Impact of donepezil hydrochloride on the care burden of family caregivers of patients with Alzheimer's disease

Background: To evaluate the impact of donepezil hydrochloride on the care burden on family members of patients with Alzheimer's disease (AD). At present, donepezil is the only drug approved for the treatment of AD in Japan. Although the care burden on primary caregivers of AD patients comprises both physical and psychological burdens and donepezil is recognized to improve cognitive dysfunction and associated symptoms, there are few data on the effects of the drug on the care burden. Methods: Of the uninstitutionalized AD patients who visited a dementia clinic between June 2008 and May 2009 with their primary family caregivers, 416 subjects who satisfied the enrollment criteria were registered for the study. All participants provided informed consent. Assessment included changes in scores on the Japanese version of the Zarit Caregiver Burden Interview (J‐ZBI) and the Mini‐Mental State Examination (MMSE), as well as the presence of behavioral and psychological symptoms of dementia (BPSD). Caregivers answered the questionnaires at baseline and after 12 weeks treatment with donepezil (starting dose 3 mg, p.o., once daily, followed by 5 mg after 1 or 2 weeks). Results: There were significant changes in mean scores on the J‐ZBI (?1.9 ± 9.5; P < 0.01) and MMSE (+0.9 ± 2.9; P < 0.01) from baseline to Week 12, without significant correlation between these two scores. In patients with BPSD, there was a significant decrease in J‐ZBI scores over the 12 weeks (P = 0.013); in contrast, in patients without BPSD, the decrease in the J‐ZBI score did not reach statistical significance (P = 0.418). Conclusions: The results indicate that donepezil improves cognitive function and some of the BPSD. As a possible consequence of improvements in BPSD, donepezil may also reduce caregivers' burden.     

Impact of rivastigmine on costs and on time spent in caregiving for families of patients with Alzheimer's disease

BACKGROUND: Alzheimer's disease (AD) places a significant burden on health care systems worldwide. As new treatments are developed, their cost-effectiveness is often assessed to help health care professionals make informed decisions. In addition to the more common practice of assessing direct medical costs, indirect costs, including time spent in caregiving, should be evaluated. METHODS: This study examined the potential effects of the dual cholinesterase inhibitor rivastigmine (Exelon) on caregivers of patients with AD. Results from two 26-week, placebo-controlled trials have demonstrated the clinically relevant and statistically significant efficacy of rivastigmine (6-12 mg/day) compared to placebo, on cognition, activities of daily living, and global functioning. By delaying progression of AD, significant savings in caregiver burden are anticipated, as measured by time spent caregiving and its related costs. Data collected in a prospective, observational study of AD patients and their caregivers were used to establish the relationship between disease severity (based on Mini-Mental State Examination [MMSE] score) and time spent caregiving (according to the 5-item Caregivers Activity Survey score). A significant correlation was observed between the two scores (N = 43, r = -.56, p < .0001), demonstrating that more time for supervision from caregivers is required as the disease progresses. This finding was used to estimate the reduced caregiver burden resulting from the delay in disease progression that was demonstrated with use of rivastigmine. RESULTS: Over a 2-year period, the reduction in time spent in caregiving reached 691 hours for caregivers of patients with mild AD (MMSE score 21-30), resulting in a total savings of approximately 11,253 dollars. Treatment of patients with moderately severe AD was also evaluated. The trend was similar but the impact was less, suggesting an economic benefit to early therapy. CONCLUSION: Early diagnosis and a pharmacologic intervention that allows the patients to remain at home longer by delaying disease progression would have a beneficial impact on patients, caregivers, and payers, and should therefore be encouraged through initiatives designed to identify and treat patients early in the course of disease.     

Verbal repetition in patients with Alzheimer's disease who receive donepezil

BACKGROUND: Current outcome measures for Alzheimer's disease (AD) drugs have been criticized as insufficiently patient-centred. One commonly unmeasured goal of patients and caregivers is verbal repetition. OBJECTIVES: We examined how often reducing repetition (of questions, statements or stories) was set as treatment goal, whether and when it responded, and how change in repetition correlated with change in other domains. METHODS: This is a secondary analysis of the open-label Atlantic Canada Alzheimer's Disease Investigation of Expectations study of donepezil for mild-moderate AD in 100 community-dwelling people. Goal Attainment Scaling, an individualized account of the goals of treatment, was the primary outcome measure. RESULTS: Reducing repetition was a treatment goal in 46%, who were not systematically different from others. Of 18 patients in whom repetition improved for 9 months, 83% (15) showed a response at 3 months. Early (3-month) response correlated best with the overall level of goal attainment (r = 0.74) and changes in leisure activities (r = 0.69) and social interactions (r = 0.68) compared with changes in cognition (r = 0.44) or behaviour (r = 0.11). Correlations with the ADAS-Cog and MMSE change scores remained only modest (at 12 months = -0.25 and 0.19, respectively). Correlations with the CIBIC-Plus were higher (-0.47 at 3 months and -0.43 at 12 months). CONCLUSION: Diminution of repetition is common, and appears to mark response to cholinesterase inhibition in some patients. Responders generally also show improved cognition and function, perhaps as an aspect of improved executive function.     

Goal setting and attainment in Alzheimer's disease patients treated with donepezil

OBJECTIVES: To understand the treatment goals of Alzheimer's disease (AD) patients, carers, and physicians; to estimate whether clinically important goals are met during treatment with donepezil; and to compare a measure of goal attainment with standard measures used to evaluate AD treatment. METHODS: In a 12 month phase IV trial, 108 patients with mild to moderate AD, their primary carers, and treating physicians set goals assigned to five domains, using Goal Attainment Scaling (GAS) as the primary outcome. Goal attainment was assessed quarterly. GAS scores were correlated with standard outcomes, including the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog), and the Clinician's Interview-Based Impression of Change-Plus (CIBIC-plus). RESULTS: Physicians set fewer goals (342, mean (SD) per patient=3 (1)) than patients/carers (855, mean=9 (3)), particularly in leisure (20% by physicians compared with 76% by patients/carers), and social interaction (24% versus 49%). Physicians observed statistically significant improvement in global goal attainment for six months, and patients/carers for nine months. Patients/carers described consistent goal attainment, whereas physicians observed variable effects, such as decline in cognition but improved social interaction and behaviour. Physician global GAS scores correlated highly with the CIBIC-plus at weeks 12 (r= -0.82) and 52 (r=-0.80), but not with the ADAS-cog (r=0.12 and r=-0.45, respectively). Patient/carer global GAS scores correlated moderately with the physician's CIBIC-plus (week 12 r=-0.51; week 52 r=-0.56), and nominally with the ADAS-cog. CONCLUSIONS: Patients/carers and physicians differ in their expectations and impressions of treatment effects. Clinically important changes correlated only modestly with psychometric tests. Attainment of treatment goals does not accord with a simplistic model in which successful AD treatment means that all declines uniformly improve.     

The effects of donepezil on quantitative EEG in patients with Alzheimer's disease.

Donepezil is a cholinesterase inhibitor which has been previously shown to affect the cognitive evoked potentials (EPs) of patients with Alzheimer's Disease (AD) during treatment with the drug. The purpose of this study was to determine the effect of treatment with donepezil 5 mg daily for 1 month on quantitative EEG (QEEG) in patients with AD. Treatment was associated with no significant differences between the pre- and post-treatment QEEGs for (1) absolute power (all four frequency bands), (2) percent relative power (all four frequency bands), (3) total mean frequency, (4) mean frequency for theta and beta, (5) absolute power asymmetry across homologous electrode pairs (all four frequency bands), and (6) interhemispheric coherence across homologous electrode pairs (all four frequency bands). There were significant decreases in mean alpha and delta frequencies that were consistent across broad electrode arrays except for an increase in the delta frequency at T3. The implications of these changes are not yet clear. Studies of QEEG changes with higher doses of donepezil over longer periods of time may yield a better understanding of the neurophysiological effects of the medication.     

EEG changes during long-term treatment with donepezil in Alzheimer's disease patients

Summary. In this pilot study, we examined the long-term treatment effect of donepezil on the quantitative EEG (qEEG) in 12 Alzheimer's disease patients. The qEEGs of the mean absolute and relative amplitudes of betal, alpha, theta and delta activities were obtained at baseline and during donepezil treatment. Comparisons of awake qEEG prior to and during treatment were performed using a 2-way analysis of variance (ANOVA) with repeated measures. In patients with mild dementia (n = 5), the qEEG analysis showed a significant reduction of the mean absolute theta activity (p = 0.05) by donepezil, particularly in frontal and temporo-parietal areas. In patients with moderate/severe dementia (n = 7), a significant decrease in the mean absolute beta 1 activity (p = 0.02), particularly in the frontal and occipital areas may be attributed to disease progression which was not counteracted by the long-term treatment. The differences in qEEG in patients with different stages of dementia under donepezil treatment may be related to different compensatory capacities due to structural and functional brain disturbances. Received January 27, 2001; accepted June 8, 2001     

Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer's disease

OBJECTIVE: This subanalysis of a large, double-blind, placebo-controlled trial examined the prevalence of behavioral symptoms in moderate to severe Alzheimer's disease (AD), and the effect of treatment with donepezil. METHODS: Two hundred ninety patients with moderate to severe AD (standardized Mini-Mental State Examination scores 5-17) were randomized to receive 24 weeks of once-daily doses of donepezil 5 mg/day for 28 days, and 10 mg/day thereafter per the clinician's judgment (n = 144), or placebo (n = 146). The outcome measure of interest was the 12-item Neuropsychiatric Inventory (NPI). RESULTS: Baseline demographics were similar between the treatment groups. Least squares mean (+/- SE) baseline NPI 12-item total scores were 19.55 +/- 1.48 and 19.30 +/- 1.45, respectively. At baseline, the most common symptoms were apathy/indifference (67%), aberrant motor behavior (53%), depression/dysphoria (52%), anxiety (49%), and agitation/aggression (45%). NPI individual item change from baseline scores at Week 24 using a last observation carried forward (LOCF) analysis showed benefits with donepezil treatment compared with placebo for all items, with significant treatment differences for depression/dysphoria, anxiety, and apathy/indifference (p < .05). Symptoms present at baseline that improved significantly for donepezil- compared with placebo-treated patients at Week 24 LOCF included anxiety, apathy/indifference, and irritability/lability (p < .05). When patients who were not receiving psychoactive medications at baseline were analyzed separately, significant improvements in NPI (continued) 12-item total score were observed with donepezil compared with placebo at most visits and at Week 24 LOCF (p < .05). CONCLUSIONS: Behavioral symptoms of the magnitude observed in this moderate to severe AD population improved with donepezil.     

Clinical effects of high oral dose of donepezil for patients with Alzheimer's disease in Japan

Background:  Donepezil 10 mg/day gained approval in Japan in August 2007 for the treatment of cognitive dysfunction in advanced Alzheimer's disease.
Methods:  We evaluated the efficacy and adverse effects of donepezil when the dose was increased to 10 mg/day in 61 Japanese patients with Alzheimer's disease. Cognitive function was evaluated using the Revised Hasegawa Dementia Scale and mini-mental state examination at the day before starting, and at 4, 8 and 24 weeks after starting donepezil 10 mg/day. The relationship with apolipoprotein E4 was also investigated.
Results:  The Revised Hasegawa Dementia Scale and mini-mental state examination scores were not statistically significantly different at any time after starting donepezil 10 mg/day. It can be anticipated that donepezil 10 mg/day will especially inhibit deterioration of cognitive function in advanced Alzheimer's disease. The incidence of adverse events was 11.5%, lower than the rate of 40% or higher recorded during previous clinical trials.
Conclusions:  The progression of cognitive dysfunction could be inhibited by increasing the dose of donepezil to 10 mg/day. It was suggested that longer-term treatment with 5 mg/day might lead to fewer adverse events when the dose is increased to 10 mg/day.     

小剂量多奈哌齐联合美金刚治疗老年性痴呆的疗效及安全性

目的观察多奈哌齐联合美金刚治疗老年性痴呆患者认知功能和行为能力的改善作用及安全性。方法将30例老年性痴呆患者随机分为多奈哌齐对照组和多奈哌齐联合美金刚试验组。疗程16周,每4周随访1次,评估简易精神状态量表(MMSE);治疗16周后进行有效性评估:采用阿尔茨海默病评定量表的认知分量表(ADAS-Cog)评定患者认知功能;采用临床医生访谈时对病情变化的印象补充量表(CIBIC-Plus)评价患者总体功能变化情况;采用神经精神科问卷(NPI)了解患者精神行为症状的变化;采用日常生活能力量表(ADL)了解患者日常功能情况。结果 29例患者完成最后随访,对照组MMSE,ADAS-Cog,CIBIC-Plus,NPI,ADL评分治疗前后比较有统计学意义(P<0.05);试验组MMSE,ADAS-Cog,CIBIC-Plus,NPI,ADL评分治疗前后比较有统计学意义(P<0.05);治疗前两组各量表评分比较无统计学意义;治疗16周后,两组比较,试验组较对照组患者NPI评分明显下降(P<0.05),表现在脱抑制和激越等情绪方面;CIBIC-Plus总体功能变化实验组较对照组好转明显(P<0.05),余各项评分两组间无显著性差异(P>0.05)。结论多奈哌齐及多奈哌齐联合美金刚治疗老年性痴呆均有效,后者更优于前者,尤其对情绪方面的阳性症状控制较好,且具有良好的安全性和耐受性。     

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.     

Long-term effects of donepezil on P300 auditory event-related potentials in patients with Alzheimer's disease

The P300, one of the cognitive event-related potentials (ERPs) of the cerebral cortex, reflects the functioning of the neurochemical system involved in cognitive processes. We investigated clinical significance of the components of auditory P300 ERPs, in comparison with neuropsychologic tests including the Mini-Mental State Examination and the Japanese version of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-J cog), for evaluating of the effect of donepezil (DPZ) (5 mg daily for 6 months), an acetylcholinesterase inhibitor, in patients with Alzheimer's disease (AD). Reduction of P300 latency associated with a parallel improvement of ADAS-J cog scores was observed after administration of 5 mg/day of DPZ in patients with AD. P300 latency gives very useful information on the progression of AD, especially in the longitudinal follow-up of patients with AD during treatment with DPZ acting on cholinergic pathways.     

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.     

美金刚联合多奈哌齐对阿尔茨海默病患者认知功能及神经递质的影响

目的 探讨美金刚联合多奈哌齐对阿尔茨海默病(AD)患者认知功能及神经递质的影响.方法 选取北京航天总医院收治的AD患者100例,随机分为试验组(n=50)、对照组(n=50),对照组予以多奈哌齐治疗,试验组在此基础上予以盐酸美金刚治疗,比较2组临床疗效、AD评定量表的认知分量表(ADAS-Cog)评分、神经精神科问卷(...     

Cognitive stimulation therapy for Alzheimer's disease: the effect of cognitive stimulation therapy on the progression of mild Alzheimer's disease in patients treated with donepezil

BACKGROUND: There is general consensus regarding the benefit of acetylcholinesterase inhibitors (e.g. donepezil) in Alzheimer's disease (AD). However, the combined effect of acetylcholinesterase and cognitive stimulation therapy (CST) is still controversial. OBJECTIVE: This study examines their combined effect on the progression of cognitive decline in AD by comparing the cognitive performance of 17 AD patients treated with CST and donepezil (combined treatment group) and 13 AD patients treated with donepezil alone (control group). METHODS: Patients in the combined treatment group received 5 mg of donepezil per day and about 20 one-hour CST sessions for one year, whereas the control group received only 5 mg of donepezil per day. The first eight sessions were carried out once a week, and subsequent sessions were generally once every two weeks. The patients were evaluated for changes in cognitive ability by administering the Mini-mental State Examination (MMSE) before the start of CST (baseline) and about one year later (follow-up). RESULTS: A repeated-measure analysis of variance revealed a significant group x time interaction. The MMSE score decreased significantly in the control group, but did not change significantly in the combined treatment group. Three patients in the control group declined by four points on the MMSE, compared to none in the combined treatment group. Effect size (ES) in the control group was relatively large and negative, while the ES in the combined treatment group was close to zero. CONCLUSIONS: The results suggest the possibility that donepezil plus CST slowed the rate of cognitive decline more than the administration of donepezil alone.     

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.     

Sustained cognitive improvement following treatment of Alzheimer's disease with donepezil

OBJECTIVES: To audit response to the anticholinesterase inhibitor donepezil in patients referred to a specialist memory clinic, to identify possible means of targeting the drug more accurately. DESIGN: All referrals to the clinic who were assessed and treated against a protocol, with structured follow-up. SUBJECTS: All referrals of any age with the diagnosis of probable Alzheimer's disease, mild to moderately severe. Main outcome measures Cognitive improvement as measured by serial ADAS-cog and MMSE examinations. RESULTS: Two hundred and eight-two patients commenced on treatment, improved cognitive functioning in over 65% of patients reaching 3 months (N=184), 51% on intention to treat analysis (N=231), with significantly greater improvement (p=0.03) in those aged 65 and under. Carer reports of behavioural improvement not always linked to cognitive improvement. Trend to increased response in those on concomitant antidepressants. CONCLUSION: Three-month assessment for response prior to agreeing continuation of treatment selects a group who maintain their response. Younger patients should be targeted for early assessment and treatment.