Richard J. Harvey

Background Alzheimer's disease is the most common cause of dementia in older people. One approach to symptomatic treatment of Alzheimer's disease is to enhance cholinergic neurotransmission in the brain by blocking the action of the enzyme responsible for the breakdown of the neurotransmitter acetylcholine. This can be done by a group of drugs known as cholinesterase inhibitors. Donepezil is a cholinesterase inhibitor. This review is an updated version of a review first published in 1998. Objectives To assess the clinical efficacy and safety of donepezil in people with mild, moderate or severe dementia due to Alzheimer's disease; to compare the efficacy and safety of different doses of donepezil; and to assess the effect of donepezil on healthcare resource use and costs. Search methods We searched Cochrane Dementia and Cognitive Improvement’s Specialized Register, MEDLINE, Embase, PsycINFO and a number of other sources on 20 May 2017 to ensure that the search was as comprehensive and up‐to‐date as possible. In addition, we contacted members of the Donepezil Study Group and Eisai Inc. Selection criteria We included all double‐blind, randomised controlled trials in which treatment with donepezil was administered to people with mild, moderate or severe dementia due to Alzheimer's disease for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two different doses of donepezil were compared. Data collection and analysis One reviewer (JSB) extracted data on cognitive function, activities of daily living, behavioural symptoms, global clinical state, quality of life, adverse events, deaths and healthcare resource costs. Where appropriate and possible, we estimated pooled treatment effects. We used GRADE methods to assess the quality of the evidence for each outcome. Main results Thirty studies involving 8257 participants met the inclusion criteria of the review, of which 28 studies reported results in sufficient detail for the meta‐analyses. Most studies were of six months' duration or less. Only one small trial lasted 52 weeks. The studies tested mainly donepezil capsules at a dose of 5 mg/day or 10 mg/day. Two studies tested a slow‐release oral formulation that delivered 23 mg/day. Participants in 21 studies had mild to moderate disease, in five studies moderate to severe, and in four severe disease. Seventeen studies were industry funded or sponsored, four studies were funded independently of industry and for nine studies there was no information on source of funding. Our main analysis compared the safety and efficacy of donepezil 10 mg/day with placebo at 24 to 26 weeks of treatment. Thirteen studies contributed data from 3396 participants to this analysis. Eleven of these studies were multicentre studies. Seven studies recruited patients with mild to moderate Alzheimer's disease, two with moderate to severe, and four with severe Alzheimer's disease, with a mean age of about 75 years. Almost all evidence was of moderate quality, downgraded due to study limitations. After 26 weeks of treatment, donepezil compared with placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale‐Cognitive (ADAS‐Cog, range 0 to 70) (mean difference (MD) ‐2.67, 95% confidence interval (CI) ‐3.31 to ‐2.02, 1130 participants, 5 studies), the Mini‐Mental State Examination (MMSE) score (MD 1.05, 95% CI 0.73 to 1.37, 1757 participants, 7 studies) and the Severe Impairment Battery (SIB, range 0 to 100) (MD 5.92, 95% CI 4.53 to 7.31, 1348 participants, 5 studies). Donepezil was also associated with better function measured with the Alzheimer's Disease Cooperative Study activities of daily living score for severe Alzheimer's disease (ADCS‐ADL‐sev) (MD 1.03, 95% CI 0.21 to 1.85, 733 participants, 3 studies). A higher proportion of participants treated with donepezil experienced improvement on the clinician‐rated global impression of change scale (odds ratio (OR) 1.92, 95% CI 1.54 to 2.39, 1674 participants, 6 studies). There was no difference between donepezil and placebo for behavioural symptoms measured by the Neuropsychiatric Inventory (NPI) (MD ‐1.62, 95% CI ‐3.43 to 0.19, 1035 participants, 4 studies) or by the Behavioural Pathology in Alzheimer's Disease (BEHAVE‐AD) scale (MD 0.4, 95% CI ‐1.28 to 2.08, 194 participants, 1 study). There was also no difference between donepezil and placebo for Quality of Life (QoL) (MD ‐2.79, 95% CI ‐8.15 to 2.56, 815 participants, 2 studies). Participants receiving donepezil were more likely to withdraw from the studies before the end of treatment (24% versus 20%, OR 1.25, 95% CI 1.05 to 1.50, 2846 participants, 12 studies) or to experience an adverse event during the studies (72% vs 65%, OR 1.59, 95% 1.31 to 1.95, 2500 participants, 10 studies). There was no evidence of a difference between donepezil and placebo for patient total healthcare resource utilisation. Three studies compared donepezil 10 mg/day to donepezil 5 mg/day over 26 weeks. The 5 mg dose was associated with slightly worse cognitive function on the ADAS‐Cog, but not on the MMSE or SIB, with slightly better QoL and with fewer adverse events and withdrawals from treatment. Two studies compared donepezil 10 mg/day to donepezil 23 mg/day. There were no differences on efficacy outcomes, but fewer participants on 10 mg/day experienced adverse events or withdrew from treatment. Authors' conclusions There is moderate‐quality evidence that people with mild, moderate or severe dementia due to Alzheimer's disease treated for periods of 12 or 24 weeks with donepezil experience small benefits in cognitive function, activities of daily living and clinician‐rated global clinical state. There is some evidence that use of donepezil is neither more nor less expensive...

The high prevalence of comorbid illicit drug use in persons with chronic psychotic illness represents a strong determinant of psychotic relapse and rehospitalization. Epidemiological studies indicate changing patterns of illicit drug use in Australia, which are concerning because of increased use of crystal methamphetamine, also known as “ice.” An important complication of habitual use of crystal methamphetamine is the development of a dose-dependent acute psychotic reaction. We report a case of an acute psychotic relapse in response to polydrug use most notable for multiple recent binges of crystal methamphetamine. Unlike previously described case reports, our patient’s acute psychosis was refractory to ultra-high doses of multiple antipsychotic medications. This presented safety challenges due to the risk of serious side effects with high-dose antipsychotic medications. A 30-year-old white man with a past history of schizoaffective disorder was brought to our emergency department by the police in a state of extreme agitation, combativeness, and paranoia after use of cannabis and crystal methamphetamine. Despite existing compliance with zuclopenthixol decanoate depot medication, he required multiple emergency injections of zuclopenthixol acetate, and regular high-dose droperidol, chlorpromazine, and lorazepam. However, he remained severely agitated and psychotic with continuous threats of harm to others. A test of antipsychotic drug metabolism by cytochrome P450 enzymes did not reveal a pharmacogenetic cause for the poor therapeutic efficacy of antipsychotic medications. His psychosis did not appear to be modified by psychoactive medications but was instead self-limited to the presence of endogenous methamphetamine within his system. He fully recovered 96 to 120 hours post-presentation and was discharged home with out-patient clinic follow-up. The current case highlights the challenging nature of a severe psychotic relapse precipitated by illicit substances that is resistant to medical management. High doses of multiple antipsychotic medications may be required to manage dangerous behaviors associated with these acute psychotic relapses. These patients require close monitoring for adverse effects with adjustment of dosing to ensure the optimal balance of risk versus benefit while the patient is acutely psychotic. The results are of relevance for the management of psychiatric emergencies in emergency departments and acute mental health settings.

Objective: Thyroid function tests are a common screening investigation for patients admitted to a psychiatric inpatient unit. Method: This study aimed to retrospectively assess the clinical utility of routine thyroid function testing performed on newly admitted psychiatric patients over a 4-year period in Victoria, Australia via chart review of all abnormal results identified. Results: Our retrospective audit revealed only two cases where identification of thyroid dysfunction informed patient management. In each case, the patient had a known history of thyroid disease. In this audit period, 893 patients required screening to yield one clinically relevant abnormal result, costing AU$24,975.57. Conclusion: Such low clinical utility does not support routine admission thyroid function tests for psychiatric inpatients. We conclude that thyroid function tests should only be performed where the history and clinical signs suggest a likely contribution of thyroid dysfunction to the psychiatric presentation.

Objectives The Health of the Nation Outcome Scales (HoNOS) are mandated outcome-measures in many mental-health jurisdictions. When HoNOS are used in different care settings, it is important to assess if setting specific bias exists. This article examines the consistency of HoNOS in a sample of psychiatric patients transitioned from acute inpatient care and community centres. Setting A regional mental health service with both acute and community facilities. Participants 111 psychiatric patients were transferred from inpatient care to community care from 2012 to 2014. Their HoNOS scores were extracted from a clinical database; Each inpatient-discharge assessment was followed by a community-intake assessment, with the median period between assessments being 4 days (range 0–14). Assessor experience and professional background were recorded. Primary and secondary outcome measures The difference of HoNOS at inpatient-discharge and community-intake were assessed with Pearson correlation, Cohen's κ and effect size. Results Inpatient-discharge HoNOS was on average lower than community-intake HoNOS. The average HoNOS was 8.05 at discharge (median 7, range 1–22), and 12.16 at intake (median 12, range 1–25), an average increase of 4.11 (SD 6.97). Pearson correlation between two total scores was 0.073 (95% CI −0.095 to 0.238) and Cohen's κ was 0.02 (95% CI −0.02 to 0.06). Differences did not appear to depend on assessor experience or professional background. Conclusions Systematic change in the HoNOS occurs at inpatient-to-community transition. Some caution should be exercised in making direct comparisons between inpatient HoNOS and community HoNOS scores.

To date, our ability to accurately identify patients at high risk from suicidal behaviour, and thus to target interventions, has been fairly limited. This study examined a large pool of factors that are potentially associated with suicide risk from the comprehensive electronic medical record (EMR) and to derive a predictive model for 1–6 month risk. 7,399 patients undergoing suicide risk assessment were followed up for 180 days. The dataset was divided into a derivation and validation cohorts of 4,911 and 2,488 respectively. Clinicians used an 18-point checklist of known risk factors to divide patients into low, medium, or high risk. Their predictive ability was compared with a risk stratification model derived from the EMR data. The model was based on the continuation-ratio ordinal regression method coupled with lasso (which stands for least absolute shrinkage and selection operator). In the year prior to suicide assessment, 66.8% of patients attended the emergency department (ED) and 41.8% had at least one hospital admission. Administrative and demographic data, along with information on prior self-harm episodes, as well as mental and physical health diagnoses were predictive of high-risk suicidal behaviour. Clinicians using the 18-point checklist were relatively poor in predicting patients at high-risk in 3 months (AUC 0.58, 95% CIs: 0.50 – 0.66). The model derived EMR was superior (AUC 0.79, 95% CIs: 0.72 – 0.84). At specificity of 0.72 (95% CIs: 0.70-0.73) the EMR model had sensitivity of 0.70 (95% CIs: 0.56-0.83). Predictive models applied to data from the EMR could improve risk stratification of patients presenting with potential suicidal behaviour. The predictive factors include known risks for suicide, but also other information relating to general health and health service utilisation.

Background Alzheimer's disease is the most common cause of dementia in older people. One of the aims of therapy is to inhibit the breakdown of a chemical neurotransmitter, acetylcholine, by blocking the relevant enzyme. This can be done by a group of chemicals known as cholinesterase inhibitors. Objectives The objective of this review is to assess whether donepezil improves the well‐being of patients with dementia due to Alzheimer's disease. Search methods The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' and 'Aricept' on 5 April 2006. This Register contains up‐to‐date records of all major health care databases and many ongoing trial databases. Members of the Donepezil Study Group and Eisai Inc were contacted. Selection criteria All unconfounded, double‐blind, randomized controlled trials in which treatment with donepezil was compared with placebo for patients with mild, moderate or severe dementia due to Alzheimer's disease. Data collection and analysis Data were extracted by one reviewer (JSB), pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment estimated. Main results 24 trials are included, involving 5796 participants, of which 15 reported results in sufficient detail for the meta‐analyses. Most trials were of 6 months or less duration in selected patients. Patients in 20 trials had mild to moderate disease, in two trials moderate to severe, and in two severe disease. Available outcome data cover domains including cognitive function, activities of daily living, behaviour, global clinical state, adverse events and health care resource costs. For cognition there is a statistically significant improvement for both 5 and 10 mg/day of donepezil at 24 weeks compared with placebo on the ADAS‐Cog scale (‐2.01 points MD, 95%CI ‐2.69 to ‐1.34, P < 0.00001); ‐2.80 points, MD 95% CI ‐3.74 to ‐2.10, P < 0.00001) and for 10 mg/day donepezil compared with placebo at 24 weeks (5.55 SIB points, 95% CI 3.60 to 7.49, p<0.00001) and 52 weeks (1.84 MMSE points, 95% CI, 0.53 to 3.15, P =0.006). The results show some improvement in global clinical state (assessed by a clinician) in people treated with 5 and 10 mg/day of donepezil compared with placebo at 24 weeks for the number of patients showing improvement (OR 2.38, 95% CI 1.78 to 3.19, P = < 0.00001, OR 1.82, 95% CI 1.42 to 2.35, P < 0.00001). Benefits of treatment were also seen on measures of activities of daily living and behaviour, but not on the quality of life score. There were significantly more withdrawals before the end of treatment from the 10 mg/day (289/1125 24% 10 mg/day vs 219/1079 20% placebo, OR 1.35, 95% CI 1.11 to 1.65, P = 0.003) but not the 5 mg/day, (100/561 18% 5 mg/day vs 109/568 19% placebo, OR 0.91, 95% CI 0.68 to 1.24, P = 0.56) donepezil group compared with placebo which may have resulted in some overestimation of beneficial changes at 10 mg/day. Benefits on the 10 mg/day dose were marginally larger than on the 5 mg/day dose. The results were similar for all severities of disease. Two studies presented results for health resource use, and the associated costs. There were no significant differences between treatment and placebo for any item, the cost of any item, and for the total costs, and total costs including the informal carer costs. Many adverse events were recorded, with more incidents of nausea, vomiting, diarrhoea, muscle cramps, dizziness, fatigue and anorexia (significant risk associated with treatment) in the 10 mg/day group, compared with placebo. There were more incidents of anorexia, diarrhoea, and muscle cramps in the 5 mg/day group compared with placebo, but not of dizziness, fatigue, nausea or vomiting. Very few patients left a trial as a direct result of the intervention. Authors' conclusions People with mild, moderate or severe dementia due to Alzheimer's disease treated for periods of 12, 24 or 52 weeks with donepezil experienced benefits in cognitive function, activities of daily living and behaviour. Study clinicians rated global clinical state more positively in treated patients, and measured less decline in measures of global disease severity. There is some evidence that use of donepezil is neither more nor less expensive compared with placebo when assessing total health care resource costs. Benefits on the 10 mg/day dose were marginally larger than on the 5 mg/day dose. Taking into consideration the better tolerability of the 5 mg/day donepezil compared with the 10 mg/day dose, together with the lower cost, the lower dose may be the better option. The debate on whether donepezil is effective continues despite the evidence of efficacy from the clinical studies because the treatment effects are small and are not always apparent in practice.

The amygdala is severely atrophied at post-mortem in frontotemporal lobar degeneration (FTLD), and may contribute to the prominent behavioural changes that are early features of FTLD. The aim of this study was to assess amygdala atrophy using MRI in the main syndromic variants of FTLD and Alzheimer’s disease (AD). Brain and amygdala volumes, adjusted for intracranial volume, were measured on 46 clinically diagnosed FTLD patients [22 frontal variant FTD (FTD), 14 semantic dementia (SD), 10 progressive non-fluent aphasia (PNFA)], 20 AD patients, and 17 controls. While severe amygdala atrophy was present in both FTLD (41% smaller than controls on the left; 33% on the right) and in AD (22% on the left; 19% on the right), the FTLD group had significantly greater amygdala atrophy (z = 3.21, p = 0.001 left, z = 2.50, p = 0.01 right) and left/right asymmetry (z = 2.03, p = 0.04) than AD. Amygdala atrophy was greater in SD than FTD, PNFA and AD (p < 0.02 for all). Highly asymmetrical atrophy was present in SD, greater on the left (z = 3.23, p = 0.001), and to a lesser extent in PNFA. Despite an overlap between clinical and radiological features of FTLD and AD, marked amygdala atrophy points towards a diagnosis of FTLD, with left greater than right atrophy suggestive of one of the language variants.

Objectives: To determine the prevalence of dementia in people under the age of 65 in a large catchment area, and use these figures to estimate the number of younger people affected by dementia in the UK. Design: Epidemiological catchment area prevalence survey. Setting: The London boroughs of Kensington and Chelsea, Westminster, and Hillingdon with a total population of 567 500 people. Participants: All residents of the catchment area with dementia, where the illness began before the age of 65 years. Participants were notified to the study by medical and care professionals. The diagnosis and age of onset was established from all available health and social care records. In total, 227 people were identified, of whom 185 fulfilled the inclusion criteria of having a dementia which started before their 65th birthday. Main outcome measures: Diagnosis of dementia and differential diagnosis of the cause of the dementia. Results: The prevalence of dementia in those aged 30–64 was 54.0 per 100 000 (95% CI 45.1 to 64.1 per 100 000). For those aged 45–64 years, the prevalence was 98.1 per 100 000 (95% CI 81.1 to 118.0 per 100 000). From the age of 35 onwards, the prevalence of dementia approximately doubled with each 5 year increase in age. Extrapolating these figures nationally suggests that there are 18 319 (15 296–21 758) people with dementia under the age of 65 in the UK. Conclusions: The study confirms previous “guestimates” of the number of younger people affected by dementia in UK. The prevalence figures generated are robust, and are supported by other smaller and targeted prevalence surveys. The prevalence figures provided by this study will allow health planners to accurately estimate need and plan services.

Background: Three causative genes have been identified for autosomal dominant AD. Objective: To determine the proportion of patients with early onset AD with a positive family history accounted for by mutations in these genes. Methods: A mutational analysis of the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes was performed in 31 probands with probable or definite AD from UK families with an age at onset (AAO) Results: The mean AAO was 46.9 years (median 45 years; range 33 to 60 years). The majority of patients (23 of 31; 74%) fulfilled recognized criteria for autosomal dominant inheritance. In 17 (55%) probands the authors identified eight novel PSEN1 sequence variants and eight recognized pathogenic mutations. In 4 (13%) probands the authors identified one novel APP sequence variant (H677R) and two recognized mutations. Thus in this series 21 of 31 (68%) probands were associated with a sequence variant in APP or PSEN1. Nine of the 11 (82%) probands with neuropathologically confirmed AD who additionally fulfilled recognized criteria for autosomal dominant inheritance were associated with a sequence variant in APP or PSEN1. The 10 patients in whom the authors were unable to identify a mutation in APP, PSEN1, or PSEN2 were older than the probands with sequence variants (55.4 vs 44.7 years: p = 0.001). Conclusions: Sequence variants in APP and PSEN1 accounted for the majority of neuropathologically confirmed autosomal dominant early onset AD; no mutations in PSEN2 were detected. There may be a further genetic factor involved in the etiology of autosomal dominant early onset AD.