Antipsychotic Prescribing to Patients Diagnosed with Dementia Without a Diagnosis of Psychosis in the Context of National Guidance and Drug Safety Warnings: Longitudinal Study in UK General Practice.

INTRODUCTION: Policy interventions to address inappropriate prescribing of antipsychotic drugs to older people diagnosed with dementia are commonplace. In the UK, warnings were issued by the Medicines Healthcare products Regulatory Agency in 2004, 2009 and 2012 and the National Institute for Health and Care Excellence guidance was published in 2006. It is important to evaluate the impact of such interventions. METHODS: We analysed routinely collected primary-care data from 111,346 patients attending one of 689 general practices contributing to the Clinical Practice Research Datalink to describe the temporal changes in the prescribing of antipsychotic drugs to patients aged 65 years or over diagnosed with dementia without a concomitant psychosis diagnosis from 2001 to 2014 using an interrupted time series and a before-and-after design. Logistic regression methods were used to quantify the impact of patient and practice level variables on prescribing prevalence. RESULTS: Prescribing of first-generation antipsychotic drugs reduced from 8.9% in 2001 to 1.4% in 2014 (prevalence ratio 2014/2001 adjusted for age, sex and clustering within practices (0.14, 95% confidence interval 0.12-0.16), whereas there was little change for second-generation antipsychotic drugs (1.01, confidence interval 0.94-1.17). Between 2004 and 2012, several policy interventions coincided with a pattern of ups and downs, whereas the 2006 National Institute for Health and Care Excellence guidance was followed by a gradual longer term reduction. Since 2013, the decreasing trend in second-generation antipsychotic drug prescribing has plateaued largely driven by the increasing prescribing of risperidone. CONCLUSIONS: Increased surveillance and evaluation of drug safety warnings and guidance are needed to improve the impact of future interventions.

Molecular phenotyping of a UK population: defining the human serum metabolome.

Phenotyping of 1,200 'healthy' adults from the UK has been performed through the investigation of diverse classes of hydrophilic and lipophilic metabolites present in serum by applying a series of chromatography-mass spectrometry platforms. These data were made robust to instrumental drift by numerical correction; this was prerequisite to allow detection of subtle metabolic differences. The variation in observed metabolite relative concentrations between the 1,200 subjects ranged from less than 5 % to more than 200 %. Variations in metabolites could be related to differences in gender, age, BMI, blood pressure, and smoking. Investigations suggest that a sample size of 600 subjects is both necessary and sufficient for robust analysis of these data. Overall, this is a large scale and non-targeted chromatographic MS-based metabolomics study, using samples from over 1,000 individuals, to provide a comprehensive measurement of their serum metabolomes. This work provides an important baseline or reference dataset for understanding the 'normal' relative concentrations and variation in the human serum metabolome. These may be related to our increasing knowledge of the human metabolic network map. Information on the Husermet study is available at http://www.husermet.org/. Importantly, all of the data are made freely available at MetaboLights (http://www.ebi.ac.uk/metabolights/).

Outcomes following hip fracture surgery: a 2-year prospective study.

OBJECTIVES: To describe the health outcomes in older people following hip fracture surgery. DESIGN, SETTING, AND PARTICIPANTS: A naturalistic prospective study of people who had undergone hip fracture surgery undertaken in three specialist inpatient orthopaedic units in Manchester, England, with follow-up for 2 years in primary care. One hundred forty-two people, age 60 and older who had undergone hip fracture surgery of whom 74 were interviewed at follow-up. MEASUREMENTS: Assessment of mood (using the Geriatric Depression Scale and Hospital Anxiety and Depression Scale), cognitive function (Mini-Mental State Examination), pain (Wong-Baker and McGill scales), tests of function (Up and Go Test, Gait Test and Functional Reach), and Sickness Impact Profile. RESULTS: Twenty-six percent of the original group had died by the time of the 2-year follow-up and associated with increasing age, poorer mobility, and higher levels of support. Sixteen percent of the group were found to be depressed, the only robust predictor of this being depression at entry to the study. There was a consistency in the presence or absence of depressive symptoms over the duration of the study. Forty-nine percent were able to walk independently at 2 years. CONCLUSION: The presence of depressive symptoms is associated with poor outcomes at 2 years. Few people recover from, or develop, depression over 2 years.

Peripheral inflammatory markers in amnestic mild cognitive impairment.

OBJECTIVE: To prospectively monitor plasma inflammatory marker concentrations in peripheral blood, over 12 months, in subjects with amnestic mild cognitive impairment (MCI), and to determine the relationship between peripheral inflammatory markers and cognitive decline. METHODS: Seventy patients with amnestic MCI were recruited from two sites providing specialist memory assessment services in Manchester. The baseline assessment included physical examination, neuro-psychological testing and venous blood samples for C-reactive protein (CRP) and interleukin 6 (IL-6) concentrations. Sixty two participants were followed up after 12 months and the assessments were repeated. RESULTS: Data analysis revealed a significant rise in CRP, but not IL-6 concentrations over 12 months, which was not confounded by demographic variables. The neuro-psychological test scores had no association with CRP or IL-6 concentrations at baseline or 12 months follow-up. CONCLUSION: This study adopted the unique approach of prospectively investigating peripheral inflammatory markers in a cohort with amnestic MCI. A significant rise in CRP concentrations over 12 months, but lack of significant association with cognition, provide no evidence for a relationship between systemic inflammation and cognitive decline in amnestic MCI.

A double-blind placebo-controlled randomized trial of Melissa officinalis oil and donepezil for the treatment of agitation in Alzheimer's disease.

BACKGROUND/AIMS: Behavioural and psychological symptoms (BPSD) are frequent in people with Alzheimer's disease and cause considerable stress to patients and their carers. Antipsychotics have been widely used as a first-line treatment, resulting in an estimated 1,800 excess strokes and 1,600 excess deaths in the UK alone. Safe and effective alternatives are urgently needed. Based upon preliminary evidence from clinical trials, aromatherapy with melissa oil may be such an alternative, but initial studies have been modest in size, and adequate blinding has been problematic. Our objective was to assess the efficacy of melissa aromatherapy in the treatment of agitation in people with Alzheimer's disease in an adequately powered and robustly blinded randomized controlled trial comparing it with donepezil, an anticholinesterase drug used with some benefit to treat BPSD. METHODS AND FINDINGS: The study was a double-blind parallel-group placebo-controlled randomized trial across 3 specialist old age psychiatry centres in England. Participants had probable or possible Alzheimer's disease, were resident in a care home, had clinically significant agitation (defined as a score of 39 or above on the Cohen Mansfield Agitation Inventory) and were free of antipsychotics and/or anticholinesterase for at least 2 weeks. Participants were allocated to 1 of 3 groups: placebo medication and active aromatherapy; active medication and placebo aromatherapy or placebo of both. MAIN OUTCOME: The primary outcome measure was reduction in agitation as assessed by the Pittsburgh Agitation Scale (PAS) at 4 weeks. This is an observational scale, and raters were required to wear nose clips to ensure that full blinding was maintained. The PAS, Neuropsychiatric Inventory (NPI; another measure of BPSD) and other outcome measures were completed at baseline, 4-week and 12-week follow-ups. 114 participants were randomized, of whom 94 completed the week 4 assessment and 81 completed the week 12 assessment. Aromatherapy and donepezil were well tolerated. There were no significant differences between aromatherapy, donepezil and placebo at week 4 and week 12, but importantly there were substantial improvements in all 3 groups with an 18% improvement in the PAS and a 37% improvement in the NPI over 12 weeks. CONCLUSION: When assessed using a rigorous design which ensures blinding of treatment arms, there is no evidence that melissa aromatherapy is superior to placebo or donepezil, in the treatment of agitation in people with Alzheimer's disease. However, the sizeable improvement in the placebo group emphasizes the potential non-specific benefits of touch and interaction in the treatment of agitation in people with Alzheimer's disease.

Treatment and prevention of depression after surgery for hip fracture in older people: cost-effectiveness analysis.

OBJECTIVE: For older people who have had hip fracture surgery, to evaluate the cost-effectiveness of a nurse-led intervention in treating depression compared to treatment as usual (TAU), and to evaluate the cost-effectiveness of a psychological treatment for the prevention of depression. DESIGN: Two linked cost-effectiveness studies for the treatment and prevention of depression after hip surgery, from the perspective of health, social care, voluntary sector agencies and unpaid carers. SETTING: Orthopaedic units in Manchester, England. PARTICIPANTS: One hundred and twenty-one patients with Geriatric Depression Scale (GDS) scores greater than 6 were included in the treatment study and 172 patients with GDS scores less than or equal to 6 were enrolled in the prevention study. INTERVENTIONS: Nurse-led intervention for treating depression versus TAU; and cognitive behaviour therapy (CBT) for preventing depression following surgery for hip fracture. MAIN OUTCOME MEASURES: Outcomes were changes in HADS-depression scores at 6 weeks. Costs covered treatment and all service impacts. RESULTS: After 6 weeks, there were no significant differences in cost. However, the nurse-led intervention group had a lower mean HADS-depression score compared to TAU. In the prevention study, there were no significant differences in cost and depression score between patients treated with CBT and TAU. CONCLUSION: The results for this parallel randomized controlled study show that after hip fracture surgery a nurse-led intervention may be a cost-effective option for the treatment of depression in older people with depression. However CBT does not appear to be a cost-effective option for the prevention of depression in this population.

Cerebrovascular damage in late-life depression is associated with structural and functional abnormalities of subcutaneous small arteries.

Late-life depression is increasingly viewed as a vascular illness because of patients exhibiting characteristic white matter brain lesions and in vivo large artery endothelial dysfunction. However, the "vascular depression" hypothesis pertains to the microvasculature, and this circulation has not been studied in this context. Our objective was to examine structure and function of small subcutaneous arteries in patients with late-life depression. Thus, 16 patients aged 71.8±4.0 years with late-life depression were compared with 15 control participants aged 72.1±5.9 years. There were similar cardiovascular profiles between the 2 groups. All of the participants underwent MRI brain scans and subcutaneous gluteal fat biopsy from which small arteries were isolated and studied using pressure myography. Cerebral microvascular damage in depressed patients was confirmed by assessment of basal ganglia Virchow-Robin space scores (depressed patients 3.9±1.7 versus controls: 2.5±1.6; P=0.01). Contractility to norepinephrine was equivalent in both groups, but relaxation of the small arteries to acetylcholine was significantly reduced in depressed patients (84.0±4.0%) compared with control participants (96.0±1.4%; P=0.012). This difference in arterial relaxation was reduced but not entirely eliminated when NO synthase was inhibited. Depressed patients also exhibited hypertrophic wall growth with an increase in medial cross-sectional area (P=0.035, multiple ANOVA and wall thickness; P=0.04, multiple ANOVA). In conclusion, despite similar cardiovascular profiles, depressed patients with cerebral microvascular damage show abnormalities of subcutaneous small artery structure and function.