George Grossberg - Academia.edu (original) (raw)

Papers by George Grossberg

Alzheimer's Disease Drug Development

Journal of Geriatric Psychiatry and Neurology, 2021

According to the Parkinson’s Foundation, at present nearly one million persons in the US suffer f... more According to the Parkinson’s Foundation, at present nearly one million persons in the US suffer from Parkinson’s Disease (PD). More than 60,000 Americans are newly diagnosed annually and world-wide, more than 10 million persons are living with PD. In this volume, we bring together experts in the field to share important, state of-the-art concepts relative to a variety of neuro-psychiatric aspects of PD. An important paper by Gallop et al reviews exciting developments in our understanding of the gut microbiota and PD. This emerging area promises to enhance our knowledge as to how microbial dysbiosis, specifically in the gut, may contribute to the neuropathophysiology of PD. This arena is already producing new, potentially promising treatment approaches for PD. The motor symptoms of PD are key in the early diagnosis of the disease and are the most-impactful throughout the course of PD. Current pharmacotherapies can dramatically improve the quality of life of PD patients. However, they come with a variety of side effects, may often need to be combined with other PD therapies, and may not work for all PD patients. The paper by Al Majali et al discusses a variety of promising pharmacotherapies which are in the pipeline for the motor symptoms of PD. These emerging treatments bring hope to PD patients who are not responding or cannot tolerate current drugs. Psychosis in PD (PDP) is common and associated with poorer quality of life for patients and increased care partner burden. The paper by Segal et al discusses the phenomenon of PDP in detail and our understanding of the neuroanatomic and neurochemical underpinnings of PDP. Also detailed are a variety of treatment approaches including pimavanserin, the first FDA-approved treatment for PDP. Mood disorders, and in particular depression, as well as symptoms of anxiety impact more than 50% of PD patients and are a source of excess disability. Lintel et al share current concepts in early recognition and management of anxiety, depression and other mood disorders in PD patients. Nonpharmacologic as well as current pharmaco-therapeutic approaches are detailed. Emerging treatments are also profiled. Current pharmacologic and non-pharmacologic approaches can dramatically improve clinical symptoms in PD. Unfortunately, they are less effective in the later stages of PD. Hwang et al address the difficult clinical scenario of managing advanced PD. They discuss a variety of available and emerging therapeutic options to help clinicians to better manage these challenging patients. Cleary et al discuss the use of neuromodulatory approaches in PD. They detail the indications for and clinical utility of Deep Brain Stimulation (DBS), which has brought hope to many advanced PD patients and their care partners. They also share their excitement relative to emerging neuromodulatory approaches, including the utility of transcranial magnetic stimulation. Cognitive-behavioral-therapy (CBT) has been shown to be an important non-pharmacologic treatment option for a variety of neuro-psychiatric disorders, including PD. Lopes et al share current concepts and data relative to the utility of CBT as an adjunct to pharmacotherapy for PD patients. They also detail how CBT can be useful in managing associated symptoms of PD, such as anxiety and mood disturbances. The importance of exercise (the universal prescription) as a non-pharmacologic therapy in PD cannot be overstated. Emig, et al remind us of the beneficial effects of exercise on motor symptoms, on non-motor symptoms of cognition, mood, sleep and in activation of key regions of the brain in PD. Prescribing exercise for PD patients is vitally important in improving motor symptoms in PD as well in improving anxiety/mood symptoms and quality of life. We hope you enjoyed reading this issue as much as we enjoyed bringing it to you.

<jats:p>Alzheimer disease is thought to have an insidious progression, with asymptomatic br... more <jats:p>Alzheimer disease is thought to have an insidious progression, with asymptomatic brain changes occurring decades prior to formal diagnosis. In recent years, efforts have been made to identify and characterize these changes into a spectrum beginning with subjective cognitive decline through the development of major neurocognitive disorder. Through this process, progress has been made into the predictive factors, prevention, and treatment modalities for the various stages of cognitive decline. In addition to pharmacologic therapies, studies have shown the value in physical, mental, social, and spiritual activity combined with support from physicians, family, and caregivers. Furthermore, individualized care, open and honest physician-patient dialogue, and emphasis on lifestyle modifications have been shown to achieve optimal quality of life and may also decrease the rate of cognitive decline. This review contains 5 figures, 5 tables, and 36 references. Key words: age-related cognitive decline, Alzheimer disease, major neurocognitive disorder, mild cognitive impairment, mild neurocognitive disorder, senior moment, subjective cognitive impairment</jats:p>

Journal of the American Medical Directors Association, 2022

and Takeda; receives research support from NIA, Janssen, and Roche; is on the safety monitoring c... more and Takeda; receives research support from NIA, Janssen, and Roche; is on the safety monitoring committee for Anavex, EryDel, ITI, Newron, Intra-Cellular Therapies, Merck, and Newron; and on the speakers bureau for Acadia Pharmaceuticals Inc and Biogen.

Alzheimer's & Dementia, 2021

Introduction: Hallucinations and delusions (H+D) are common in dementia, but screening for these ... more 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.

International Journal of General Medicine, 2021

The presence of hallucinations and delusions in patients with neurodegenerative disease correlate... more 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 televisit 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.

Clinics in Geriatric Medicine, 2022

As the number of older adults worldwide continues to grow, we observe a proportional growth of su... more 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.

International Journal of Geriatric Psychiatry, 2021

To describe characteristics and compare clinical outcomes including falls, fractures, infections,... more To describe characteristics and compare clinical outcomes including falls, fractures, infections, and neuropsychiatric symptoms (NPS) among long‐term care residents with dementia with and without agitation.

The American Journal of Geriatric Psychiatry, 2019

Introduction: Despite its significant impact, geriatric depression remains both underdiagnosed an... more Introduction: Despite its significant impact, geriatric depression remains both underdiagnosed and undertreated (1). In the absence of specific diagnostic criteria, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria currently represent the gold standard diagnostic tool for late-life depression. Given the fact that most elderly patients receive mental health care in primary care settings (2), there is an increasing need to develop practical diagnostic tools to be used by primary care practitioners. The Saint Louis University (SLU) AMSAD tool is a brief (5-item) questionnaire that was recently developed to screen for latelife depression. The 5 items reference appetite, mood, sleep, activity and death ideation using simple language and scaling. Previous research has supported its validity and reliability in cognitively intact older adults, in relation to the Geriatric Depression Scale (GDS)-15 and the Montgomery-Asberg Depression Rating Scale (MADRS) (3). However, few studies have examined the diagnostic accuracy of depression screening instruments in older adults. The objective of this study was to evaluate the accuracy and reliability of the SLU AMSAD regarding diagnosis of major depressive disorder (MDD) per DSM-5 criteria in a sample of older adults without major neurocognitive disorder. Methods: A convenience sample of 50 patients, ≥ 65 years of age was enrolled through our specialized geriatric psychiatry outpatient clinic. Patients with a clinical suspicion/diagnosis of major neurocognitive disorder as reflected by a Saint Louis University Mental Status (SLUMS) score of < 20 were excluded. MDD diagnosis was determined by the treating physician using the DSM-5 criteria. The SLU AMSAD, GDS-15 and MADRS, were then independently administered by a member of the research team who was blind to the MDD diagnosis. Internal consistency reliability of the SLU AMSAD was determined using Cronbach's coefficient alpha. Diagnostic accuracy was evaluated using receiver operating characteristic curve (ROC) analysis, with area under the curve (AUC) and sensitivity/specificity parameters calculated. Correlations coefficients (Spearman rho) were calculated between the various screening measures and MDD diagnosis. Results: Descriptive Analysis The sample had a mean (SD) age of 73.5 (7.1) years; 58% (n = 28) were women, 88% (n = 44) were Caucasian, and 86% (n = 43) had at least a high school level of education. The mean SLUMS score was 25.9 (2.9). For the depression measures, mean scores were 6.5 (4.5) for the GDS-15; 15.6 (11.4) for the MADRS; and 4.9 (3.2) for the SLU AMSAD. The SLU AMSAD evidenced adequate internal consistency reliability (alpha = .77). 30% (n = 15) of patients met DSM-5 criteria for MDD diagnosis. Diagnostic Accuracy and Correlations In the initial ROC analysis, total scores (continuous variables) for the GDS-15, MADRS, and SLU AMSAD were evaluated in relation to the DSM-5 designation of No MDD vs. MDD. AUC values were uniformly high (≥ .93), with correspondingly high levels of sensitivity (.93) and specificity (≥ .80). Optimal cutoffs were 9+ for GDS-15, 18+ for MADRS, and 7+ for SLU AMSAD. The SLU AMSAD was equivalent to GDS-15 and superior to MADRS in these analyses.

US Neurology, 2018

The physiological effects of vitamin D on calcium/phosphorus metabolism have been well studied si... more The physiological effects of vitamin D on calcium/phosphorus metabolism have been well studied since its discovery in the early 20th century. With recent advances in cellular and molecular biology, its role in maintaining normal brain functions and the protection of neurons via maintenance of cellular homeostasis, immune regulation, modulation of synaptic structure and function are more clearly known. Recently, its deficiency is increasingly implicated in major neurocognitive disorders including Alzheimer’s disease, Parkinson’s disease, and vascular dementia. Older adults are particularly vulnerable not only because vitamin D deficiency becomes more prevalent with aging, but they also are often complicated with other comorbid illnesses. This article reviews the role of vitamin D in maintaining normal brain functions, and implications for vitamin D deficiency in cognitive disorders.

Journal of Alzheimer's Disease, 2019

An estimated 47 million people live with Alzheimer's disease (AD) and other forms of dementia wor... more 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.

Therapeutic advances in drug safety, 2018

Alzheimer's disease (AD) is the most common cause of major neurocognitive disorders worldwide... more Alzheimer's disease (AD) is the most common cause of major neurocognitive disorders worldwide. Despite all research efforts, therapeutic options for AD are still limited to two drug classes: cholinesterase inhibitors (ChEIs) and the NMDA-receptor antagonist memantine. Donepezil, rivastigmine and galantamine are the three ChEIs FDA-approved as first-line treatment for AD. Although they share the same mode of action, they differ in terms of their pharmacologic characteristics and route of administration, which can impact their safety and tolerability profile. Rivastigmine, available in both oral and transdermal patch formulations, is a slowly reversible dual inhibitor of acetyl and butyryl cholinesterase, selective for the G1 isoform of acetylcholinesterase, without hepatic metabolism by the CYP-450 system. Despite its unique features, it has been associated with a higher incidence of adverse events in comparison to other ChEIs. The oral form, approved for the treatment of mild to...

Alzheimer disease and associated disorders, Jan 16, 2018

Memantine extended release (ER) significantly outperformed placebo on co-primary endpoints of Cli... more Memantine extended release (ER) significantly outperformed placebo on co-primary endpoints of Clinician's Interview-based Impression of Change Plus Caregiver Input (CIBIC-Plus) and baseline to endpoint changes on the Severe Impairment Battery (SIB) in a 24-week, randomized trial (NCT00322153) in patients with moderate to severe Alzheimer's disease taking a cholinesterase inhibitor (ChEI). A post hoc analysis compared patients receiving memantine ER/ChEI to placebo/ChEI for time to onset of response and if the response was maintained (achieving improvement at weeks 8, 12, or 18 and maintaining through endpoint/week 24) on the SIB, the Neuropsychiatric Inventory (NPI), CIBIC-Plus, and Activities of Daily Living (ADL) using Fisher exact test. A second post hoc analysis compared percentages of patients for all possible combinations of 2 to 4 assessments with either no decline or clinically notable response using Wald χ. Significantly greater percentages of memantine ER/ChEI pati...

Drug design, development and therapy, 2016

Currently available therapies for the treatment of Alzheimer's disease (AD) consist of cholin... more 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 i...

Degenerative Neurological and Neuromuscular Disease, 2011

Alzheimer's disease (AD) is a progressive, degenerative brain disease. Currently available US FDA... more Alzheimer's disease (AD) is a progressive, degenerative brain disease. Currently available US FDA-approved pharmacological management options for AD are cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and the N-methyl-D-aspartate receptor antagonist (memantine). These treatment options may provide symptomatic benefits. Medication adherence is one of the many problems faced by the caregivers of patients with dementia. The currently available FDA-approved memantine immediate-release (IR) has been found safe and efficacious at a dose of 10 mg twice daily (20 mg/day) both as monotherapy and in combination with cholinesterase inhibitors in moderate to severe dementia. Memantine extended-release (ER) 28 mg, a new once-daily form at a higher dose, has also been found to be safe and well tolerated in 2 studies: one in 24 healthy volunteers which showed relatively minor fluctuation in plasma levels of memantine during the steady-state dosing interval and second, a multinational multi-center study, comparing memantine ER 28 mg and placebo in patients with moderate to severe AD stable on concurrent cholinesterase inhibitor (ChEI). In this study, memantine ER was found to be an efficacious drug with a good safety and tolerability profile. Both memantine IR 20 mg and memantine ER 28 mg are now FDA-approved for the treatment of moderate to severe AD, either alone, or in combination with a ChEI. Both are efficacious, safe, and well tolerated. Medication adherence with the ER preparation should improve because of once-daily dosing. There is a possibility of superior efficacy of the higher dose memantine ER (28 mg) over the currently approved dosage of memantine IR (20 mg). However, further randomized, controlled, double-blind comparator studies of memantine ER 28 mg vs memantine IR 20 mg and/or 30 mg in single and/or divided doses are required to assess the possible benefits of memantine ER over memantine IR.

Primary Psychiatry, 2007

The elderly, especially those >85 years of age, have an increased prevalence of psychotic symp... more The elderly, especially those >85 years of age, have an increased prevalence of psychotic symptoms. Several factors may contribute to the onset of psychotic symptoms, such as age-related changes, environmental changes, medical conditions, and mental conditions. Psychotic symptoms can be primary or secondary. Primary causes are known to be schizophrenia, schizoaffective disorder, and delusional disorders. The common secondary causes seen in most clinical practices are delirium, dementia, and depression. Knowledge of delirium is of great importance to clinicians as underlying causes have to be differentiated and treated appropriately. Psychotic symptoms are common in dementia and depression and are of interest as the psychotic features can be persistent and difficult to treat. Psychotic symptoms, if not recognized and treated, will increase the morbidity of the elderly patient. Determining the accurate diagnosis when psychotic features are present can be difficult, especially when little is known about premorbid functioning, psychiatric history, or medical history. This article systematically discusses the possible diagnostic categories in which to place these patients, including the typical symptoms and illness course most commonly seen with each, which in turn can help guide further evaluation and treatment decisions.

Missouri medicine

This paper reviews the emergence of geriatric psychiatry in the United States and Missouri. It di... more This paper reviews the emergence of geriatric psychiatry in the United States and Missouri. It discusses current and future needs for geriatric psychiatrists. Lastly, it focuses on recent developments in key psycho-geriatric syndromes with an emphasis on current and emerging treatments.

Current Alzheimer Research, 2015

Background: ACTION, a 24-week, prospective, randomized, parallel-group, double-blind study in pat... more Background: ACTION, a 24-week, prospective, randomized, parallel-group, double-blind study in patients with severe Alzheimer's disease (AD), demonstrated significant efficacy of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch on the Severe Impairment Battery (SIB) and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV). Overall, 61% of the study population received at least 1 dose of concomitant memantine, regardless of dose or duration. This retrospective analysis investigated the effects of concomitant memantine on the efficacy, safety and tolerability of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch. Methods: Patients were stratified according to whether or not they received at least one dose of concomitant memantine during the double-blind phase. Changes from baseline on the SIB and ADCS-ADL-SIV were compared using analysis of covariance (ANCOVA) with treatment, pooled center, memantine usage and treatment-by-memantine as factors, and baseline as a covariate. Safety and tolerability were assessed. Results: Memantine-treated patients were younger than those not receiving memantine (mean 75.9 and 78.8 years, respectively), with a lower screening Mini-Mental State Examination (8.6 and 9.2, respectively). ANCOVA confirmed there was no significant interaction (p>0.1) between study treatment and memantine use on the SIB or ADCS-ADL-SIV. The incidence of adverse events was: 71.4%, 13.3 mg/24 h patch with memantine; 79.7%, 13.3 mg/24 h patch alone; 74.7%, 4.6 mg/24 h patch with memantine; and 71.1%, 4.6 mg/24 h patch alone. Conclusion: These data suggest benefit of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch, regardless of concomitant memantine use. The incidence of adverse events with highdose patch was similar in memantine-treated patients and those not receiving memantine.

The American Journal of Geriatric Psychiatry, 2015

Objectives: Combining five commonly observed symptoms of late-life depression to develop a short ... more Objectives: Combining five commonly observed symptoms of late-life depression to develop a short depression screening tool with similar sensitivity and specificity as the conventional, more time consuming tools. Methods: We developed the St. Louis University (SLU) "AM SAD" (Appetite, Mood, Sleep, Activity and thoughts of Death) questionnaire. The frequency of each symptom in the prior two weeks is quantified as 0, 1 and 2. Patients ≥65 y/o from our clinics were administered the AM SAD, the Geriatric Depression Scale (GDS-15), the Montgomery-Asberg Depression Rating Scale (MADRS) and the St. Louis University Mental Status Exam (SLUMS). Results: 100 patients above 65yrs were selected. AM SAD correlation with GDS was 0.72 and MADRS 0.80. AM SAD yielded a sensitivity and specificity of 79% and 62% against diagnosis of depression; of 88% and 62% with GDS-15; and 92% and 71% with MADRS. Conclusions: The AM SAD can be reliably used as a short depression screening tool in patients with a SLUMS score ≥20.