Servicio de Información Comunitario sobre Investigación y Desarrollo - CORDIS

Periodic Report Summary 1 - TACTICS (Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndromes)

Project Context and Objectives:

Compulsivity, which is the central concept of TACTICS, is defined as the repetitive, irresistible urge to perform a behaviour, the experience of loss of voluntary control over this intense urge, the diminished ability to delay or inhibit thoughts or behaviours, and the tendency to perform repetitive acts in a habitual or stereotyped manner (Chamberlain et al. 2006). Compulsivity is a cross-disorder trait underlying phenotypically distinct psychiatric disorders that emerge at early age (autism spectrum disorder, ASD), in late childhood (obsessive-compulsive disorder, OCD) or during adolescence (substance use disorders, SUD, and behavioural addictions such as gambling, gaming and internet addiction). Compulsivity is closely linked to two other concepts, namely impulsivity and addictive behaviour. Indeed, a recent expert meeting indicated that compulsivity is an overarching concept that includes both failure to resist an impulse or an urge (impulsivity), maladaptive habitual patterns of behaviours (addiction), repetitive motor behaviours, ritualistic and stereotyped patterns of behaviour, and feelings of loss of control. The psychiatric disorders linked to compulsivity, impulsivity and addiction (ASD, OCD, Attention-deficit Hyperactivity Disorder (ADHD), SUD) are rather common with a total prevalence of around 10% and pose a considerable burden for patients, their families and society. For none of these disorders curative treatments are available.

The overall aim of TACTICS is to identify, over a 5-year period, the neural, genetic and molecular factors involved in the pathogenesis of compulsivity in (i) normally developing children and adolescents, (ii) high risk samples, i.e. children and adolescents with ADHD, and (iii) children and adolescents with specific disorders, such as ASD, OCD, impulse control disorders and behavioural addictions. In order to identify these factors, the researchers active in TACTICS will perform preclinical (animal) and clinical studies that are closely matched to each other, being based on identical paradigms and methodology This allows for optimal transfer and cross-validation of findings from animal models to humans, and vice versa. In addition to the identification of risk factors, there is a focus on the translation of results to clinical practice by (i) establishing neural, genetic, cognitive and molecular markers that predict the development of compulsivity from childhood through adolescence and predict important clinical outcomes of compulsivity in various domains (school, peer-interactions, family), (ii) using the acquired knowledge to construct clinically feasible Risk Assessment tools that can be used for early identification and intervention in high-risk children, and (iii) performing proof-of-concept clinical trials with medication shown to be promising in our animal studies.

Project Results:
To date, work has been completed in the rat signal attenuation model of OCD. Memantine but not riluzole reverses the increase in compulsive lever pressing seen in vehicle treated animals in this task. Moreover, this is observed in male but not female juvenile animals. The rat quinpirole model has been selected for further imaging profiling. For further neurochemical / molecular profiling, microarrays and micro-RNA sequencing has been performed on the orbitofrontal cortex and dorsomedial striatum of the brains from the signal attenuation task.
Based on the initial genetic network of OCD, both MTOR and insulin growth factor receptor are candidates for the production of animal models. The role of MTOR is being validated by testing rapamycin (MTOR antagonist) in the rat signal attenuation model which is expected to be completed by Dec 2013.

To closely examine the development of the frontro-striatal circuits in rats, serial anatomical, structural and functional MRI data of control group animals have been acquired. MRI acquisition in rat OCD model should start in second half of 2013. Analyses of rs-fMRI data reveal developmental changes in functional connectivity that vary between brain networks. Analyses of DTI/DKI data reveal increase in white matter diffusion parameters during development. Rates of change of kurtosis parameters and their contrast properties are different from conventional diffusion measures, particularly during early life
Anatomical MRI data show increase of cerebral white matter volume by 98% between P25-P88, and overall by 143% at P284. White matter T2 decreases over time

Medical-ethical permission for performing the MRI follow-up of the NeuroIMAGE sample has been obtained for Nijmegen. Subject recruitment and data collection has started. Further, medical-ethical permission has been obtained for scanning the new ASD, OCD and control subjects, including MRS, for the Netherlands (RUNMC and UMCU).The other sites are in the progress of applying form medical ethical approval. Mannheim has submitted to the ethics committee; outcome expected within 6 weeks; London will submit within next weeks.
All centres are capable of performing the MRS acquisition needed for the study. Phantom scans have been performed at all centres. The scans at Utrecht omitted the acquisition without water suppression which is required for absolute quantitation. The centre at Mannheim has sent us an electronic version of the protocol they used, which has been forwarded to Utrecht for implementation on their scanner. (Both centres have Siemens equipment.). The results from each centre are comparable, but further testing needs to be performed in human volunteers. When these pilots have been finished, data collection can start.

Using the data of the NeuroIMAGE cohort, we examined the structural brain correlates of stereotypy symptoms of subjects with ADHD and controls. The presence of stereotypy symptoms was measured by the stereotypy subscale within the parent-reported Children's Social and Behavioural Questionnaire (CSBQ) in ADHD subjects, their unaffected siblings and healthy controls. ADHD symptoms were assessed by a structured interview (K-SADS-PL) and the Conners' ADHD questionnaires. Whole brain T1-weighted MPRAGE images were acquired and the structural MRI correlates of stereotypy symptom scores were analysed by stereotypy symptoms scores against white matter (WM) and grey matter (GM) volumes using mixed effects models which controlled for ADHD symptom levels. Stereotypy symptoms were significantly elevated in ADHD subjects relative to both controls and unaffected siblings. Stereotypy scores were predicted by the GM volumes, with increasing stereotypy scores associated with greater GM volume. The current findings indicate that increased GM volume in ADHD may be a structural correlate of raised stereotypy scores. Conversely, changes in WM volume do not appear to be correlated with stereotypy scores in ADHD subjects or their unaffected siblings.
Stereotypy scores were unrelated to reward processing as measured by the Knutson task

Genetic pathway approach is a powerful tool for the investigation of association with human traits, as evidenced by significant associations between 3 pathways (dopamine/noradrenaline, serotonin, and neurite outgrowth) and impulsive behavior (Bralten et al., manuscript in revision). Biological pathways leading to autism spectrum disorders supported by genetic evidence from GWAS include neurite outgrowth, synaptic function and steroid synthesis (Poelmans et al., Translational Psychiatry 2013).
Insulin metabolism in the brain has found to be linked to OCD (van de Vondervoort, Poelmans et al., in preparation).

We applied the Bayesian Constraint-based Causal Discovery (BCCD) algorithm to a human MRI-genetic data set provided by WP5. The data set describes the results of behavioral performance and neural activations to a reward anticipation tasks in adults with ADHD. The aim of the research was to understand the influence of the ADHD candidate genes on the brain functioning. One of the candidate genes for ADHD is DAT1, encoding the dopamine transporter. As described in Hoogman et al. (2012), standard statistical techniques, however, did not show any significant dependencies between the DAT1 gene and brain activation. Application of the BCCD algorithm confirmed that there is no direct link between the DAT1 gene and brain activation, but that there is an indirect link mediated through other variables. Including background knowledge, such as information that no other variables in the model cause DAT1 genotype, the BCCD algorithm is able to find the direction of the causal effect. Based on this study we concluded that the dependency between DAT1 gene and brain activation is mediated through other variables in the model, which might explain existing discrepancies between findings in the current literature. The evaluation of BCCD algorithms on other data is in progress.

Concerning trainng and ethics, all preclinical and initial clinical training has been completed. The SOPs have been standardized across preclinical WPs. Ethical approval was obtained from the preclinical review panels. The DMSB has been established and has completed its initial duties (advice on protocol design).

Potential Impact:
Social and economic impact
Compulsivity and compulsivity-related disorders affect altogether more than 10% of the paediatric population worldwide. In more than 50% of the cases, the disorders have a chronic persistent course far into adulthood. It is precisely this combination of high prevalence and strong persistence which poses a major medical and socioeconomic problem in our society, and leads to substantial economic costs. For example, the cost of illness of autism is very similar to that of schizophrenia, and in the USA and Australia is estimated at between 3.5 and 5.0 million US dollars per patient lifetime! The direct and indirect costs of ADHD are estimated at 15,000 US dollar per patient per year (Pelham et al., 2006). Reports of the European Brain Council in 2005 indicate that the annual costs of addiction are around 10,000 euro per patient per year, and of OCD around 800 euro per patient per year. Current treatments have limited efficacy or only benefit a subsample of the clinical population. Designing new and more effective interventions requires a much better understanding of the neural, genetic, cognitive and biomarker mechanisms involved in compulsivity. Despite protracted public health campaigns, addictive behaviour, especially adolescent smoking and alcohol abuse is not declining, particularly among females and lower income groups.

Evidently, there is no one-dimensional one-strike solution to the complex problem of compulsivity and compulsivity-related disorders. TACTICS, if accomplished, will have the following concrete impact:

1. Availability of more effective medication for OCD, ASD and high-impulsive subjects who are at increased risk to develop addictive behaviours. The data to be provided by TACTICS on efficacy and safety of new medication for compulsivity disorders may facilitate companies to develop Paediatric Investigational Plans and submit requests for Paediatric Use Marketing Authorisations to EMA.
2. The development of specific preventive interventions targeting compulsivity-related behaviour in childhood will reshape our way of thinking about developmental issues of brain and behaviour, and may lead starting interventions earlier, before adolescence.
3. The identification of neural, cognitive, genetic and biomarkers predicting disease-relevant compulsivity will facilitate research by allowing for stratification and early intervention in at risk groups.
4. The development of clinically feasible Risk Assessment Charts to be used in routine clinical practice will provide clinicians with the tools to prioritize and identify youngsters with increased risks and in need of early interventions. The application of staging models and description of cross-disorder risk syndromes will revitalize efforts in early identification and intervention.
5. Eventually, the impact will be further in lowering the persistence of compulsivity disorders over age by lowering the burden of adult psychiatric disease, which will result in substantial benefits for patients, families and society.

To bring about these impacts, the following steps will be taken:
1. Prepare final reports and publish in major journals
2. Contact the relevant professional societies, the European College for Neuropsychopharmacology (ECNP), and the European Society for Child and Adolescent Psychiatry (ESCAP) to get their support to establish an EU Clinical Guidelines Group for the assessment and treatment of compulsivity disorders. These guidelines groups will consist of several participants of this grant proposal.
3. The guideline group will produce draft concepts of these guidelines that will be circulated and discussed at meetings of ECNP and ESCAP.
4. The finalized and approved guidelines will be published in European Child and Adolescent Psychiatry (ECAP) and/or European Neuropsychopharmacology, respectively the journals of ESCAP and ECNP.

The project will have further spin-off in areas outside those primarily targeted:
1. The acquired new knowledge will also impact on the broader issue of the use of medication to intervene in the glutamate system and alter the functioning and connectivity of fronto-striatal circuits. This knowledge will inform and fuel research in many other disorders such as schizophrenia and bipolar disorders.
2. Collaborating together in the proposed preclinical and clinical studies will strengthen the research infrastructure in paediatric psychopathology and psychopharmacology in the EU consisting of academic centres with high levels of expertise that will be very able to undertake other collaborative studies.

Dissemination and/or exploitation of project results, and management of intellectual property
In coordination with the business development and dissemination strategy outlined in WP8, the aim is to generate a durable set of information assets, easily accessible for investigators through the study website, incorporating main issues from training sessions, good practices, guidelines and relevant protocols.
An efficient dissemination of information throughout the network is needed in order to solve possible problems of recruitment, data collection, and assessment, ensure ongoing quality control, and inform participants of the projects progress. Interactive exchange of data within the network will be facilitated by a restricted access part of the study website, completed by electronic newsletters (twice yearly, by e-mail). Objectives of this internal dissemination are to provide information access for investigators and leaders of WP’s and to facilitate their contribution to information up-date. Activity data and project calendar will be accessible through the web site and completed by bulletins as requested by the study board, on the basis of the project’s progress and findings. The dissemination WP’s will also research, summarize and disseminate relevant information in the field of clinical trials with antipsychotics in children and adolescents. Finally, user feedback and evaluation will inform the network about any necessary reviews and updates of the published on-line material.

Appropriate distribution lists will be created to ensure optimal dissemination of the CT relevant information and results to different target groups: secondary care professionals, primary care professionals, scientists, regulatory bodies, patient organizations.

The full exploitation of the project results and the appropriate management of intellectual property rights (IPR) on the biomarkers of compulsivity in both preclinical and clinical data sets generated within WP1-7 will be fully valorised to encourage rapid applicability to future clinical use.

From the machine learning analysis in WP7, biomarker profile databases will be developed and maintained of both the preclinical and clinical data in order to ascertain translational biomarkers of compulsivity (RUNMC). Regulatory advice will be sought from EMEA on qualification requirements for surrogate endpoints of efficacy and qualification criteria for biomarker label. Particular attention will be paid to the FDA's Critical Path Initiative, the EMEA's “Road Map to 2015” document, and the recent report from the European Medicines Agency Innovation Think-Tank group, all of which have focused on the importance of regulatory support in conjunction with biomarkers. Together, these will assist in identifying qualifying novel biomarker profiles of compulsivity with high predictive or diagnostic validity for patenting. Exploitation of these patents and the biomarker profile database will be explored in the context of the formation of a shared SME spin-out company between the partners that are actively involved in generating the data, from which access licences to utilise the data will be available on a commercial basis to the Pharma consortia partners and at a reduced rate to academic groups / health professionals.

In order to bring this knowledge directy to the patient, the possibility of developing serum-based readouts of these biomarkers will be evaluated as diagnostic, outcome and treatment stratification aids (Psynova). Given the experience of Psynova from their participation in the IMI NewMeds consortium and the development of a diagnostic biomarker aid for schizophrenia (VeriPsychTM) which is currently on the market, they are ideally placed to make a strategic evaluation for the marketing of candidate compulsivity biomarkers as a product available for use.

The further exploitation of the results from TACTICS concerns the initiation of the next steps for full scale clinical trials of the most promising candidate drug identified in WP6 to treat childhood compulsivity in OCD & ASD populations. This is a key strategic objective of this consortium towards improving the treatment of compulsivity in these populations beyond the state of the art. A strategic report will be generated into the feasibility of clinical trial studies funded by participating companies or via a publically funded consortium. Based on the outcome of this report, the consortium will work together with a clinical research organisation and the company holding IPR rights to that medication with the highest chance of success identified in WP6. This partnership will either involve company sponsorship of more extensive clinical or the application for clinical trial funding with the end-objective of securing a Paediatric Use Medical Authorisation from EMEA for that medication. In terms of the pharmaceutical industry’s contribution within this consortium, this is based on the supply of ligands in return for access to the data to determine whether future full scale trials are viable.

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