The article mentions the conclusions of most evidential works investigating donepezil in the treatment of cognitive deficit in schizophrenia. It focuses on an analysis of a sub-group of 20 patients receiving treatment of the donepezil in an extended Czech double-blind placebo controlled study.

Research into Gingko biloba extract EGb 761® has been ongoing for many years. Early studies showed that the extract was superior to placebo in improving symptoms of dementia, and this has been confirmed by more recent research. The GINDEM-NP, GOTADAY and GOT-IT! studies showed that 240 mg/day EGb 761® improved cognitive function, neuropsychiatric symptoms, activities of daily living, and quality of life in patients with mild to moderate dementia compared with placebo, with results reproducible in independent trials. The strength of the effect in terms of improvements in neurosensory symptoms associated with old age and dementia was strong enough to be detected by caregivers and independent clinicians. A combination of 240 mg/day EGb 761® and 10 mg/day (initially 5 mg/day) donepezil was also more effective than either drug alone. Regarding the improvement of neuropsychiatric symptoms, a cross-comparison of studies with different antidementia agents suggests that EGb 761® is at least as effective as memantine, galantamine, and donepezil. Safety data revealed no important safety concerns with EGb 761®.

The occurrence of mania in the geriatric population is rare. Furthermore, there were only six case reports of elderly patients with secondary mania resulting from treatment with cholinesterase inhibitors. In all cases, patients had a prior psychiatric history. We report the case of an elderly patient with no prior history of psychiatric or other organic disorders who experienced first episode mania following treatment with rivastigmine. We discuss the possible mechanism of mania in this patient.

Background: Cholinesterase inhibitors (ChEIs) represent the mainstay of symptomatic treatment in Alzheimer's disease. Three medications belonging to this class are presently widely available. These agents differ in their individual mechanisms of action and pharmacokinetic properties. Switching ChEIs can be a reasonable option in cases of intolerance or lack of clinical benefit.

Methods: A systematic literature search of switching ChEIs was conducted, and all studies specifically evaluating this issue were identified. Published consensus guidelines were also searched for recommendations on ChEI switching.

Results: Eight clinical studies are summarized and discussed. All of these studies are open-label or retrospective and they cannot be readily compared because of heterogeneity in design, number of patients, agents used, and endpoints. Switching in most of these studies was done for both “lack of benefit” or “loss of response” after up to 29 months of treatment. Nevertheless, the majority of studies did not include individuals switched for lack of response after several years of treatment. Lack of satisfactory response or intolerance with the initial agent was not predictive of similar results with the second agent.

Conclusions: In light of these findings, we propose the following practical approach to switching ChEIs: (1) in the case of intolerance, switching to a second agent should be done only after the complete resolution of side-effects following discontinuation of the initial agent; (2) in the case of lack of efficacy, switching can be done overnight, with a quicker titration scheme thereafter; (3) switching ChEIs is not recommended in individuals who show loss of benefit several years after initiation of treatment.

Background: This study sought to examine the trends in the prescribing of subsidized and unsubsidized cognition enhancing drugs (CEDs) in Australia over five years from 2002 to 2007. Subsidized cholinesterase inhibitor medication could be prescribed to people with mild to moderate Alzheimer's disease (AD) once a specialist physician had confirmed this diagnosis. Memantine was available for use in moderately severe AD but not subsidized.

Methods: We analyzed the Medicare Australia and Drug Utilisation Sub-Committee databases for CED prescription data, 2002–2007, by gender, age and prescriber class. Aggregated prescription data for each medication were converted to defined daily doses (DDD) per 1000 persons per day using national census data.

Results: There were 1,583,667 CED prescriptions dispensed during the study period. CED use increased 58% from 0.91 to 1.56 DDD/1000 persons/day between 2002 and 2007. Peak use was in those aged 85–89 years. Age-adjusted utilization was slightly higher in females than males. Donepezil was the most widely used CED (66%), followed by galantamine (27%) then memantine (4%). General practitioners prescribed the majority of CEDs. Geriatricians exhibited a greater preference for galantamine than other prescribers. CED dispensing peaked towards the end of each calendar year, reflecting stockpiling by patients under the influence of a federal safety net subsidy.

Conclusions: Despite subsidized access to CEDs in Australia, only a minority of people with AD was prescribed these drugs during the period of the study. It is likely that the combination of complex prescribing rules and negative perceptions about efficacy or cost-effectiveness might have contributed to these findings.

Background: We aimed to develop a standardization method to pool data recorded on different activities of daily living (ADL) scales in order to reduce variability of functional outcome data from Alzheimer's disease (AD) clinical trials and to better evaluate the effect of donepezil treatment on function in patients with AD.

Methods: Based on pre-specified criteria, six studies were selected from among all donepezil clinical trials in AD. Individual items from nine ADL scales used in these trials were mapped to a standardized functional scale comprising 12 domains (six basic, six instrumental); scores were transformed to a 0–100 scale. External validation of this scale yielded a concordance rate of 90.8%. For each domain, mean change from baseline to 24 weeks in the placebo and donepezil groups was compared for the total population and for subgroups stratified by baseline disease severity. Study settings included outpatient, assisted living, and skilled nursing facilities. Participants comprised 2183 patients (donepezil, 1261; placebo; 922) with baseline Mini-mental State Examination (MMSE) scores 5–26.

Results: Significant treatment differences favoring donepezil were observed for five items (two instrumental and three basic). Patients with moderate AD at baseline (MMSE 10–17) demonstrated the greatest treatment effect.

Conclusion: Functional data were successfully pooled using standardizing methodology. A beneficial effect of donepezil treatment on function was demonstrated using this standardized functional scale. Similar analyses from studies with other anti-dementia drugs may help to determine the generalizability of these findings and potentially encourage use of functional assessment as a clinical tool.

The acetylcholinesterase (AChE) inhibitor donepezil is also a σ1 receptor agonist. We examined whether donepezil binds to σ1 receptors in the living human brain after a single oral administration. Dynamic positron emission tomography (PET) data acquisition using the selective σ1 receptor ligand [11C]SA4503 was performed to evaluate quantitatively the binding of [11C]SA4503 to σ1 receptors in eight healthy male volunteers. Each subject had a PET scan before and after receiving a single dose of donepezil (5 or 10 mg). The binding potential of [11C]SA4503 was calculated. Doses of 5 mg and 10 mg donepezil bound to σ1 receptors in the human brain with occupancies of ~60% and ~75%, respectively, in a dose-dependent manner. This study demonstrated that donepezil binds to σ1 receptors in the living human brain at therapeutic doses. Therefore, σ1 receptors may be implicated in the pharmacological mechanism of donepezil in the human brain.

Background: Maintaining continuous pharmacological treatment of patients with dementia is often difficult. In the current study we surveyed the discontinuation of donepezil, a cholinesterase inhibitor, for the treatment of Alzheimer's disease in a Japanese geriatric outpatient clinic in a university hospital.

Methods: Using a retrospective chart review from 1 July 2003 to 30 June 2005, prescriptions of donepezil and the reasons for discontinuing the prescription in a university hospital were determined. The severity of dementia was evaluated by the clinical dementia rating (CDR).

Results: Out of 264 patients, 140 (53.1%) discontinued taking donepezil during the two-year observation period. The mean age of the continued group and the discontinued group did not differ significantly (79.5 ± 6.7, 79.8 ± 6.4, respectively). Kaplan-Meier analysis showed that the patients with more severe cognitive impairment (CDR score = 3) discontinued donepezil earlier and more frequently. The reasons for discontinuation were a change in the doctors treating the patients (n = 71), ineffectiveness (n = 16), gastrointestinal side-effects (n = 11), and others (n = 41). In patients with CDR = 1 or 2, changes of doctors were the most frequent reason for discontinuation. However, in patients with CDR = 3, ineffectiveness of the medication was the major reason for discontinuation.

Conclusion: Donepezil was frequently discontinued, and the rate of discontinuation was higher in patients with advanced dementia.

Acetylcholine (ACh) esterase inhibitors like galantamine and donepezil have been tested as adjunct treatment in schizophrenia. Although ACh esterase inhibition might confer some antipsychotic activity, the role of allosteric potentiation of nicotinic ACh receptors (nAChRs), which is an additional mechanism of galantamine, remains elusive. Therefore, the potential antipsychotic-like effects of galantamine and donepezil, respectively, alone, and in combination with the dopamine D2/3 receptor antagonist, raclopride, were tested in the conditioned avoidance response (CAR) test and extrapyramidal side-effect liability was assessed with the catalepsy test. Neither galantamine nor donepezil alone suppressed CAR selectively. Galantamine, but not donepezil, enhanced the raclopride-induced suppression of CAR, predicting augmentation of antipsychotic activity. In contrast to donepezil, galantamine did not increase catalepsy, alone or combined with raclopride. These data suggest that allosteric potentiation of nAChRs may mediate the antipsychotic-like effect of adjunctive galantamine and provide support for the development of α7 nAChR-selective allosteric potentiators for schizophrenia.

Objective: This paper reviews the key lessons learned from the first published short-term, placebo-controlled trial of a cholinesterase inhibitor for treatment of mild cognitive impairment (MCI).

Methods: The study was a 24-week placebo-controlled trial designed to evaluate the efficacy and safety of donepezil HCl (donepezil) in the treatment of cognitive impairment in subjects with MCI. Primary outcome measures were the NYU Paragraphs Test and the ADCS Clinicians Global-Impression of Change in the intent-to-treat last-observation-carried-forward group.

Results: There was no benefit of donepezil treatment on primary outcome measures (NYU Paragraphs and ADCS CGI-C) in the ITT-LOCF group but positive findings were seen on NYU Paragraphs in the fully evaluable group and in certain secondary outcome measures across both groups.

Conclusions: The results highlight the need for the use of primary cognitive and functional measures that are reliable and sensitive to change in patients with MCI. Measures of episodic memory, psychomotor speed and complex attention were most sensitive in this study. Functional rating scales are needed that measure change in individual subjects' key areas of functional deficit, which typically involve executive aspects of instrumental ADLs. Tolerability can be increased by use of flexible dosing and efficacy is likely to be enhanced by increasing the length of the trial from six to 12 months and by enriching the sample with subjects more likely to decline during the trial.

Acetylcholinesterase inhibitors have demonstrated safety and efficacy in patients with mild to moderate Alzheimer's disease (AD). Although studies of biomarkers in AD suggest a neurobiological rationale for continuing cholinomimetic therapy in patients with severe AD, there have been few studies on the effects of these drugs in such patients. While the interpretation of earlier studies on therapy for severe AD has been complicated by the inclusion of patients with moderate AD, a recent study in Swedish nursing home residents demonstrates the clinical utility of donepezil in a population of exclusively severe patients – i.e. those with Mini-Mental State Examination scores of 1 to 10 inclusive. Significant differences favoring donepezil treatment were observed at the end of this six-month, double-blind placebo-controlled study on the two primary outcome measures: the Severe Impairment Battery (SIB) and Modified Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory for Severe AD (ADCS-ADL-severe). Donepezil-treated patients showed a mean improvement on the SIB after six months compared with baseline, and less decline on the ADCS-ADL-severe than would be expected for untreated patients. These results extend and confirm earlier data suggesting that donepezil is effective in patients with moderate and severe AD.

The pathological processes that lead to Alzheimer's disease (AD) begin decades before the onset of dementia. Brain abnormalities in genetically susceptible individuals have been observed even in young adults. Patients with AD differ from normal elderly patients in brain morphology and neurochemistry. Important observations include increasing appearance of amyloid plaques and neurofibrillary tangles, progressive loss of hippocampal volume, reduced cerebral glucose utilization, inflammatory processes, glial activation, and impairment of cholinergic function with losses of nicotinic acetylcholine receptors. These changes appear to begin in the asymptomatic stages and continue as cognition and then function and behavior are disrupted. Mild cognitive impairment (MCI) may be the first cognitive manifestation of this pathogenic process moderated by ongoing compensatory neurochemical mechanisms in the cholinergic system. Recent advances in positron emission tomography imaging techniques, including the development of the Pittsburgh B compound (PIB), allow in vivo visualization of amyloid plaques. These techniques have the potential to enable brain amyloid load to be monitored over time and to be related to brain function. Emerging evidence suggests that β-amyloid may interact with nicotinic receptors. This interaction may have clinically significant downstream effects and may mediate amyloid neurotoxicity. The cholinesterase inhibitors may have multiple actions, depending on the stage of the disease, from very mild to severe.