NIHRDataInsights/HRCSData huggingface dataset:
Title: A FEKADU, ADDIS ABABA UNIVERSITY-IMPROVING DETECTION OF DEPRESSION IN PRIMARY CARE IN SUB-SAHARAN AFRICA (IDEAS STUDY)
Funder: Medical Research Council

Abstract: Depression is established as a major public health problem owing to its high prevalence, association with high disability, premature mortality and cost burden. 90% of patients in high income countries get treatment from primary care (PC) as a matter of preference or opportunity. However, nearly half with depression go undetected. The situation is much worse in low income countries. For example, studies from African countries indicate a detection rate close to 0%. Simple training does not improve detection. The current plan for scaling up of mental healthcare, task-shifted care in PC, advocated by nations, WHO and NGOs, will not succeed unless detection of depression improves drastically. There is no intervention that can be implemented in low income countries to improve detection of depression. Such intervention should be based on a solid understanding of the construct of depression, and the interactive contextual factors that impact on detection. The intervention also has to be affordable and scalable. The primary aim of this study is to develop an intervention that improves the detection of depression in PC in Ethiopia. We will use a multi-phase mixed methods approach. Initially, we will develop a comprehensive understanding of the construct of depression and of factors that hinder and facilitate detection. In the next phases, using data from the first phase, we will collate an intervention package, which will be tested for feasibility, acceptability, affordability and scalability in a pilot implementation. The study will be a major departure to what has been done in the past to understand the construct of depression or develop interventions to improve its detection. The study will be a major contribution to the effort of scaling up mental healthcare in Ethiopia as well as other low income countries. The study may also contribute to international classification systems, particularly given the contention around the validity of depression in other cultures.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: MENTAL HEALTH
Title: Consortium on Vulnerability to Externalizing Disorders and Addictions [c-VEDA]
Funder: Medical Research Council

Abstract: Alcohol use disorders (AUD) account for a high share of the health burden in India. While environmental and genetic factors conveying risk for AUD and related externalizing disorders have been identified it is not established if these factors are dependent on the socio-cultural and psychosocial context, or whether they are influenced by epigenetic and genetic factors specific for certain ethnicities. Furthermore, some environmental risk factors are specific to emerging societies, including exposure to nutritional stress, environmental neurotoxins and culturally dependent forms of psychosocial stress. We will investigate in collaboration with the National Institute for Mental Health and Neurosciences, Bangalore and partners from Bangalore, Mysore, Calcutta, Chandigarh and Pune if environmental and genetic risk factors in industrialised countries and emerging societies shape brain function and behaviour in distinct ways, thus leading to different risk constellations and neurobehavioural trajectories for substance misuse and externalising disorders. Our objectives are: (1)Establishment of an accelerated longitudinal cohort of >10.000 individuals in India aged 6-23 years. (2)Assessment of addictive behaviour and detailed behavioural and clinical characterisation, with emphasis on externalising behaviour. (3)Assessment of environmental exposures to risk and resilience factors impacting gene expression, brain development, temperaments and behaviours. (4)Collection of biological samples in all participants. (5)Assessing neural processes using functional and structural neuroimaging in a subgroup of 1000 individuals. (6)Investigation of gene x environment modulation of brain development, and externalising and addictive behaviour through genetic and epigenetic studies. (7)Establishment of a bioresource with integrated database and biobank. (8)Capacity building through joint UK-Indian research activities. (9)Providing pilot data for a nationwide mental health cohort in India.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Psychosocial and nutritional predictors of child mental health: longitudinal study of shared and distinctive risk and protective factors in UK & India
Funder: Medical Research Council

Abstract: The aims of the proposed research are to study early risk and protective factors for childhood mental health problems, to identify prenatal and infancy risks that are common to Western and South Asian populations and those that are distinctive. Using a prospective longitudinal design we will recruit members of the new ICMR funded South Indian PRAMM study (n= 650; Prospective Assessment of Maternal Mental Health study), currently being assessed at 3 time points during pregnancy to 8 weeks of age, into a study of infant development with assessment at 6 months, 12 months and 24 months. We will use common measurement between an existing MRC funded UK cohort, the Wirral Child Health and Development Study (WCHADS), and the Indian cohort, to enable data analyses to be conducted of merged UK - Indian datasets. Methods designed to facilitate cross-cultural comparability of measurement will be employed. Aspects of the prenatal and early postnatal environment such as maternal mental health, nutrition and patterns of early caregiving likely to be distinctively relevant to the South Asian setting with be assessed, and examined alongside factors identified in previously in predominantly Western research. Evidence for gene-environment interplay will also be evaluated in the prediction of early emotional and behavioural problems in infancy. We will aim to contribute to capacity building in the Indian clinical research domain sharing experience and expertise in conducting longitudinal cohort studies, sampling and retention, measurement, data management and state of the art statistical methods for analysis of longitudinal complex data sets. The study findings on psychosocial and nutritional predictors of child mental health will inform the refinement of existing early interventions for child mental health in both UK and South Asian settings in the longer term.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: MENTAL HEALTH
Title: The role of parental factors in the development and treatment of paediatric obsessive-compulsive disorder.
Funder: Medical Research Council

Abstract: AIM: To investigate whether parental factors, including style of parenting and parental mental health, influence the development and treatment of paediatric obsessive-compulsive disorder (OCD). OBJECTIVES: 1) Examine whether maternal parenting style and parental mental health in early childhood predict OCD in later childhood. 2) Establish if maternal parenting style and attitudes predict onset of obsessive-compulsive behaviour (OCB) in childhood, controlling for genetic influences. 3) Identify the direction of effects between maternal parenting style, parenting attitudes, and child OCB. 4) Test whether maternal parenting style and psychopathology predict response to cognitive behaviour therapy (CBT) for OCD in youth. METHODS: Objective 1 Sample: Over 7,600 children and their mothers Analyses: Linear and logistic regression models will test the extent to which parenting style and maternal psychopathology predict subsequent OCD symptoms, controlling for potential confounders. Objective 2 Sample: Over 2,000 monozygotic (MZ) twin pairs and their mothers Analyses: Linear regression models will test whether MZ differences in maternal parenting style and attitudes at age 4 predict MZ differences in OCB at age 7, controlling for OCB at age 4. Objective 3 Sample: Approximately 6,000 twin pairs (MZ and dizygotic) and their mothers. Analyses: Longitudinal phenotypic associations between maternal parenting style, attitudes and child OCB will be examined using genetically informative cross-lagged models. Objective 3 Sample: 100 young people with OCD receiving CBT and their mothers. Analyses: Linear regression models will test whether maternal psychopathology and parenting style assessed at pre-treatment predict post-treatment OCD severity, controlling for potential confounders. SCIENTIFIC AND MEDICAL OPPORTUNITIES: Results may have far reaching implications for understanding the aetiology of paediatric OCD and its prevention and treatment.


Research activity codes: 4.3 INFLUENCES AND IMPACT
Health categories: MENTAL HEALTH
Title: Glutamatergic dysfunction as a cause of aberrant salience.
Funder: Medical Research Council

Abstract: Psychosis is a key feature of schizophrenia and several other neuropsychiatric disorders. Current thinking suggests that psychosis is a disorder of aberrant salience. Salience comprises the ability of a stimulus to grab attention and drive action. Aberrant salience describes when a stimulus continues to grab inappropriately high levels of attention, and is likely mediated via elevated dopamine. However, the causes of this dopamine dysregulation are unknown. We propose that it may be a consequence of glutamatergic dysfunction, which is strongly implicated in the aetiology of schizophrenia. For example, the GluA1-AMPA and GluN2A-NMDA glutamate receptor subunit loci are now genome-wide significant for schizophrenia. Notably, genetically modified mice that lack these genes exhibit deficits in short-term habituation, such that they continue to pay inappropriately high levels of attention to recently presented stimuli. We hypothesise that these deficits in short-term habituation could be a mediator of aberrant salience and elevated dopamine signals, leading to psychosis. We will test this hypothesis empirically by recording phasic dopamine transients in real time in the striatum of genetically modified mice that lack GluA1 or GluN2A, using fast-scan cyclic voltammetry. Recordings will be made in freely moving mice in response to recently presented neutral stimuli. Moreover, we will investigate the neural circuits that might lead to these hyper-dopaminergic responses and, in particular, the role of the hippocampus and hippocampal glutamate receptors. Finally, we will also look at the downstream consequences of these changes in attention, and how they affect dopamine prediction error signals during associative learning. The work will advance understanding of glutamate-dopamine links in psychosis, and the basis of aberrant salience, as well as having novel therapeutic implications.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Multicenter RCT to evaluate the clinical and cost-effectiveness of a culturally adapted therapy (C-MAP) in patients with a history of self-harm
Funder: Medical Research Council

Abstract: Design: A multicenter Randomised Control Trial to compare Treatment As Usual (TAU) plus the Culturally adapted Manual Assisted Psychological therapy (C-MAP) with TAU in patients with a recent history of self-harm. There is a built in 12 months internal pilot phase with clear stop/go criteria to prove viability to proceed to a full trial across all the study sites. Setting: Participants will be recruited from general practices, emergency departments and medical wards of participating hospitals. Health Technologies being assessed: A culturally adapted brief psychological intervention, based on the principles of Cognitive Behavioural Therapy (CBT). The intervention has 6 sessions, approximately 50 minutes each, and its feasibility has previously been established. Sample Size: This trial will use repetition of self-harm as its primary outcome measure because it is a strong predictor of completed suicide. Brown et al (2005) saw a reduction from 41.6% to 24.1% in the rate of repetition of self-harm over an 18 month period. The sample size calculation assumes an event rate of 27.7% in the control arm and 16.1% in the talking therapy (C-MAP) arm of the study, an ICC of 0.05 and a 75% follow-up rate. Under the these assumptions a sample of 624 randomised patients will be required for a cluster adjusted test of proportions to have 80% power to detect this difference assuming a 5% significance level. Measurement: The statistical analysis of the primary outcome measure repetition of self-harm episode and binary secondary outcome measures will be based on a cluster adjusted test of proportions. Economic analysis will estimate costs of primary, secondary/tertiary health care use, Disability Adjusted Life Years (DALYs) and quality adjusted life years (QALYs). Qualitative methods will explore patient and professional experiences. We will use an established approach in order to understand what factors block and facilitate successful delivery of the programme.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: MENTAL HEALTH
Title: The MRC Addiction Research Clinical Training programme: MARC
Funder: Medical Research Council

Abstract: MARC will develop and support the future UK clinical research leaders in addiction by 1. Increasing exposure to addiction earlier in clinical training by increasing addiction psychiatry in foundation year posts, specialist interest sessions and 2. Supporting attendance at Summer schools, training and conferences. We will continue to run courses and scientific meetings within our institutions and national organisations eg Royal College of Psychiatrists, Society for Study of Addiction, British Association of Psychopharmacology. 3. Establising PhD posts. Each institution will establish at least 2 PhD posts (two from MARC and others through additional matched funding) that are modelled on '3+1' studentships where the first year involves research method training and completion of mini-projects plus formal training, followed by a 3 year PhD project. We offer a range of expertise - Imperial College: neuroimaging, neuropharmacology; King's College London: addiction psychiatry, imaging, genetics, clinical trials; Univeristy of Bristol: epidemiology, genetics, neuroscience. Their research project will add value to existing MRC projects and grants already established in the host institutions. 4. Supporting MARC fellows to make them competitive for existing schemes: MRC, Wellcome, NIHR clinical training research fellowships and career development/intermediate fellowships. This will be also offered to those outstanding individuals who are unable to take up a MARC posts. 5. Providing academic mentorship for those in the UK interested in a clinical academic career in addictions complementary to those run by Academy of Medical Sciences and utilizing institutional training and support. 6. Each Institution committing to sustaining MARC through strategic development of their strong track record in clinical addiction research and through associating posts with MARC to support additional training and PhD opportunities.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: MENTAL HEALTH
Title: MICA: Valium without the sedation: Non-sedating anxiolytic GABAA receptor modulators for the treatment of anxiety disorders.
Funder: Medical Research Council

Abstract: Generalised anxiety disorder (GAD) has a lifetime prevalence of 5% and is a debilitating disorder that produces a functional impairment that is comparable to major depressive disorder. It has an estimated UK societal cost of c.£10 billion/year, largely due to the significant limitations of current treatments. Hence, only around 25% of GAD patients are adequately treated due to a lack of efficacy and/or appreciable side effects and the paucity of effective treatments results in over half of patients remaining untreated. Therefore, since approaching 90% of patients receive inadequate or no treatment, there is a large unmet need for new drugs to treat GAD. Benzodiazepines, typified by diazepam (Valium), have rapid and robust anxiolytic efficacy but their clinical utility is limited by side-effects, most notably sedation, and the search for a non-sedating anxiolytic has continued since Valium was introduced over 50 years ago but with little success, until recently. Benzodiazepines are positive allosteric modulators (PAMs) of four GABAA receptor (GABAAR) subtypes (i.e., GABAAR a1/a2/a3/a5 PAMs). Recent evidence suggests that by avoiding effects at the a1 (sedation) subtype, GABAAR a2/a3 PAMs should be non-sedating anxiolytics. Such compounds, AZD7325 and TPA023, were identified by AstraZeneca and Merck and in man both were non-sedating with preliminary anxiolytic-like efficacy. However, both companies stopped development of these drugs and their GABAAR a2/a3 PAM projects for a variety of reasons unrelated to the mechanism. Encouraged by the robust preclinical and preliminary clinical proof of concept, this proposal aims to build upon these data and identify novel non-sedating anxiolytic GABAAR a2/a3 PAMs. Such compounds will be suitable for early preclinical development with the ultimate aim being the identification of a first-in-class, non-sedating anxiolytic - "Valium without the sedation" - which could transform the treatment of GAD and other anxiety disorder


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MENTAL HEALTH
Title: Information Bias in Depression
Funder: Medical Research Council

Abstract: Depression is a common and debilitating illness. While a range of treatments are available, remission rates are low and relapse common. It is therefore essential that new, more effective treatments are developed. In order to do this we must first understand the full range of interconnected mechanisms, from abnormal brain function to maladaptive cognitive habits, which cause people to become, or to remain, depressed. Recently, computational modelling techniques have been successfully used to link cognitive and neurobiological function with symptoms of psychiatric illness. One of the insights of this approach is that events with a high "information content", defined as the degree to which the event improves prediction of the future, are preferentially processed. Activity of the central norepinephrine (NE) system and of the anterior cingulate cortex covaries with the information content of stimuli indicating that these systems may underpin this phenomenon. Depression is characterised by negative cognitive biases which are causally implicated in the illness. In terms of the information theoretic account described above, depressed patients behave as if negative events provided more information than positive events. In the current proposal I will use computational modelling to investigate why patients show this "information bias", what neural systems support it and how it can be altered by cognitive and pharmacological interventions. Specifically, I will: a) characterise the computationally defined information bias of depressed patients b) investigate the neural mechanisms by which an information bias is acquired c) test the degree to which it may be modified with a simple training intervention or by manipulation of the NE system using atomoxetine. By using recent advances in computational neuroscience to better understand the causes of depression this project will guide the development of the novel treatments which are needed for the illness.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Characterising mice syntenic for human 16p11.2 duplications or deletions in relation to schizophrenia and autism
Funder: Medical Research Council

Abstract: Autism spectrum disorders (ASD) and schizophrenia are both diseases which place a large health burden on society and upon individual patients and their carers. An understanding of the neurobiological effects of high penetrance (albeit rare) genetic variants has substantially advanced our understanding of many human diseases with complex genetic influences. Genetic factors exert powerful but complex effects on risk of both ASD and schizophrenia. Most of the risk reflects the action of common variants of small effect, but recent advances have revealed the influence also of rare variants of much larger effect. In a few cases, there is a reciprocal relationship on disease risk for small chromosomal deletions or duplications. The 16p11.2 locus provides a dramatic example. 16p11.2 deletions (DEL) dramatically increase risk for autism and intellectual disability, while in contrast duplications (DUP) of the same region markedly increase risk for schizophrenia. It is not clear how these opposing genetic changes impact on the development of these diseases, but the neurobiological effects of the genetic changes can be studied in mice with the equivalent genetic lesion. In this programme of research, we propose to study mice with a deletion (DEL) or duplication (DUP) at the region of the genome corresponding to the 16p11.2 variants in humans. We will assess cognitive performance (using tests aligned to those where patients show deficits), CNS metabolic activity and functional connectivity (parameters that can be monitored in patients), and also glutamate receptor function and cortical neurochemistry (testing parameters known to be affected in patients). The neurochemical studies will illuminate the nature of the dysfunction caused by the lesion, and the behavioural and imaging studies will determine the extent to which the mouse strains can model aspects of the corresponding diseases, using highly translatable paradigms.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: The role of hypothalamic astrocytes in homeostatic regulation of feeding behaviour
Funder: Medical Research Council

Abstract: Obesity is a major public health crisis in the UK, but currently available pharmacological therapies are of limited/transient effectiveness. An improved understanding of the normal homeostatic regulation of food intake will inform development of new therapies for diseases characterised by dysregulated feeding such as obesity and anorexia-cachexia. The most abundant cell type in the CNS, astroglia (AG) modify the "tone" of hypothalamic gonadotrophin-releasing hormone and magnocellular neurons to regulate reproduction and blood-pressure respectively. In contrast, little information is available on the role of AG in regulation of hypothalamic neural circuitry associated with the control of feeding. We recently discovered a novel role for AG in the homeostatic response to acute high-fat feeding in mice. Critically we discovered that preventing high-fat diet-induced AG activation in mice, by inhibiting the NFkappaB signalling pathway, increased food intake, supporting a physiological role for AG NFkappaB signalling in a homeostatic feedback loop that regulates feeding. To follow up on this important finding, a vital next step is to define the mechanisms by which AG respond to systemic nutritional imbalance. Our central hypothesis is that AG are key metabolic sensors that contribute to the restoration of systemic energy homeostasis in the face of acute metabolic perturbations by modulating the firing activity of hypothalamic melanocortin neurons. We will address this hypothesis using the following specific aims: 1. To determine how AG activity is altered in response to acute changes in systemic energy availability in vivo. 2. To determine whether modulation of AG NFkappaB signalling alters the homeostatic response to acute changes in energy availability. 3. To determine the role of AG in neurophysiological modulation of hypothalamic neurons in response to acute changes in systemic nutrient availability.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH