Exploratory analysis of seven Alzheimer's disease genes: disease progression.

The relationships between genome wide association study-identified and replicated genetic variants associated with Alzheimer's disease (AD) risk and disease progression or therapeutic responses in AD patients are almost unexplored. Seven hundred and one AD patients with at least 3 different cognitive evaluations and genotypic information for APOE and 6 genome wide association study-significant single-nucleotide polymorphisms were selected for this study. Mean differences in Global Deterioration Score and Mini Mental State Examination (MMSE) were evaluated using nonparametric tests, general linear model and mixed models for repeated measurements. Each chart was also reviewed for evidence of treatment with any cholinesterase inhibitor, memantine, or both. Relationships between therapeutic protocols, genetic markers, and progression were explored using stratified analysis looking for specific effects on progression in each therapeutic category separately. Neither calculation rendered a Bonferroni-corrected statistically significant difference in any genetic marker. Mixed model results suggested differences in the average point in MMSE test for patients carrying PICALM GA or AA genotype compared with GG carriers at the end of the follow-up (MMSE mean difference = -0.57; 95% confidence interval, -1.145 to 0.009; p = 0.047). This observation remained unaltered after covariate adjustments although it did not achieve predefined multiple testing significance threshold. The PICALM single-nucleotide polymorphism also displayed a significant effect protecting against rapid progression during pharmacogenetic assays although its observed effect displayed heterogeneity among AD therapeutic protocols (p = 0.039). None of the studied genetic markers were convincingly linked to AD progression or drug response. However, by using different statistical approaches, the PICALM rs3851179 marker displayed consistent but weak effects on disease progression phenotypes.

Aripiprazole for the treatment of psychoses in institutionalized patients with Alzheimer dementia: a multicenter, randomized, double-blind, placebo-controlled assessment of three fixed doses.

OBJECTIVE: To assess the efficacy and safety of aripiprazole for psychosis associated with Alzheimer dementia (AD). METHODS: In this double-blind, multicenter study, 487 institutionalized patients with psychosis associated with AD were randomized to placebo or aripiprazole, 2, 5 or 10 mg/day. Primary efficacy assessment was the mean change from baseline to week 10 on the Neuropsychiatric Inventory-Nursing Home (NPI-NH) version Psychosis Subscale score. Secondary measures included NPI-NH Total, Clinical Global Impression-Severity of Illness (CGI-S), Brief Psychiatric Rating Scale (BPRS) Core and Total, and the Cohen-Mansfield Agitation Inventory (CMAI) scores. RESULTS: Aripiprazole 10 mg/day showed significantly greater improvements (mean change [2 x SD]) than placebo on the NPI-NH Psychosis Subscale (-6.87 [8.6] versus -5.13 [10.0]; F = 6.29, df = 1, 422, p = 0.013 by analysis of covariance [ANCOVA]); CGI-S (-0.72 [1.8] versus -0.46 [1.6]; F = 4.68, df = 1, 419, p = 0.031 [ANCOVA]); BPRS Total (-7.12 [18.4] versus -4.17 [21.6]; F = 4.72, df = 1, 399, p = 0.030 [ANCOVA]); BPRS Core (-3.07 [6.9] versus -1.74 [7.8]; F = 7.30, df = 1, 407, p = 0.007 [ANCOVA]); CMAI (-10.96 [22.6] versus -6.64 [28.6]; F = 5.23, df = 1, 410, p = 0.023 [ANCOVA]), and NPI-NH Psychosis response rate (65 versus 50%; chi(2) = 5.52, df = 1, p = 0.019 [CMH]). Aripiprazole 5 mg/day showed significant improvements versus placebo on BPRS and CMAI scores. Aripiprazole 2 mg/day was not efficacious. Cerebrovascular adverse events were reported: aripiprazole 2 mg/day, N = 1; 5 mg/day, N = 2; 10 mg/day, N = 4; placebo, N = 0. No deaths in any group (aripiprazole 2 mg/day, 3%; 5 mg/day, 2%; 10 mg/day, 7%; placebo, 3%) were considered to be treatment-related. CONCLUSION: Aripiprazole 10 mg/day was efficacious and safe for psychosis associated with AD, significantly improving psychotic symptoms, agitation, and clinical global impression. However, clinicians should be aware of the safety considerations of atypical antipsychotic uses in this population.

A retrospective study of the safety of intramuscular ziprasidone in agitated elderly patients.

OBJECTIVE: Authors evaluated the safety of intramuscular ziprasidone for use in acute agitation in an elderly population. METHOD: Medical records were reviewed retrospectively to identify consecutive patients who were admitted to our neuropsychiatry service with the presenting complaint of dementia (DSM-IV) with agitation and who were given intramuscular ziprasidone and then administered an electrocardiogram (ECG) (N = 23). Some patients also had a baseline ECG (N = 14). QTc intervals were recorded, and significance was defined as a QTc of > or =450 ms or a 10% prolongation from baseline. A paired-samples t test was performed to compare the baseline and postmedication QTc intervals. Confounding factors were examined, and cardiac events (torsades de pointes, cardiac arrest) were recorded. RESULTS: There was no significant difference in the QTc interval between the baseline and the post-ziprasidone values. One patient had a QTc greater than 500 ms and 25% over baseline, and therefore the medication was discontinued. The mean prolongation of the QTc interval was only 0.5 ms. There were no episodes of torsades de pointes. Other medications that the patients were taking did not appear to affect the QTc interval in an expected manner. CONCLUSION: Larger studies need to be done to evaluate the safety of intramuscular ziprasidone in agitated elderly patients, a population with an increased risk of QT prolongation and torsades de pointes because of their age, comorbid conditions, and concomitant use of multiple medications.

Cognitive, behavioral, and physiological changes in Alzheimer disease patients as a function of incontinence medications.

OBJECTIVE: Authors evaluated the cognitive, neurophysiologic, and behavioral effects of incontinence medications in patients with Alzheimer disease (AD). METHODS: Nine patients were evaluated, both on and off incontinence medication, for cognitive status, neuropsychiatric status, activities of daily living, and serum anticholinergic level. Caregivers were interviewed to evaluate behavioral status and caregiver burden. RESULTS: Patients showed better performance on specific measures of cognition and behavior when not taking medication for incontinence. A significant, inverse correlation was found between mental status and anticholinergic level. CONCLUSION: Although the sample size was small, the findings suggest that, in patients with AD, incontinence medications with anticholinergic properties may have detrimental effects on mental status and behavior.

Correlates of anticholinergic activity in patients with dementia and psychosis treated with risperidone or olanzapine.

BACKGROUND: Older individuals with dementia are highly sensitive to the effects of muscarinic receptor blockade. STUDY DESIGN: This was a 6-week multisite, randomized clinical trial. SUBJECTS: Eighty-six patients with probable Alzheimer's disease, vascular dementia, or mixed-etiology dementia (DSM-IV criteria) were randomly assigned to treatment with olanzapine or risperidone. ASSESSMENTS: Anticholinergic activity was measured with a radioreceptor assay, and plasma levels of antipsychotic medications were determined. Primary outcomes were assessed with the Udvalg for Kliniske Undersogelser (UKU) scale and somnolence adverse events; secondary outcome measures included scores on the Neuropsychiatric Inventory (NPI) and other scales. RESULTS: There were no between-treatment differences in the UKU scale or in somnolence adverse events. Statistically significant improvements (p < .001) from baseline were found for the NPI measures, with no between-treatment group differences. Olanzapine was associated with significant increases from baseline in anticholinergic activity, while risperidone was not; the between-treatment group differences were not statistically significant. Increase in anticholinergic activity was associated with an increase in anticholinergic side effects and slower performance on the Trail Making Test Part A. Higher endpoint anticholinergic activity was associated with higher endpoint scores on several items from the NPI, including delusions, anxiety, and aberrant motor behavior. IMPLICATIONS: Efficacious doses of olanzapine increased anticholinergic activity in older patients with dementia, while similarly efficacious doses of risperidone did not. Patients whose anticholinergic activity increased were more likely to experience anticholinergic side effects and to have worsening in certain cognitive domains. These data suggest that certain patients may be vulnerable to the anticholinergic activity associated with antipsychotic treatment.

Chronic exposure to anticholinergic medications adversely affects the course of Alzheimer disease.

OBJECTIVE: Authors examined the effect of chronic exposure to anticholinergics in a cohort of Alzheimer disease (AD) patients. METHODS: All patients were examined annually with standard neuropsychologic tests and received the cholinesterase inhibitor donepezil hydrochloride at a dose of 10 mg/day. The study population (N=69) was divided into two groups: those receiving one or more concomitant medications with significant anticholinergic properties (N=16) and those receiving no concomitant medications with anticholinergic properties (N=53). RESULTS: At 2 years, MMSE scores were significantly worse for patients receiving anticholinergic medications than for those not on anticholinergics. CONCLUSION: Although very preliminary, these data suggest that concomitant therapy with anticholinergics may be associated with significant deleterious effects on acetylcholinesterase therapy, or, more speculatively, that chronic exposure to anticholinergics may have adverse effects on the clinical course of AD.

Schizophrenia in late life.

Antipsychotics, whether conventional or atypical, are the primary class of medications for the treatment of late-life psychosis. Although the efficacy of neuroleptics in controlling agitation and psychosis associated with late-life dementia has been established, evidence for their efficacy in treating core symptoms of late-life schizophrenia other than behavioral dyscontrol is just emerging. More controlled clinical trials are needed. The available data suggest that atypical neuroleptics are therapeutically efficacious, with a more favorable side-effect profile than conventional neuroleptics. This literature further suggests the importance of low therapeutic doses and careful attention to the emergence of side effects. Future studies must distinguish between patients with true schizophrenic disorder and patients with psychosis secondary to dementia, affective illness, or organic impairment. Patients must be characterized further as having EOS versus LOS because these disorders may differ in symptom profile, course, and response to treatment. There is also a need in future studies to separate out the results of treatment of patients with EOS who have been severely ill for most of their lives from those whose course has been less devastating. Within these two groups, treatment response, effective dose ranges, and sensitivity to side effects can be scrutinized more carefully.

Donepezil HCl (E2020) maintains functional brain activity in patients with Alzheimer disease: results of a 24-week, double-blind, placebo-controlled study.

OBJECTIVE: The authors evaluated the effects of donepezil (10 mg/day) versus placebo on brain glucose metabolism. METHODS: This was a randomized, double-blind, parallel-group, 24-week pilot study in 28 patients with mild-to-moderate Alzheimer disease (AD). Functional brain activity was quantified by measuring average glucose metabolism in an axial brain slice and regional brain glucose metabolism using positron emission tomography. RESULTS: At Week 24, relative to the pons metabolic rate, mean brain glucose metabolism in an axial slice at the level of the striatum was maintained within 0.5% of mean baseline levels for donepezil-treated patients, whereas it declined by an average of 10.4% in placebo-treated patients. This observation was confirmed by an analysis of differences in the mean slopes of glucose metabolism in the striatal slice in donepezil- and placebo-treated patients during the 24-week period. Significant treatment differences at Week 24 favoring donepezil for the mean percentage change from baseline in regional brain glucose metabolism were observed in four predefined regions of interest: the right parietal lobe 1, left temporal lobe 2, right frontal lobe 2, and left frontal lobe 2. CONCLUSION: Placebo-treated patients with AD show a decline in functional brain activity, relative to the pons, in several regions, and treatment with donepezil may slow this decline.

The role of antipsychotics in treating delirium.

The mainstay of the pharmacologic management of delirium remains typical antipsychotics, primarily haloperidol. Typical antipsychotics are associated with significant side effects, particularly in the elderly. This article reviews the literature on the use of both typical and atypical antipsychotics in the management of acute delirium, with a focus on the elderly. In this population, typical antipsychotics are associated with substantially more drug induce side effects--either extrapyramidal side effects or anticholinergic effects from the antipsychotics alone or in combination with benztropine or trihexyphenidyl. Anticholinergic toxicity is especially problematic in delirious, demented patients, because most dementias are associated with pre-existing deficiencies in cholinergic neurotransmission. These issues will be reviewed for typical antipsychotics as well as the emerging literature on the use of atypical antipsychotics-- risperidone, olanzapine, and quetiapine--for pharmacologic management of acute delirium. Data from two studies conducted at the Wesley Woods Center at Emory University will be briefly reviewed as they constitute the largest series to date investigating the pharmacologic management of delirious demented patients.