Alzheimer Disease: Mintzer J

Salloway S, Mintzer J, Weiner MF, Cummings JL. · Department of Clinical Neuroscience, Division of Biology and Medicine, Brown Medical School, Providence, RI, USA. · Alzheimers Dement. · Pubmed #18631951 No free full text.

Abstract: Alzheimer's disease (AD) is a chronic, progressive, neurodegenerative disorder that places a substantial burden on patients, their families, and society. The disease affects approximately 5 million individuals in the United States, with an annual cost of care greater than $100 billion. During the past dozen years, several agents have been approved that enhance cognition and global function of AD patients, and recent advances in understanding AD pathogenesis has led to the development of numerous compounds that might modify the disease process. A wide array of antiamyloid and neuroprotective therapeutic approaches are under investigation on the basis of the hypothesis that amyloid beta (A beta) protein plays a pivotal role in disease onset and progression and that secondary consequences of A beta generation and deposition, including tau hyperphosphorylation and neurofibrillary tangle formation, oxidation, inflammation, and excitotoxicity, contribute to the disease process. Interventions in these processes with agents that reduce amyloid production, limit aggregation, or increase removal might block the cascade of events comprising AD pathogenesis. Reducing tau hyperphosphorylation, limiting oxidation and excitotoxicity, and controlling inflammation might be beneficial disease-modifying strategies. Potentially neuroprotective and restorative treatments such as neurotrophins, neurotrophic factor enhancers, and stem cell-related approaches are also under investigation.

Broadway J, Mintzer J. · Adult and Geriatric Psychiatry, Medical University of South Carolina, Charleston, SC 29425, USA. · Curr Opin Psychiatry. · Pubmed #17921754 No free full text.

Abstract: PURPOSE OF REVIEW: As the population ages, the number of older patients with psychosis will greatly rise. This review focuses on the etiology, biologic and clinical findings, and treatments of common causes of psychosis in the elderly. RECENT FINDINGS: Recent studies on psychosis related to Alzheimer's disease indicate that antipsychotic drugs have equivocal efficacy in improving psychotic symptoms and may have side effects or risks that outweigh their benefits. Behavioral interventions for agitation in dementia are showing some promise. In older adults with schizophrenia, intramuscular ziprasidone was found to be effective, and evidence is emerging for the use of hormone replacement therapy. For depression with psychosis, a recent study found that the combination of an antidepressant with an antipsychotic is no more effective than an antidepressant alone. SUMMARY: There is support for the use of antipsychotic drugs for all types of psychosis in the elderly. While the atypical antipsychotics have a 'black box warning' on risk of death in elderly patients with dementia, the typical antipsychotics carry an even higher risk of death and adverse effects. Weighing the potential risks and benefits of treatment options is essential. Please refer to your country's regulations regarding the use of antipsychotic drugs.

McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, Cohen-Mansfield J, Dickson D, Dubois B, Duda JE, Feldman H, Gauthier S, Halliday G, Lawlor B, Lippa C, Lopez OL, Carlos Machado J, O'Brien J, Playfer J, Reid W, Anonymous00116. · Institute for Ageing and Health, University of Newcastle, Newcastle upon Tyne, UK. · Lancet Neurol. · Pubmed #14693108 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is the second commonest cause of neurodegenerative dementia in older people. It is part of the range of clinical presentations that share a neuritic pathology based on abnormal aggregation of the synaptic protein alpha-synuclein. DLB has many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's disease. Here we review the current state of scientific knowledge on DLB. Accurate identification of patients is important because they have specific symptoms, impairments, and functional disabilities that differ from those of other common types of dementia. Severe neuroleptic sensitivity reactions are associated with significantly increased morbidity and mortality. Treatment with cholinesterase inhibitors is well tolerated by most patients and substantially improves cognitive and neuropsychiatric symptoms. Clear guidance on the management of DLB is urgently needed. Virtually unrecognised 20 years ago, DLB could within this decade be one of the most treatable neurodegenerative disorders of late life.

Mintzer J, Targum SD. · Medical University of South Carolina, Institute of Psychiatry, Charleston 29406, USA. · J Geriatr Psychiatry Neurol. · Pubmed #14653427 No free full text.

Abstract: Psychosis in elderly patients is a growing clinical concern because psychotic symptoms most frequently occur as noncognitive manifestations of Alzheimer's disease, as side effects of drug therapy for Parkinson's disease, or as the primary abnormalities in schizophrenia, and the clinical characteristics of psychosis are distinct for each. In planning antipsychotic pharmacotherapy for elderly patients, age-related pharmacokinetic changes, polypharmacy for comorbid diseases, and concerns about the underlying conditions responsible for the psychotic symptoms must be considered. Traditional antipsychotic agents bind to dopamine receptors and effectively relieve positive schizophrenic symptoms but frequently cause tardive dyskinesia and other extrapyramidal symptoms, a problem for elderly patients, particularly for those with Parkinson's disease. Atypical antipsychotics bind to dopamine and serotonin receptors, relieving both positive and negative symptoms, and are less likely to cause extrapyramidal symptoms. The authors review common diagnostics associated with psychosis in the elderly and clinical guidelines to selecting antipsychotic pharmacotherapy.

Grundman M, Petersen RC, Ferris SH, Thomas RG, Aisen PS, Bennett DA, Foster NL, Jack CR, Galasko DR, Doody R, Kaye J, Sano M, Mohs R, Gauthier S, Kim HT, Jin S, Schultz AN, Schafer K, Mulnard R, van Dyck CH, Mintzer J, Zamrini EY, Cahn-Weiner D, Thal LJ, Anonymous00151. · Alzheimer's Disease Cooperative Study, Department of Neurosciences, University of California-San Diego, 8950 Villa La Jolla Drive, Suite 227, La Jolla, CA 92037, USA. · Arch Neurol. · Pubmed #14732621 links to  free full text

Abstract: BACKGROUND: Mild cognitive impairment (MCI) represents a transitional state between the cognitive changes of normal aging and very early dementia and is becoming increasingly recognized as a risk factor for Alzheimer disease (AD). The Memory Impairment Study (MIS) is a multicenter clinical trial in patients with MCI designed to evaluate whether vitamin E or donepezil is effective at delaying the time to a clinical diagnosis of AD. OBJECTIVE: To describe the baseline characteristics of patients with MCI recruited for the MIS and compare them with those of elderly controls and patients with AD in another clinical trial. DESIGN: Descriptive and comparative study of patients with MCI participating in a multicenter clinical trial. SETTING: Memory disorder centers in the United States and Canada. PATIENTS: A total of 769 patients with MCI, 107 cognitively normal elderly controls, 122 patients with very mild AD (Clinical Dementia Rating [CDR] 0.5), and 183 patients with mild AD (CDR 1.0) were evaluated. Patients in the MIS met operational criteria for amnestic MCI. Controls were recruited in parallel with the MCI group, underwent the same assessments, and had a CDR of 0. MAIN OUTCOME MEASURES: Clinical, neuropsychologic, functional, neuroimaging, and genetic measures. RESULTS: Mean +/- SD Alzheimer's Disease Assessment Scale-Cognitive Subscale scores were 5.6 +/- 3.3 for controls, 11.3 +/- 4.4 for patients with MCI, 18.0 +/- 6.2 for the AD CDR 0.5 group, and 25.2 +/- 8.8 for the AD CDR 1.0 group. Compared with controls, patients with MCI were most impaired on memory tasks, with less severe impairments in other cognitive domains. Patients with MCI were more likely than controls but less likely than patients with AD to carry the apolipoprotein E epsilon4 allele. Patients with MCI had hippocampal volumes that were intermediate between those of controls and patients with AD. CONCLUSIONS: Patients with MCI had a predominant memory impairment with relative sparing of other cognitive domains and were intermediate between clinically normal individuals and patients with AD on cognitive and functional ratings. These results demonstrate the successful implementation of operational criteria for this unique group of at-risk patients in a multicenter clinical trial.

Krishnan KR, Charles HC, Doraiswamy PM, Mintzer J, Weisler R, Yu X, Perdomo C, Ieni JR, Rogers S. · Department of Psychiatry, Duke University Medical Center, Durham, NC 27710, USA. · Am J Psychiatry. · Pubmed #14594748 links to  free full text

Abstract: OBJECTIVE: The authors examined the effect of the acetylcholinesterase inhibitor donepezil on magnetic resonance markers of neurodegeneration in Alzheimer's disease. METHOD: In this randomized, double-blind, placebo-controlled pilot study, 67 patients with mild to moderate Alzheimer's disease received 24 weeks of treatment with donepezil (5 mg/day for the first 28 days and 10 mg/day thereafter) or placebo. Patients were reevaluated at 6-week intervals to measure change from baseline in several outcome measures, including right, left, and total hippocampal volumes, measured with magnetic resonance imaging; brain concentrations of N-acetylaspartate, measured with proton magnetic resonance spectroscopy; and cognition, assessed with the Alzheimer's Disease Assessment Scale cognitive subscale. RESULTS: At some interim assessments, mean normalized measures of N-acetylaspartate concentration tended to be higher in the donepezil-treated patients than in the patients who received placebo, but these differences were not significant at endpoint. At endpoint, the donepezil-treated patients had significantly smaller mean decreases in total and right hippocampal volumes and a smaller, nearly significant mean decrease in left hippocampal volume, compared with the placebo-treated patients. Mean Alzheimer's Disease Assessment Scale cognitive subscale scores were improved after treatment with donepezil, relative to placebo, at weeks 6, 12, 18, and 24. CONCLUSIONS: These preliminary results suggest that donepezil may have a potentially protective effect in Alzheimer's disease. Larger, longer-term confirmatory studies of the medication's effects are warranted.

Tariot PN, Cummings JL, Katz IR, Mintzer J, Perdomo CA, Schwam EM, Whalen E. · Department of Psychiatry, University of Rochester Medical Center, Monroe Community Hospital, Rochester, New York 14620, USA. · J Am Geriatr Soc. · Pubmed #11843990 No free full text.

Abstract: OBJECTIVES: To evaluate the safety and efficacy of donepezil in the management of patients with Alzheimer's disease (AD) residing in nursing home facilities. DESIGN: Twenty-four-week, randomized, multicenter, parallel-group, double-blind, placebo-controlled trial. SETTING: Twenty-seven nursing homes across the United States. PARTICIPANTS: Two hundred eight nursing home patients with a diagnosis of probable or possible AD, or AD with cerebrovascular disease; mean Mini-Mental State Examination (MMSE) score 14.4; mean age 85.7. MEASUREMENTS: The primary outcome measure was the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH). Secondary efficacy measures were the Clinical Dementia Rating (Nursing Home Version)-Sum of the Boxes (CDR-SB), MMSE, and the Physical Self-Maintenance Scale (PSMS). Safety was monitored by physical examinations, vital signs, clinical laboratory tests, electrocardiograms (ECGs), and treatment-emergent adverse events (AEs). RESULTS: Eighty-two percent of donepezil- and 74% of placebo-treated patients completed the trial. Eleven percent of donepezil- and 18% of placebo-treated patients withdrew because of AEs. Mean NPI-NH 12-item total scores improved relative to baseline for both groups, with no significant differences observed between the groups at any assessment. Mean change from baseline CDR-SB total score improved significantly with donepezil compared with placebo at Week 24 (P < .05). The change in CDR-SB total score was not influenced by age. Differences in mean change from baseline on the MMSE favored donepezil over placebo at Weeks 8, 16, and 20 (P < .05). No significant differences were observed between the groups on the PSMS. Overall rates of occurrence and severity of AEs were similar between the two groups (97% placebo, 96% donepezil). Gastrointestinal AEs occurred more frequently in donepezil-treated patients. In general, AEs were similar in older and younger donepezil-treated patients, with the majority of patients experiencing only AEs that were transient and mild or moderate in severity. Weight loss was reported as an AE more frequently in older patients, although a loss at last visit of >or=7% of screening weight occurred at the same rate in older and younger patients (9% of donepezil- and 6% of placebo-treated patients). No significant differences between groups in vital sign changes, bradycardia, or rates of clinically significant laboratory or ECG abnormalities were observed. CONCLUSION: Patients treated with donepezil maintained or improved in cognition and overall dementia severity in contrast to placebo-treated patients who declined during the 6-month treatment period. The safety and tolerability profile was comparable with that reported in outpatient studies of donepezil. These findings also suggest that advanced age, comorbid illnesses, and high concomitant medication usage should not be barriers to donepezil treatment. Given the apparent improvement in behavior in the placebo group, and the high use of concomitant medications in both groups, the impact of donepezil on behavior in the nursing home setting is unresolved and merits further investigation. In summary, effects on cognition, overall dementia severity, and safety and tolerability findings are consistent with previous findings in outpatients and support the use of donepezil in patients with AD who reside in nursing homes.

Mintzer J, Faison W, Street JS, Sutton VK, Breier A. · Medical University of South Carolina, Alzheimer's Research and Clinical Programs Charleston, SC 29406-6076, USA. · Int J Geriatr Psychiatry. · Pubmed #11748790 No free full text.

Abstract: BACKGROUND: Alzheimer's disease (AD) is associated with both cognitive and behavioral symptoms. Agitation, hallucinations, delusions, aggression, irritability, and anxiety are observed in up to 90% of patients with dementia. Although new information has emerged in recent years on the treatment of psychosis and agitation in dementia, very little information is available about the treatment of anxiety symptoms in this population. OBJECTIVES: To assess the efficacy and tolerability of olanzapine in the treatment of significant anxiety symptoms in patients with AD. METHODS: A post hoc analysis of a previously published study was performed. Those post hoc analysis evaluated the response to treatment with olanzapine of a subgroup of AD patients presenting with significant symptoms of anxiety. Patients were considered to have significant symptoms of anxiety if their baseline in the Nursing home version of the Neuropsychiatric Instrument NPI/NH anxiety scores were > or = 2. The analysis included 120 patients. RESULTS: Patients receiving olanzapine 5 mg/d were statistically significantly improved on the NPI/NH Anxiety item compared to those receiving placebo (olanzapine, 5 mg/d: -3.72; placebo: -1.67; p = 0.034). In the group of patients with clinically significant anxiety, somnolence was the only treatment-emergent event that was statistically different in any olanzapine treatment group compared with placebo (olanzapine 5 mg/d: 9 patients [25%], p = 0.034; 10 mg/d: 7 [23%], p = 0.054; 15 mg/d: 7 [26%], p = 0.050; placebo: 1 [3.7%]). When controlling for treatment-emergent somnolence, the improvement in anxiety in the olanzapine 5 mg/d group remained statistically significant (p = 0.049). CONCLUSIONS: These findings suggest that olanzapine could be a safe and effective treatment for anxiety in Alzheimer's disease.

Rockwood K, Mintzer J, Truyen L, Wessel T, Wilkinson D. · Centre for Health Care of the Elderly, QEII Health Sciences Centre, 1421-5955 Veterans' Memorial Lane, Halifax, Canada B3H 2E1. · J Neurol Neurosurg Psychiatry. · Pubmed #11606667 links to  free full text

Abstract: OBJECTIVE: To assess the efficacy and safety of galantamine in Alzheimer's disease at 3 months using flexible dose escalation. METHODS: A randomised, double blind, placebo controlled trial in 43 centres in the United States, Canada, Great Britain, South Africa, Australia, and New Zealand. Patients with probable Alzheimer's disease (n=386; 171 women) with a score of 11-24 on the mini mental state examination, and a score> or =12 on the cognitive subscale of the Alzheimer's disease assessment scale (ADAS-cog) were randomised to placebo, or galantamine escalated over 4 weeks to a maintenance dose of 24 or 32 mg/day. The primary outcome measures were the change in ADAS-cog score and the clinician's interview based impression of change plus caregiver input (CIBIC-plus) score. Activities of daily living (ADL) and behavioural symptoms were secondary outcomes. To compare the effects of highest levels of dosing, an observed cases (OC) analysis was undertaken, with classic intention to treat (ITT) and ITT with last observation carried forward (LOCF) as confirmatory analyses. RESULTS: At 3 months, galantamine (24-32 mg/day) produced a significantly better outcome on cognitive function than placebo (treatment difference=1.9 points on ADAS-cog, p=0.002) and a significantly better global response than placebo, as measured by CIBIC-plus (deterioration in 21% of patients on galantamine v 37% on placebo; p<0.001). Galantamine produced significant benefits on basic and instrumental ADL. Behavioural symptoms did not change significantly from baseline levels in either group. Adverse events (primarily gastrointestinal) were of mild to moderate intensity. There were no important differences between the OC, ITT, and ITT/LOCF analyses. Most patients (82%) who were maintained on the higher dose of galantamine completed the study. CONCLUSIONS: Patients on galantamine, compared with those on placebo, experienced benefits in cognitive function and instrumental and basic activities of daily living. Flexible dose escalation of galantamine was well tolerated.

Thal LJ, Ferguson JM, Mintzer J, Raskin A, Targum SD. · Department of Neurosciences, University of California, San Diego School of Medicine, La Jolla 92093-0624, USA. · Neurology. · Pubmed #10214735 No free full text.

Abstract: OBJECTIVE: To evaluate the safety and efficacy of controlled-release physostigmine, an acetylcholinesterase inhibitor, in patients with probable AD of mild to moderate severity. METHODS: A prospective, 24-week, randomized, multicenter, double-blind, parallel group study of patients was conducted. The study enrolled 475 patients at 24 sites. Patients met criteria for probable AD and were randomized to one of three arms: placebo, controlled-release (CR) physostigmine 30 mg daily, or CR physostigmine 36 mg daily. Dosage was escalated by a forced upward titration during the first 6 to 9 weeks of the trial, then maintained at a constant dose to 24 weeks. Primary outcome measures were the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Clinician's Interview-Based Impression of Change-Plus with caregiver input (CIBIC+). Secondary outcome measures included the Clinical Global Impression of Change (CGIC), the Geriatric Evaluation by Relatives Rating Instrument, and an Instrumental Activities of Daily Living Scale. RESULTS: In an intent-to-treat population, the last observation carried forward analysis revealed a 2.9-point ADAS-Cog (p = 0.002) difference between physostigmine and placebo-treated patients for both dosages, and a 0.26 to 0.31-point difference on the CIBIC+ (p = 0.048). There were no significant differences on the secondary outcome measures except for a difference on the CGIC when analyzed by use of the Cochran-Mantel-Haenszel statistic (p = 0.014). There were significant increases in gastrointestinal side effects including nausea, vomiting, diarrhea, anorexia, dyspepsia, and abdominal pain for patients on either dose of physostigmine, resulting in a high dropout rate. Agitation was decreased significantly. There was no evidence of cardiac rhythm disturbance or liver function abnormalities. CONCLUSION: CR physostigmine enhanced cognitive and global function. It is relatively safe for the treatment of cognitive dysfunction secondary to AD. However, in light of the gastrointestinal side effects, a lower starting dose and a flexible titration schedule might lead to a more favorable adverse event profile in the clinical arena.

McNeal KM, Meyer RP, Lukacs K, Senseney A, Mintzer J. · Alzheimer's Research and Clinical Programs, VA Medical Center and Medical University of South Carolina, Geriatrics and Extended Care, Charleston, SC, 29406-6076, USA. · Expert Opin Pharmacother. · Pubmed #18778191 No free full text.

Abstract: BACKGROUND: Alzheimer's dementia (AD) occurs in 6 - 8% of persons older than 65 years. The prevalence increases to 30% among those 85 years or older. Among AD patients, the incidence of psychosis is 30 - 50%. Safe and appropriate use of psychotropic agents is a relevant clinical concern for this population. OBJECTIVE: This review addresses risks and potential benefits when risperidone is used for treating AD-associated psychosis. METHODS: Through literature review and clinical experience, the authors discuss the clinical efficacy, safety, and regulatory issues concerning risperidone treatment for this group of patients. CONCLUSION: Despite concerns about safety, risperidone remains a popular therapeutic choice for AD patients with psychosis. Subsets of these patients with more severe agitation and aggression may experience greater behavioral benefit.

Kirbach S, Simpson K, Nietert PJ, Mintzer J. · Department of Biostatistics, Bioinformatics and Epidemiology, Medical University of South Carolina, Charleston, South Carolina, USA. · Clin Drug Investig. · Pubmed #18407715 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: Antipsychotics have long been used to treat agitation and psychosis related to Alzheimer's disease, but in a limited fashion because of troubling adverse effects. The new atypical antipsychotics are thought to be at least as effective as first-generation drugs and to cause fewer adverse effects. These drugs, however, are currently not US FDA-approved for use among elderly demented subjects due to a slight increase in the risk of death and serious cardiovascular events within this population. However, their favourable adverse effect profile has led many physicians to prescribe these drugs as first-line therapy for behaviourally disturbed patients with Alzheimer's disease. Clinical trials to evaluate the use of atypical antipsychotics have produced varying results, and clarity has not yet been achieved. Thus, a quantitative summary of the risks and benefits may help inform complex decisions that must be made in this area. In this study we set out to compare the expected costs and outcomes for a community-dwelling cohort of patients with Alzheimer's disease with agitation and/or psychosis who are (a) untreated, or (b) treated with olanzapine. METHODS: We constructed a Markov state-transition model using the best published data from several sources for Alzheimer's disease patient progression and treatment. This model allowed us to compare the expected costs and outcomes associated with olanzapine treatment compared with no treatment for a synthetic cohort of US adults aged > or =65 years. The model cycles every 6 months and continues until all patients die from Alzheimer's disease progression or from co-morbid conditions. Outcome estimates included the incremental cost-effectiveness ratio (ICER) and cost per quality-adjusted life-year (QALY) gained. The robustness of the estimates was examined by sensitivity analyses of key parameters, including cost of care, olanzapine effectiveness and Alzheimer's disease progression rates. RESULTS: Results indicated that olanzapine was a cost-effective treatment for agitation and psychosis related to Alzheimer's disease when compared with no treatment (ICER <$US50,000). In addition, sensitivity analyses demonstrated that olanzapine remained cost effective despite multiple variations of several parameters, both alone and concurrently. CONCLUSION: Olanzapine treatment for agitation and psychosis related to Alzheimer's disease is cost effective when compared with no treatment. Further analysis should be performed as atypical antipsychotics become generic, as more information on health utilities in the Alzheimer's disease population becomes available, and to compare atypical antipsychotics with first-generation antipsychotics.

Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT, Anonymous00337. · Alzheimer's Disease Care, Research and Education Program, University of Rochester, School of Medicine and Dentistry, Rochester, NY 14620, USA. · Curr Alzheimer Res. · Pubmed #18288936 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy and safety of memantine in patients with mild to moderate Alzheimer's disease (AD) receiving cholinesterase inhibitor (ChEI) treatment. METHODS: Participants (N= 433) with probable AD, Mini-Mental State Exam (MMSE) scores between 10-22 (inclusive), and concurrent stable use of ChEIs (donepezil, rivastigmine, galantamine) were randomized to placebo or memantine (20 mg once daily) for 24 weeks. Primary outcomes were changes from baseline on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and on Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) score. Secondary measures comprised the 23-item Alzheimer Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL(23)), Neuropsychiatric Inventory (NPI), and MMSE. RESULTS: At the end of the trial, there were no statistically significant differences between the memantine- and placebo group on primary and secondary outcome measures. The incidence of adverse events (AEs) was similar between the two groups, with no AE occurring in more than 5% of memantine-treated patients and at a rate twice that of the placebo group. CONCLUSIONS: In this trial, memantine did not show an advantage over placebo based on protocol-specified primary or secondary analyses in patients with mild to moderate AD on stable ChEI regimens. There were no significant differences in tolerability and safety between the memantine- and placebo groups.

Katz I, de Deyn PP, Mintzer J, Greenspan A, Zhu Y, Brodaty H. · Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA, and Department of Neurology, Memory Clinic, Middelheim Hospital, ZNA, Wilrijk-Antwerp, Belgium. · Int J Geriatr Psychiatry. · Pubmed #17471598 No free full text.

Abstract: BACKGROUND: Dementia typically includes behavioral and psychological symptoms of dementia (BPSD) as well as cognitive decline. Psychosis of Alzheimer's disease (AD) is a specific component of AD, characterized by delusions, misidentifications, and hallucinations. METHODS: This study is a meta-analysis of patients with psychosis of AD from four large placebo-controlled clinical trials of risperidone in dementia. Three trials included patients diagnosed with heterogeneous symptoms of BPSD (those with psychosis of AD were included in this analysis), while one trial included only those diagnosed with psychosis of AD. Efficacy was measured using the Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD) Psychosis subscale and Clinical Global Impression (CGI). RESULTS: Primary analyses in the psychosis of AD population demonstrated that risperidone significantly improved scores on the BEHAVE-AD Psychosis subscale and CGI scale compared with placebo. Secondary analyses demonstrated that patients with more severe symptoms showed a more pronounced response to treatment with risperidone compared with placebo than those patients with less severe symptoms. Extrapyramidal symptoms and somnolence were more frequent with risperidone than placebo (p=0.04). Cerebrovascular adverse events and all-cause mortality were observed more frequently, although not statistically significantly, with risperidone versus placebo. CONCLUSIONS: This meta-analysis of psychosis of AD showed improvement in psychotic symptoms and general clinical improvement in patients with psychosis of AD treated with risperidone compared with placebo. The benefits of treatment were most significant in patients with severe symptoms. The safety profile of risperidone in this psychosis of AD population was similar to the more general BPSD population.

Wagner MT, Wymer JH, Carlozzi NE, Bachman D, Walker A, Mintzer J, Anonymous00396. · Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, United States. <> · Arch Clin Neuropsychol. · Pubmed #17296283 No free full text.

Abstract: African Americans are at significantly increased risk for the development of Alzheimer's disease (AD), yet are seriously underrepresented in research trials. Preliminary experiences on a large scale, multi-site, 5-year longitudinal trial investigating the psychometric expression and progression of AD targeting an aging Southern rural cohort of African Americans are reported. Sixty-five participants, ranging from asymptomatic to severely demented, underwent extensive individual diagnostic and psychometric evaluation. Results indicated that cultural factors strongly influenced the data. Recruitment with asymptomatic volunteers were found to have greater educational attainment than other participant groups. Psychomotor measures showed greater impairment in African Americans compared to Caucasians suggesting increased cerebrovascular burden. African Americans' performance on the Boston Naming Test and the Wechsler Test of Adult Reading tests were significantly different than performance of Caucasian groups. The findings demonstrated that a better understanding of sociocultural factors associated with AD in the African American population may facilitate the development of primary and secondary preventions, especially when considering the role of cerebrovascular comorbidity which is a modifiable risk factor.

Mintzer J, Greenspan A, Caers I, Van Hove I, Kushner S, Weiner M, Gharabawi G, Schneider LS. · Department of Psychiatry and Behavioral Sciences, VA Medical Center, Medical University of South Carolina, Charleston, 29406, USA. · Am J Geriatr Psychiatry. · Pubmed #16505133 No free full text.

Abstract: OBJECTIVE: The objective of this study was to evaluate efficacy and safety of low-dose risperidone for treating psychosis of Alzheimer disease (AD). METHOD: The authors conducted a randomized, eight-week, double-blind, placebo-controlled, multicenter trial involving nursing home residents diagnosed with AD and psychosis. Four hundred seventy-three patients were randomly assigned to placebo (N = 238) or 1.0 to 1.5 mg risperidone per day (N = 235). Coprimary efficacy end points were: changes in scores on the Behavioral pathology in Alzheimer's Disease (BEHAVE-AD) Psychosis subscale and Clinical Global Impression of Change (CGI-C). Protocol-specified subgroup analyses were performed by demographics and dementia severity. RESULTS: Efficacy analysis included 416 patients. Both groups improved significantly on the BEHAVE-AD Psychosis subscale and CGI-C with no significant difference between groups. In the subgroups analyses, a statistically significant treatment by Mini-Mental Status Examination (MMSE) interaction on the CGI-C (F([2,381]) = 3.90, p = 0.021) was observed with patients with more severe dementia (MMSE <10) showing significant differences at end point favoring risperidone treatment (chi(2) ([1]) = 5.11, p = 0.024). Mean risperidone dose was 1.03 +/- 0.24 mg per day. All-cause discontinuation rates were 25% for both risperidone and placebo. Treatment-emergent adverse events occurred in 74% risperidone versus 64% placebo patients, with somnolence occurring significantly more frequently with risperidone (16.2% versus 4.6%). Nine (3.8%) risperidone- and six (2.5%) placebo patients died during or within 30 days after treatment. CONCLUSION: This trial did not confirm earlier findings in this population.

Tariot PN, Raman R, Jakimovich L, Schneider L, Porsteinsson A, Thomas R, Mintzer J, Brenner R, Schafer K, Thal L, Anonymous00302, Anonymous00303. · Department of Psychiatry, The Center for Aging and Developmental Biology, Univ. of Rochester Medical Center, Rochester, NY, USA. · Am J Geriatr Psychiatry. · Pubmed #16286437 No free full text.

Abstract: OBJECTIVE: Three placebo-controlled clinical trials have suggested the benefit of valproate for treatment of agitation associated with dementia; one was used as the basis for this multicenter trial, conducted by the Alzheimer's Disease (AD) Cooperative Study. It addresses the efficacy, safety, and tolerability of divalproex sodium for the treatment of agitation associated with dementia. METHODS: This was a randomized, double-blind, placebo-controlled clinical trial in 153 nursing home residents with probable or possible AD complicated by agitation; 110 (72%) completed the trial. Participants were randomized to treatment with divalproex sodium at a target dose of 750 mg/day (N = 75) or placebo (N = 78) for 6 weeks. The primary outcome measure was change from baseline on the Brief Psychiatric Rating Scale (BPRS) Agitation factor. Secondary outcomes included total BPRS, Clinical Global Impression of Change, Cohen-Mansfield Agitation Inventory score, and measures of safety and tolerability. RESULTS: Compliance averaged 88%. Participants receiving divalproex achieved a mean dose of 800 mg/day. Change in mean BPRS Agitation factor scores did not differ between patients treated with divalproex and placebo, nor did secondary behavioral measures. Measures of safety and tolerability did not reveal clinically important drug/placebo differences. CONCLUSIONS: This multicenter trial showed no benefit of divalproex sodium for treatment for agitation in dementia at a mean dose of 800 mg/day over 6 weeks. The results do not support findings from previous trials indicating possible benefit.