Effects of donepezil on emotional/behavioral symptoms in Alzheimer's disease patients

BACKGROUND: This open-label study examined the effects of the reversible cholinesterase inhibitor donepezil on emotional/behavioral symptoms in Alzheimer's disease (AD) patients. METHOD: Patients were diagnosed as having probable/possible AD by National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria. This study used the CERAD Behavior Rating Scale for Dementia (CBRSD) and its subscales to evaluate a group of 25 AD patients treated with donepezil. Dosage was increased at 4 months for most patients from 5 to 10 mg q.h.s. Analysis of variance was used to compare scores over a period of 12 months. These patients were also compared, using t tests, to a reference group that had received no donepezil or other anticholinesterase. RESULTS: Donepezil administration was associated with improvement in Mini-Mental State Examination (MMSE) and CBRSD total scores at 3-month evaluation (p< or =.05). CBRSD depression and behavioral dysregulation scores improved transiently at 4 months (p< or =.05). MMSE, CBRSD total, CBRSD depression, and CBRSD behavioral dysregulation scores returned to baseline levels at 12 months, in contrast to the reference group, whose MMSE and CBRSD total scores worsened minimally over the 12 months. CONCLUSION: Donepezil has a mildly positive effect on emotional/behavioral symptoms in AD in addition to its effect on cognitive function.     

Prediction of psychiatric response to donepezil in patients with mild to moderate Alzheimer's disease

Donepezil is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). Since behavioral symptoms severely affect quality of life for AD patients and their caregivers, predicting behavioral responses to donepezil will be useful in managing patients with AD. In this study, we analyzed 70 consecutive cases with mild to moderate AD. Caregivers were interviewed with the Neuropsychiatric Inventory for behavioral assessment and 4-point improvement at week 12 was accepted as a treatment response. Twenty-one (30.0%) patients showed a behavioral response, while 42 (60.0%) showed no behavioral change and 7 (10.0%) worsened. Dysphoria, anxiety and apathy significantly improved after treatment among the responder group. The baseline profile including age, sex, Mini-Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Geriatric Depression Scale did not differ significantly among the three groups. Statistical Parametric Mapping analysis of single photon emission computed tomography (SPECT) images at baseline showed that cerebral blood flow in the premotor and parietotemporal cortices was significantly higher in the responder group than in the worse group. The present study suggested usefulness of SPECT imaging in the prediction of behavioral response to donepezil among AD patients even with similar psychiatric symptoms and cognitive functions.     

Safety and effectiveness of donepezil on behavioral symptoms in patients with Alzheimer disease

The objective of this study was to evaluate the prevalence and treatment responsiveness of neuropsychiatric symptoms in patients with mild to moderately severe Alzheimer disease recruited in a naturalistic treatment setting in Spain. All the patients, who matched the prescribing recommendations for donepezil and were able to participate in the study, received donepezil (5 to 10 mg/d) for 6 months. The primary outcome measure was the incidence of adverse events. Secondary outcome measures were neuropsychiatric function measured by the Neuropsychiatric Inventory (NPI), the Mini-Mental State Evaluation, and caregiver burden measured by the Zarit scale. Five hundred and twenty-nine patients were included of which 455 completed the study. The mean baseline NPI score was 19.1. Sixty-five patients (12.3%) experienced an adverse event. The most frequent adverse events were diarrhea and agitation (<2%). Seventeen patients (3%) presented with a neuropsychiatric adverse event and 11 (2%) patients presented with a neurologic adverse event over the course of the study. NPI scores improved by 34.4% over the course of the study, with all items showing a statistically significant improvement. Mini-Mental State Evaluation scores and Zarit caregiver burden scores also improved by 1.27 points and 5.9 points, respectively. This study showed a low incidence of adverse events accompanied by an improvement in the neuropsychiatric and cognitive functions in patients with mild to moderately severe Alzheimer disease treated with donepezil in a community setting in Spain. Donepezil also reduced caregiver burden.     

Effects of donepezil on neuropsychiatric symptoms in patients with dementia and severe behavioral disorders.

OBJECTIVE: The objective of this study was to conduct exploratory analyses of data pertaining to the efficacy of donepezil treatment of patients with severe behavioral disturbances. Preliminary studies suggest that cholinesterase inhibitors, including donepezil, may reduce behavioral disturbances in patients with Alzheimer disease (AD). Most patients included in clinical trials have had low levels of psychopathology at baseline, and the effect of cholinesterase inhibitors on patients with more severe behavioral disturbances is unknown. The authors report the effects of donepezil on behavioral disturbances in patients with relatively severe psychopathology at baseline. METHODS: This is a hypothesis-driven secondary analysis of a three-phase study involving donepezil and sertraline. In phase 1, psychotropic agents were withdrawn; in phase 2, patients were treated in an open-label fashion with donepezil for 8 weeks; and in phase 3, patients on donepezil were randomized to receive placebo or sertraline for an additional 12 weeks. The data set analyzed is comprised of the patient population treated with donepezil (without sertraline) for 20 weeks. One hundred twenty patients were included in the analyses. Mean age was 76 years, average Mini-Mental State Examination Score was 18, and mean Neuropsychiatric Inventory (NPI) total score was 30. Primary efficacy assessments were the NPI, the Clinical Global Impression-Improvement, and the Clinical Global Impression-Severity scales. Secondary measures included the Behavioral Pathology in Alzheimer's Disease Rating Scale, The Hamilton Depression Rating Scale, and the Alzheimer's Disease Functional Assessment and Change Scale. RESULTS: Excellent concurrent validity was noted between the NPI and the Behavioral Pathology in Alzheimer's Disease Rating Scale. The total score of the NPI was significantly reduced over the 20 weeks of therapy with donepezil. Sixty-two percent of patients had at least a 30% reduction in the total NPI score (significantly greater than the number with no meaningful response). Likewise, more patients had total or partial resolution of depression and delusions than those who had no meaningful change. Factor analysis of baseline NPI data revealed five factors, including a psychosis factor, an agitation factor, mood factor, frontal lobe function factor, and appetite and eating disorders factor. Clinically meaningful treatment effect sizes were notable for the delusion factor (0.340) and the mood factor (0.39). There were significant correlations between the Clinical Global Impression-Improvement and reductions in mood and agitation scores. CONCLUSION: The results of these analyses suggest that donepezil reduces behavioral symptoms, particularly mood disturbances and delusions, in patients with AD with relatively severe psychopathology.     

A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease

OBJECTIVE: To investigate the efficacy and safety of donepezil in patients with moderate to severe AD (standardized Mini-Mental State Examination [sMMSE] scores of 5 to 17; Functional Assessment Staging score < or =6 at baseline). METHODS: Two-hundred ninety patients were randomized to treatment in this 24-week, double-blind, placebo-controlled trial. Patients received either donepezil 5 mg/day for the first 28 days and 10 mg/day thereafter as per the clinician's judgment (n = 144) or placebo (n = 146). The primary outcome measure was the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+). RESULTS: Patients' mean age was 73.6 years (range 48 to 92 years). Baseline demographics were similar between the treatment groups. Least squares (LS) mean +/- SE sMMSE scores at baseline were 11.7 +/- 0.35 for the donepezil group and 12.0 +/- 0.34 for the placebo group. Patients receiving donepezil showed benefits on the CIBIC+, compared with placebo, at all visits up to week 24 (p < 0.001) and at week 24 last observation carried forward (LOCF) (p < 0.0001). All other secondary measures (including sMMSE, Severe Impairment Battery, Disability Assessment for Dementia, Functional Rating Scale, and Neuropsychiatric Inventory) showed significant differences between the groups in favor of donepezil at week 24 LOCF. Eighty-four percent of donepezil- and 86% of placebo-treated patients completed the trial. Adverse events (AE) were experienced by 83% of donepezil- and 80% of placebo-treated patients, the majority of which were rated mild in severity; 8% of donepezil- and 6% of placebo-treated patients discontinued because of AE. Laboratory and vital sign abnormalities were similar between the treatment groups. CONCLUSION: These data suggest that donepezil's benefits extend into more advanced stages of AD than those previously investigated, with very good tolerability.     

The relationship between donepezil and behavioral disturbances in patients with Alzheimer's disease.

The authors tested the hypothesis that behavioral disturbances are reported at significantly lower rates by caregivers of Alzheimer's disease (AD) patients receiving the antidementia drug donepezil, compared with a group of patients receiving no antidementia drug treatment. Patients administered donepezilfor 6 months (n=84) were compared with patients not on donepezil (n=248). Patients taking donepezil had significantly lower levels of behavioral disturbances than patients not receiving this agent (P< or =0.011). Specifically, donepezil patients were described as significantly (P< or =0.05) less likely to be threatening, destroy property, and talk loudly. Also, significantly fewer patients receiving donepezil were treated with sedatives (P< or =0.005). These findings support the growing body of evidence that cholinesterase inhibitors have psychotropic properties and reduce behavioral disturbances in patients with AD.     

Improvement in behavioural symptoms in patients with moderate to severe Alzheimer's disease by memantine: a pooled data analysis

INTRODUCTION: Behavioural disturbances are a common and distressing aspect of Alzheimer's disease (AD). This pooled analysis evaluated the specific benefits of memantine on behavioural disturbances in patients with moderate to severe AD. METHODS: Data were pooled from six 24/28-week, randomised, placebo-controlled, double-blind studies. Of the 2,311 patients included in these studies, 1,826 patients with moderate to severe AD (MMSE <20) were included in this analysis, corresponding to the extended indication for memantine in Europe. In this subgroup, 959 patients received memantine 20 mg/day and 867 received placebo. Behavioural symptoms were rated using the Neuropsychiatric Inventory (NPI) total and single-item scores at weeks 12 and 24/28. RESULTS: At weeks 12 and 24/28, ITT analysis demonstrated that memantine treatment produced statistically significant benefits over placebo treatment in NPI total score (p=0.001 and p=0.008), and in NPI single items: delusions (p=0.007 week 12, p=0.001 week 24/28), hallucinations (p=0.037 week 12), agitation/aggression (p=0.001 week 12, p=0.001 week 24/28), and irritability/lability (p=0.005 week 24/28), LOCF population. Analysis of the patients without symptoms at baseline indicated reduced emergence of agitation/aggression (p=0.002), delusions (p=0.047), and disinhibition (p=0.011), at week 12, and of agitation/aggression (p=0.002), irritability/lability (p=0.004), and night-time behaviour (p=0.050) at week 24/28 in those receiving memantine. OC analyses yielded similar results. CONCLUSIONS: The data suggest that memantine is effective in treating and preventing the behavioural symptoms of moderate to severe AD. Specific persistent benefits were observed on the symptoms of delusions and agitation/aggression, which are known to be associated with rapid disease progression, increased caregiver burden, early institutionalisation, and increased costs of care.     

多奈哌齐治疗轻中度阿尔茨海默病作用机制研究进展

多奈哌齐是第2代胆碱酯酶抑制剂,对轻中度阿尔茨海默病有较好疗效。近年关于多奈哌齐作用机制的相关研究较为丰富,本文拟就我国阿尔茨海默病诊断与治疗现状和多奈哌齐治疗轻中度阿尔茨海默病作用机制研究进展进行概述。     

Cost-effectiveness analysis of donepezil for mild to moderate Alzheimer's disease in Taiwan

BACKGROUND: Donepezil is a drug used for treatment in patients with Alzheimer's disease (AD). Information regarding the cost-effectiveness of this medication was previously rare in Asia. We used techniques of decision analysis and economic evaluation in conjunction with available local epidemiological and clinical data on costs of mild to moderate AD to assess the cost-effectiveness of donepezil in Taiwan. METHODS: A four-state Markov model was built to simulate the disease progression of AD patients. Local transition probabilities and costs of different stages were from the studies published earlier. RESULTS: Over a 5-year span, donepezil treatment for mild or moderate AD patients is predicted to result in the gain of 0.505 QALYs when comparing to usual care, while at the same time reducing the cost by US$7,691. The incremental cost was US$3,647 from the payer perspective; thus, the incremental cost-effectiveness ratio was estimated to be US$7,226 when considering only the medical expenditures. CONCLUSIONS: Under some assumptions, donepezil treatment might be a cost saving strategy for mild to moderate AD patients in Taiwan from a societal perspective. It is inconclusive from the payer's part since we still lack a consensus for judging the cost-effectiveness of a new health care technology.     

Pooled analyses on cognitive effects of memantine in patients with moderate to severe Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, constituting the most common cause of dementia. Memantine, an N-methyl-D-aspartate receptor antagonist indicated for the treatment of moderate to severe AD, has been shown to provide benefits in cognitive, functional, and behavioral domains in large, randomized clinical trials. The current analysis combined data from six previously published studies and assessed the effect of memantine on various cognitive functions in 1826 patients (867 on placebo and 959 on memantine) with moderate to severe AD (MMSE<20). The Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) and the Severe Impairment Battery (SIB) scores from all six studies were pooled and combined into three clusters representing discrete cognitive domains: language, memory, and praxis. At baseline, there were no clinically significant differences between the memantine- and placebo-treated groups. After 24 weeks, responder analyses revealed that memantine treatment resulted in statistically significantly more patients improving on each of the three clusters, language, memory, and praxis, compared with placebo, and a lower percentage of patients treated with memantine showed any worsening on any of the three clusters compared with patients receiving placebo. It is concluded that treatment with memantine provides benefits in all three cognitive functions.     

Treatment effects of Memantine on language in moderate to severe Alzheimer's disease patients

BackgroundLanguage impairment is one of the most troublesome manifestations of Alzheimer's disease (AD). The objective of this post hoc analysis was to assess the treatment effects of Memantine on language in patients with moderate to severe AD, using the recently developed Severe Impairment Battery-Language (SIB-L) scale.MethodsFrom a combined database including four Memantine clinical trials in moderate-to-severe AD, we analyzed 801 patients with SIB-L scores of <38 and Mini-Mental State Examination scores of <15. Patients were treated with either 20 mg Memantine per day or placebo. Mean changes in SIB-L scores from baseline were calculated. For responder analyses, a change in SIB-L score greater than or equal to the SIB-L measurement error of 3.7 points was considered a clinically relevant response.ResultsThe mean change from baseline in SIB-L score at week 12 and weeks 24/28 (study end) significantly favored Memantine over placebo treatment (P < .0001 and P = .0182, respectively). Overall, more Memantine-treated patients than placebo-treated patients benefited from treatment. The effect was especially pronounced in patients with substantial language impairment on the SIB-L (baseline score, ≤20). At weeks 24/28, significantly more Memantine-treated patients experienced a clinically relevant improvement (25.4% vs. 10.8%, P = .0414), and significantly fewer patients experienced clinically relevant worsening (32.8% vs. 60.0%, P = .0029).ConclusionsMemantine treatment of AD patients results in significant benefits for language function. Our results suggest that it is worth considering this therapeutic option, even for AD patients with marked language impairment.     

Specific functional effects of memantine treatment in patients with moderate to severe Alzheimer's disease

Treatment of Alzheimer's disease (AD) that combats progressive functional deterioration can improve the patient's quality of life and reduce caregiver burden. Memantine, a moderate affinity N-methyl-D-aspartate receptor antagonist, reduces global deterioration in AD patients and provides cognitive and functional benefits relative to placebo. Two previous studies reported statistically significant benefits of memantine for overall functional ability on the Alzheimer Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia (ADCS-ADL(19)), Functional Assessment Staging, and G2 scale. The present study reports a single-item analysis of the ADL scales from the two trials and shows that patients treated with memantine demonstrated a numerical advantage over placebo on all items assessed. These results help to translate the positive effects of memantine into specific aspects of functional ability, information that is relevant to AD patients and their families as well as to researchers interested in the assessment of functional ability in AD clinical trials.     

Donepezil for the treatment of behavioral symptoms in patients with Alzheimer's disease

Behavioral and psychologic symptoms of dementia (BPSD) are common manifestations in mid- and late-stage Alzheimer's disease (AD). Traditional treatments for BPSD are neuroleptics and sedatives, which are not devoid of serious adverse effects. A number of studies show beneficial effects in the treatment of BPSD with acetylcholinesterase inhibitors (AChEI). The present study aimed to evaluate the effect of donepezil (using the generic drug Memorit) as monotherapy for AD patients suffering from BPSD. Twenty-eight consecutive patients followed at the Memory Outpatient Clinic and Psychogeriatric Department of the Abarbanel Mental Health Center were treated with donepezil for 6 months. Starting dose was 5 mg daily during the first 4 weeks and continuation with 10 mg daily thereafter. Treatment effects were evaluated using the Mini Mental State Examination (MMSE), the Neuro-Psychiatric Inventory (NPI), and the Clinical Global Impression of Change Scale (CGIC) caregiver version. Twenty-four of 28 patients completed the study. Of these, five patients needed additional rescue neuroleptic treatment due to incomplete response. The mean dose of donepezil was 9.10 mg/day (median 10 mg/day). The overall NPI improved significantly from 33.4 to 21.2 (p = 0.008). The mean CGIC at study's end was 3.0 (mild improvement). The cognitive scores did not change significantly. When compared to the patients who completed the study, patients who discontinued had higher mean scores on the irritability and agitation subscales of the NPI, they were older, and they had longer disease duration and lower MMSE mean scores. Three adverse events were recorded: one syncope causing a toe phalanx fracture and gastrointestinal complaints that resolved over time in two additional patients. Acetylcholinesterase inhibitors should be considered for the treatment of BPSD before neuroleptic treatment is instituted in AD patients with low levels of irritability and agitation.