NIHRDataInsights/HRCSData huggingface dataset:
Title: Co-design of an intervention to address alcohol use among adolescent boys and young men in Tanzania
Funder: Medical Research Council

Abstract: Alcohol is a leading driver of preventable morbidity and mortality worldwide and a driver of injury, violence, and risk behaviours among male youth in Africa. Early initiation leading to hazardous drinking predisposes to long term alcohol abuse across the life-course. While interventions exist in western countries few have been adopted in African settings. Large gaps remain in what complex interventions can be embedded within communities which promote the necessary local ownership and engagement to enable implementation to be sustained and scaled up. Our overall aim is to co-create a package of school and community interventions and develop strategies to optimise the interplay between them in order to prevent, delay and reduce alcohol use among ABYM in Tanzania. We will scope current laws and statues, identify and collaborate with key stakeholders within the ministry and community, and conduct qualitative studies (focus group discussions, key informant and in-depth interviews, participatory mapping) to define drivers and risk factors influencing uptake, and barriers to current alcohol strategies. Findings will be used to develop a logic model theory of change with stakeholders to select intervention approaches to create a multi-component intervention. We will collaboratively assess stakeholder and participant satisfaction, adequacy of community resources for a large-scale trial examining the impact of a multi-component intervention on drinking culture among boys, prevalence of alcohol initiation, frequency of drunkenness, and subsequent harms. Our project will build capacity in field research, writing and analysis and we will inform alcohol prevention policy and programmes at national and international level by widely disseminating reviews, materials, tools, and findings.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: MENTAL HEALTH
Title: A novel TMS-EEG study of GABAergic and glutamatergic neurotransmission in antipsychotic treatment response in schizophrenia
Funder: Medical Research Council

Abstract: Treatment non-response to antipsychotics (APs) is a major unmet medical need in schizophrenia (SCZ), with as many as a third to half of the patients experiencing significant positive symptoms (i.e. delusions and hallucinations) despite optimal treatment with APs. Patients are exposed to trials of APs and their side effects, as there are no robust predictors of non-response. All available APs act through dopamine D2 receptor blockade but their ineffectiveness to treat positive psychotic symptoms in all patients but also the cognitive symptoms of SCZ, which are almost ubiquitous across patients with SCZ, and negative symptoms, has led to the implication of glutamatergic and GABAergic neurotransmission dysfunction in the emergence and persistence of SCZ symptoms. Among the cognitive symptoms of SCZ, cognitive control (CC) is thought to play a central role in the formation and persistence of psychotic symptoms. The underlying mechanisms of response to APs are still poorly understood. The combination of transcranial magnetic stimulation with electroencephalography (TMS-EEG) is a powerful clinical research tool that directly probes cortical properties, such as excitability, inhibition and oscillatory activity and provides direct functional neurotransmission indices. We propose to use TMS-EEG to measure the effects of APs on GABAergic and glutamatergic neurotransmission and study their association with CC in 40 responders and 40 non-responders to APs with SCZ. The study will develop our understanding on the pathophysiological mechanisms of AP response in SCZ and will contribute to the identification of candidate neurophysiological biomarkers predictive of response to APs, which can guide treatment in a more effective and safe, patient-centred manner as soon as possible after the initial diagnosis and ultimately aid the development of novel candidate therapies modulating the GABA and glutamatergic systems.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Investigating Neurobehavioural Problems and The Role of Oxytocin in Children with Abnormalities of the Hypothalamo-Pituitary Axis
Funder: Medical Research Council

Abstract: Objectives: 1. To define the neurobehavioural and neurocognitive phenotype of children with HP axis defects (SOD or craniopharyngioma). 2. To characterise the underlying neuroanatomical and endocrine deficits in these patients. 3. To investigate potential differences in the pattern of neurobehavioural and neurocognitive deficits as a function of disorder type (SOD, craniopharyngioma), neuroanatomical and endocrine deficits and developmental stage when the insult to the HP axis developed. 3. To assess plasma oxytocin (OT) levels as a potential marker for the deficiency the OTergic system, characterise the stability of plasmatic levels of OT in this cohort over a 6 month interval, and investigate plasma OT level deficits as a function of disorder type, underlying neuroanatomical deficits, developmental stage when the insult to the HP axis developed 4. To investigate the association between plasma OT levels and severity of neurobehavioural/neurocognitive deficits. Methodology: Patient Population: Prospective cohort analysis of patients with SOD and craniopharyngioma attending King's Paediatric Endocrinology service. Intervention: the neurobehavioural phenotype of both our patient and control groups will be characterised twice over a 6 month interval using the HealthTrackerTM platform-based Profile Of Neuropsychiatric Symptoms, the HowRU, and the Assessment of Concerning Behaviours. We will assess their neurocognitive profile using a battery of tasks to assess intellectual ability, empathy, social cognition and attachment style. Finally, we will use gold-standard practices in the field to assay plasma OT concentrations using radioimmunoassay in extracted samples that we will obtain at the same time as the neurobehavioural/neurocognitive assessments. We will use existing neuroimaging and clinical data from the patient group to characterise neuroanatomical/ endocrine deficits and associate them to neurobehavioural/neurocognitive profiles and OT levels.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Allosteric modulators of extrasynaptic delta-GABAA receptors for the treatment of postpartum depression
Funder: Medical Research Council

Abstract: Postpartum depression (PPD) is an extreme version of the "baby blues" and occurs in 15-20% of mothers within a year of giving birth. It is associated with symptoms such as depression, anxiety, and feelings of worthlessness. The recent FDA approval of Brexanolone (allopregnanolone) supports the hypothesis that PPD is caused by a reduction in the endogenous neurosteroid allopregnanolone. However, the serious side-effects, cost, and the need for a 60-h i.v. infusion are significant barriers to Brexanolone's impact within the PPD patient population. Circulating allopregnanolone readily enters the CNS where it is a non-selective positive allosteric modulator (PAM) of various subtypes of the Y-aminobutyric acid type A receptor (GABAAR). Evidence suggests that the beneficial effects of allopregnanolone in PPD may be mediated by extrasynaptic a4Bd-GABAARs whereas the serious side-effects (sedation and unconsciousness) are caused by effects at synaptic GABAARs. Hence, a PAM that is selective for extrasynaptic d-containing GABAARs (d-GABAARs) should be efficacious in PPD, but devoid of the side-effects of allopregnanolone. The literature delta-selective compound 2 (DS2) is a valuable tool for in vitro but not in vivo studies due to its low CNS penetration. We have synthesised and tested 300 compounds based on DS2 and have identified structurally novel d-GABAAR-selective PAMs, an exemplar of which also has good in vivo pharmacokinetics and excellent brain penetration in rats. The aim of this proposal is to combine all the desired features (i.e., selectivity, potency, membrane permeability, pharmacokinetics and brain penetration) into the same molecule(s) which can then be used to demonstrate an ex vivo and in vivo Proof-of-Mechanism for d-GABAAR-selective PAMs. Our ultimate target will be an orally bioavailable, first-in-class drug with a much-reduced cost and increased convenience relative to allopregnanolone, thereby providing significant benefit for patients with PPD.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Consortium Against Pain inEquality (CAPE) - The impact of adverse childhood experiences on chronic pain and responses to treatment
Funder: Medical Research Council

Abstract: The WHO describes adverse childhood experiences (ACEs) as the commonest and most intense childhood stressors. About 50% of people experience at least one and those exposed to several are more likely to suffer health problems later in life, including chronic pain, misuse of pain medications and polysubstance dependence. Recent evidence in young people suggests that ACEs are associated with an exposure-dependent increase in the prevalence of chronic pain. ACEs are emerging as leading contributors to multiple health disparities, disproportionately affecting the poorest in society. However, although there is increasing recognition that ACEs contribute to health inequalities, there is a lack of widespread screening, which might otherwise enable stratified health interventions. There are several reasons for this including inconsistencies regarding ACE assessment and poor understanding of additional factors that may contribute to vulnerability to ACE exposure. The aim of CAPE is to determine whether exposure to ACEs, contributes to inequalities in chronic pain, its treatment and adverse outcomes of opioid analgesics, influenced by vulnerabilities to early life stress. In consultation with our patient advisory group (PAG), CAPE will: 1) Develop a comprehensive tool for assessing the impact of ACEs on chronic pain and its treatment 2) Enrich existing large population cohort data, examining associations between ACE exposure, adverse events in adulthood, chronic pain and opioid analgesic treatment in those exposed to ACEs 3) Examine associations between ACE exposure and divergent pain trajectories in a deeply phenotyped juvenile idiopathic arthritis patient cohort 4) Establish neuroimaging markers of vulnerability/resilience to chronic pain in those exposed to ACEs 5) Identify biomarkers of vulnerability/resilience to chronic pain in those exposed to early life stress


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: Schools-based digital therapy for adolescent social anxiety disorder.
Funder: Medical Research Council

Abstract: Aims: To produce a digital therapy tailored to the needs of adolescents with social anxiety disorder (SAD) for delivery in school mental health teams. Background: SAD is common, persistent, and impairing. Unfortunately, outcomes for adolescents with SAD with the current standard treatment are disappointing. In contrast, powerful and accessible treatment is available for adults in the form of internet-delivered cognitive therapy (iCT-SAD). With minor adaptations to adult iCT-SAD for adolescents I found good outcomes in a preliminary waitlist trial. However, findings from the trial and my studies using experimental and prospective methods suggest further additions to iCT-SAD could enhance effectiveness and acceptability for adolescents. Also, there is a need to refine iCT-SAD delivery so it can be delivered in the newly developed school mental health teams where adolescents with SAD are increasingly being seen. Objectives: (1) To tailor iCT-SAD for adolescents. (2) To make it easy to deliver in school mental health services. (3) To undertake a feasibility RCT of iCT-SAD vs standard care. (4) To establish acceptability of treatment and trial procedures Design and Methodology: (1) New modules developed using research and clinical expertise. Therapeutic potential examined in a between-groups experimental study with random allocation to a module or control condition. Assessments at baseline, post and 1-week follow-up. (2) Young person and parent apps produced via co-design. (3) Delphi consultation with service leads, practitioners, and training providers to develop an efficient training programme and ensure easy delivery in services. (4) Feasibility RCT of iCT-SAD vs standard care (exposure-based CBT) in school mental health teams (N=72). (5) Qualitative study with adolescents, parents, and practitioners. Scientific and Medical Opportunities: Findings could be rapidly translated to patient benefit and yield further understanding of mechanisms.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: Integrating psychological models with biological pathways in psychosis
Funder: Medical Research Council

Abstract: Patients with schizophrenia and bipolar disorders who report childhood adverse events respond less well to treatment, have poorer functioning, and shorter telomeres (a marker of accelerated ageing) highlighting the pivotal need to understand if this group has a specific biological pathway that could be pharmacological targeted which we aim to clarify in this project. In the long run this knowledge can help improve specialized medicine by focusing on specific biological pathways affected by early life events and prediction models for disease outcomes and ageing. The overall objective of this study is to use environmental (focus on early trauma) and genetic data to understand the biological pathways in patients with schizophrenia and bipolar disorders. The main specific objectives include: Firstly, to find out if polygenic risk and childhood adverse events increase the relative risk of mental illness above that of its individual case-control explained variance. Secondly, Investigate the effect of both polygenic risk and childhood adverse events on clinical characteristics, neuroimaging, and ageing processes. Thirdly, investigate the relationship between childhood adverse events and biological pathways in schizophrenia and bipolar disorder and how this is related to clinical features of these disorders, and lastly, using an in vitro stem cell stress and ageing model, I will investigate how telomere length in neuronal cells from patients with psychosis and healthy controls respond to treatment with cortisol (the main biological stress hormone) and if the effect of cortisol can be reversed by treating the cells with neuroprotective agents, such as Brain-derived-neurotropic factor (BDNF) or lithium. Participants will be included from large national and international studies, and stem cells have been gathered from patients with a first-episode psychosis and healthy controls. All data for this study have already been collected.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH
Title: The role of the endocannabinoid system and cannabis use in the expression of psychosis
Funder: Medical Research Council

Abstract: My research project focuses on examining the endocannabinoid system to identify peripheral biomarkers associated with the expression of psychosis, and violence and aggression, in cannabis users compared to non-users. First, using two large independent non-clinical samples, I will work at identifying whether genetic variations of the endocannabinoid system, summarised in a genetic score, explain differences in subclinical psychotic experiences and violence and aggression outcomes between individuals who use and do not use cannabis. Second, I will examine if the newly developed endocannabinoid genetic score and peripheral plasma levels of endocannabinoids differ between patients with a psychotic disorder who use cannabis compared with their non-user counterparts. I will recruit a) a clinical sample of patients in the acute phase of psychosis and admitted to psychiatric intensive care unit (N=150), and b) patients living in the community with a psychotic disorder and undergoing a cannabis discontinuation intervention (N=100). I shall collect clinical data, psychopathology scores, violent and aggressive behaviour data, blood samples for DNA extraction, and plasma levels of endocannabinoids and cannabinoid metabolites. I will analyse these newly collected data, and the endocannabinoid genetic score developed from the independent dataset to predict: a) those cannabis users susceptible to psychosis and violence and aggression outcomes; b) differences between individuals who develop psychosis using and not-using cannabis and their clinical correlates. This research covers an important topic at a time of increasing cannabis consumption in the general population and the case of legalising its recreational use. It makes a significant contribution to research into the endocannabinoid system and how cannabis use impacts on its functioning. Finally, this research addresses both psychosis and violence and aggression outcomes and may inform primary and secondary prevention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH
Title: Pathways to psychosis among cannabis users
Funder: Medical Research Council

Abstract: My research focuses on the effect of cannabis use on the mental health of young adults, an important topic at a time of global trends towards legalising cannabis, and increasing availability of potent cannabis with high tetrahydrocannabinol (THC) and low cannabidiol (CBD). I seek to establish biological and psychological mechanisms,which determine why some heavy cannabis users develop clinical psychotic disorder, or intermediate phenotypes such as paranoia in the non-clinical population. I will assess the genetic and epigenetic factors that underlie this susceptibility by examining a) a non-clinical sample of daily cannabis users (n=400), b) never/past users (n=200) and c) 70 first episode psychosis patients using cannabis daily. I shall collect clinical data, paranoia scores, blood samples for DNA methylation and plasma cannabinoids, and carry out a virtual reality (VR) experiment measuring propensity to develop paranoid ideas in social situations. I will analyse the above, and data from large GWAS samples to generate genetic pathways and epigenetic profiles to predict: a) those daily cannabis users susceptible to disabling paranoia and b) why some users develop only paranoia and others frank psychotic disorder. In the patients, I will test if these biological markers predict cannabis cessation/reduction and improvement in paranoia and VR social response. Finally, I shall expand a mouse experiment run by my collaborators by collecting a) blood DNA pre and post THC and CBD juvenile exposure, b) post exposure behavioral data and c) brain epigenome data. I will compare the epigenetic changes associated with exposure to cannabinoids in mouse brain and blood to those measured in human blood. This program will clarify the mechanisms underlying the effects of cannabis use in inducing paranoia and other psychotic symptoms within, and beyond, frank clinical disorder, why some users are susceptible, and provide guidance for treating psychosis in the context of cannabis use.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: A digital approach to grief support and the treatment of post-loss mental health problems
Funder: Medical Research Council

Abstract: Research question: The primary objective is to develop and provide preliminary empirical support for a therapist-assisted digital Cognitive Therapy programme for the treatment of prolonged grief disorder (PGD), a psychological problem that can result from the death of a significant person. Background: PGD is associated with increased risk of mortality, particularly suicide, and poorer physical health outcomes but is not currently treated within the NHS. Sufferers are often inappropriately treated for depression or not treated at all. PGD has recently been included in the international classification of diseases manual (ICD-WHO) meaning the NHS will likely need to provide services as early as 2022. Aims: To develop an empathic interactive, multi-media, internet cognitive therapy programme for prolonged grief (iCT-PG), designed specifically for bereaved people, to be delivered on computers, tablets and smart phones. The programme's content will target factors shown in my recent DPhil work to be linked to severe and enduring grief reactions. Users will work through core modules and, in collaboration with their therapist, decide on specific modules relevant to their type of loss (e.g. suicide) and most pressing concerns (e.g. guilt). The result will be a highly individualised treatment approach. Methods: A small developmental case series (N=8-10) on the whole treatment with bereaved individuals who have experienced different kinds of losses (i.e. who died and by what means) will ensure relevance for a wide range of losses. Final iterations will be incorporated before running a randomised wait-list controlled feasibility trial (N=46). This design will provide process data on feasibility, acceptability, compliance, retention and delivery. A trial of this size will provide point estimates of the effect sizes (and confidence intervals) of treatment on the symptom outcomes (PGD, PTSD, anxiety and depression) necessary to inform the sample size of a full trial.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;7.1 INDIVIDUAL CARE NEEDS
Health categories: MENTAL HEALTH