Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial. 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. The effects of donepezil in Alzheimer's disease - results from a multinational trial. A double-blind, placebo controlled, cross-over trial of adjunctive donepezil for cognitive impairment in schizophrenia. Effects of donepezil adjunctive treatment to ziprasidone on cognitive deficits in schizophrenia: a double-blind, placebo-controlled study. Randomized placebo-controlled trial of donepezil in cognitive impairment in Parkinson's disease. Clinical efficacy and safety of donepezil on cognitive and global function in patients with Alzheimer's disease. A 24-week, multicenter, double-blind, placebo-controlled study in Japan. E2020 Study Group. Effects of cognitive-communication stimulation for Alzheimer's disease patients treated with donepezil.
To evaluate the efficacy and safety of the acetylcholinesterase inhibitor donepezil in a placebo-controlled trial in patients with mild cognitive impairment (MCI).
                A total of 270 patients with MCI were enrolled in a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Patients were randomized to receive donepezil (n = 133; 5 mg/day for 42 days, followed by forced dose escalation to 10 mg/day) or placebo (n = 137). Primary efficacy measures were the New York University (NYU) Paragraph Delayed Recall test and the Alzheimer disease (AD) Cooperative Study Clinician's Global Impression of Change for MCI (ADCS CGIC-MCI). Secondary efficacy measures included the modified AD Assessment Scale-cognitive subscale (ADAS-cog), the Patient Global Assessment (PGA), and additional neuropsychologic measures. Efficacy analyses were performed on intent-to-treat (ITT) and fully evaluable (FE) populations.
                Primary efficacy measures of the NYU Paragraph Recall test and the ADCS CGIC-MCI did not show significant treatment effects in the ITT population. Some secondary measures showed effects favoring donepezil. More donepezil-treated patients showed improvements in ADAS-cog total scores, in tests of attention and psychomotor speed, and in PGA scores. More donepezil-treated than placebo-treated patients experienced adverse events, most of which were mild to moderate and transient.
                Although significant treatment effects were not seen in the primary efficacy measures, outcomes on secondary measures suggest promising directions for further evaluation of donepezil treatment in patients with MCI. Treatment of mild cognitive impairment (MCI) with cholinesterase inhibitors may improve symptoms.
                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.
                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 < or = 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%).
                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. 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. Donepezil has been shown to be well tolerated and to improve cognition and global function in patients with mild to moderately severe Alzheimer's disease (AD). The current trial was undertaken to investigate further the efficacy and safety of donepezil, in a multinational setting, in patients with mild to moderately severe AD. This 30-week, placebo-controlled, parallel-group study consisted of a 24-week, double-blind treatment phase followed by a 6-week, single-blind, placebo washout. Eight hundred and eighteen patients with mild to moderately severe AD were randomly allocated to treatment with single, daily doses of 5 or 10 mg donepezil, or placebo. The two primary efficacy measures were: a cognitive performance test, the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and a global evaluation, the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC plus). Secondary outcome measures included the Sum of the Boxes of the Clinical Dementia Rating Scale (CDR-SB), a modified Interview for Deterioration in Daily living activities in Dementia (IDDD) and a patient rated quality of life assessment. Statistically significant improvements in cognitive and global function were observed, as evaluated by ADAS-cog and CIBIC plus, respectively, in both the 5 and 10 mg/day donepezil groups, compared with placebo. Treatment-associated changes were also observed in functional skills, as shown by improved scores on the CDR-SB and the complex-tasks component of the IDDD. A dose-response effect was evident, with the 10 mg/day donepezil group demonstrating greater benefits in all outcome measures than the 5 mg/day group. Donepezil was well tolerated by this patient population and did not produce any clinically significant laboratory test abnormalities. The results of this study confirm that donepezil is effective and well tolerated in treating the symptoms of mild to moderately severe AD. Although there have been several case reports suggesting the beneficial effect of acetylcholinesterase inhibitors in the cognitive deficits seen in schizophrenia, controlled studies have revealed contradictory results. The aim of this study was to investigate if donepezil could improve cognitive functions in schizophrenia. Twelve schizophrenic patients, who were diagnosed according to DSM-IV criteria and who had been on a stable dose of a high-potency typical antipsychotic for a minimum period of 3 months, participated in this 12-wk double-blind, placebo controlled, cross-over study of donepezil adjunctive treatment. Patients were randomly assigned under double-blind conditions to receive 5 mg/d donepezil or placebo for 6 wk, and then were crossed over to the alternate condition for 6 additional weeks. At baseline, 6 and 12 wk, patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, the Wechsler Memory Scale Revised (WMS-R), a test for Verbal Fluency, Trail Making Test, Parts A and B, and Wisconsin Card Sorting Test (WCST). Treatment effect was not significant in any of the cognitive measures. There were also no significant changes in the PANSS and depression scores. Nicotinic receptor desensitization may cause non-responsiveness to acetylcholine as previously suggested, but the most likely explanation appears to be that defects in other neurotransmitter systems account for the cognitive deficits seen in schizophrenic patients. The objective of this study was to examine the effects of adjunctive treatment with the acetylcholinesterase inhibitor, donepezil, on cognitive deficits and psychopathology in schizophrenic patients treated with the antipsychotic, ziprasidone. The design of the study was double blind, placebo controlled, and longitudinal. Patients were treated with ziprasidone for 8 weeks, thereafter randomized to 4 months of double-blind adjunctive treatment with either donepezil (dose, 5-10 mg) or placebo. The severity of psychopathology (PANSS) and the cognitive deficits were examined at baseline and after 4 months. A total of 21 schizophrenic patients were enrolled, of whom 11 patients completed the trial (donepezil, n = 7; placebo, n = 4). There were no within- or between-group differences in changes on the Positive and Negative Syndrome Scale scores or a global cognitive score. Within-group improvements (all at trend level P = 0.07) were seen in the placebo group on Trail-Making Test B, immediate verbal recall, and set-shifting errors. The donepezil group showed a significant deterioration on planning efficiency (P = 0.04). Between-group differences were found between the lack of improvement in immediate verbal recall in the donepezil group and the improvement in the placebo group (P = 0.02), and between the deterioration of planning efficiency in the donepezil group and the stability in the placebo group (trend level, P = 0.07). Linear regression analyses showed that neither baseline psychopathology scores, baseline levels of cognitive deficits, nor psychopathology changes over time accounted for these changes in cognitive scores. The study found no evidence of improved cognition after treatment with donepezil, although the conclusions that can be drawn are limited by the small sample size. To evaluate the efficacy and safety of donepezil, an acetylcholinesterase inhibitor, as a treatment for cognitive impairment and dementia in patients with Parkinson' s disease (PD).
                Using a randomized, double-blind, placebo-controlled design, nine patients received placebo and seven patients received donepezil (2.5-10 mg/day) for a mean (SD) duration of 15.2 (3.4) weeks. The primary efficacy outcomes were derived from a neuropsychological battery that assessed global cognitive status as well as memory, attention, psychomotor speed, and visuospatial and executive functions. Secondary efficacy outcomes were psychiatric symptom and activities of daily living ratings. Primary safety measures were motor signs and assessments of adverse effects.
                Patients on donepezil showed selective and significant (p<0.05) improvement on the memory subscale of the Dementia Rating Scale. There was also a trend toward improvement on a measure of psychomotor speed and attention. There were no group differences in psychiatric status, motor function, or activities of daily living as measured at baseline or end-point. Adverse effects resulted in premature withdrawal of four patients on donepezil, two for peripheral cholinergic effects and one for increased parkinsonism. Side effects were associated with dosage increases.
                Donepezil has a beneficial effect on memory and may improve other cognitive deficits in patients with PD and cognitive impairment. However, variable tolerability in our sample underscores the need for careful monitoring when prescribing donepezil to patients with PD, especially with dosage increases.
                Copyright 2004 John Wiley & Sons, Ltd. This study evaluated efficacy and safety of donepezil hydrochloride (donepezil) at 5 mg/day in patients with mild to moderately severe Alzheimer's disease for 24 weeks in a double-blind, placebo-controlled comparative trial. In this study, 268 patients were enrolled and 39 of these (15%) were withdrawn. In the evaluable population of efficacy, Protocol-Compatible (PC) analyzed patients (n = 228), better effects than that of placebo were confirmed using two primary efficacy measures: a cognitive performance test, the Japanese version of the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-J cog, p = 0.003) and a clinical global assessment, the Japanese version of the Clinical Global Impression of Change (J-CGIC, p = 0.000). The superiority of donepezil was also shown by secondary measures: the Sum of the Boxes of the Clinical Dementia Rating (CDR-SB), the Mental Function Impairment Scale (MENFIS) and the caregiver-rated modified Crichton scale (CMCS). The same results were obtained in the intention-to-treat (ITT) analysis (n = 263). The incidence of drug-related adverse events was 10% (14/136) in the donepezil and 8% (10/131) in the placebo group; no significant difference was seen between the two groups. The main adverse events were gastrointestinal symptoms, and these were almost all mild, and they all disappeared with continued administration or temporary discontinuation of donepezil. These results indicate that the donepezil appears to be effective and well tolerated in patients with mild to moderately severe Alzheimer's disease.
                Copyright 2000 S. Karger AG, Basel This randomized study evaluated the combined effect of a cognitive-communication program plus an acetylcholinesterase inhibitor (donepezil; donepezil-plus-stimulation group; n = 26), as compared with donepezil alone (donepezil-only group; n = 28) in 54 patients with mild to moderate Alzheimer's disease (AD; Mini-Mental Status Examination score of 12- 28) ranging in age from 54 to 91 years. It was hypothesized that cognitive-communication stimulation in combination with donepezil would positively affect the following: (a) relevance of discourse, (b) performance of functional abilities, (c) emotional symptoms, (d) quality of life, and (e) overall global function, as measured by caregiver and participant report and standardized measures. Cognitive-communication, neuropsychiatric, functional performance, and quality of life evaluations were conducted at baseline and Month 4, the month after the 2-month active stimulation period. Follow-up evaluations were performed at Months 8 and 12. The stimulation program consisted of 12 hr of intervention over an 8-week period and involved participant-led discussions requiring homework, interactive sessions about AD, and discussions using salient life stories. Additive effects of active stimulation with donepezil were examined in 2 ways: (1) comparing mean group performance over time and (2) evaluating change scores from baseline. A Group x Time interaction was found for the donepezil-plus-stimulation group in the emotional symptoms of apathy and irritability as compared with the donepezil-only group. Evaluation of change scores from baseline to 12 months revealed a positive effect for the donepezil-plus-stimulation group on discourse and functional abilities with a trend on apathy, irritability, and patient-reported quality of life. In sum, the research revealed benefits to the donepezil-plus-stimulation group in the areas of discourse abilities, functional abilities, emotional symptoms, and overall global performance. This study adds to growing evidence that active cognitive stimulation may slow the rate of verbal and functional decline and decrease negative emotional symptoms in AD when combined with acetylcholinesterase inhibitors, indicating a need to advance research in the area of cognitive treatments. The fact that AD is a progressive brain disease should not preclude ameliorative treatment.
There are two included studies which reported results for cognitive function. One study demonstrated a modest treatment effect in cognitive function as assessed by ADAS-Cog13 but not for other outcomes assessing different domains of cognitive function. Donepezil was associated with significantly more adverse effects compared with placebo, mostly gastrointestinal. From the second study, there is no evidence that donepezil delays the onset of AD. There is no evidence to support the use of donepezil for patients with MCI. The putative benefits are minor, short lived and associated with significant side effects.