NIHRDataInsights/HRCSData huggingface dataset:
Title: A protocol for assessing the effects of treatment on the function of brain networks implicated in cognitive impairment in schizophrenia and ADHD
Funder: Medical Research Council

Abstract: Current treatments for cognitive impairments in disorders such as schizophrenia and ADHD are inadequate. The accumulating evidence that these impairments arise from disordered glutamatergic and/or GABAergic transmission within and between distributed cerebral networks suggests that drugs that modulate glutamatergic and/or GABAergic transmission might provide effective treatment. Efficient development of such treatments requires a procedure for measuring the effects of drugs on regional levels of GABA, glutamate (GLU) and its metabolite, glutamine (GLN), and also of measuring the function of the neural networks that support cognition. We will develop a procedure that employs Magnetic Resonance Spectroscopy (MRS) at 7 Tesla (7T) to measure GABA, GLU and GLN, and a 275 channel MEG system to measure electrical activity in the relevant networks with high temporal and spatial resolution. In comparison with MRS at 3T, at 7T it is possible to clearly distinguish GLU and GLN resonances, while GABA can be measured without the need for J-editing to resolve overlap with other metabolites, thereby allowing measurement of GLU, GLN and GABA in a single spectrum. We have developed MEG analysis techniques, including beamforming and Independent Components Analysis, to measure brain activity in networks, and trial-by-trial supervised linear discriminant analysis for sensitive assessment of change in brain activity over time. Participants will undergo cognitive training during MEG acquisition to test the hypothesis that cognitive training and pharmacological treatment can act synergistically. We will employ the established antibiotic, minocyline, which has been shown to produce moderate cognitive enhancement in schizophrenia. If this project is successful, we plan to apply this procedure to evaluating other agents such metabotropic glutamatergic modulators and alpha7 nicotinic agonists, in collaboration with academic pharmacologists, and with the pharmaceutical industry.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL;5.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: D-cycloserine augmented single-session CBT for panic disorder
Funder: Medical Research Council

Abstract: Panic disorder (PD) is associated with high disability and economic burden, and conventional treatments are cost-intensive. Understanding the basic mechanisms of treatment action is essential to elucidate key proxy markers for treatment improvement and patient stratification. We have recently shown that hypervigilance to threat is normalised the day after a single session of CBT, highlighting processing change as a key mechanism of CBT action. These early changes were predictive of symptom improvement after a further 4 weeks and led to remission in 30% of treated compared to 0% of untreated patients. The proposed study aims to assess whether this efficacy can be improved by the addition of the NMDA receptor agonist d-cycloserine (DCS), known to improve retention of information by enhancing markers of neural plasticity. This pharmacological strategy has previously been applied to standard CBT and found to double its overall efficacy. We will establish the combination of single-session CBT with DCS as a stand-alone treatment, and we will determine the cognitive and neural basic mechanisms of such an augmentation effect. In a double-blind between-groups design, 50 PD patients will be randomised to a group receiving an acute dose of DCS versus placebo prior to acute CBT. The following day, we will measure automatic threat vigilance, neural response to threat and brain tissue GABA levels. Self-reported clinical symptoms will be recorded the day following treatment and at 1- and 6-months follow-up. We hypothesise that the DCS group will show decreased attentional and neural responses to threat the day after treatment compared to the placebo group, that these changes will lead to greater levels of symptom improvement over the following 4 weeks, and that they will remain stable during the following 6-months. This novel intervention would have wide spread implications for the treatment of a large number of patients in a cost-effective and feasible manner.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Web-based Integrated Bipolar Parenting Intervention (IBPI) for Bipolar Parents of Young Children
Funder: Medical Research Council

Abstract: BD is a long term mental health problem characterised by instability in a range of important areas including mood, sleep and behaviour(3,5,17). Children of parents with BD (CPB) experience up to a 2.5-fold increased risk of developing any psychiatric disorder compared to controls (19), in addition to up to a 14-fold increased risk of developing BD (rates between 4% and 15% compared to 1%-2% in the general population)(4,5,9,19).Research indicates that family and parental communication problems are increased in CPB and that such problems are prospectively related to transition to BD(2,3, 10). All children in our pilot study (6) had emotional and behavioural problems above the clinical threshold on the Strengths and Difficulties Questionnaire (SDQ:16). Jones et al (2006) found similar high rates of psychological problems in adolescent CPB, yet none of the children were in receipt of psychological input. Triple P (a positive parenting intervention to improve parenting skills) has demonstrated effectiveness in reducing emotional and behavioural problems in children(11). There is also increasing evidence for psychoeducational approaches and practical support for BD(21,22). Interventions that provide both treatment and prevention in a variety of modalities, including web-based interventions, are needed to reduce the burden of mental health problems(13). To address this clinical need, we intend to combine Triple P Online with evidenced-based BD support materials into an integrated intervention (IBPI) in a phase II feasibility trial. It is anticipated improved parenting skills and improved management of BD symptoms will lead to better outcomes for the children of participants with BD(9). We will use a mixed methods approach using qualitative data to finalise the intervention, and a pilot RCT evaluate feasibility acceptability of the intervention to determine indicative effect sizes for clinical outcome measures of child behaviour parenting and parent symptoms


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: Developing a test battery for evaluating treatment effects on emotional, motivational and social function in neuropsychiatry
Funder: Medical Research Council

Abstract: Emotional, motivational and social impairments are increasingly thought to be fundamental to the pathology of psychiatric disorders. Therefore any comprehensive assessment of neuropsychiatric patients should include measures of these aspects of behaviour. However, in contrast to measures of non-affective aspects of cognition via neuropsychological assessment, standardised and well-validated tests of affective functions are lacking, limiting the scope of clinical trials and hampering scientific progress. Well-designed, carefully validated and widely accepted measures of a comprehensive range of affective functions would facilitate clinical trials, both of drugs and psychological therapies which particularly aim to target emotional, motivational and social processes. Characterising deficits in these processes systematically across studies would also contribute to the definition of endophenotypes relevant to neuropsychiatric disorders with implications for understanding aetiology. In this proposal, we seek to develop a computerised battery comprising tests of emotional, motivational and social function. The battery will be optimised for use in clinical trials and multi-centre studies. Having developed and piloted a set of tests, we will then validate this battery in a group of 200 young, healthy volunteers and determine test-retest reliability by follow-up testing of 40 of the volunteers. Establishing reliability is critical to confirm the utility of the battery in longitudinal contexts such as clinical trials.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH
Title: Deep brain stimulation for severe obsessive compulsive disorder: efficacy and mechanisms of ventral striatum and subthalamic nucleus targets
Funder: Medical Research Council

Abstract: The study aim is to establish the potential of deep brain stimulation (DBS) for people with obsessive compulsive disorder (OCD) who have failed to respond to the best medical treatment and who are significantly disabled by their symptoms Previous studies indicate that DBS of the ventral striatum/ventral capsule (VS/VC) and the subthalamic nucleus (STN) are effective for OCD. About two-thirds showed clear improvement but remained moderately symptomatic. The objectives of this study are to investigate whether this efficacy can be improved by determining: i) whether DBS at both sites is more efficacious than DBS at either site alone; ii) the mechanisms of action of DBS at these two brain sites; and iii) whether adjunctive cognitive behavioural therapy improves DBS-mediated clinical outcomes. We will test the hypothesis that DBS alleviates OCD symptoms by improving mood/anxiety with VS/VC DBS and by directly affecting obsessions and compulsions with STN DBS. We plan to study DBS at these sites in the same patients and compare the effects of DBS at each site and in combination. Studies of the cognitive and neurobiological phenotypes of OCD allow us to additionally hypothesise that the VS/VC DBS effects are secondary to improvement in reinforcement learning and that of STN are due to the direct inhibition of ongoing thought and motor acts. To test this we will employ novel cognitive paradigms and predict different patterns of results from DBS at each of these sites. We will also investigate mechanisms of action at the synaptic level by using transmagnetic stimulation to examine the hypothesis that OCD symptoms are mediated by abnormal cortical excitability due to aberrant long term depression synaptic plasticity and/or reduced GABA-mediated intracortical inhibition and that these are improved by DBS. Understanding more completely the effects of DBS on OCD symptoms has the potential of providing an effective treatment for a severely disabled group of patients.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH
Title: Atomoxetine as a pharmacological treatment for chronic cocaine and heroin abusers
Funder: Medical Research Council

Abstract: Our overall objective is to conduct a proof-of-principle study to find a potential treatment for cocaine dependence, a largely unmet need, and to influence current treatment strategies for alleviating the vast socio-economic burden associated with drug abuse. We will focus on a particularly difficult-to-treat group of drug-dependent patients: Individuals dependent on both cocaine and heroin. Treatments currently available for these patients consist mainly of opiate substitution treatments, which are not effective in reducing relapse to cocaine use, thus hindering overall treatment success. We propose that atomoxetine, a safe, non-stimulant and non-abused drug already used clinically for the treatment of ADHD, could potentially be 'repurposed' to treat cocaine dependence. Atomoxetine improves sustained attention and reduces impulsivity, both effects which could contribute to reducing drug-seeking behaviour. The possible utility of atomoxetine in remediating cocaine seeking in methadone-maintained cocaine and heroin abusers will be assessed using an experimental medicine approach, in a double-blind, placebo-controlled design (N=30 per group). Effects of atomoxetine on several measures of fronto-executive functioning, including Stroop bias to drug cues, sustained attention and the stop-signal reaction time in a combined fMRI paradigm will be assessed before and after 12 weeks of treatment with atomoxetine or placebo. Additional measures include clinical scales of compulsivity and impulsivity, self-reported drug intake as well as resting state MRI activity, peripheral biomarkers (including plasma cortisol), cardiovascular function and measures of integration into the community. We predict that atomoxetine relative to placebo will reduce bias to both cocaine and heroin related cues, improve sustained attention and reduce impulsivity in this critical population of drug users. We anticipate that further controlled trials of atomoxetine would be warranted.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: CANNABIDIOL AS A NOVEL THERAPEUTIC AGENT FOR PATIENTS AT ULTRA HIGH-RISK OF PSYCHOSIS: AN EXPERIMENTAL MEDICINE APPROACH
Funder: Medical Research Council

Abstract: Safe and effective treatments for patients who are at ultra high-risk of developing psychosis (UHR) are currently unavailable. UHR individuals commonly experience short-lasting and mild anxiety and psychotic symptoms We propose to investigate whether Cannabidiol (CBD), a naturally available cannabinoid, can be a potential treatment for UHR individuals as it displays anti-anxiety and anti-psychotic like properties in animal models and in man and has also been tolerated very well in human studies. Employing a parallel-group, randomized, double-blind design we plan to examine the effects of CBD or placebo on anxiety and psychotic symptoms and their underlying neural substrate by employing functional MRI, both acutely and in the short-term following three weeks of treatment. Antipsychotic drug naïve UHR individuals satisfying standard diagnostic criteria will be randomly allocated to CBD or placebo treatment groups. On day 1 of the study, they will be asked to take either one 600 mg capsule of CBD or an identical placebo capsule orally. Anxiety and psychotic symptoms will be measured using standard rating scales both before and after drug administration on day 1. On the same day they will also undergo brain scanning while they perform a learning, salience processing and emotional (fear) processing tasks that have been previously employed in conjunction with CBD. Outside the scanner, they will complete two psychological tasks that are meant to temporarily trigger feelings of anxiety and paranoia: a public speaking task and virtual reality task. Only those UHR individuals who tolerate all aspects of the experiment on day 1 of the study will be asked to continue on the same drug, once a day, for 3 weeks. Otherwise, they will be withdrawn from the study. All the experimental procedures carried out on day 1 will be repeated on day 21. By comparing the two treatment groups this study will provide proof-of-concept for the beneficial effect of CBD in UHR individuals.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Risks, benefits and NHS costs associated with antipsychotic medications prescribed to individuals diagnosed with serious mental illness
Funder: Medical Research Council

Abstract: Part 1: I will model cross-sectional and longitudinal antipsychotic medication profiles to identify prescribing patterns exploring polypharmacy, medication switching, antipsychotic load and antipsychotic action ( based on known target receptors). I will explore associations between antipsychotic profiles and cause-specific mortality in people with SMI. Text mining algorithms and structured fields in CRIS will provide data on antipsychotics and potential confounders making it possible to control for confounders including disease severity (using HONOS and level of mental health service contact) and other medications. Routine mortality tracing already provides data on deaths, and cause of death will be retrieved by the Medical Research Information Service. Part 2: I will investigate associations between cross-sectional/longitudinal antipsychotic medication profiles (identified in part 1) and physical illness in people with SMI. CRIS will provide data on use of mental health services, psychotropic medications and mental health outcomes. A linkage between CRIS and Hospital Episode Statistics (HES), will provide data on emergency and acute hospital care, diagnosis and length of stay for physical illness in those with SMIs and control for potential confounders including disease profile/management and pre-existing illness. In addition, in a subsample of SMI cases I will examine primary care outcomes through a link between CRIS and Lambeth DataNet, a primary care database for one of four SLAM catchment boroughs. Part 3: Using the CRIS to HES and Lambeth DataNet linkage, I will calculate costs associated with different antipsychotic medication profiles, allocating costs to admissions and medications prescribed while in contact with SLAM services as well as costs associated with acute and emergency hospital care. Benefit will be estimated with longitudinal observational data in nested studies comparing good and poor disorder control under different pharmacotherapy profiles.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;2.4 SURVEILLANCE AND DISTRIBUTION;8.2 HEALTH AND WELFARE ECONOMICS;6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH
Title: Self-harm with and without suicidal intent in adolescence: causes and consequences in the ALSPAC cohort
Funder: Medical Research Council

Abstract: The prevalence of self-harm in adolescence is between 13 and 18%. Most adolescent self-harm is carried out with no suicidal intent and the majority of cases never come to medical attention. Current understanding of the causes and consequences of community presenting self-harm is limited. Furthermore, there is international uncertainty, exemplified by recent debates during the Diagnostic and Statistical Manual (DSM) revisions, of the diagnostic and clinical utility of distinguishing self-harm with and without suicidal intent. We propose investigating these issues in the ALSPAC cohort of over 13,000 children followed up since birth. Participants completed detailed interview/ questionnaires about self-harm at ages 11 and 16 years with n=905 participants reporting episodes of self-harm. Through regular follow-up they continue to provide information on their health and social circumstances. We will investigate differences in risk factors (e.g. depression, substance misuse) and medium term health and social outcomes (to age 19 years) for community presenting self-harm with and without suicidal intent and for those cases known/not known to services, to test the hypotheses that these two behaviours differ in aetiology and outcome. The principle outcomes we will investigate in our prospective analyses are a) mental health (clinical interview scale-revised (CIS-R) at age 18) b) alcohol and cannabis abuse at ages 18 and 19; c) educational performance (ages 14, 16 and 18 and d) early employment record. We will perform a series of regression models to test the main hypotheses, and use multiple imputation to assess the impact of missing covariate data on the associations we identify. We will also use recently established linkages with GPRD and HES to carry out sensitivity analyses taking account of any random or systematic error associated with self-report data and non-response (n=6,400 respondents age 11 and n=5,000 age 16).


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: MENTAL HEALTH
Title: MICA: A comprehensive genomic and functional approach to discover new ion channel targets for human pain treatment
Funder: Medical Research Council

Abstract: Objective one. Ascertaining and phenotyping three cohorts of people with extreme pain phenotypes is detailed in the main application but will be performed by the investigators and with research ethics approval. All consented study participants will have a blood sample stored and QST performed. Objective two. We will perform next generation sequencing of all ion channel gene exons in 300 individuals with the most severe pain phenotypes. This will be done in the MRC sponsored East of England Sequencing and Bioinformatics Hub (EASIH). Currently exon capture is by Agilent SureSelect-All Exon 50mb, sequencing by Illumina machines, and alignment to the NCBI36 freeze of the human genome and potential pathogenic DNA change prediction by custom designed and Broad Institute software. This method currently results in all but 11 exons being captured - those will be sequenced at the Sanger Inst. Next generation methodology is rapidly evolving and we will reassess our approach in early 2012. Objective three. Each potentially pathogenic mutation will be confirmed to be present in genomic DNA (and where necessary sought in our control panels). For each we will make a wild type construct of the gene and one containing the mutation. Gene constructs will be tranfected into cells, usually HEK293, and subjected to patch clamp electrophysiological analysis. If required we will co-transfect essential accessory genes. We will confirm that the wild type performs as expected and then seek differences for the mutation. If no response is seen for the mutation we will assess whether the protein formation, trafficking and intra-cellular localization are perturbed. Objective four. Surety that we have identified new human pain genes will usually require further studies including, but not restricted to, discovering further mutations in each gene. Expression studies will be carried out to determine where in the pain pathway the gene/protein acts and in which cell types.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH
Title: Identifying the prevalence of antibodies to neuronal membrane targets in first episode psychosis
Funder: Medical Research Council

Abstract: anti-NMDAR and anti-VGKC complex antibodies have been identified as treatment responsive causes of limbic encephalitis. In both disorders psychotic symptoms are the predominant presenting symptoms There are strong theoretical reasons to associate both of these antibodies with psychotic illness. We have identifed cases of primary psychotic illness, without the other features typical of disorders, with both of these antibodies. We have identified some cases prospectively and have successfully treated 4 cases solely with immunotherapy. These preliminary findings suggest that these antibodies are pathogenic in some cases of first episode psychosis. We therefore wish to establish the prevalence of these antibodies in a cohort of patients at first presentation psychosis. This is a pilot study to establish the prevalence of the disorder. If the number of cases warrants further investigation we would then wish to undertake a larger project to fully characterise the phenotype of this disorder and guide treatment planning in first episode psychosis


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