Given the high costs associated with the care of those with Alzheimer’s disease (AD) dementia, we examined the likely impact of a reduction in the rate of cognitive decline upon cost outcomes associated with this disease.

Objectives Evaluate the reliability of using diagnosis codes and prescription data to identify the timing of symptomatic onset, cognitive assessment and diagnosis of Alzheimer’s disease (AD) among patients diagnosed with AD. Methods This was a retrospective cohort study using the UK Clinical Practice Research Datalink (CPRD). The study cohort consisted of a random sample of 50 patients with first AD diagnosis in 2010–2013. Additionally, patients were required to have a valid text-field code and a hospital episode or a referral in the 3 years before the first AD diagnosis. The earliest indications of cognitive impairment, cognitive assessment and AD diagnosis were identified using two approaches: (1) using an algorithm based on diagnostic codes and prescription drug information and (2) using information compiled from manual review of both text-based and coded data. The reliability of the code-based algorithm for identifying the earliest dates of the three measures described earlier was evaluated relative to the comprehensive second approach. Additionally, common cognitive assessments (with and without results) were described for both approaches. Results The two approaches identified the same first dates of cognitive symptoms in 33 (66%) of the 50 patients, first cognitive assessment in 29 (58%) patients and first AD diagnosis in 43 (86%) patients. Allowing for the dates from the two approaches to be within 30 days, the code-based algorithm’s success rates increased to 74%, 70% and 94%, respectively. Mini-Mental State Examination was the most commonly observed cognitive assessment in both approaches; however, of the 53 tests performed, only 19 results were observed in the coded data. Conclusions The code-based algorithm shows promise for identifying the first AD diagnosis. However, the reliability of using coded data to identify earliest indications of cognitive impairment and cognitive assessments is questionable. Additionally, CPRD is not a recommended data source to identify results of cognitive assessments.

BACKGROUND:Prior diagnosis of Alzheimer's disease (AD) among patients later diagnosed with vascular dementia (VaD) has been associated with excess costs, suggesting potential benefits of earlier rule-out of AD diagnosis.OBJECTIVE:To investigate whether prior diagnosis with AD among patients with VaD is associated with excess costs in the UK.METHODS:Patients with a final VaD diagnosis, continuous data visibility for≥6 months prior to index date, and linkage to Hospital Episode Statistics data were retrospectively selected from de-identified Clinical Practice Research Datalink data. Patients with AD diagnosis before a final VaD diagnosis were matched to similar patients with no prior AD diagnosis using propensity score methods. Annual excess healthcare costs were calculated for 5 years post-index, stratified by time to final diagnosis.RESULTS:Of 9,311 patients with VaD, 508 (6%) had prior AD diagnosis with a median time to VaD diagnosis exceeding 2 years from index date. Over the entire follow-up period, patients with prior AD diagnosis had accumulated healthcare costs that were approximately GBP2,000 higher than those for matched counterparts (mostly due to higher hospitalization costs). Cost differentials peaked particularly in the period including the final VaD diagnosis, with excess costs quickly declining thereafter.CONCLUSION:Potential misdiagnosis of AD among UK patients with VaD resulted in substantial excess costs. The decline in excess costs following a final VaD diagnosis suggests potential benefits from earlier rule-out of AD.

Alzheimer’s disease (AD), the commonest cause of dementia, represents a significant cost to UK society. This analysis describes resource utilisation, costs and clinical outcomes in non-institutionalised patients with AD in the UK.

To investigate baseline demographics and disease characteristics as predictors of the analgesic effect of duloxetine and pregabalin on diabetic peripheral neuropathic pain (DPNP).

This was a flexible‐dosed study to evaluate the efficacy and safety of duloxetine 30–120 mg once daily in the treatment of generalized anxiety disorder (GAD) in older adult patients.

Background: This study examined medical resource utilisation patterns in the United Kingdom (UK) prior to and following Alzheimer's disease (AD) diagnosis.Methods: A patient cohort aged 65 years and older with newly diagnosed AD between January 2008 and December 2010 was identified through the UK's Clinical Practice Research Datalink (CPRD). Patients with a continuous record in the CPRD (formerly the General Practice Research Database [GPRD]) for both the 3 years prior to, and the 1 year following, AD diagnosis were eligible for inclusion. A control cohort was identified by matching general older adult (GOA) patients to patients with AD based on year of birth, gender, region, and Charlson Comorbidity Index at a ratio of 2:1. Medical resource utilisation was calculated in 6-month intervals over the 4-year study period. Comparisons between AD and GOA control cohorts were conducted using conditional logistic regression for patient characteristics and a generalised linear model for resource utilisation.Results: Data for the AD cohort (N = 3,896) and matched GOA control cohort (N = 7,792) were extracted from the CPRD. The groups were 65% female and the AD cohort had a mean age of 79.9 years (standard deviation 6.5 years) at the date of diagnosis. Over the entire study period, the AD cohort had a significantly higher mean primary care consultation rate than the GOA cohort (p<.0001). While the GOA cohort primary care consultation rate gradually increased over the 4-year period (ranging from 5 to 7 consultations per 6-month period), increases were more pronounced in the AD cohort (ranging from 6 to 11 consultations per 6-month period, peaking during the 6-month periods immediately prior to and post diagnosis). The AD cohort also had a higher overall specialty referral rate than the GOA cohort over the 4-year period (37% vs. 25%, respectively; p<.0001); the largest difference was during the 6 months immediately prior to AD diagnosis (17% vs. 5%, respectively; p<.0001).Conclusions: In the UK, AD diagnosis is associated with significant increases in primary and secondary care resource utilisation, continuing beyond diagnosis. This evidence may be important to health care commissioners to facilitate effective mobilisation of appropriate AD-related health care resources.

An increasing rate of antidepressant trials fail due to large placebo responses. This analysis aimed to identify variables influencing signal detection in clinical trials of major depressive disorder. Patient-level data of randomized patients with a duloxetine dose >= 60 mg/day were obtained from Lilly. Total scores of the Hamilton Depression Rating scale (HAM-D) were used as efficacy endpoints. In total, 4661 patients from 14 studies were included in the analysis. The overall effect size (ES), based on the HAM-D total score at endpoint, between duloxetine and placebo was -0.272. Although no statistically significant interactions were found, the following results for factors influencing ES were seen: a very low ES (-0.157) in patients in the lowest baseline HAM-D category and in patients recruited in the last category of the recruitment period (-0.122). A higher ES in patients recruited in centers with a site-size at but not more than 2.5 times the average site-size for the study (-0.345). Study characteristics that resulted in low signal detection in our database were: <80% study completers, a HAM-D placebo response >5 points, a high variability of placebo response (SD > 7 points HAM-D), >6 post baseline visits per study, and use of an active control drug. Simpler trial designs, more homogeneous and mid-sized study sites, a primary analysis based on a higher cutoff blinded to investigators to avoid the influence of score inflation in mild patients and, if possible, studies without an active control group could lead to a better signal detection of antidepressive efficacy. (C) 2014 The Authors. Published by Elsevier Ltd. All rights reserved.

The aim of treatment of depression is remission of symptoms and functioning. Although there is a relationship between remission of symptoms and remission of functioning, it is not known how individual residual symptoms are related to functioning. Here we report a post-hoc analysis of two studies which treated depressed patients with duloxetine in an open fashion for 10–12 weeks. We evaluated the association of individual residual symptoms and functional impairment in patients who remitted or partially remitted after acute treatment. Logistic regression was used to investigate residual symptoms associated with functional impairment at endpoint. Our results suggest that in partial remitters, the only residual symptom associated with a reduction in the risk of having impaired function was the resolution of painful physical symptoms (PPS). In patients who remitted, the presence of residual core mood symptoms (CMS), particularly in patients without any anxiety, predicted impaired functioning. The resolution of PPS in the presence of residual CMS was associated with less risk of impaired functioning. Our results contribute to understand better the role of specific residual symptoms on functional impairment. To achieve normal functioning, intervention on specific residual symptoms is recommended.

Background: Remission is the goal in depression, but in practice many patients only experience a partial response to treatment. We sought to determine the prevalence, management and subsequent outcomes of partial responder patients.Methods: Patients enrolled in the naturalistic Factors Influencing Depression Endpoints Research (FINDER) study with the Hospital Anxiety and Depression Scale depression subscale (HADS-D) score > 10 at baseline who received only SSRI(s) between 0 and 3 months comprised the study cohort (n=1147). Patients were categorized as remitters, partial responders or non-responders at 3 months and then followed up at 6 months.Results: At 3 months, 294%, of the study population were considered non-responders, 27.6% were partial responders, and 39.3% were remitters. Most partial responders at 3 months remained on the same SSRI for the next 3 months. Of the 247 partial responders at 3 months and remained on the same SSRI (s) between 3 and 6 months, 10.9% met criteria for non-response at 6 months, 32.4% remained partial responders, and 56.3% achieved remission. Quality of life outcomes for the partial responders were significantly worse than those in remission (p <005).Limitations: FINDER was an observational study; the current; analysis was conducted post-hoc. Multi-variable methods were not applied and findings are primarily descriptive and exploratory.Conclusions: Partial response is common and patients in partial response have a poorer quality of life than those achieving remission. Despite this, the majority of partial responders continue to take the same SSRI. Our findings underscore the importance of continuing to strive for remission. (C)) 2014 Elsevier B.V. All rights reserved.

Selective serotonin reuptake inhibitors (SSRIs) are recommended as first-line pharmacological treatment for depression and are the most commonly prescribed class of antidepressants. However, there is substantial evidence that noradrenaline has a role in the pathogenesis and treatment of depression. This review aims to examine the evidence of including noradrenaline reuptake inhibition with serotonin reuptake inhibition with respect to increasing efficacy in the treatment of depression. Evidence from meta-analysis of randomised controlled trials (RCTs) and randomised pragmatic trials was found in support of greater efficacy of the serotonin noradrenaline reuptake inhibitors (SNRIs), venlafaxine and duloxetine, in moderate to severe depression compared to SSRIs but no evidence was found for superiority of milnacipran. There is sufficient current evidence that demonstrates an increase in efficacy, when noradrenaline reuptake is added to serotonin (5-HT) reuptake, to suggest that patients with severe depression or those who have failed to reach remission with a SSRI may benefit from treatment with a SNRI. However, as these conclusions are drawn from the evidence derived from meta-analyses and pragmatic trials, large adequately powered RCTs using optimal dosing regimens and clinically relevant outcome measures in severe depression and SSRI treatment failures are still required to confirm these findings.

Objectives: To investigate the impact of depression and its treatment on health-related quality of life (HRQoL) in a naturalistic, primary care setting in the UK.Methods: The Factors Influencing Depression Endpoints Research (FINDER) study was a European, 6-month, prospective, observational study designed to estimate HRQoL in patients with a clinical diagnosis of depression. This paper examines primary care patients recruited in the UK. HRQoL was measured at baseline and at 3 and 6 months after starting antidepressant therapy using the Short Form 36 Health Status Survey and the European Quality of Life-5 Dimensions (EQ-5D). Regression analysis was used to identify baseline and treatment variables independently and significantly associated with HRQoL. Further analyses included the effect of caseness for depression on HRQoL, the effect of moderate/severe pain at baseline on HRQoL, changes in overall pain, pain interference scores, and the use of different antidepressants by pain cohort.Results: A total of 608 patients was recruited from 58 centres and mean HRQoL was significantly below reported population norms at baseline. Most improvement in HRQoL was seen at 3 months for EQ-5D, with small additional improvement at 6 months. Worse HRQoL outcomes at 6 months were associated with higher somatic symptoms score, duration of depression at baseline, and switching within antidepressant classes. Patients meeting the criteria for caseness for depression, or with significant pain at baseline showed less improvement in HRQoL scores at 6 months.Conclusion: Patients presenting with depression in primary care show reduced HRQoL compared to population norms. HRQoL improves during antidepressant treatment particularly within the first 3 months. Nonpainful somatic symptoms, socioeconomic factors, depression variables and switching within antidepressant class predict poor HRQoL outcome. Pain is a common symptom in depressed patients and remains after 6 months' treatment. Pain and somatic symptoms should be assessed in all patients with depression in primary care.

Depression and anxiety disorders are among the most common disorders treated by general practitioners (GPs) in the UK. Since both disorders are associated with a significantly increased risk of suicide, including with antidepressant overdose, the safety of antidepressants in overdose is of paramount importance. Numerous updates relating to antidepressant safety have been issued by regulators in the UK which may have eroded GP confidence in antidepressants. Venlafaxine, a serotonin nor adrenaline reuptake inhibitor (SNRI) had primary care prescribing restrictions placed on it in 2004 due to concerns about cardiotoxicity and mortality in overdose. Although a review of the evidence led to a reversal of the majority of restrictions in 2006, evidence suggests GPs may still be cautious in their prescribing of venlafaxine and possibly other SNRI antidepressants for patients with depression and anxiety disorders. This paper reviews the evidence pertaining to the safety of SNRI antidepressants from a perspective of cardiovascular safety and overdose. The currently available evidence suggests a marginally higher toxicity of venlafaxine in overdose compared with another SNRI duloxetine and the selective serotonin reuptake inhibitors (SSRIs), although this may be related to differential patterns of prescribing in high-risk patients. Based on this review SNRIs have a positive risk benefit profile in the treatment of depression and generalized anxiety disorder in primary care, especially as second-line agents to SSRIs.

Introduction: Patient support programmes are assuming greater importance in the UK in many therapeutic areas, mostly with the aim of improving adherence to medication and many being provided by the pharmaceutical industry. Atomoxetine is a noradrenaline reuptake inhibitor for the treatment of attention deficit hyperactivity disorder that has recently demonstrated incremental efficacy for at least 12 weeks. Issues of adherence may be predicted over this initial period particularly if adverse events are reported. The Strattera Support Service was initiated in 2006 ( funded by Eli Lilly) to provide advice, initially through telephone contact, by trained nurses during the first 12 weeks of atomoxetine therapy and is offered to carers of patients diagnosed with ADHD after atomoxetine has been prescribed. The aim of this pilot service evaluation is to assess discontinuation rates and compare them with historical control data. Methods: Data from patients in the service who initiated atomoxetine between 1 January 2009 and 31 March 2010 were analysed to provide a pilot service evaluation. Continuation rates of patients in the service who were taking atomoxetine at week 12 were assessed and compared with historical control data. Results: Between 1 January 2009 and 31 March 2010, 346 patients (300 male patients) enrolled in the programme and commenced treatment with atomoxetine. The mean age of patients was 10.5 years. At 12 weeks, 33 (9.5%) patients had discontinued treatment; continuation rates were similar regardless of age and sex. Discontinuation rates of 39% are reported from historical control data. Conclusions: Preliminary data from a 12-week atomoxetine patient support programme are supportive that discontinuation rates may be lower than historically expected. Further service evaluations of this programme may be required.

To examine medical resource utilization patterns prior to and post Alzheimer’s disease (AD) diagnosis in UK primary care. Newly diagnosed patients with non-early onset AD between January 1, 2008 and December 31, 2010 were identified from the UK CPRD-GOLD database. The index date was defined as the first AD diagnosis. Eligible patients had a continuous record for the 3-year prior (index) period and 1-year post period, and were ≥65 years of age. Controls were identified by matching to AD patients on year of birth, gender, region, and Charlson co-morbidity index with a 2:1 matching ratio. Medical resource utilization was calculated over the 4-year study period at 6-monthly intervals. T-tests, chi-square tests, and Wilcoxon sum-rank tests (depending on the data type and distribution) were used comparing between AD and control. Cohorts of 3896 AD patients and 7792 controls were extracted. At index date, patients had a mean age (SD) of 79.8 (6.5) years and 65% were female. The mean primary care consultation rate per 6-month was higher in the AD cohort than the control cohort over the total study period (p<0.05) and showed a gradual increase in the controls over the 4 years (from 5 - 7 consultations), while the AD cohort showed a clear increase in the 6-months prior to the index (10 consultations) and stayed at this high rate over the 1-year post-diagnosis period. The proportion of patients with a secondary care referral was higher within the AD cohort than the control cohort (37% vs. 25% over the 4-year period, p<0.05), with the difference peaking in the 6-month prior to AD diagnosis (17% vs. 5%, p<0.05). A clear increase in primary care consultations in the 6-month period prior to AD diagnosis and its continuation in the year post-diagnosis suggest AD imposes a substantial burden on UK primary care.

Background: Depression is characterized by low mood, low self-esteem, and loss of interest or pleasure. Painful physical symptoms (PPS) associated with depression have a negative impact on the probability of remission. Because both norepinephrine and serotonin are involved with the central regulation of pain, the serotonin-norepinephrine reuptake inhibitors (SNRIs) may have more success than the selective serotonin reuptake inhibitors (SSRIs) in impacting PPS as well as the core emotional symptoms of depression. Methods: Published preclinical and clinical data on the SNRIs (i.e., milnacipran, venlafaxine, and duloxetine) have been reviewed, paying special attention to the differentiation of the pharmacological aspects of the SNRIs. The efficacy and safety results on depression and associated PPS have also been summarized. Results: Each of the SNRIs has different profiles regarding the inhibition of binding to human serotonin and norepinephrine uptake transporters and clinical pharmacokinetics. All SNRIs have data for alleviating the core symptoms of depression; duloxetine and venlafaxine show efficacy for PPS associated with depression. There are also differences in tolerability and adverse events profiles. Conclusions: Although all SNRIs have the same dual mechanism of action for the treatment of depression, they have different pharmacologic profiles that may impact clinical outcomes.

Purpose: To determine the incidence of diabetic peripheral neuropathic pain (DPNP) in the United Kingdom (UK) primary care population using the General Practice Research Database (GPRD).Patients and methods: This retrospective cohort study identified incident cases of DPNP in the UK GPRD between July 1, 2002 and June 30, 2011, using diagnostic codes. Trends in the incidence rate were examined by dividing the study period into 3-year periods: (1) July 1, 2002-June 30, 2005; (2) July 1, 2005-June 30, 2008; and (3) July 1, 2008-June 30, 2011. Patient characteristics (age, sex, comorbidities) and initial pharmacological treatment were described; the proportion of patients with incident DPNP, who had previously been screened for neuropathic symptoms, was determined.Results: Among almost 7.5 million persons contributing 38,118,838 person-years of observations in the GPRD, 6,779 new cases of DPNP were identified (45.5%, women), giving an incidence rate of 17.8 per 100,000 person-years (95% confidence interval [CI] 17.4-18.2). The incidence of DPNP increased with age, but it was stable over the three consecutive 3-year periods: 17.9, 17.2, and 18.4 cases per 100,000 person-years. Of the 6,779 patients with incident DPNP, 15.5% had prior neuropathic screening during the study period. The majority of patients with incident DPNP (84.5%) had a treatment for pain initiated within 28 days of first diagnosis. The most common first-line treatments prescribed were tricyclic antidepressants (27.2%), anticonvulsants (17.0%), and nonsteroidal anti-inflammatory drugs (14.9%), with 26.6% of patients receiving combination therapy as their initial treatment.Conclusion: The incidence of DPNP in UK primary care has remained steady over the past 10 years. Our results suggest that DPNP is underdiagnosed, and initial treatment prescribed does not follow clinical guidelines.

Further to your recent Editorial by Nutt (2009), we fully support the notion of using the best available evidence to improve the prescribing of antidepressants. However, we are concerned that the meta-analysis as conducted by Cipriani et al. (2009) is not sufficiently robust to allow a ranking of antidepressants in terms of efficacy and tolerability, in particular as suggested in Figure 1 of Nutt (2009). Cipriani et al. (2009) have performed a network meta-analysis based on 117 clinical trials of 12 antidepressants. From their analysis they draw conclusions about all possible pair-wise comparisons of treatments. We believe this meta-analysis should not be used as a foundation for conclusive prescribing guidance and a number of other authors have voiced similar opinions in their reply to Cipriani et al.’s original publication (Jefferson et al., 2009). Their warnings about the validity of this network meta-analysis were based on the limited representativeness, the heterogeneity, and the selectivity of the included data. They also emphasized the limitations of indirect comparisons in general and criticized the choice of the categorical parameters for efficacy ( 50% response rate) and tolerability (drop-out rate) and the restriction of the treatment duration (8 weeks). Since there is a clear risk of drawing false conclusions from this publication we would like to illustrate some key weaknesses by addressing the data on duloxetine as an example, although we feel that the issues raised herein are equally relevant to all of the other antidepressants included in the analysis by Cipriani et al. In this meta-analysis, direct within-study comparisons are included between duloxetine and only 3 of the other 11 antidepressants, and for 1 of these 3 there are very few patients. Most of the inferences about duloxetine are therefore being drawn from indirect comparisons across studies, more than for all of the other antidepressants. This is an issue if there is relevant ‘‘incoherence’’ in the network of 66 pair-wise comparisons, which remains uncertain. In clinical terms, the combination of some of these studies in the meta-analysis is questionable. Included are placebo-controlled and non-placebo-controlled studies, open-label studies and double-blind studies, studies of severely depressed hospitalized patients and studies of mild to moderately depressed outpatients, studies in the elderly and studies in all adults, and studies run up to 18 years apart, so confounding may be an issue. In particular, there was a larger proportion of the duloxetine studies that included a placebo arm (75%) than for most of the other treatments (30% overall). Results have not been provided separately for placebo-controlled and non-placebo-controlled studies, although this may be an important confounder because early drop-out rate is likely to be higher in placebo-controlled studies. On the other hand, treatment arms on doses below the therapeutic range were not excluded from the meta-analysis. Three of the eight duloxetine studies were early studies and included treatment arms on duloxetine 40mg/day, a dose below the defined therapeutic range. The use of indirect comparisons clearly has an advantage in that one can make comparisons for which head-to-head data are lacking, but it also has the risk of resulting in incorrect conclusions. For example, the Cipriani et al. analysis comes to a different conclusion in the comparison between duloxetine and venlafaxine compared with a head-to-head study (Perahia et al. (2008), available on-line at the time of the meta-analysis but not included): the odds ratio (OR) for the intention to treat (ITT) response rate from the head-to-head study was closer to 1 and not significant (OR 0.86 with 95% confidence interval (CI): 0.64–1.17), while the network analysis, based entirely on indirect comparisons,