How much is spent on mental health research: developing a system for categorising grant funding in the UK.

Knowing how much money is invested in funding mental health research, and in which areas, is essential to inform strategy and track trends to achieve the best allocation of limited resources. However, no comprehensive categorisation system for mental health research is available and, therefore, national and international data on mental health research funding are minimal and not comparable. In this Health Policy paper, we consider the complexities involved in generating such data and propose an approach to classify mental health research grants. We then describe a method using search terms and algorithms for automatic identification and categorisation of mental health research grants listed in a major international database (Dimensions, Digital Science). The automated approach was validated using manually categorised grants data from funders based in the UK, which showed that the accuracy of this approach is satisfactory and comparable to manual classification. Finally, we consider areas of research that are difficult to classify, and how the automated approach can be refined using machine-learning. We argue that agreed definitions and automated approaches could facilitate collaborative reporting of mental health research funders nationally and internationally and improve the strategic dialogue in this area of research.

Impact of issuing longer- versus shorter-duration prescriptions: a systematic review.

BACKGROUND: Long-term conditions place a substantial burden on primary care services, with drug therapy being a core aspect of clinical management. However, the ideal frequency for issuing repeat prescriptions for these medications is unknown. AIM: To examine the impact of longer-duration (2-4 months) versus shorter-duration (28-day) prescriptions. DESIGN AND SETTING: Systematic review of primary care studies. METHOD: Scientific and grey literature databases were searched from inception until 21 October 2015. Eligible studies were randomised controlled trials and observational studies that examined longer prescriptions (2-4 months) compared with shorter prescriptions (28 days) in patients with stable, chronic conditions being treated in primary care. Outcomes of interest were: health outcomes, adverse events, medication adherence, medication wastage, professional administration time, pharmacists' time and/or costs, patient experience, and patient out-of-pocket costs. RESULTS: From a search total of 24 876 records across all databases, 13 studies were eligible for review. Evidence of moderate quality from nine studies suggested that longer prescriptions are associated with increased medication adherence. Evidence from six studies suggested that longer prescriptions may increase medication waste, but results were not always statistically significant and were of very low quality. No eligible studies were identified that measured any of the other outcomes of interest, including health outcomes and adverse events. CONCLUSION: There is insufficient evidence relating to the overall impact of differing prescription lengths on clinical and health service outcomes, although studies do suggest medication adherence may improve with longer prescriptions. UK recommendations to provide shorter prescriptions are not substantiated by the current evidence base.

Clinical effectiveness and cost-effectiveness of issuing longer versus shorter duration (3-month vs. 28-day) prescriptions in patients with chronic conditions: systematic review and economic modelling.

BACKGROUND: To reduce expenditure on, and wastage of, drugs, some commissioners have encouraged general practitioners to issue shorter prescriptions, typically 28 days in length; however, the evidence base for this recommendation is uncertain. OBJECTIVE: To evaluate the evidence of the clinical effectiveness and cost-effectiveness of shorter versus longer prescriptions for people with stable chronic conditions treated in primary care. DESIGN/DATA SOURCES: The design of the study comprised three elements. First, a systematic review comparing 28-day prescriptions with longer prescriptions in patients with chronic conditions treated in primary care, evaluating any relevant clinical outcomes, adherence to treatment, costs and cost-effectiveness. Databases searched included MEDLINE (PubMed), EMBASE, Cumulative Index to Nursing and Allied Health Literature, Web of Science and Cochrane Central Register of Controlled Trials. Searches were from database inception to October 2015 (updated search to June 2016 in PubMed). Second, a cost analysis of medication wastage associated with < 60-day and ≥ 60-day prescriptions for five patient cohorts over an 11-year period from the Clinical Practice Research Datalink. Third, a decision model adapting three existing models to predict costs and effects of differing adherence levels associated with 28-day versus 3-month prescriptions in three clinical scenarios. REVIEW METHODS: In the systematic review, from 15,257 unique citations, 54 full-text papers were reviewed and 16 studies were included, five of which were abstracts and one of which was an extended conference abstract. None was a randomised controlled trial: 11 were retrospective cohort studies, three were cross-sectional surveys and two were cost studies. No information on health outcomes was available. RESULTS: An exploratory meta-analysis based on six retrospective cohort studies suggested that lower adherence was associated with 28-day prescriptions (standardised mean difference -0.45, 95% confidence interval -0.65 to -0.26). The cost analysis showed that a statistically significant increase in medication waste was associated with longer prescription lengths. However, when accounting for dispensing fees and prescriber time, longer prescriptions were found to be cost saving compared with shorter prescriptions. Prescriber time was the largest component of the calculated cost savings to the NHS. The decision modelling suggested that, in all three clinical scenarios, longer prescription lengths were associated with lower costs and higher quality-adjusted life-years. LIMITATIONS: The available evidence was found to be at a moderate to serious risk of bias. All of the studies were conducted in the USA, which was a cause for concern in terms of generalisability to the UK. No evidence of the direct impact of prescription length on health outcomes was found. The cost study could investigate prescriptions issued only; it could not assess patient adherence to those prescriptions. Additionally, the cost study was based on products issued only and did not account for underlying patient diagnoses. A lack of good-quality evidence affected our decision modelling strategy. CONCLUSIONS: Although the quality of the evidence was poor, this study found that longer prescriptions may be less costly overall, and may be associated with better adherence than 28-day prescriptions in patients with chronic conditions being treated in primary care. FUTURE WORK: There is a need to more reliably evaluate the impact of differing prescription lengths on adherence, on patient health outcomes and on total costs to the NHS. The priority should be to identify patients with particular conditions or characteristics who should receive shorter or longer prescriptions. To determine the need for any further research, an expected value of perfect information analysis should be performed. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015027042. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The National Institute for Health Research at 10 Years: An Impact Synthesis: 100 Impact Case Studies.

The National Institute for Health Research (NIHR) funds and supports world-leading clinical and applied health and social care research, as well as research infrastructure in the NHS. Providing £1 billion of funding each year, NIHR aims to: drive the faster translation of new treatments, technologies and diagnostics to improve outcomes for health and care services; promote the wealth of the nation, including via inward investment from the health research community; pull basic science discoveries through into tangible benefits for patients and the public; and provide research evidence to support more effective and cost-effective NHS delivery. To mark its tenth anniversary, the Department of Health commissioned the Policy Research in Science and Medicine unit to consider the question: "What are the ways in which NIHR has benefited the health research landscape in the past ten years?" This study identifies and celebrates 100 examples of positive change resulting from NIHR's support of research. A synthesis of 100 case studies is provided, which highlights the benefits and wider impacts of research, capacity building, and other activities undertaken with NIHR's support since its creation in 2006. The study concludes with a reflection of how the NIHR has transformed R&D in and for the NHS and wider health service, and the people they serve. The study draws together---for the first time---examples of the breadth of NIHR's impacts in a single resource. It will be of interest to healthcare professionals involved in research, academics working in health and social care, and members of the public wishing to understand the value of research in the NHS and the wider health and care system.

A 'DECISIVE' Approach to Research Funding: Lessons from Three Retrosight Studies.

The Retrosight approach consists of looking at research that was conducted in the past and, using Payback case studies, tracing that research through to the present day to understand both the extent to which the research has had impacts, within academia and more widely, and how these impacts came about. RAND Europe has conducted three studies based on this approach in different research fields: arthritis research, cardiovascular research and mental health research. Each drew out a set of observations and recommendations for policymakers and research funders in those research fields. By reviewing and comparing the findings of the three studies, we have identified eight lessons which combine to provide a "DECISIVE" approach to biomedical and health research funding: Different skills: Fund researchers with more than just research skills-individuals are key when it comes to translation of research into wider impact. Engaged: Support your researchers to engage with non-academic stakeholders to help their work have a wider impact. Clinical: For greater impact on patient care within 10-20 years, fund clinical rather than basic research. Impact on society: If you want to have a wider impact, don't just fund for academic excellence. Size: Bigger isn't necessarily better when it comes to the size of a research grant. International: For high academic impact, fund researchers who collaborate internationally and support them to do so. Variety: Simple metrics will only capture some of the impact of your research. Expectations: Most broader social and economic impact will come from just a few projects.

Mapping the Global Mental Health Research Funding System.

This study maps the global funding of mental health research between 2009 and 2014. It builds from the bottom up a picture of who the major funders are, what kinds of research they support and how their strategies relate to one another. It uses the funding acknowledgements on journal papers as a starting point for this. The study also looks to the future, considering some of the areas of focus, challenges and opportunities which may shape the field in the coming few years.

The impact of the National Institute for Health Research Health Technology Assessment programme, 2003-13: a multimethod evaluation.

BACKGROUND: The National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme supports research tailored to the needs of NHS decision-makers, patients and clinicians. This study reviewed the impact of the programme, from 2003 to 2013, on health, clinical practice, health policy, the economy and academia. It also considered how HTA could maintain and increase its impact. METHODS: Interviews (n = 20): senior stakeholders from academia, policy-making organisations and the HTA programme. Bibliometric analysis: citation analysis of publications arising from HTA programme-funded research. Researchfish survey: electronic survey of all HTA grant holders. Payback case studies (n = 12): in-depth case studies of HTA programme-funded research. RESULTS: We make the following observations about the impact, and routes to impact, of the HTA programme: it has had an impact on patients, primarily through changes in guidelines, but also directly (e.g. changing clinical practice); it has had an impact on UK health policy, through providing high-quality scientific evidence - its close relationships with the National Institute for Health and Care Excellence (NICE) and the National Screening Committee (NSC) contributed to the observed impact on health policy, although in some instances other organisations may better facilitate impact; HTA research is used outside the UK by other HTA organisations and systematic reviewers - the programme has an impact on HTA practice internationally as a leader in HTA research methods and the funding of HTA research; the work of the programme is of high academic quality - the Health Technology Assessment journal ensures that the vast majority of HTA programme-funded research is published in full, while the HTA programme still encourages publication in other peer-reviewed journals; academics agree that the programme has played an important role in building and retaining HTA research capacity in the UK; the HTA programme has played a role in increasing the focus on effectiveness and cost-effectiveness in medicine - it has also contributed to increasingly positive attitudes towards HTA research both within the research community and the NHS; and the HTA focuses resources on research that is of value to patients and the UK NHS, which would not otherwise be funded (e.g. where there is no commercial incentive to undertake research). The programme should consider the following to maintain and increase its impact: providing targeted support for dissemination, focusing resources when important results are unlikely to be implemented by other stakeholders, particularly when findings challenge vested interests; maintaining close relationships with NICE and the NSC, but also considering other potential users of HTA research; maintaining flexibility and good relationships with researchers, giving particular consideration to the Technology Assessment Report (TAR) programme and the potential for learning between TAR centres; maintaining the academic quality of the work and the focus on NHS need; considering funding research on the short-term costs of the implementation of new health technologies; improving the monitoring and evaluation of whether or not patient and public involvement influences research; improve the transparency of the priority-setting process; and continuing to monitor the impact and value of the programme to inform its future scientific and administrative development.

Postnatal neurodevelopmental expression and glutamate-dependent regulation of the ZNF804A rodent homologue.

The zinc finger protein ZNF804A rs1344706 variant is a replicated genome-wide significant risk variant for schizophrenia and bipolar disorder. While its association with altered brain structure and cognition in patients and healthy risk allele carriers is well documented, the characteristics and function of the gene in the brain remains poorly understood. Here, we used in situ hybridization to determine mRNA expression levels of the ZNF804A rodent homologue, Zfp804a, across multiple postnatal neurodevelopmental time points in the rat brain. We found changes in Zfp804a expression in the rat hippocampus, frontal cortex, and thalamus across postnatal neurodevelopment. Zfp804a mRNA peaked at postnatal day (P) 21 in hippocampal CA1 and DG regions and was highest in the lower cortical layers of frontal cortex at P1, possibly highlighting a role in developmental migration. Using immunofluorescence, we found that Zfp804a mRNA and ZFP804A co-localized with neurons and not astrocytes. In primary cultured cortical neurons, we found that Zfp804a expression was significantly increased when neurons were exposed to glutamate [20µM], but this increase was blocked by the N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801. Expression of Comt, Pde4b, and Drd2, genes previously shown to be regulated by ZNF804A overexpression, was also significantly changed in an NMDA-dependent manner. Our results describe, for the first time, the unique postnatal neurodevelopmental expression of Zfp804a in the rodent brain and demonstrate that glutamate potentially plays an important role in the regulation of this psychiatric susceptibility gene. These are critical steps toward understanding the biological function of ZNF804A in the mammalian brain.

Quantitatively and qualitatively different cellular processes are engaged in CA1 during the consolidation and reconsolidation of contextual fear memory.

Whether the consolidation and reconsolidation long-term memory relies on qualitatively different molecular and cellular processes is controversial. Using a novel experimental strategy of combining intrahippocampal antisense oligodeoxynucleotides targeting BDNF or zif268 to the block consolidation or reconsolidation of contextual fear memory respectively, and Affymetrix microarray technology, we identified a comprehensive list of nonoverlapping candidate genes regulated in CA1 during the initial stages consolidation and reconsolidation. Using RT-qPCR in subsequent validation experiments, we estimated that over 80% of the candidates reflect gene transcripts truly regulated following the acquisition or retrieval of contextual fear memory. Statistical and over-representation bioinformatics analyses revealed that cellular processes and signaling mechanisms were differentially regulated during consolidation and reconsolidation, particularly those associated with pro-inflammatory cytokine signaling. This predicts that the two mnemonic processes are qualitatively as well as quantitatively distinct. This experimental strategy was further validated because the cytokine interleukin 1 (IL-1) was reciprocally regulated in CA1 after contextual fear conditioning and fear memory retrieval, and we showed for the first time that that IL-1 receptor mediated signaling in the hippocampus was necessary for reconsolidation.

The exclusive induction of extinction is gated by BDNF.

We have previously reported that the reconsolidation and extinction of hippocampal-dependent contextual fear memory can be initiated by a single context conditioned stimulus (CS) presentation of either short or long duration, and that both processes require protein synthesis in this brain region. Furthermore, reconsolidation depends on Zif268 activity in this region. Here we show that by infusing a recombinant brain-derived neurotrophic factor (rBDNF) directly into the brain of rats, that high levels of mature BDNF in the hippocampus at retrieval constrain the extinction of the fear memory after prolonged memory recall. We also show after a short CS exposure that reconsolidation was impaired using antisense oligonucleotides targeting Zif268, and that, similarly, reductions in conditioned behavior were observed after prolonged CS presentation when extinction is constrained by high levels of BDNF. This is direct evidence that in the mammalian brain extinction proceeds exclusively after prolonged CS exposure. In addition, that BDNF activity in the hippocampus contributes to a molecular switch for the extinction of hippocampal-dependent memory.