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Craig Chepke,1– 3 Lynn W Shaughnessy,4 Stephen Brunton,5,6 Jill G Farmer,7,8 Andrew S Rosenzweig,9 George T Grossberg,10 Wendy L Wright11 1Excel Psychiatric Associates, Huntersville, NC, USA; 2Atrium Health, Charlotte, NC, USA; 3University of North Carolina School of Medicine, Chapel Hill, NC, USA; 4Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; 5Primary Care Education Consortium, Winnsboro, SC, USA; 6Department of Family Medicine, Touro University, Vallejo, CA, USA; 7Parkinson’s Disease and Movement Disorder Program, Center for Neurosciences, Robert Wood Johnson University Hospital Hamilton, Lawrenceville, NJ, USA; 8Department of Emergency Medicine, Drexel College of Medicine, Philadelphia, PA, USA; 9Forefront TeleCare, Providence, RI, USA; 10Department of Psychiatry, St. Louis University School of Medicine, St. Louis, MO, USA; 11Wright & Associates Family Health Care, Concord and Amherst, NH, USACorrespondence: Craig Chepke Email cchepke@excelpsychiatric.comAbstract: The presence of hallucinations and delusions in patients with neurodegenerative disease correlates negatively with function, cognition, quality of life, and survival. When these patients still have insight, the treatment of mild hallucinations may reduce the risk of progression to more severe symptoms, specifically hallucinations without insight or delusions. On October 22, 2020, a multidisciplinary consensus panel comprising United States-based experts in geriatric psychiatry, geriatric medicine, family medicine, movement disorders, and neuropsychology was convened remotely to discuss best practices for using telemedicine to evaluate, diagnose, and treat psychosis in patients with neurodegenerative diseases. This review reflects the opinions and recommendations discussed at this meeting. Despite drawbacks, telemedicine can offer several advantages over in-person care, particularly for older adults, and may be a unique opportunity for care of patients with neuropsychiatric symptoms. While telemedicine may not be suitable for all patients, it allows the involvement of specialists from multiple geographic locations and the extension of care to homebound individuals. Patients with neurodegenerative diseases who are likely to become homebound as the disease advances may benefit greatly from telemedicine as a standard of care. Healthcare provided via telemedicine should be nothing less than what would be offered to the patient in person. Telemedicine may present some difficulties, including technological issues and inherent constraints of remote care, but with proper planning many problems could be diminished. Technical issues associated with telemedicine are inevitable but may be partially offset by providing clear directions ahead of any tele-visit to ensure connectivity and access to the videoconferencing platform. Alternative procedures to communicate should be established in the eventuality of technological issues. Using these strategies, telemedicine can serve as a valuable complement to traditional in-person practices for the diagnosis and management of hallucinations and delusions associated with Parkinson’s disease psychosis or dementia-related psychosis.Keywords: telemedicine, Parkinson’s disease, psychosis, primary care, hallucinations, delusions

William James Deardorff, George T Grossberg Department of Psychiatry, St Louis University School of Medicine, St Louis, MO, USA Abstract: Currently available therapies for the treatment of Alzheimer’s disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified. Keywords: Alzheimer’s disease, cholinesterase inhibitor, donepezil, fixed-dose combination, memantine

Today patients with mild to moderate Alzhiemer's disease (AD) have a treatment approach choice: oral or transdermal delivery. The aim of this review was to provide a concise, comprehensive overview of the clinically relevant safety, tolerability and efficacy information available for the rivastigmine transdermal system. Relevant articles were identified through a MEDLINE search of publications in the past 3 years using the terms 'rivastigmine' and 'transdermal' or 'patch'. Efficacy, safety and tolerability of the rivastigmine patch vs. placebo were established in a large, international, 24-week, double-blind, randomised clinical trial and subsequent 28-week open-label extension study. Drug exposure with the 9.5 mg/24 h rivastigmine patch was not significantly different to that provided by an oral capsule dose of 12 mg/day. Most frequently observed adverse events were gastrointestinal. In the primary study, incidences of nausea, vomiting and diarrhoea were: 5%, 3% and 3% respectively in the placebo group; 7%, 6% and 6% in the 9.5 mg/24 h rivastigmine patch group; and 23%, 17% and 5% in the 12 mg/day capsule group. Most patients experienced no, slight or mild application-site skin reactions. De novo patients or those taking oral rivastigmine or donepezil may tolerate a switch to rivastigmine patch. By providing drug exposure that is not significantly different to the highest recommended rivastigmine capsule dose (12 mg/day), with less fluctuation over 24 h, rivastigmine patch offers similar efficacy with an improved tolerability profile. The rivastigmine patch provides a viable treatment option for patients with mild to moderate AD. [ABSTRACT FROM AUTHOR]

As a consequence of global aging, the occurrence of cognitive impairment and dementia is rapidly becoming a significant burden for medical care and public health systems. The worldwide prevalence of dementia, including Alzheimer's disease, is estimated at 24.3 million people. This number is expected to increase ~4-fold by the year 2050 unless suitable interventions can be found. Current treatments have not been demonstrated to prevent the onset of Alzheimer's disease; either they improve patients symptomatically or stabilize cognitive decline for periods ranging from months to a few years. Primary prevention, therefore, remains the Holy Grail for this disease and reducing this imminent risk. While not all risk factors for Alzheimer's disease can be controlled, intervention relative to some Alzheimer's disease risk factors is possible. The impact of these risk factors in causing dementia depends on the genetic makeup, environment, and lifestyle of the patient Physicians may advocate lifestyle modification such as exercising regularly and engaging in social and intellectual activities. Other areas that affect the onset of Alzheimer's disease include head trauma, hormone therapy depression, and environmental exposure. Primary prevention may reduce the effect of possible Alzheimer's disease risk factors and possibly delay the onset of or prevent Alzheimer's disease. [ABSTRACT FROM AUTHOR]

As a consequence of global aging, the occurrence of cognitive impairment and dementia is rapidly becoming a significant burden for medical care and public health systems. The worldwide prevalence of dementia, including Alzheimer's disease, is estimated at 24.3 miliion people. This number is expected to increase ~4-fold by the year 2050 unless suitable interventions can be found. Current treatments have not been demonstrated to prevent the onset of Alzheimer's disease; either they improve patients symptomatically or stabilize cognitive decline for periods ranging from months to a few years. Therefore, primary prevention remains the Holy Grail for this disease and reducing this imminent risk. We cannot control all risk factors for Alzheimer's disease; we can, however, inten/ene relative to some Alzheimer's disease risk factors. Mounting evidence points toward vascular disease as a major risk factor for both Alzheimer's and vascular dementia. Controlling vascular risk factors such as lack of exercise, diabetes, hypertension, dietary fat intake, high cholesterol, and obesity have emerged as important influences relative io the risk of both vascular and Alzheimer's dementia. However, the impact of these risk factors in causing dementia depends on the genetic makeup, environment, and lifestyle of the patient. There is insufficient evidence to make a firm recommendation for the primary prevention of dementia, and no primary prevention trial has successfully delayed the development of Alzheimer's disease. Physicians may advocate for some actions which may reduce the effect of possible Alzheimer's disease risk factors such as iowering cholesterol and homoeysteine levels, lowering high biood pressure, controiiing diabetes, increased consumption of fish, reducing consumption of dietary fat, and recommending moderate consumption of wine. [ABSTRACT FROM AUTHOR]

Memantine is a moderate-affinity, uncompetitive antagonist of N-methyl-D-aspartate receptors, approved for the treatment of moderate to severe Alzheimer's disease (AD). Available data suggest that, in addition to its benefits on cognition, function, and global status, memantine treatment may also help alleviate behavioral symptoms. This article provides an overview of the prevalence, assessment, and treatment of behavioral disturbances in AD, and summarizes current knowledge regarding the effects of memantine on the behavior of community-dwelling patients. We searched EMBASE and PubMed (January 1992 to October 2008) for reports on memantine trials that involved outpatients with moderate to severe AD. All previously unpublished data were obtained from Forest Laboratories, Inc. Behavioral outcomes were assessed in three completed, double-blind, placebo-controlled trials.Overall, patients who received memantine performed better on behavioral measures than those treated with placebo. Post-hoc analyses suggest that memantine treatment was associated with a reduced severity or emergence of specific symptoms, particularly agitation and aggression. Prospective, well-designed trials are warranted to evaluate the efficacy of memantine in patients with significant behavioral symptoms. [ABSTRACT FROM AUTHOR]

Background: Cholinesterase (ChE) inhibitors currently used in the treatment of Alzheimer's disease (AD) are the acetylcholinesterase (AChE)-selective inhibitors, donepezil and galantamine, and the dual ACNE and butyrylcholinesterase (BuChE) inhibitor, rivastigmine. In addition to differences in selectivity for ACNE and BuChE, ChE inhibitors also differ in pharmacokinetic and pharmacodynamic properties, and these differences could significantly impact on safety, tolerability, and efficacy.Objective: The aim of this article was to provide an overview of the ChE inhibitors widely used in AD, focusing on key pharmacologic differences among agents and how these may translate into important differences in safety, tolerability, and efficacy in clinical practice.Methods: Using published literature collected over time by the author, a review was conducted, focusing on the pharmacology and clinical data of donepezil, galantamine, and rivastigmine.Results: All ChE inhibitors have the potential to induce centrally mediated cholinergic adverse events (AEs), such as nausea and vomiting, if the dose is increased too rapidly or in increments that are too large. These AEs, which are most likely to occur during the 'getting on,' or dose-escalation, phase of treatment, may result in patients discontinuing treatment early without achieving optimum therapeutic benefit. To reduce the incidence of these AEs, a slow dose-escalation schedule has been established in clinical practice, consisting of a 'start low, go slow' procedure with a minimum of 4 weeks between dose increases. After 'getting on' treatment, maintaining treatment in the long term, or 'staying on,' may be achieved with good safety, tolerability, and sustained symptomatic efficacy across the key symptom domains (activities of daily living, behavior, and cognition).Conclusions: ChE inhibitors provide symptomatic benefit in AD across key symptom domains. Factors influencing the safety, tolerability, and efficacy of these agents in clinical practice include ChE enzymes inhibited, brain and brain-region ChE selectivity, and metabolism route. Class-specific cholinergic AEs can be minimized using slow, flexible dose escalation. [ABSTRACT FROM AUTHOR]

A typical elderly patient takes 13 different medications each year -- and 4-5 every day. Simplifying the regimen can help avoid renal damage, bleeding, mental impairment, and other side effects. [ABSTRACT FROM AUTHOR]

Depression is prevalent in elderly patients but frequently missed or undertreated. A practical, systematic approach can help you improve quality of life for the depressed elderly and reduce disability, suicide rates, and unnecessary health care costs in the process. [ABSTRACT FROM AUTHOR]

There are two important articles presented in part 2 of this double issue on 'Innovative Treatment Approaches in Alzheimer's Disease: Present and Future. ' [ABSTRACT FROM AUTHOR]

The search for effective treatments of Alzheimer's disease (AD) is one of the major challenges facing modern medicine. Acetylcholinesterase (AChE) inhibitors (AChEIs) are effective for the treatment of mild to moderate AD, and memantine, an N-methyl-d-aspartate (NMDA) inhibitor, has been approved for moderate to severe AD. Galantamine is of particular interest because it has a dual mechanism of action: it is postulated to be both an AChEI and an allosteric modulator of nicotinic receptors. Modulation of NMDA and nicotinic receptors by memantine and galantamine may provide an optimal combination therapy for AD. The cholinergic and glutamatergic neurotransmitter systems, which share a close functional relationship, may play a role in the pathogenesis of AD. Close examination of the pharmacology of the 2 compounds suggests that galantamine can augment memantine's glutamatergic noise suppression while simultaneously enhancing the physiologic glutamatergic signal. The link between these systems suggests that AD therapies, which capitalize on this relationship, may be more effective in improving cognition than approaches focusing on a single system. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The purpose of this study was to determine the prevalence of uncorrected visual disorders in nursing home patients with Alzheimer's disease (AD) and to determine whether appropriate corrective measures were taken by nursing home staff. This study was conducted at 2 community nursing homes in the St Louis area. Whereas previous studies have shown that visual impairment is common among all residents of nursing facilities, our study was focused specifically on residents with AD. This population is less able to effectively express needs and more likely to endure unaddressed visual deficits. For AD patients, it is important to offer appropriate corrective remedies in order to maintain as much functional independence as possible. METHODS: A retrospective cohort study was conducted in 2 private, skilled nursing facilities in St Louis County thought to be representative of community nursing homes in the United States. All subjects were patients with a diagnosis of dementia of probable AD. Demographic information collected included age, sex, and race. Mini-Mental State Examination scores were also obtained. The patients, their families, and nursing staff were interviewed to determine the patients' visual history, corrective measures, and the usage of corrective eyewear before and after admission to the nursing homes. The data were summarized to demonstrate how many patients suffered from uncorrected errors of refraction and what factors contributed to their visual status. RESULTS: Of the total of 85 patients included in the study, 80 (94.1%) required glasses for correction of presbyopia, myopia, or both. However, 25 of the 80 residents had not actively been using glasses since entering the nursing home. Of these 25 residents not wearing proper eyewear, 9 residents were too cognitively impaired to request them, 8 residents had broken or misplaced them, and 8 residents had prescriptions that were no longer sufficient to correct their vision. DISCUSSION: Our study found that nearly one third of the visually impaired nursing home residents with AD (25 of 80 patients) were not using their required eyewear. These 25 patients were the population of most interest because they were most likely to benefit from intervention. Many of these patients were not using glasses because they had been lost, damaged, or were no longer sufficient to correct their vision. CONCLUSIONS: We have presented 3 recommendations intended to prevent uncorrected visual acuity in nursing home residents with dementia: (1) Label eyewear in appropriate patient populations to provide rapid identification in the event of misplacement, (2) recommend that an extra pair of glasses be made available if the current pair would be lost or damaged, and (3) ensure that all residents have annual or biannual eye exams. If adequate steps are taken to prevent unnecessary visual impairment in AD patients, it would limit their dependence on others, reduce the burden on nursing staff, and improve the patients' overall quality of life. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease is the most common form of dementia worldwide. Aducanumab, a monoclonal antibody targeting amyloid-beta, became the first disease-modifying treatment for mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia and suggested that removing amyloid from the brain, especially in early AD, might make a difference in slowing cognitive decline., Areas Covered: In this review, the authors outline aducanumab's clinical efficacy as shown through key clinical trials and discuss its approval by the Food and Drug Administration under the accelerated pathway, which sparked both hope and controversy. We also discuss the importance of amyloid-related imaging abnormalities as a major side effect of aducanumab and all subsequent monoclonal antibodies targeting amyloid-beta., Expert Opinion: Aducanumab, became the first monoclonal antibody that provided at least partial support for the amyloid hypothesis by demonstrating slowed cognitive decline by removing amyloid from the brain, although full FDA approval now seems unlikely due to discontinuation of its development. Its introduction raised awareness of ARIA, highlighted the significant costs and need for informed consent in treatment, and emphasized the importance of long-term, diverse, and combination therapy data for future AD treatments targeting amyloid and tau.

Introduction: Cholinesterase inhibitors, along with memantine, are the mainstay of symptomatic treatment for AD (Alzheimer's disease); however, these medications are typically administered orally, which can be difficult for people with AD and their caregivers., Areas Covered: In this drug profile and narrative review, the authors trace the development of the new FDA-approved transdermal donepezil. The authors discuss the studies showing its bioequivalence with the oral formulation, including two double-blinded placebo controlled non-inferiority trials. The authors also compare the patch to the only other transdermal cholinesterase inhibitor on the market, rivastigmine, and highlight the potential advantages and disadvantages between these two treatments., Expert Opinion: While the patch is bio-equivalent, it is rather large and may not be affordable for some patients. In addition, there is no high dose (e.g. 23 mg) equivalent. Nevertheless, transdermal donepezil will be useful for people with AD and their caregivers, given its effectiveness and potential convenience.

Introduction: Donanemab is a humanized monoclonal antibody that significantly reduces cerebral amyloid plaques in Alzheimer's Disease (AD). It can delay disease progression and cognitive decline, making it one of the most promising disease-modifying treatments in the current treatment landscape., Areas Covered: This paper covers the current literature available on pharmacokinetics, pharmacodynamics, safety, and tolerability of donanemab. Publications from PubMed and Google were reviewed. A summary of regulatory approvals and current clinical data is also provided., Expert Opinion/commentary: Donanemab as a therapy for AD has more effective disease-modifying effects compared to lecanemab. Donanemab appears generally well-tolerated; however, it may have higher rates of severe side effects, such as amyloid-related imaging abnormalities (ARIA), that could lead to death. Guidelines for frequency of MRI monitoring for ARIA/safety are pending but will be integral to determining its use. Despite some limitations, donanemab is expected to receive FDA approval, giving clinicians access to another disease-modifying drug. Overall, more data is needed about donanemab, especially relating to safety, efficacy, cost, and integration with other treatments, but its development signifies progress in AD treatment.

Introduction: In July 2023, the U.S. Food and Drug Administration (FDA) granted full approval to lecanemab for the treatment of mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and mild AD dementia. Considering the limited treatment options for AD, the approval of lecanemab offers hope and opens the door for other disease-modifying therapies in the pipeline., Areas Covered: In this review, the authors summarize the FDA treatment guidelines, other anti-amyloid agents, and drug information relevant to prescribers, such as pharmacology and pharmacokinetics. Relevant clinical trial outcomes are discussed along with their significance and controversies., Expert Opinion: While questions remain about the magnitude of lecanemab's clinical impact, its approval signifies major progress in addressing the underlying pathology of AD. The authors have confidence in lecanemab as a promising treatment option and foresee exciting advancements on the 5-year horizon. Yet, further research is needed regarding trials beyond 18 months, post-marketing surveillance, and lecanameb in combination with existing treatments and lifestyle interventions.

Importance: Agitation is a prevalent, distressing, and burdensome manifestation of Alzheimer dementia in need of an efficacious, safe, and well-tolerated treatment., Objective: To confirm the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer dementia., Design, Setting, and Participants: This randomized clinical trial was a 12-week, double-blind, placebo-controlled, fixed-dose, parallel-arm trial that ran from May 2018 to June 2022 at 123 clinical trial sites in Europe and the United States. Participants included patients with agitation in Alzheimer dementia in a care facility or community-based setting. Stable Alzheimer disease medications were permitted., Interventions: In this 2-arm trial, patients were randomized to receive oral brexpiprazole or placebo (2:1 ratio) for 12 weeks. Within the brexpiprazole arm, patients were further randomized to receive fixed doses of 2 mg/d or 3 mg/d in a 1:2 ratio., Main Outcomes and Measures: The primary end point was change in Cohen-Mansfield Agitation Inventory total score (which measures the frequency of 29 agitated behaviors) from baseline to week 12 for brexpiprazole, 2 or 3 mg, vs placebo. Safety was assessed by standard measures, including treatment-emergent adverse events., Results: A total of 345 patients were randomized to receive brexpiprazole (n = 228) or placebo (n = 117); completion rates were 198 (86.8%) for brexpiprazole and 104 (88.9%) for placebo. Mean (SD) age was 74.0 (7.5) years, and 195 of 345 patients were female (56.5%). Patients receiving brexpiprazole, 2 or 3 mg (n = 225), demonstrated statistically significantly greater improvement than those taking placebo (n = 116) in Cohen-Mansfield Agitation Inventory total score from baseline to week 12 (brexpiprazole baseline, 80.6, mean change, -22.6; placebo baseline, 79.2, mean change, -17.3; least-squares mean difference, -5.32; 95% CI, -8.77 to -1.87; P = .003; Cohen d effect size, 0.35). No treatment-emergent adverse events had an incidence of 5% or more with brexpiprazole and greater incidence than placebo. The proportion of patients who discontinued because of adverse events was 12 of 226 (5.3%) for brexpiprazole and 5 of 116 (4.3%) for placebo., Conclusions and Relevance: In this study, patients with Alzheimer dementia who took brexpiprazole, 2 or 3 mg, showed a statistically significant improvement vs placebo in agitation over 12 weeks. Brexpiprazole was generally well tolerated over 12 weeks in this vulnerable patient population., Trial Registration: ClinicalTrials.gov Identifier: NCT03548584.

Introduction: Although there are several FDA-approved treatments for Alzheimer's disease (AD), only recently have disease-modifying therapies received approval for use in patients. In this narrative review, we examine the history of aquaporin-4 (AQP4) as a therapeutic target for NMOSD (neuromyelitis optica spectrum disorder) and as a potential therapeutic target for AD., Areas Covered: We review the basic science and discovery of AQP4, a transmembrane water-channel essential to regulating water balance in the central nervous system (CNS). We also review the pathogenesis of NMOSD, an autoimmune disease characterized by the destruction of cells that express AQP4. Then, we review how AQP4 is likely involved in the pathogenesis of Alzheimer's disease (AD). Finally, we discuss future challenges with drug design that would modulate AQP4 to potentially slow AD development. The literature search for this article consisted of searching Google Scholar and PubMed for permutations of the keywords 'Alzheimer's disease,' 'aquaporin-4,' 'neuromyelitis optica,' and their abbreviations., Expert Opinion: We place research into AQP4 into context with other recent developments in AD research. A major difficulty with drug development for Alzheimer's is the lack of strategies to cleanly target the early pathogenesis of the disease. Targeting AQP4 may provide such a strategy.

Introduction: Alzheimer's disease (AD) is a debilitating disease, with no cure. Recently, a monoclonal antibody (aducanumab) directed toward amyloid aggregates was approved as a disease-modifying treatment (DMT) for the disease. Other compounds (symptomatic or DMTs) are at different stages of clinical trial development., Areas Covered: The authors conducted a search on PUBMED, MEDLINE, and clinicaltrials.gov for compounds in phase III clinical trials for cognitive impairment due to AD. Mechanisms of action and clinical trial data related to these compounds are discussed in this paper., Expert Opinion: There is an unmet need for both treatment approaches (symptomatic and DMTs) to improve outcomes in individuals at different stages of the AD continuum. Future trials with symptomatic therapies should rely on biomarkers to improve enrollment of participants with pure AD. More sensitive, innovative, and composite assessment tools should be used. Given the complexity and heterogeneity of AD, combining several DMTs with synergistic mechanisms of action is a promising approach to achieve a significant impact on reversing cognitive decline. We recommend testing DMTs early on in the disease continuum, even in asymptomatic individuals at risk for AD. Longer duration of follow-up in clinical trials with DMTs is recommended.

Purpose of Review: Increasing evidence points toward the importance of diet and its impact on cognitive decline. This review seeks to clarify the impact of four diets on cognition: the Mediterranean diet, the anti-inflammatory diet, the Seventh Day Adventist diet, and the Ketogenic diet., Recent Findings: Of the diets reviewed, the Mediterranean diet provides the strongest evidence for efficacy. Studies regarding the anti-inflammatory diet and Seventh Day Adventist diet are sparse, heterogeneous in quality and outcome measurements, providing limited reliable data. There is also minimal research confirming the cognitive benefits of the Ketogenic diet. Increasing evidence supports the use of the Mediterranean diet to reduce cognitive decline. The MIND-diet, a combination of the Mediterranean and DASH diets, seems especially promising, likely due to its anti-inflammatory properties. The Ketogenic diet may also have potential efficacy; however, adherence in older populations may be difficult given frequent adverse effects. Future research should focus on long-term, well-controlled studies confirming the impact of various diets, as well as the combination of diets and lifestyle modification., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Over-the-counter (OTC) products such as pharmaceuticals, dietary supplements, vitamins, and herbal remedies are widely available and copiously used by older adults for health maintenance and symptom management. Owing to physiology, multimorbidity, and polypharmacy, this population is particularly vulnerable to inappropriate use of OTC products, adverse effects, and drug interactions. While OTC pharmaceuticals are bound by FDA-approved standards, dietary supplements are regulated differently, resulting in variable quality and increased possibility for adulteration. Internationally, standards for OTC products vary widely. Accessible educational information, improved provider-patient communication, and revision of regulatory policy could improve safety for older adult users of OTC products., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic., (© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Mood disorders and anxiety significantly impact the prognosis and disease course of Parkinson's disease. Non-motor symptoms of Parkinson's disease such as apathy, anhedonia, and fatigue overlap with diagnostic criteria for anxiety and depression, thus making accurate diagnosis of mood disorders in Parkinson's disease patients difficult. Furthermore, treatment options for mood disorders can produce motor complications leading to poor adherence and impaired quality of life in Parkinson's disease patients. This review aims to clarify the current state of diagnostic and treatment options pertaining to anxiety and mood disorders in Parkinson's disease. It explores both the pharmacologic and non-pharmacologic treatment modalities for various mood disorders in comorbid Parkinson's disease with a brief discussion of the future outlook of the field given the current state of the literature.

Parkinson's disease (PD) is the second most common neurodegenerative disease seen in older adults after Alzheimer's disease, with increasing prevalence worldwide. Parkinson's disease psychosis (PDP) is a common, non-motor feature of PD, which increases caregiver stress and is a risk-factor for nursing home placement. In this paper we review PDP epidemiology, features, diagnosis, and treatment. PDP most often presents with sequential development of minor and then increasingly complex visual hallucinations mediated by dopaminergic-serotonergic interactions activating the mesolimbic pathway, with contributions from other structures and neurotransmitters. Appropriate evaluation of differential diagnoses for psychosis is vital before diagnosing PDP. Initial treatment should involve non-pharmacologic approaches. If these are unsuccessful and PDP symptoms significantly impact the patient's and or their caregivers' quality of life and functions, then pharmacotherapy is indicated. Pimavanserin is a recently FDA-approved pharmacologic treatment for PDP with a better profile of balanced effectiveness and safety compared to previous use of atypical antipsychotics. Early diagnosis and safer, more effective treatments for PDP should help reduce caregiver burden and enable caregivers to continue to provide care at home versus institutionalization.

Introduction: To date, there is no FDA-approved treatment for agitation in Alzheimer's disease (AD). Medications currently used off-label have modest clinical efficacy and serious side effects., Areas Covered: The authors review the pharmacology, mechanism of action, pharmacokinetics, efficacy, safety and tolerability data of AVP-786, for the treatment of agitation in AD., Expert Opinion: AVP-786, the deuterated form of dextromethorphan/quinidine (AVP-923) which is an approved treatment for Pseudo-Bulbar Affect, emerges as a promising and safe treatment for agitation in AD. Deuteration is an innovative technology that accelerates drug development by conducting faster and less costly clinical trials. No phase II trial was conducted with AVP-786 for the treatment of agitation in AD; the decision to expedite the development of this drug was based on a successful phase II study with AVP-923. Phase III trials with AVP-786 (TRIAD-1 and TRIAD-2) showed mixed findings probably due to the difference in study design. Future phase III studies should use innovative study designs such as the Sequential Parallel Comparison Design to mitigate high placebo response, and the Cohen-Mansfield Agitation Inventory for agitation assessment. They should also include positron emission tomography studies to assess occupancy of various receptors in the brain after AVP-786 is administered.

Frontotemporal dementia is a heterogeneous spectrum of neurodegenerative disorders. The neuropathological inclusions are tau proteins, TAR DNA binding protein 43 kDa-TDP-43, or fused in sarcoma-ubiquitinated inclusions. Genetically, several autosomal mutations account for the heritability of the disorder. Phenotypically, frontotemporal dementia can present with a behavioral variant or a language variant called primary progressive aphasia. To date, there are no approved symptomatic or disease-modifying treatments for frontotemporal dementia. Currently used therapies are supported by low-level of evidence (mostly uncontrolled) studies. The off-label use of drugs is also limited by their side-effect profile including an increased risk of confusion, parkinsonian symptoms, and risk of mortality. Emerging disease-modifying treatments currently target the progranulin and the expansion on chromosome 9 open reading frame 72 genes as well as tau deposits. Advancing our understanding of the pathophysiology of the disease and improving the design of future clinical trials are much needed to optimize the chances to obtain positive outcomes.

Background: The management of major neurocognitive disorder (MNCD), formerly known as dementia, is of increasing concern as the elderly population continues to grow. Doll therapy (DT) is a controversial method observed in clinical practice that has both promising benefits and potential ethical concerns. To date, little research has been done on this therapy., Methods: A PubMed search was performed using the keywords "dementia," "elderly," "dolls," "doll therapy," and "Alzheimer's disease." A list of pertinent articles was assembled, with irrelevant articles excluded. References from these articles were also reviewed and additional articles were included in the final list., Results: Research on the utility of DT for patients with MNCD is limited. Current literature suggests that DT may be beneficial in decreasing the use of pharmacologic interventions and alleviating symptoms such as agitation and anxiety. However, most studies consisted of small, unrepresentative sample populations., Conclusions: Preliminary studies favor DT as an effective management strategy for behavioral symptoms of MNCD. However, the few existing randomized controlled trials are limited in size and demographics. Further research involving larger, more diverse study samples with more male patients is needed. Additionally, the exact parameters to guide this therapy have not been established and require investigative study.

Dementia is the major cause of mortality and morbidity in older adults, with Alzheimer's disease (AD) being the most common cause. AD has a significant impact on economic and psychosocial status. Cholinesterase inhibitors (ChEIs) are currently the mainstay in the management of AD. Rivastigmine is the only ChEI that inhibits both acetylcholinesterase and butyrylcholinesterase enzymes in the brain. This dual inhibition makes it potentially more effective for AD patients. Its availability as both a transdermal formulation and oral capsule, may improve adherence rates and care giver satisfaction compared with other ChEIs. To date, the data from randomized clinical trials and post marketing observational studies have shown evidence for an impact on cognitive functions in AD with good safety and tolerability.

Background: Alzheimer's disease (AD) is the 6th leading cause of death in the United States and has no cure or progression prevention. The Cognitive Reserve (CR) theory poses that constant brain activity earlier in life later helps to deter pathological changes in the brain, delaying the onset of disease symptoms., Objective: To determine the reliability and validity of the Cognitive Reserve Index questionnaire (CRIq) in AD patients., Methods: Primary data collection was done using the CRIq to quantify CR in 90 participants. Correlations and multivariable linear regressions were used to assess reliability and validity., Results: Reliability was tested in 34 participants. A Pearson correlation coefficient of 0.89 ( p  < 0.001) indicated a strong positive correlation. Validity was tested in 33 participants. A Pearson correlation coefficient of 0.30 ( p  = 0.10) indicated an insignificant weak positive correlation., Conclusion: The CRIq was found reliable. Gaining a better understanding of how CR tools can be used in various cognitive populations will help with the establishment of a research tool that is universally accepted as a true CR measure., Competing Interests: The authors have no conflict of interest to report., (© 2020 – IOS Press and the authors. All rights reserved.)

Psychosis is common among individuals with neurocognitive disorders, is difficult to manage, and causes considerable burden and stress to patients and caregivers. Developing effective treatments is a substantial unmet medical need but research has been slowed by the need for updated consensus diagnostic criteria. To address this need, the International Psychogeriatrics Association initiated a process to develop criteria for clinical use, research, and treatment development efforts. The process included clinical, regulatory, and industry stakeholders as well as input from a global network of experts in geriatric psychiatry responding to two surveys (N = 336). Results from the consensus process confirmed that clinicians wanted elaboration of aspects of the definition proposed by Jeste and Finkel in 2000 to ensure that the criteria are applied appropriately. Based on discussions, the survey, and emerging research, criteria were revised to apply to psychosis occurring with all major and mild neurocognitive disorders. Other important changes include providing examples of hallucinations and delusions and clarifying time course, impact, and exclusionary criteria. This definition of psychosis in major and mild neurocognitive disorders can be used to advance many types of research including development of much needed pharmacologic and nonpharmacologic interventions for psychosis in patients with neurocognitive disorders., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Schizophrenia has a prevalence of approximately 1% in the general population, with 15.2 per 100,000 persons affected. Iloperidone is a second-generation antipsychotic drug approved for the treatment of schizophrenia in adults. It acts primarily by D2/5HT2a receptor antagonism, with greater affinity for the 5HT2a receptor than for the D2 receptor., Areas Covered: This article discusses iloperidone and aims to provide useful information for clinicians to determine which circumstances would best suit the use of iloperidone to treat schizophrenic patients. In this review, the authors briefly discuss schizophrenia and its treatment, before they discuss properties of iloperidone, its indications, approval process, and adverse effects. Finally, the authors review the specific strengths and weaknesses of the medication., Expert Opinion: Iloperidone would be an attractive option in patients who are particularly prone to EPS, or who are showing prominent negative symptoms, as well as cognitive deficits. Its availability only in an oral formulation makes it a better option for patients with good medication adherence, and though it could be useful in patients prone to weight gain or hepatic dysfunction on other second generation antipsychotics, it should be used with caution in patients prone to side effects related to alpha adrenergic blockade.

Purpose of Review: A variety of potentially modifiable risk factors have been investigated in an attempt to delay/prevent Alzheimer's disease (AD). Among these, dietary regimens and nutritional supplements have been most extensively studied. The purpose of this article is to critically review recent evidence for the Mediterranean/MIND diets along with the use of various vitamins and popular herbal supplements, including curcumin, Ginkgo biloba, and fish oil, among others., Recent Findings: The Mediterranean and MIND diets are supported by observational studies performed in community settings, especially in the group with high adherence to the Mediterranean diet and with moderate-high adherence to the MIND diet. Randomized controlled trials of various vitamins and supplements have, in general, not shown statistically significant results, although there has been some promising evidence for vitamin D supplementation and curcumin use. There is sufficient data to recommend the Mediterranean and MIND diets to delay the onset of AD. It is judicious to supplement vitamin D, especially in deficient patients, and to consider the use of curcumin to improve cognitive performance. Future research should focus on larger, controlled trials in diverse populations.

Introduction: There is no cure for Alzheimer's disease (AD). One explanation may pertain to the need to intervene as early as possible upstream from the accumulation of β-amyloid plaques and tau tangles., Areas Covered: A PUBMED literature search was completed to review the biological or pathological changes at the basis of disease initiation; this includes neuroinflammation, oxidative stress, microbiome changes and glymphatic system dysfunction. Innovative therapeutic strategies based on these mechanisms are also discussed., Expert Opinion: Improved understanding of the pathophysiological mechanisms that underly AD would assist in the identification of drug targets for clinical trials. Furthermore, pharmacokinetic and pharmacodynamic studies are key for the characterization of the properties of disease-modifying drugs and the improvement of their penetration of the blood-brain barrier. Drug targets can be examined at different stages of the disease, hence the importance of selecting and recruiting the appropriate participants, preferably at the earliest stage of AD. New trial designs should be established which primarily involve combination therapies that can work synergistically on common pathways. Going forward, innovative treatment strategies involving nanotechnology, young blood products transfusion and photobiomodulation also offer promise for the future.

Objectives: To evaluate the diagnostic accuracy of a short depression screening tool, the Saint Louis University (SLU) AMSAD depression scale, relative to the Geriatric Depression Scale-15 (GDS-15) and Montgomery-Asberg Depression Rating Scale (MADRS), and in relation to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) criteria for major depressive disorder, in cognitively intact older adults., Design: Cross-sectional., Setting: Outpatient geriatric psychiatry clinic., Participants: Fifty older adults (aged ≥65 years) without dementia., Measurements: GDS-15, MADRS, SLU AMSAD, and DSM-5 criteria for major depressive disorder were administered., Results: Total scores (continuous variables) for the GDS-15, MADRS, and SLU AMSAD correlated significantly with the DMS-5 criteria for major depressive disorder (MDD) [area under the curve (AUC) ≥ 0.93, sensitivity = 0.93, and specificity ≥ 0.80]. Optimal cutoffs were 9+ for GDS-15, 18+ for MADRS, and 7+ for SLU AMSAD. When score results were categorized according to their known cutoffs for mild, moderate, and severe depression, AUC values were again high (range = 0.82-0.89), with adequate levels of sensitivity (0.87-0.93) and specificity (0.71-0.86), distinguishing no or mild depression from moderate or severe depression in relation to the DSM-5 diagnostic criteria for MDD., Conclusions and Implications: Strong diagnostic accuracy was shown for the 3 scales. The SLU AMSAD performed as well as the GDS-15 and slightly better than the MADRS. The superiority of the SLU AMSAD is supported by the fact that it encompasses only 5 simply worded, simply scaled items to be used in busy clinical settings., (Copyright © 2019 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

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 (316)  = -2.06; p = 0.040; MMRM). Brexpiprazole 1 mg/day did not show meaningful separation from placebo (0.23; -3.40, 3.86; t (314)  = 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 (230)  = -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 (144)  = -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 (337)  = -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 (222)  = -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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Alzheimer's disease (AD) is a major cause of morbidity worldwide and its prevalence is expected to rise. Previous studies involving compounds that target the accumulation of amyloid β protein have been unsuccessful, renewing interest in therapies directed against intracellular deposits of tau proteins. Derived from methylene blue, hydromethylthionine is a tau aggregation inhibitor that recently emerged as a promising disease-modifying treatment for AD., Areas Covered: Herein, the authors cover the chemistry, pharmacodynamics and pharmacokinetics of hydromethylthionine and its oxidized form methylthionine chloride (MTC) that was first studied, as well as clinical efficacy and safety of hydromethylthionine in the treatment of mild to moderate AD., Expert Opinion: Randomized clinical trials with hydromethylthionine failed to show any impact of the doses used on the disease course. Data analysis from a non-randomized cohort showed that a smaller dose of the drug previously thought to be ineffective and used as placebo, prescribed as monotherapy rather than as add-on to AD approved symptomatic therapies may slow cognitive decline. This finding was further confirmed by a pharmacokinetic analysis study showing a dose/response relationship with doses around 16 mg daily. Future trials need to study the pharmacological properties of hydromethylthionine and ascertain the optimal safe and effective dose to be used.

Introduction : Alzheimer's disease (AD) is the most common cause of major neurocognitive disorders with a prevalence in the US of about 5.7 million in 2018. With the disease burden projected to increase dramatically in the coming years, it is imperative to review the current available treatment regimens for their safety and utility. The cholinesterase inhibitors (ChEIs) have continued to play a pivotal role in managing the symptoms and possibly slowing the rate of progression of AD since 1993. Owing to their being a mainstay in the treatment of AD, the safety and efficacy of prescribing these drugs needs to be reviewed often, especially with the approval of new formulations and doses. Areas covered : The three ChEIs currently approved by the FDA are donepezil, rivastigmine and galantamine. This article will review the safety and tolerability of these ChEIs and analyze the potential disease modifying properties of these drugs. The authors have reviewed all recent literature including review articles, meta-analyzes, clinical trials and more. Expert opinion : These ChEIs differ subtly in their mechanisms of action, in their tolerability and safety and FDA-approved indications. All are considered first-line, symptomatic treatments of the various phases of AD and may even have potentially disease-modifying effects.

Non-Alzheimer's dementias constitute 30% of all dementias and present with major cognitive and behavioral disturbances. Cholinesterase inhibitors improve memory by increasing brain acetylcholine levels and are approved symptomatic therapies for Alzheimer's disease (AD). They have also been investigated in other types of dementias with potential cholinergic dysfunction. There is compelling evidence for a profound cholinergic deficit in Lewy Body dementia (LBD) and Parkinson's disease dementia (PDD), even to a greater extent than AD. However, this deficit is difficult to objectivize in vascular dementia (VaD) given the increased comorbidity with AD. Furthermore, there is minimal to no evidence for cholinergic loss in frontotemporal dementia (FTD). Although cholinesterase inhibitors showed significant improvement in cognitive, behavioral, and functional measures in both LBD and PDD clinical trials, only rivastigmine is approved for PDD, due to the heterogeneity of the scales used, the duration of trials, and the limited sample sizes impacting data interpretation. Similarly, the interpretation of findings in VaD trials are limited by the lack of pre-defined inclusion criteria for 'pure VaD' and the wide heterogeneity of patients enrolled with respect to location and extent of cerebrovascular disease. In FTD patients, cholinesterase inhibitors were mostly associated with worsening of cognitive and behavioral symptoms. In non-AD dementias, cholinesterase inhibitors were well tolerated, with increased reports of mild to moderate cholinergic side effects and a non-significant trend for increased cardio and cerebrovascular events with rivastigmine in VaD, justifying their cautious use on a case-by-case basis, especially when there is evidence for cholinergic deficit.

Background: Polypharmacy, defined as being prescribed 5 or more medications, has been shown to be associated with a decline in mental and physical functioning in elderly patients. Despite this, elderly patients are currently being prescribed a median of 7 medications, which often causes more harm than benefit, and emphasizes the importance of deprescribing., Methods: Five classes of potentially inappropriate medications for the elderly population, especially for the aging brain, are discussed, including anticholinergics, benzodiazepines, antipsychotics, opioids, and proton pump inhibitors. Recommendations regarding these medications were collected from the 2015 Beer's Criteria, the Screening Tool of Older Person's Prescriptions (STOPP) criteria, the Screening Tool to Alert doctors to the Right Treatment (START) criteria, and the Fit fOR The Aged (FORTA) list. The PubMed database was also searched for the most recent evidence regarding prescription patterns, adverse effects, and recommendations regarding discontinuation of these medications in older adults., Results: Anticholinergics, benzodiazepines, antipsychotics, and opioids were all found to have significant adverse effects in the elderly population. All of the discussed medication classes have been shown to be successfully deprescribable., Conclusions: Polypharmacy increases the risk of adverse drug reactions and hospitalizations in geriatric patients. Rational deprescribing of anticholinergics, benzodiazepines, antipsychotics, opioids, and proton pump inhibitors in selected patients may be a good first step to reducing this risk.

An estimated 47 million people live with Alzheimer's disease (AD) and other forms of dementia worldwide. Although no disease-modifying treatments are currently available for AD, earlier diagnosis and proper management of the disease could have considerable impact on patient and caregiver quality of life and functioning. Drugs currently approved for AD treat the cognitive, behavioral, and functional symptoms of the disease and consist of three cholinesterase inhibitors (ChEIs) and the N-methyl-D-aspartate receptor antagonist memantine. Treatment of patients with mild to moderate AD is generally initiated with a ChEI. Patients who show progression of symptoms while on ChEI monotherapy may be switched to another ChEI and/or memantine can be added to the treatment regimen. In recent years, putative disease-modifying therapies have emerged that aim to slow the progression of AD instead of only addressing its symptoms. However, many therapies have failed in clinical trials in patients with established AD, suggesting that, once developed, disease-modifying agents may need to be deployed earlier in the course of illness. The goal of this narrative literature review is to discuss present treatment algorithms and potential future therapies in AD.

Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent and represent a significant burden for patients and their caregivers. Early recognition and management of these symptoms is crucial as they are associated with increased risk of institutionalization, impairments in daily functioning, reduced quality of life, and more rapid progression to severe dementia. This chapter will discuss the pathophysiology, proposed diagnostic criteria, clinical features, and management of BPSD, including apathy, depression, agitation/aggression, psychosis, and sleep disturbances. Apathy and depression are the most common overall, and apathy is associated with high symptom severity likely because of its greater persistence. Symptoms such as agitation, aggression, hallucinations, and delusions may be especially distressing and dangerous to patients and caregivers. Nonpharmacologic management should be considered first-line therapy in most cases due to the modest and inconsistent evidence base for pharmacologic agents and greater risk of harm. However, the judicious use of pharmacologic agents may be warranted when symptoms are dangerous and/or severely distressing., (Copyright © 2019 Elsevier B.V. All rights reserved.)