Pharmacokinetic evaluation of donanemab for the treatment of Alzheimer's.

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.

Alzheimer's Disease (AD) is a brain disorder that severely impacts memory, behavior, and thinking. The most common treatments manage symptoms but do not slow disease progression or improve function. Accumulation of proteins called amyloid-beta plaques in the brain are one of the main causes of the disease. Donanemab is an antibody that helps the body remove these plaques. This review summarizes what is currently known about the safety of donanemab, how it works, and the extent to which it can help people with AD.Results suggest that donanemab significantly decreases the amount of plaques in the brain, delays disease progression, and improves cognition. Treatment can prevent reaccumulation of plaques for an extended period of time. There are some side effects associated with treatment, but they are generally manageable and resolve when the drug is stopped. In rare cases, more serious side effects were reported. These require careful monitoring and an evaluation of potential risk compared to benefit. Overall, current information on donanemab is extensive and shows promise. However, to help caregivers and people with AD make informed decisions on using the drug, further research is needed to fully explore donanemab's safety, cost, and efficacy compared to other therapies in the same class.

The donepezil transdermal system for the treatment of patients with mild, moderate, or severe Alzheimer's disease: a critical review.

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.

Progress in Pharmacologic Management of Neuropsychiatric Syndromes in Neurodegenerative Disorders: A Review.

Importance: Neuropsychiatric syndromes (NPSs) are common in neurodegenerative disorders (NDDs); compromise the quality of life of patients and their care partners; and are associated with faster disease progression, earlier need for nursing home care, and poorer quality of life. Advances in translational pharmacology, clinical trial design and conduct, and understanding of the pathobiology of NDDs are bringing new therapies to clinical care. Observations: Consensus definitions have evolved for psychosis, agitation, apathy, depression, and disinhibition in NDDs. Psychosocial interventions may reduce mild behavioral symptoms in patients with NDD, and pharmacotherapy is available for NPSs in NDDs. Brexpiprazole is approved for treatment of agitation associated with Alzheimer disease dementia, and pimavanserin is approved for treatment of delusions and hallucinations associated with psychosis of Parkinson disease. Trials are being conducted across several of the NDDs, and a variety of mechanisms of action are being assessed for their effect on NPSs. Conclusions and Relevance: Detection and characterization of NPSs in patients with NDDs is the foundation for excellent care. New definitions for NPSs in NDDs may inform choices regarding clinical trial populations and translate into clinical practice. Psychosocial and pharmacologic therapies may reduce behavioral symptoms and improve quality of life for patients and caregivers. Approved agents may establish regulatory precedents, demonstrate successful trial strategies, and provide the foundation for further advances in treatment development.

Profiling lecanemab as a treatment option for Alzheimer's disease.

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.

How promising are the latest monoclonal antibodies targeting amyloid-ß for the treatment of early Alzheimer's disease?

INTRODUCTION: Monoclonal antibodies targeting amyloid-ß are the first disease-modifying treatments for Alzheimer disease to have received FDA-approval. There are three different drugs approved or pending FDA-approval: aducanumab, lecanemab, and donanemab. These three drugs are each in different stages of regulatory approval by the FDA. AREAS COVERED: We discuss the development of these drugs, the data regarding their clinical efficacy, their dosing regimens, and side effects. In addition, we examine pragmatic issues with their potential implementation as common treatments to slow the rate of decline in Alzheimer disease, and what unanswered questions remain regarding this new class of drugs. EXPERT OPINION: We conclude that these new monoclonal antibodies that target amyloid-ß represent a genuine advance in the treatment of Alzheimer disease. However, questions remain regarding their clinical significance. Additionally, it is presently unclear which patients would most benefit from these expensive drugs given the risk of side effects and the logistical difficulties concerning administration and the determination of eligibility.

Reduction and prevention of agitation in persons with neurocognitive disorders: an international psychogeriatric association consensus algorithm.

OBJECTIVES: To develop an agitation reduction and prevention algorithm is intended to guide implementation of the definition of agitation developed by the International Psychogeriatric Association (IPA). DESIGN: Review of literature on treatment guidelines and recommended algorithms; algorithm development through reiterative integration of research information and expert opinion. SETTING: IPA Agitation Workgroup. PARTICIPANTS: IPA panel of international experts on agitation. INTERVENTION: Integration of available information into a comprehensive algorithm. MEASUREMENTS: None. RESULTS: The IPA Agitation Work Group recommends the Investigate, Plan, and Act (IPA) approach to agitation reduction and prevention. A thorough investigation of the behavior is followed by planning and acting with an emphasis on shared decision-making; the success of the plan is evaluated and adjusted as needed. The process is repeated until agitation is reduced to an acceptable level and prevention of recurrence is optimized. Psychosocial interventions are part of every plan and are continued throughout the process. Pharmacologic interventions are organized into panels of choices for nocturnal/circadian agitation; mild-moderate agitation or agitation with prominent mood features; moderate-severe agitation; and severe agitation with threatened harm to the patient or others. Therapeutic alternatives are presented for each panel. The occurrence of agitation in a variety of venues-home, nursing home, emergency department, hospice-and adjustments to the therapeutic approach are presented. CONCLUSIONS: The IPA definition of agitation is operationalized into an agitation management algorithm that emphasizes the integration of psychosocial and pharmacologic interventions, reiterative assessment of response to treatment, adjustment of therapeutic approaches to reflect the clinical situation, and shared decision-making.

Agitation in cognitive disorders: Progress in the International Psychogeriatric Association consensus clinical and research definition.

BACKGROUND: The International Psychogeriatric Association (IPA) published a provisional consensus definition of agitation in cognitive disorders in 2015. As proposed by the original work group, we summarize the use and validation of criteria in order to remove "provisional" from the definition. METHODS: This report summarizes information from the academic literature, research resources, clinical guidelines, expert surveys, and patient and family advocates on the experience of use of the IPA definition. The information was reviewed by a working group of topic experts to create a finalized definition. RESULTS: We present a final definition which closely resembles the provisional definition with modifications to address special circumstances. We also summarize the development of tools for diagnosis and assessment of agitation and propose strategies for dissemination and integration into precision diagnosis and agitation interventions. CONCLUSION: The IPA definition of agitation captures a common and important entity that is recognized by many stakeholders. Dissemination of the definition will permit broader detection and can advance research and best practices for care of patients with agitation.

A real-world assessment of healthcare costs associated with agitation in Alzheimer's dementia.

AIMS: To describe and compare clinical characteristics, healthcare costs, and institutionalization/mortality outcomes among patients with and without agitation associated with Alzheimer's dementia (AAD). METHODS: Data from the Reliant Medical Group database (01/01/2016-03/31/2020) were used, including claims, electronic medical records, and clinical information/physician notes abstracted from medical charts. Patients aged ≥55 years with Alzheimer's dementia (AD) were observed during a randomly selected 12-month study period after AD diagnosis. Using information recorded in medical charts, patients were classified into cohorts based on experiencing (agitation cohort) and not experiencing (no agitation cohort) agitated behaviours during the study period. Entropy balancing was used to create reweighted cohorts with similar characteristics. Study outcomes (patient demographic and clinical characteristics, treatments received, healthcare costs, institutionalization and death events) were compared between cohorts; agitation characteristics were described for the agitation cohort only. RESULTS: Among 711 patients included in the study, 240 were classified in the agitation cohort and 471 in the no agitation cohort. After reweighting, several comorbidities were more frequently observed in the agitation versus no agitation cohort, including infection, depression, and altered mental status. Use of antidepressants, anticonvulsants, antipsychotics, and antianxiety medications was more common in the agitation versus no agitation cohort. Common agitated behaviours included hitting (20.8%), pacing/aimless wandering (17.5%), and cursing/verbal aggression (15.0%). Total all-cause healthcare costs were $4287 per-patient-per-year higher in the agitation cohort versus no agitation cohort (p = 0.04), driven by higher inpatient costs. Death was more common and time to death and institutionalization were shorter in the agitation versus no agitation cohort. LIMITATIONS: Results may not be generalizable to the US population with AD. CONCLUSIONS: Among patients with AD, agitation was associated with shorter time to death/institutionalization and increased comorbidities, medication use, and healthcare costs, highlighting the additional clinical and economic burden that agitation poses to patients and the healthcare system.

Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia: A Randomized Clinical Trial.

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.

Over the Counter Supplements for Memory: A Review of Available Evidence.

In 2021, the Global Brain Health Supplement Industry Market size was valued at US$7.6 billion. It is predicted to increase to US$15.59 billion by 2030. Memory and its enhancement are a segment of the market that comprised the highest global revenue share in 2021. In the USA alone, dietary supplement sales reached US$18 billion in 2018. The US Food and Drug Administration (FDA) does not have the authority to approve dietary supplements' safety, effectiveness, or labeling before products go on the market. The FDA often does not even review supplements before they go to market. Supplement manufacturers are thus responsible for ensuring their products are safe and that their claims are truthful. An extensive review of current supplements on the market was performed by surveying memory products for sale at local and national pharmacies and grocery stores. A list of 103 supplements was compiled and the ingredients in these memory supplements were reviewed. The 18 most common ingredients in these supplements were identified. Each of the supplements included at least one of the 18 most common ingredients. Scientific data relative to these ingredients and their effect on memory was searched using PubMed and Cochrane library databases. Currently, there is no compelling evidence for use of apoaequorin, coenzyme Q10, coffee extracts, L-theanine, omega-3 fatty acids, vitamin B6, vitamin B9, or vitamin B12 supplementation for memory. On the other hand, there is some current evidence for memory benefit from supplementation with ashwagandha, choline, curcumin, ginger, Lion's Mane, polyphenols, phosphatidylserine, and turmeric. There are current studies with mixed results regarding the benefit of carnitine, gingko biloba, Huperzine A, vitamin D, and vitamin E supplementation for memory. Dietary supplements geared toward improving cognition are a billion-dollar industry that continues to grow despite lacking a solid scientific foundation for their marketing claims. More rigorous studies are needed relative to the long-term use of these supplements in homogenous populations with standardized measurements of cognition. Health care providers need to be aware of any and all supplements their older adult patients may be consuming and be educated about their side effects and interactions with prescription medications. Lastly, the FDA needs to take an active position relative to monitoring marketed supplements regarding safety, purity and claims of efficacy.

The aquaporin-4 water channel and updates on its potential as a drug target for Alzheimer's disease.

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.

Substance Use Disorders in Postacute and Long-Term Care Settings.

Substance use disorders (SUDs) have not been rigorously studied in postacute and long-term care (PALTC) populations. SUDs are among the fastest growing disorders in the community dwelling older population. Untreated SUDs often lead to overdose deaths, emergency department visits, and hospitalizations due to SUD-related adverse effects, especially exacerbation of comorbid physical and mental health conditions. Primary care providers (PCPs) working in PALTC settings can and should play a key role in its prevention and treatment. This clinical review identifies several practical strategies that PCPs can incorporate in their daily practice to improve lives of PALTC population having SUD.

Pharmacotherapy for Alzheimer's disease: what's new on the horizon?

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.

Comparison of the Impact of the Mediterranean Diet, Anti-Inflammatory Diet, Seventh-Day Adventist Diet, and Ketogenic Diet Relative to Cognition and Cognitive Decline.

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.

Using Telemedicine to Assess and Manage Psychosis in Neurodegenerative Diseases in Long-Term Care.

The coronavirus disease 2019 (COVID-19) epidemic has forced a sudden global implementation of telemedicine strategies, including in long-term care (LTC) facilities where many people with dementia and Parkinson disease (PD) reside. Telemedicine offers a unique set of advantages for residents in LTC facilities if effectively supported and implemented, including expanded access to specialists in rural or underserved areas or for people with dementia who cannot travel for off-site visits. Many medical and psychiatric organizations have recently issued new or updated guidelines on the use of telemedicine. On October 22, 2020, a multidisciplinary consensus panel was convened to collate a list of best practices for LTC facilities and specialists when conducting telemedicine with residents with dementia-related psychosis or PD-related psychosis (PDP). A collaborative effort between specialists, facility administrators, and facility staff is essential for the success of telemedicine in the LTC setting. Telemedicine in LTC facilities comes with increased administrative and technical challenges that fall heavily on the shoulders of the LTC facility administrators and staff. Specialists can ease this burden by maintaining flexibility and ensuring expression of empathy and thanks to the staff who are facilitating the visits. LTC staff can provide specialists with valuable information about their patients to aid in evaluation and diagnosis. Specialists can facilitate this exchange of information by speaking to staff who work closely with the resident about any signs of hallucinations or delusions they may have observed. Educational efforts can increase staff understanding of dementia and PDP and empower them to engage with, and facilitate the resident's treatment plan. Using these strategies to take advantage of the benefits of telemedicine, specialists and LTC staff can together expand and improve care for LTC facility residents with dementia-related psychosis or PDP.

Alcohol Use Disorder in Older Adults.

As the number of older adults worldwide continues to grow, we observe a proportional growth of substance use. Despite the myriad of complications alcohol use disorder (AUD) has on the body with regards to organ systems and mental health, the topic has been underresearched in the older adult population. Thus, it is important to create awareness about the growing problem of AUD among older adults. In this way, we can mitigate the long-term complications and side effects observed with alcohol abuse in this vulnerable population.

Over-The-Counter Remedies in Older Adults: Patterns of Use, Potential Pitfalls, and Proposed Solutions.

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.

Development and assessment of a brief screening tool for psychosis in dementia.

INTRODUCTION: Hallucinations and delusions (H+D) are common in dementia, but screening for these symptoms-especially in busy clinical practices-is challenging. METHODS: Six subject matter experts developed the DRP3™ screen, a novel valid tool to detect H+D in dementia, assessed its content validity through alignment with DRP reference assessments (Scale for the Assessment of Positive Symptoms-Hallucinations + Delusions, Neuropsychiatric Inventory-Questionnaire, International Psychogeriatric Association Criteria), and retrospectively investigated its ability to detect H+D in HARMONY trial (NCT03325556) enrollees. RESULTS: All items from three reference assessments demonstrated significant agreement with the DRP3 screen among raters (P < .0001). Retrospectively applying the DRP3 screen to HARMONY identified all (N = 392) trial enrollees. DISCUSSION: The DRP3 screen, comprising three yes/no questions, is a content-valid tool for detecting H+D in dementia that aligned with current reference assessments and successfully identified trial participants when retrospectively applied to a completed trial. Within busy practice constraints, the DRP3 screen provides a brief tool for sensitive detection of H+D in patients with dementia.