The Cost Effectiveness of Pharmacological Treatments for Generalized Anxiety Disorder

Background: Generalized anxiety disorder (GAD) is one of the most prevalent anxiety disorders, with important implications for patients and healthcare resources. However, few economic evaluations of pharmacological treatments for GAD have been published to date, and those available have assessed only a limited number of drugs. / Objective: To assess the cost effectiveness of pharmacological interventions for patients with GAD in the UK. / Methods: A decision-analytic model in the form of a decision tree was constructed to compare the costs and QALYs of six drugs used as first-line pharmacological treatments in people with GAD (duloxetine, escitalopram, paroxetine, pregabalin, sertraline and venlafaxine extended release [XL]) and ‘no pharmacological treatment’. The analysis adopted the perspective of the NHS and Personal Social Services (PSS) in the UK. Efficacy data were derived from a systematic literature review of double-blind, randomized controlled trials and were synthesized using network meta-analytic techniques. Two network meta-analyses were undertaken to assess the comparative efficacy (expressed by response rates) and tolerability (expressed by rates of discontinuation due to intolerable side effects) of the six drugs and no treatment in the study population. Cost data were derived from published literature and national sources, supplemented by expert opinion. The price year was 2011. Probabilistic sensitivity analysis was conducted to evaluate the underlying uncertainty of the model input parameters. / Results: Sertraline was the best drug in limiting discontinuation due to side effects and the second best drug in achieving response in patients not discontinuing treatment due to side effects. It also resulted in the lowest costs and highest number of QALYs among all treatment options assessed. Its probability of being the most cost-effective drug reached 75 % at a willingness-to-pay threshold of £20,000 per extra QALY gained. / Conclusion: Sertraline appears to be the most cost-effective drug in the treatment of patients with GAD. However, this finding is based on limited evidence for sertraline (two published trials). Sertraline is not licensed for the treatment of GAD in the UK, but is commonly used by primary care practitioners for the treatment of depression and mixed depression and anxiety

A systematic review on the clustering and co-occurrence of multiple risk behaviours.

BACKGROUND: Risk behaviours, such as smoking and physical inactivity account for up to two-thirds of all cardiovascular deaths, and are associated with substantial increased mortality in many conditions including cancer and diabetes. As risk behaviours are thought to co-occur in individuals we conducted a systematic review of studies addressing clustering or co-occurrence of risk behaviours and their predictors. As the main aim of the review was to inform public health policy in England we limited inclusion to studies conducted in the UK. METHODS: Key databases were searched from 1990 to 2016. We included UK based cross-sectional and longitudinal studies that investigated risk behaviours such as smoking, physical inactivity, unhealthy diet. High heterogeneity precluded meta-analyses. RESULTS: Thirty-seven studies were included in the review (32 cross-sectional and five longitudinal). Most studies investigated unhealthy diet, physical inactivity, alcohol misuse, and smoking. In general adult populations, there was relatively strong evidence of clustering between alcohol misuse and smoking; and unhealthy diet and smoking. For young adults, there was evidence of clustering between sexual risk behaviour and smoking, sexual risk behaviour and illicit drug use, and sexual risk behaviour and alcohol misuse. The strongest associations with co-occurrence and clustering of multiple risk behaviours were occupation (up to 4-fold increased odds in lower SES groups) and education (up to 5-fold increased odds in those with no qualifications). CONCLUSIONS: Among general adult populations, alcohol misuse and smoking was the most commonly identified risk behaviour cluster. Among young adults, there was consistent evidence of clustering found between sexual risk behaviour and substance misuse. Socio-economic status was the strongest predictor of engaging in multiple risk behaviours. This suggests the potential for interventions targeting multiple risk behaviours either sequentially or concurrently particularly where there is evidence of clustering. In addition, there is potential for intervening at the social or environmental level due to the strong association with socio-economic status

Evaluating high-cost technologies - no need to throw the baby out with the bathwater

INTRODUCTION: Evidence generation for the health technology assessment (HTA) of a new technology is a long and expensive process with no guarantees that the health technology will be adopted and implemented into a health-care system. This would suggest that there is a greater risk of failure for a company developing a high-cost technology and therefore incentives (such as increasing the funding available for research or additional market exclusivity) may be needed to encourage development of such technologies as has been seen with many high-cost orphan drugs. AREAS COVERED: This paper discusses some of the key issues relating to the evaluation of high-cost technologies through the use of existing HTA processes and what the challenges will be going forward. EXPERT OPINION: We propose that while the current HTA process is robust, its evolution into accommodating the incorporation of real-world data and evidence alongside a life-cycle HTA approach should better enable developers to produce the evidence required on effectiveness and cost-effectiveness. This should lead to reduced decision uncertainty for HTA agencies to make adoption decisions in a more timely and efficient manner. Furthermore, budget impact analysis remains important in understanding the actual financial impact on health-care systems and budgets outside of the cost-effectiveness framework used to aid decision-making

Devices for remote continuous monitoring of people with Parkinson's disease:a systematic review and cost-effectiveness analysis

Background: Parkinson's disease is a brain condition causing a progressive loss of co ordination and movement problems. Around 145,500 people have Parkinson's disease in the United Kingdom. Levodopa is the most prescribed treatment for managing motor symptoms in the early stages. Patients should be monitored by a specialist every 6-12 months for disease progression and treatment of adverse effects. Wearable devices may provide a novel approach to management by directly monitoring patients for bradykinesia, dyskinesia, tremor and other symptoms. They are intended to be used alongside clinical judgement. Objectives: To determine the clinical and cost-effectiveness of five devices for monitoring Parkinson's disease: Personal KinetiGraph, Kinesia 360, KinesiaU, PDMonitor and STAT-ON. Methods: We performed systematic reviews of all evidence on the five devices, outcomes included: diagnostic accuracy, impact on decision-making, clinical outcomes, patient and clinician opinions and economic outcomes. We searched MEDLINE and 12 other databases/trial registries to February 2022. Risk of bias was assessed. Narrative synthesis was used to summarise all identified evidence, as the evidence was insufficient for meta-analysis. One included trial provided individual-level data, which was re-analysed. A de novo decision-analytic model was developed to estimate the cost-effectiveness of Personal KinetiGraph and Kinesia 360 compared to standard of care in the UK NHS over a 5-year time horizon. The base-case analysis considered two alternative monitoring strategies: one-time use and routine use of the device. Results: Fifty-seven studies of Personal KinetiGraph, 15 of STAT-ON, 3 of Kinesia 360, 1 of KinesiaU and 1 of PDMonitor were included. There was some evidence to suggest that Personal KinetiGraph can accurately measure bradykinesia and dyskinesia, leading to treatment modification in some patients, and a possible improvement in clinical outcomes when measured using the Unified Parkinson's Disease Rating Scale. The evidence for STAT-ON suggested it may be of value for diagnosing symptoms, but there is currently no evidence on its clinical impact. The evidence for Kinesia 360, KinesiaU and PDMonitor is insufficient to draw any conclusions on their value in clinical practice. The base-case results for Personal KinetiGraph compared to standard of care for one-time and routine use resulted in incremental cost-effectiveness ratios of £67,856 and £57,877 per quality-adjusted life-year gained, respectively, with a beneficial impact of the Personal KinetiGraph on Unified Parkinson's Disease Rating Scale domains III and IV. The incremental cost-effectiveness ratio results for Kinesia 360 compared to standard of care for one-time and routine use were £38,828 and £67,203 per quality-adjusted life-year gained, respectively. Limitations: The evidence was limited in extent and often low quality. For all devices, except Personal KinetiGraph, there was little to no evidence on the clinical impact of the technology. Conclusions: Personal KinetiGraph could reasonably be used in practice to monitor patient symptoms and modify treatment where required. There is too little evidence on STAT-ON, Kinesia 360, KinesiaU or PDMonitor to be confident that they are clinically useful. The cost-effectiveness of remote monitoring appears to be largely unfavourable with incremental cost-effectiveness ratios in excess of £30,000 per quality-adjusted life-year across a range of alternative assumptions. The main driver of cost-effectiveness was the durability of improvements in patient symptoms. Study registration: This study is registered as PROSPERO CRD42022308597. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135437) and is published in full in Health Technology Assessment; Vol. 28, No. 30. See the NIHR Funding and Awards website for further award information

Cognitive or behavioural interventions (or both) to prevent or mitigate loneliness in adolescents, adults, and older adults

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To examine the effects of structured psychological interventions, based on cognitive behavioural therapy (CBT) techniques, compared to all comparators on loneliness in adolescents, adults, and older adults with diagnoses of common mental disorders, or at risk of loneliness. To examine the effects of structured psychological interventions, based on CBT techniques, compared to all comparators on depression severity, anxiety severity, social connectedness, or quality of life in adolescents, adults, and older adults, with diagnoses of common mental disorders, or at risk of loneliness

Interventions for preventing relapse or recurrence of major depressive disorder in adults in a primary care setting: a network meta‐analysis

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. The aim is to assess, using network meta-analysis (NMA), the effectiveness and safety of interventions for preventing relapse-recurrence of depression in adults in a primary care setting. NMA is a technique for comparing three or more interventions simultaneously in a single analysis by combining both direct and indirect evidence across a network of studies. The objectives are to:. estimate the relative effectiveness of pharmacological, psychological and other interventions to prevent relapse-recurrence, compared with each other and controls (e.g. pill placebo, treatment as usual) on relapse-recurrence outcomes and adverse events; assess the effect of interventions on quality of life outcomes and social and occupational functioning; estimate the relative ranking of included interventions on relapse-recurrence, quality of life, and adverse events; summarise availability and principal findings of eligible economic evaluations

Psychological and pharmacological interventions for post-traumatic stress disorder and comorbid mental health problems following complex traumatic events: systematic review and component network meta-analysis

Background: Complex traumatic events associated with armed conflict, forcible displacement, childhood sexual abuse and domestic violence are increasingly prevalent. People exposed to complex traumatic events are at not only at risk of post-traumatic stress disorder (PTSD) but also other mental health comorbidities. While evidence-based psychological and pharmacological treatments are effective for single event PTSD it is not known if people who have experienced complex traumatic events can benefit and tolerate these commonly available treatments. Furthermore, it is not known which components of psychological interventions are most effective for managing PTSD in this population. We performed a systematic review and component network meta-analysis to assess the effectiveness of psychological and pharmacological interventions for managing mental health problems in people exposed to complex traumatic events.Methods and Findings: We searched CINAHL, Cochrane Central Register of Controlled Trials, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Published International Literature on Traumatic Stress, PsycINFO, and Science Citation Index for randomised and non-randomised controlled trials of psychological and pharmacological treatments for PTSD symptoms n people exposed to complex traumatic events, published up to 25th October 2019. We adopted a non-diagnostic approach and included studies of adults who have experienced complex trauma. Complex trauma sub-groups were: veterans; childhood sexual abuse; war-affected; refugees; and domestic violence. The primary outcome was reduction in PTSD symptoms. Secondary outcomes were depressive and anxiety symptoms, quality of life, sleep quality, and positive and negative affect. We included 116 studies, of which 50 were conducted in hospital settings, 24 were delivered in community settings, seven were delivered in military clinics for veterans or active military personnel, five were conducted in refugee camps, four used remote delivery via web based or telephone platforms, four were conducted in specialist trauma clinics, two were delivered in home settings, and two were delivered in primary care clinics; clinical setting was not reported in 17 studies. Ninety-four RCTs for a total of 6158 participants were included in meta-analyses across the primary and secondary outcomes; 19 RCTs for a total of 933 participants were included in the component network meta-analysis. The mean age of participants in the included RCTs was 42.6 ±9.3 years, and 42% were male. Nine non-randomised controlled trials were included. The mean age of participants in the non-randomised controlled trials was 40.6 ±9.4 years, and 47% were male. The average length of follow-up across all included studies at post-treatment for the primary outcome was 11.5 weeks. The pair-wise meta-analysis showed that psychological interventions reduce PTSD symptoms more than inactive control (k=46; n=3389; standardised mean difference, SMD=-0.82, 95% CI: -1.02 to -0.63) and active control (k-9; n=662; SMD=-0.35, 95% CI: -0.56 to -0.14) at post-treatment, and also compared with inactive control at 6-month follow-up (k=10; n=738; SMD=-0.45, 95% CI: -0.82 to -0.08). Psychological interventions reduced depressive symptoms (k=31; n=2075; SMD=-0.87, 95% CI: -1.11 to -0.63; I2=82.7%, p=0.000) and anxiety (k=15; n=1395; SMD=-1.03, 95% CI: -1.44 to -0.61; p=0.000) at post-treatment comparted with inactive control. Sleep quality was significantly improved at post-treatment by psychological interventions compared with inactive control (k=3; n=111; SMD=-1.00, 95% CI: -1.49 to-0.51; p=0.245). There were no significant differences between psychological interventions and inactive control group at post-treatment for quality of life (k=6; n=401; SMD=0.33, 95% CI: -0.01 to 0.66; p=0.021). Antipsychotic medicine (k=5; n=364; SMD=–0.45; –0.85 to –0.05; p=0.085) and Prazosin (k=3; n=110; SMD=-0.52; -1.03 to -0.02; p=0.182) were effective in reducing PTSD symptoms. Phase-based psychological interventions that included skills based strategies along with trauma-focused strategies were the most promising interventions for emotional dysregulation and interpersonal problems. Compared with pharmacological interventions we observed that psychological interventions were associated with greater reductions in PTSD and depression symptoms and improved sleep quality. Sensitivity analysis showed that psychological interventions were acceptable with lower drop out, even in studies rated at low risk of attrition bias. Trauma-focused psychological interventions were superior to non-trauma focused interventions across trauma sub-groups for PTSD symptoms, but effects among veterans and war-affected populations were significantly reduced. The network meta-analysis showed that multi-component interventions that included cognitive restructuring and imaginal exposure were the most effective for reducing PTSD symptoms (k=17; n=1077; mean difference=-37.95, 95% CI: -60.84 to -15.16). Our use of a non-diagnostic inclusion strategy may have over-looked certain complex trauma populations with severe and enduring mental comorbidities. Additionally, the relative contribution of skills-based intervention components were not feasibly evaluated in the network meta-analysis.Conclusions: In this systematic review and meta-analysis we observed that trauma-focused psychological interventions are effective for managing mental health problems and comorbidities in people exposed to complex trauma. Multi-component interventions, which can include phase-based approaches, were the most effective treatment package for managing PTSD in complex trauma. Establishing optimal ways to deliver multicomponent psychological interventions for people exposed to complex traumatic events is a research and clinical priority

A High-Resolution Map of Human Evolutionary Constraint Using 29 Mammals

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ~4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ~60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.National Human Genome Research Institute (U.S.)National Institute of General Medical Sciences (U.S.) (Grant number GM82901)National Science Foundation (U.S.). Postdoctural Fellowship (Award 0905968)National Science Foundation (U.S.). Career (0644282)National Institutes of Health (U.S.) (R01-HG004037)Alfred P. Sloan Foundation.Austrian Science Fund. Erwin Schrodinger Fellowshi