains a crucial goal for improving the health of older adults. We investigated adding brain spatial information to temporal event-related potentials (ERPs) to increase AD identification accuracy over temporal ERPs alone. METHODS: With two-step principal components analysis, we applied multivariate analyses that incorporated temporal and spatial ERP information from a cognitive task. Discriminant analysis used temporospatial ERP scores to classify participants as belonging to either the AD or healthy control group. RESULTS: Temporospatial ERPs produced a cross-validated area under the curve of 0.84. Adding spatial information through a formal procedure significantly improves classification accuracy. DISCUSSION: A weighted combination of temporospatial ERP markers performs well in detecting AD. Because ERPs are noninvasive and inexpensive, they may be promising biomarkers for AD that can add functional information to other biomarker systems while providing the individual's probability of correct classification.

An update on the advancements in the treatment of agitation in Alzheimer's disease.

INTRODUCTION: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks safe and effective long term interventions. Nonpharmacological interventions are suggested as first-line treatment, but aren't effective for every patient, resulting in pharmacological interventions for some patients, consisting of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine, and antidepressants; where efficacy doesn't necessarily outweigh associated risks. Areas covered: Gains in understanding neurobiological mechanisms underlying agitation have fueled several recent clinical trials. This article updates our review published in 2014. Comprehensive literature search for published articles from January 2014 to December 2016 evaluating pharmacologic interventions for agitation in AD was done. A review of several clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, citalopram, escitalopram, pimavanserin, ITI-007, ORM-12741 show promise in treating agitation. Expert opinion: Neurobiological findings, innovative trials designs, statistical approaches, and preliminary paths for regulatory agency acceptance have re-ignited the area of pharmacological treatment of NPS. Though further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to find effective treatments for neuropsychiatric symptoms such as agitation in patients with dementia is well underway.

ERP C250 shows the elderly (cognitively normal, Alzheimer's disease) store more stimuli in short-term memory than Young Adults do.

OBJECTIVE: To determine how aging and dementia affect the brain's initial storing of task-relevant and irrelevant information in short-term memory. METHODS: We used brain Event-Related Potentials (ERPs) to measure short-term memory storage (ERP component C250) in 36 Young Adults, 36 Normal Elderly, and 36 early-stage AD subjects. Participants performed the Number-Letter task, a cognitive paradigm requiring memory storage of a first relevant stimulus to compare it with a second stimulus. RESULTS: In Young Adults, C250 was more positive for the first task-relevant stimulus compared to all other stimuli. C250 in Normal Elderly and AD subjects was roughly the same to relevant and irrelevant stimuli in Intratrial Parts 1-3 but not 4. The AD group had lower C250 to relevant stimuli in part 1. CONCLUSIONS: Both normal aging and dementia cause less differentiation of relevant from irrelevant information in initial storage. There was a large aging effect involving differences in the pattern of C250 responses of the Young Adult versus the Normal Elderly/AD groups. Also, a potential dementia effect was obtained. SIGNIFICANCE: C250 is a candidate tool for measuring short-term memory performance on a biological level, as well as a potential marker for memory changes due to normal aging and dementia.

Advancements in the treatment of agitation in Alzheimer's disease.

INTRODUCTION: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks well-established long-term interventions that are both effective and safe. While non-pharmacological interventions are the suggested first-line treatment, it isn't effective in managing symptoms for every patient. In such cases, clinicians turn to the use of pharmacological interventions. Traditionally, these interventions consist of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine and antidepressants, where the efficacy doesn't necessarily outweigh the associated risks. AREAS COVERED: Gains made in understanding the neurobiological mechanisms underlying agitation have fueled several recent clinical trials. A comprehensive literature search for published articles evaluating pharmacologic interventions for agitation in AD was done. A review of some of these clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, dronabinol and citalopram show promise in treating agitation. EXPERT OPINION: Neurobiological findings and enhanced trial designs have re-ignited the area of pharmacological treatment of NPS. Although further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to finding effective treatments for NPS such as agitation in patients with dementia is well underway.

Memory timeline: Brain ERP C250 (not P300) is an early biomarker of short-term storage.

Brain event-related potentials (ERPs) offer a quantitative link between neurophysiological activity and cognitive performance. ERPs were measured while young adults performed a task that required storing a relevant stimulus in short-term memory. Using principal components analysis, ERP component C250 (maximum at 250 ms post-stimulus) was extracted from a set of ERPs that were separately averaged for various task conditions, including stimulus relevancy and stimulus sequence within a trial. C250 was more positive in response to task-specific stimuli that were successfully stored in short-term memory. This relationship between C250 and short-term memory storage of a stimulus was confirmed by a memory probe recall test where the behavioral recall of a stimulus was highly correlated with its C250 amplitude. ERP component P300 (and its subcomponents of P3a and P3b, which are commonly thought to represent memory operations) did not show a pattern of activation reflective of storing task-relevant stimuli. C250 precedes the P300, indicating that initial short-term memory storage may occur earlier than previously believed. Additionally, because C250 is so strongly predictive of a stimulus being stored in short-term memory, C250 may provide a strong index of early memory operations.

Can antidepressant medication relieve agitation in Alzheimer's disease?

Neuropsychiatric symptoms (NPS) are a major concern in the treatment of Alzheimer's disease. Historically, NPS are difficult to treat effectively due to a high side-effect burden associated with commonly used medications, such as atypical antipsychotics. Non-pharmacological treatment approaches have become the first line option. However, when such treatment fails, pharmacological options are often used. Thus, a push toward finding safer alternative pharmacological treatments has occurred. Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) have shown promise in clinical trials for alleviating the burden of NPS. Lower overall agitation and caregiver stress has been reported to correlate to treatment with the SSRI citalopram. However, certain side effects of citalopram, such as QTc interval prolongation and increased cognitive decline, carry clinical concern and should be weighed when prescribing their use.