Anita Murthy

Donepezil treatment of patients with MCI: A 48-week randomized, placebo-controlled trial

Background: Treatment of mild cognitive impairment (MCI) with cholinesterase inhibitors may improve symptoms. Methods: In this multicenter, randomized, placebo-controlled trial, subjects with MCI entered a 3-week placebo run-in period followed by 48 weeks of double-blind donepezil (5 mg/day for 6 weeks, then 10 mg/day for 42 weeks) or placebo treatment. Primary efficacy variables included change from baseline in the modified Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Scale–sum of boxes (CDR-SB) after 48 weeks of treatment (modified intention-to-treat analysis). Secondary efficacy measures evaluated cognition, behavior, and function. Results: The dual primary efficacy endpoint was not reached. We noted a small, but significant, decrease in modified ADAS-Cog scores in favor of donepezil at study endpoint. Little change from baseline in CDR-SB and secondary variables was observed for either group. Patient Global Assessment scores favored donepezil at all time points except week 12 (p ≤ 0.05). Perceived Deficits Questionnaire scores favored donepezil at week 24 (p = 0.05). Clinical Global Impression of Change–MCI scores favored donepezil only at week 6 (p = 0.04). Adverse events were generally mild or moderate. More donepezil-treated subjects (18.4%) discontinued treatment due to adverse events than placebo-treated subjects (8.3%). Conclusions: Donepezil demonstrated small but significant improvement on the primary measure of cognition but there was no change on the primary measure of global function. Most other measures of global impairment, cognition, and function were not improved, possibly because these measures are insensitive to change in MCI. Responses on subjective measures suggest subjects perceived benefits with donepezil treatment.

Efficacy and safety of donepezil in patients with schizophrenia or schizoaffective disorder: Significant placebo/practice effects in a 12-week, randomized, double-blind, placebo-controlled trial

Altered expression of central muscarinic and nicotinic acetylcholine receptors in hippocampal and cortical regions may contribute to the cognitive impairment exhibited in patients with schizophrenia. Increasing cholinergic activity through the use of a cholinesterase inhibitor (ChEI) therefore represents a possible strategy for cognitive augmentation in schizophrenia. We examined the efficacy and safety of the ChEI donepezil as cotreatment for mild to moderate cognitive impairment in schizophrenia or schizoaffective disorder in a prospective, 12-week, placebo-controlled, double-blind, parallel-group study. In total, 250 patients (18–55 years) with schizophrenia or schizoaffective disorder who were clinically stabilized on risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole, alone or in combination, were enrolled at 38 outpatient psychiatric clinics in the United States. Patients were randomized to donepezil 5 mg q.d. for 6 weeks then 10 mg q.d. for 6 weeks, or placebo administered as oral tablets. The primary outcome measure was the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) neurocognitive battery composite score. In the intent-to-treat sample (donepezil, n=121; placebo, n=124), both treatments showed improvement in the composite score from baseline to week 12. At week 12, cognitive improvement with donepezil was similar to that with placebo (last-observation-carried-forward effect size, 0.277 vs 0.411; p=0.1182) and statistically significantly inferior for the observed-cases analysis (0.257 vs 0.450; p=0.044). There was statistically significant improvement in the Positive and Negative Syndrome Assessment Scale negative symptoms score for placebo compared with donepezil, while total and positive symptom scores were similar between both treatments. Statistically significant improvements in positive symptoms score and Clinical Global Impression-Improvement for donepezil compared with placebo were noted at Week 6. Treatment-emergent adverse events (AEs) were observed for 54.5% of donepezil- and 61.3% of placebo-treated patients; most AEs were rated as mild to moderate in severity. Donepezil was safe and well-tolerated but was not effective compared with placebo as a cotreatment for the improvement of cognitive impairment in this patient population. A significant and surprisingly large placebo/practice effect was observed among placebo-treated patients, and is a serious consideration in future clinical trial study designs for potential cognitive enhancing compounds in schizophrenia.

Onset of symptom relief with rabeprazole: a community-based, open-label assessment of patients with erosive oesophagitis.

In numerous clinical trials, proton pump inhibitors have demonstrated potent acid suppression and healing of erosive oesophagitis, as well as successful symptom relief for the entire spectrum of gastro‐oesophageal reflux disease.

An MRI substudy of a donepezil clinical trial in mild cognitive impairment

A magnetic resonance imaging (MRI) study was conducted as part of an intervention study in subjects with amnestic mild cognitive impairment (aMCI) to assess donepezils treatment effect on brain atrophy. Adults with aMCI were randomly assigned to double-blind treatment with 10 mg/day donepezil hydrochloride or placebo for 48 weeks. Brain MRI scans were acquired at baseline and endpoint. The primary outcome measure was annualized percentage change (APC) in hippocampal volume; the main secondary outcome measure was APC in whole brain volumes. An analysis of variance (ANOVA) model including terms for treatment, site, and age was used to compare the treatment groups. APCs for hippocampal volumes were not significantly different between treatment groups. There were significant differences favoring the donepezil group for total (p = 0.001), ventricular region (p = 0.0002), and cortical region (p = 0.003) whole brain volumes. Although the primary MRI outcome measure was negative, the main secondary MRI outcome measure showed a positive result. These findings suggest a treatment effect of donepezil on brain atrophy in aMCI.

Rabeprazole improves health-related quality of life in patients with erosive gastroesophageal reflux disease.

The purpose of this study was to assess the effect of rabeprazole 20 mg once a day on patient-reported health-related quality of life in routine clinical practice. Patients with erosive gastroesophageal reflux disease participating in an open-label, 8-week study completed the SF-36 Health Survey before and after treatment with rabeprazole. For all SF-36 scales, there was a statistically significant (p ≤ 0.007) improvement in mean scores from baseline to week 8. Improvements in each of the subscales, except for physical functioning, general health, and mental health, were at least 5% in magnitude, a level considered clinically meaningful. Furthermore, while baseline scores were significantly poorer than general United States population scores, follow-up scores for four of the subscales (role limitations due to physical problems, social functioning, role limitations due to emotional problems, and mental health) were comparable to general population scores. In conclusion, rabeprazole significantly improved health-related quality of life in erosive gastroesophageal reflux disease patients and restored social functioning and emotional well-being to levels comparable to those observed in the United States general population.

Rabeprazole is superior to omeprazole for the inhibition of peptone meal-stimulated gastric acid secretion in Helicobacter pylori-negative subjects.

Background: Peptone meal‐stimulated gastric acid output is considered to be a reliable means to evaluate drug‐mediated inhibition of stimulated gastric acid output, an important measure of the efficacy of the agents — such as proton pump inhibitors — used to treat acid‐related disorders.

Safety and Tolerability of Donepezil in Mild Cognitive Impairment: Open-Label Extension Study

Following a 48-week, double-blind, randomized, placebo-controlled trial of donepezil in 821 patients with amnestic mild cognitive impairment (aMCI), safety and tolerability of donepezil (10 mg) were further evaluated in a 28-week extension study. Of 499 participants who completed the double-blind phase, 145 enrolled in the open-label study. Adverse events (AEs) were recorded throughout. Overall, 57.4% of participants in the donepezil/donepezil group and 62.3% in the placebo/donepezil group experienced an AE, with the most frequent treatment-emergent AEs being diarrhea, muscle spasms, insomnia, and nausea. Most were mild to moderate in severity and were more common in the first several weeks after treatment initiation. More participants in the placebo/donepezil group (22.1%) discontinued donepezil due to an AE compared with the donepezil/donepezil group (10.3%). These findings support the safety of donepezil in patients with aMCI. When compared with other studies, however, the data suggest that patients with Alzheimer’s tolerate donepezil better than patients with MCI.

Identifying Amnestic Mild Cognitive Impairment in Primary Care

EnAbstract Background and Objective: Amnestic mild cognitive impairment (aMCI), characterized by episodic memory impairment in the absence of clinical dementia, often represents a transitional stage between normal aging and Alzheimer’s disease (AD). It is not known if non-expert primary-care physicians (PCPs) can differentiate individuals with no cognitive impairment (NCI), aMCI and mild AD in a primary-care practice setting. This study develops an approach to this question, which is necessary for aMCI to become a treatment target. Methods: Fourteen experts assessed subjects with memory complaints in terms of their laboratory test results, magnetic resonance imaging findings and scores on the Mini-Mental State Examination, adapted Clinical Dementia Rating Scale and Alzheimer’s Disease Assessment Scale-cognitive subscale Delayed Word Recall before designating each subject as having NCI, aMCI or AD. Subjects agreed upon by a consensus committee were assigned to nonexpert PCPs who, following brief training, assessed them using the same clinical information and utilizing the same assessment instruments. The chance-corrected inter-rater reliability (expert versus non-expert) measure κ, based on binary outcome (aMCI/not-aMCI), was estimated. Results: The study recruited 119 evaluable subjects (50 aMCI, 27 mild AD and 42 NCI) and demonstrated fair to moderate agreement (k = 0.423) between experts and non-experts in designation of aMCI. The percent agreement was 72.3%, sensitivity 62.0% and specificity 79.7%. Overall, non-experts under-rated the level of impairment compared with experts. Conclusion: This study established the feasibility of making the aMCI designation in the community and identified some likely sources of error. The results suggest that when drugs with clear benefit for aMCI patients are developed, community-based PCPs, with additional, more optimized training, will be able to accurately identify those patients who should receive treatment.

IC-P2-120: The effects of donepezil on Alzheimer's disease progression monitored by MRI

elderly faces with happy/sad expressions repeated in a block 6x, alternating with blocks of 10 circles. Participants indicated whether each face was happy or sad. After a 20-minute consolidation period, the 10 encoded faces were presented 4x each intermixed with 40 new faces (half happy, half sad). Participants identified “new” or previously learned (“old”) faces. Random effects group analysis was performed using SPM5 to compare activity in response to novel vs familiar faces. Outside the scanner, participants viewed 40 new faces (half sad, half happy), 10 faces from the encoding scan, and 80 novel faces from the recognition scan. They indicated whether each face was “new” or “old” and rated valence and arousal of each face. Results: EC showed significant activity in right fusiform and hippocampal regions in response to novel faces compared to previously learned faces (MNI coordinates FF: 40, -58, -14, T 8.07; pcorrected .0001; HC: 22, -12, -16; T 5.60, puncorrected .048). Significant activations were also observed in occipital and frontal cortices. A similar pattern was found in response to baby faces but did not hold for elderly faces, suggesting that arousal is important. MCI did not show increased activity in response to novel versus familiar faces in predicted regions. Groups did not significantly differ in overall reaction time/accuracy during encoding, valence/ arousal ratings or accuracy during the post-scan task, or on the Florida Affect Battery, suggesting MCIs’ affective perception was intact. MCIs were slower and less accurate during recognition scans. Conclusions: Lack of encoding-associated activity in MCIs suggests that continued studies of the functional correlates of the emotional-memory enhancement effect in the early stage of Alzheimer’s disease are warranted.

The future of acid suppression therapy trial with rabeprazole: preliminary analysis of acute symptom relief

The future of acid suppression therapy trial with rabeprazole: preliminary analysis of acute symptom relief