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Biomedical subjects

George T Grossberg

Publications and source records attributed to George T Grossberg.

At least 19 recordsLinked to original sources
PubMed2006

Mood disorders in the elderly.

Mood disorders in the elderly are a growing source of morbidity and mortality. Unfortunately, mood disorders in later life frequently are not diagnosed and treated. Appropriate, prompt diagnosis and treatment of late-life mood disorders can significantly improve the quality of life of patients and families and may prove life saving. Current treatments can help most older adults with mood disorders. Future treatments are promising, particularly for those with treatment-resistant depression.

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PubMed2006

Pharmacology of acetylcholinesterase inhibitors and N-methyl-D-aspartate receptors for combination therapy in the treatment of Alzheimer's disease.

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.

Acetylcholine↗
PubMed2006

Rationale for combination therapy with galantamine and memantine in Alzheimer's disease.

A combination of cholinergic and glutamatergic dysfunction appears to underlie the symptomatology of Alzheimer's disease. Therefore, one hypothesis is that treatment strategies should address impairments in both systems. Galantamine is an acetylcholinesterase inhibitor that, unlike other acetylcholinesterase inhibitors, has a postulated dual mode of action as a nicotinic receptor modulator. Galantamine has demonstrated long-term efficacy in improving or maintaining cognition, functionality, and behavior in patients with mild to moderate Alzheimer's disease. Memantine, a noncompetitive N-methyl-D-aspartate-receptor antagonist, reduces deterioration in cognition and function in patients with moderate to severe Alzheimer's disease. Pharmacokinetic and pharmacodynamic as well as ongoing observation studies support the concept of adjunctive therapy with memantine in patients with advanced moderate Alzheimer's disease currently treated with an established galantamine regimen. The potential to modulate both acetylcholine and glutamate pathways in Alzheimer's disease presents a novel treatment strategy for the management of mild to moderately severe Alzheimer's disease.

Alzheimer Disease↗
PubMed2005

Diagnosis and treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia. It is one of the principal causes of disability and decreased quality of life among older adults. Progress in our clinical knowledge of AD has led to more reliable diagnostic criteria and accuracy, and research efforts are expanding to uncover the earliest manifestations and even the presymptomatic phases of the disease. The diagnosis of AD is primarily one of inclusion and usually can be made using standardized clinical criteria. There is currently no cure for AD. Current treatment focuses on establishing an early accurate clinical diagnosis, early institution of cholinesterase inhibitors and/or N-methyl-D-aspartate (NMDA) receptor-targeted therapy. Treating medical comorbidities and dementia-related complications, ensuring that appropriate services are provided, addressing the long-term well-being of caregivers, and treating behavioral and psychological symptoms with appropriate nonpharmacologic and pharmacologic interventions also are important. The initiating and propagating pathologic processes and the anatomic location of the earliest changes will become new targets of research and therapeutic development. A possible precursor of AD, mild cognitive impairment (MCI), is under investigation as a possible therapeutic starting point for disease-modifying interventions. This article provides a research update of current understanding in the diagnosis and treatment of AD and in emerging areas of interest such as MCI, detection of AD in the predementia phase, and neuroimaging in AD.

Alzheimer Disease↗
PubMed2005

Rationalizing therapeutic approaches in Alzheimer's disease.

Deficits in cholinergic and glutamatergic neurotransmission have been linked to the symptomatology of Alzheimer's disease, and current therapies for Alzheimer's, including cholinesterase inhibitors (ChEIs) and the N-methyl-d-aspartate receptor antagonist memantine, have been developed to compensate for these deficits. This article reviews the results of clinical trials involving agents approved by the United States Food and Drug Administration for use in the treatment of Alzheimer's disease (namely, ChEIs for mild to moderate Alzheimer's and memantine for moderate to severe Alzheimer's). In particular, the efficacy of current monotherapy strategies in the treatment of cognitive and functional symptoms of Alzheimer's disease will be addressed. In addition, data from a clinical trial examining the use of a ChEI in combination with memantine will also be discussed, as it has been hypothesized that ChEIs and memantine may offer synergistic benefits due to their distinct mechanisms of action.

Activities of Daily Living↗
PubMed2005

Effect of rivastigmine in the treatment of behavioral disturbances associated with dementia: review of neuropsychiatric impairment in Alzheimer's disease.

Cognitive decline is conventionally regarded as the defining clinical symptom of Alzheimer's disease (AD), but behavioral and neuropsychiatric symptoms are also present throughout the course of the disease. In fact, behavioral symptoms may appear before cognitive decline is diagnosed. The presence of these symptoms may predict an increasing need for community-based services or even nursing home placement. The characteristic behavioral and neuropsychiatric symptoms associated with AD may be related to the same pathophysiology that underlies the cognitive abnormalities. AD is characterized by a loss of cholinergic neurons as well as by the presence of neurofibrillary tangles (NFTs) and senile plaques in brain regions with cholinergic deficits, resulting in a deficiency in acetylcholine (ACh) in areas of the brain that modulate cognition, behavior, and emotion. Cholinesterase inhibitors are thought to augment or maximize the concentration of ACh in the synaptic cleft. Rivastigmine is a dual inhibitor of both acetylcholin esterase (AChE) and butyrylcholinesterase (BuChE), enzymes involved in hydrolysis of ACh. Literature searches using MEDLINE and EMBASE databases were performed to identify studies of rivastigmine (through August 2005) that assessed neuropsychiatric aspects of AD. Rivastigmine has been demonstrated to be safe and effective in stabilizing or improving the cognitive symptoms of AD in 3 large, well-controlled, randomized clinical trials, which also demonstrated that rivastig mine improves overall global functioning. Smaller studies and meta-analyses of pooled data from the 3 large trials have suggested that rivastigmine may improve the behavioral and neuropsychiatric symptoms associated with AD.

Alzheimer Disease↗
PubMed2005

Rivastigmine for Alzheimer's disease.

Alzheimer's disease is the most common form of neurodegenerative dementia and poses considerable health challenges to both patients and their families. Rivastigmine is a powerful slow-reversible, noncompetitive carbamate cholinesterase inhibitor that is approved for the treatment of mild-to-moderate Alzheimer's disease. Randomized, double-blind, placebo-controlled trials of up to 6 months duration have shown beneficial effects of rivastigmine compared with placebo in measures of cognition and global functioning. Less rigorous but growing data suggest that the beneficial effects may endure for up to 5 years, extend to more advanced stages of Alzheimer's disease and may occur in noncognitive domains, such as activities of daily living and the behavioral symptoms of Alzheimer's disease. Evidence from controlled studies also supports the use of rivastigmine for cognitive and behavioral symptoms in Alzheimer's disease associated with vascular risk factors, dementia with Lewy bodies and Parkinson's disease dementia. Early and continued treatment of Alzheimer's disease with rivastigmine maximizes the observed beneficial effects. The most prominent adverse effect of rivastigmine is centrally mediated cholinergic gastrointestinal events, which can be minimized by slower dose-escalation intervals and administration with a full meal. Therapeutic dosing is 6-12 mg/day given twice daily, with higher doses having the potential for greater benefits.

Alzheimer Disease↗
PubMed2004

Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial.

CONTEXT: Memantine is a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. Controlled trials have demonstrated the safety and efficacy of memantine monotherapy for patients with moderate to severe Alzheimer disease (AD) but no controlled trials of memantine in patients receiving a cholinesterase inhibitor have been performed. OBJECTIVE: To compare the efficacy and safety of memantine vs placebo in patients with moderate to severe AD already receiving stable treatment with donepezil. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled clinical trial of 404 patients with moderate to severe AD and Mini-Mental State Examination scores of 5 to 14, who received stable doses of donepezil, conducted at 37 US sites between June 11, 2001, and June 3, 2002. A total of 322 patients (80%) completed the trial. INTERVENTIONS: Participants were randomized to receive memantine (starting dose 5 mg/d, increased to 20 mg/d, n = 203) or placebo (n = 201) for 24 weeks. MAIN OUTCOME MEASURES: Change from baseline on the Severe Impairment Battery (SIB), a measure of cognition, and on a modified 19-item AD Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL19). Secondary outcomes included a Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory, and the Behavioral Rating Scale for Geriatric Patients (BGP Care Dependency Subscale). RESULTS: The change in total mean (SE) scores favored memantine vs placebo treatment for SIB (possible score range, 0-100), 0.9 (0.67) vs -2.5 (0.69), respectively (P<.001); ADCS-ADL19 (possible score range, 0-54), -2.0 (0.50) vs -3.4 (0.51), respectively (P =.03); and the CIBIC-Plus (possible score range, 1-7), 4.41 (0.074) vs 4.66 (0.075), respectively (P =.03). All other secondary measures showed significant benefits of memantine treatment. Treatment discontinuations because of adverse events for memantine vs placebo were 15 (7.4%) vs 25 (12.4%), respectively. CONCLUSIONS: In patients with moderate to severe AD receiving stable doses of donepezil, memantine resulted in significantly better outcomes than placebo on measures of cognition, activities of daily living, global outcome, and behavior and was well tolerated. These results, together with previous studies, suggest that memantine represents a new approach for the treatment of patients with moderate to severe AD.

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PubMed2004

Activities of daily living in patients with dementia: clinical relevance, methods of assessment and effects of treatment.

Disability, characterised by the loss of ability to perform activities of daily living (ADL), is a defining feature of dementia that results in growing caregiver burden and the eventual need for alternative care or nursing home placement. Functional decline in patients with dementia can also result from causes other than dementia, such as comorbid medical and psychiatric illnesses and sensory impairment. ADL consists of instrumental ADL (IADL) [complex higher order skills, such as managing finances] and basic ADL (BADL) [self-maintenance skills, such as bathing]. Assessment of IADL and BADL is recommended to establish a diagnosis of dementia. Functional assessment also helps the healthcare provider to offer appropriate counselling regarding safety concerns and need for custodial care. Functional capacity measures have been used increasingly in pharmacological trials of patients with Alzheimer's disease (AD) and related dementias, although at the present time these measures are generally not primary outcome measures. Functional impairment is not a uniform construct; rather, it is multifaceted and can be measured with various clinical instruments. Many scales have been validated for use in patients with AD for characterising functional impairment and evaluating the efficacy of treatment. Research to date indicates that cholinesterase inhibitors have the potential for modest but meaningful beneficial effects on ADL in patients with mild-to-moderate AD. Memantine also has promising beneficial effects on functional abilities in persons with moderate-to-severe AD. Assessment of ADL as a primary efficacy measure using a validated scale that is non-gender biased and cross-nationally relevant is recommended in new treatment trials of patients with AD and related dementias.

Activities of Daily Living↗
PubMed2003

Electroconvulsive therapy in the elderly.

ECT is a safe, useful, and effective treatment for a variety of disorders and can be administered safely in elderly patients. Efforts need to be undertaken to increase the awareness and acceptability of ECT treatments. As Carl Salzman says in the January 1998 issue of the American Journal of Psychiatry, "Let us not perpetuate outmoded, nonscientific and incorrect attitudes toward ECT in our younger colleagues. Rather, let us stimulate scientific curiosity and research into this cost-effective and safe psychiatric treatment."

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PubMed2003

Strategies for continued successful treatment of Alzheimer's disease: switching cholinesterase inhibitors.

Cholinesterase (ChE) inhibitors represent the standard therapeutic approach to the treatment of Alzheimer's disease (AD). However, a proportion of patients experience lack or loss of therapeutic benefit with an initial agent, or discontinue due to safety/tolerability issues. In many instances, no alternative treatment is offered once the initial agent has been stopped. Thus, for many patients, the total duration of treatment is relatively short in comparison with the chronic nature of AD. Switching medications is a common therapeutic strategy within many drug classes across many clinical areas following a lack/loss of efficacy or safety/tolerability problems, and is also an increasingly important concept in the management of AD with ChE inhibitors. A number of open-label studies, where patients were switched from donepezil to rivastigmine, have indicated that approximately 50% of patients experiencing a lack/loss of efficacy with donepezil (a selective acetylcholinesterase [AChE] inhibitor) respond to subsequent treatment with rivastigmine (a dual AChE and butyrylcholinesterase inhibitor). In these studies, rivastigmine was well tolerated, and the occurrence of safety/tolerability problems with donepezil was not predictive of similar problems with rivastigmine. In the summer of 2002, leading neurologists and psychiatrists attended a medical experts meeting to discuss the clinical importance of switching ChE inhibitors in AD. The expert panel examined available clinical data, shared clinical experiences, and discussed current clinical guidelines for switching. The panel also aimed to reach consensus on 'whom to switch', 'when to switch' and 'how to switch'. The key findings from that meeting are reported in this review.

Alzheimer Disease↗
PubMed2003

Diagnosis and treatment of Alzheimer's disease.

The defining characteristic of Alzheimer's disease is cognitive impairment, but commonly this impairment is accompanied by mood and behavioral symptoms such as depression, anxiety, irritability, inappropriate behavior, sleep disturbance, psychosis, and agitation. The symptoms of Alzheimer's disease are not normative to the aging process. Diagnosis of Alzheimer's disease in the majority of cases can be made with confidence through office-based clinical assessment and informant interview. Alzheimer's disease is the most common of the dementing disorders and is exponentially increasing in incidence, projected to affect 8.64 million people in the United States by the year 2047. At present, no treatment can prevent or cure Alzheimer's disease, and the fact that Alzheimer's affects a geriatric population makes treatment all the more challenging. Therapies that could delay onset of symptoms even briefly would have a major impact on public health. As the prevalence of Alzheimer's disease increases, researchers are examining the efficacy of treatment options beyond the realm of the established cholinesterase inhibitors.

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PubMed2002

The ABC of Alzheimer's disease: behavioral symptoms and their treatment.

Behavioral and psychological symptoms of dementia (BPSD) are a common manifestation of Alzheimer's disease (AD) and other dementia syndromes. Patients experience prominent and multiple symptoms, which are both distressing and a source of considerable social, health, and economic cost. Development of symptoms is in part related to progressive neurodegeneration and cholinergic deficiency in brain regions important in the regulation of behavioral and emotional responses including the cortex, hippocampus, and limbic system. Cholinesterase (ChE) inhibitors offer a mechanism-based approach to therapy to enhance endogenous cholinergic neurotransmission. Studies using ChE inhibitors have demonstrated their clear potential to improve or stabilize existing BPSD. Differences have been noted between selective acetylcholinesterase (AChE) inhibitors (donepezil and galantamine) and dual ChE inhibitors (rivastigmine) in terms of treatment response. While donepezil has shown efficacy in moderate to severe noninstitutionalized AD patients, conflicting results have been obtained in mild to moderate patients and in nursing home patients. Galantamine has been shown to delay the onset of BPSD during a five-month study but has been otherwise poorly studied to-date. Both donepezil and galantamine have not as yet demonstrated efficacy in reducing psychotic symptoms or in reducing levels of concomitant psychotropic medication use. Studies with the dual ChE inhibitor rivastigmine in mild to moderately severe AD and in Lewy body dementia (LBD) have shown improvements in behavioral symptoms including psychosis. Improvements have been maintained over a period of up to two years. In addition, institutionalized patients with severe AD have shown symptomatic benefits with a reduction in the requirement for additional psychotropic drugs following treatment with rivastigmine. The psychotropic properties associated with rivastigmine may in part be mediated through effects on butyrylcholinesterase. Current treatment options are limited for patients with dementia syndromes other than AD. However, data concerning rivastigmine in patients with LBD and preliminary studies in Parkinson's disease dementia and vascular dementia suggest a role for ChE inhibitors across the spectrum of dementia syndromes. Finally, studies that incorporated a delayed start design demonstrate that ChE inhibitors may delay the progression of BPSD.

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