Community Research and Development Information Service - CORDIS



Project ID: 602805
Funded under: FP7-HEALTH
Country: Netherlands

Periodic Report Summary 2 - AGGRESSOTYPE (Aggression subtyping for improved insight and treatment innovation in psychiatric disorders)

Project Context and Objectives:
Aggressotype is aimed at understanding the mechanisms underlying impulsive and aggressive behaviour in individuals with childhood psychiatric disorders, ADHD and conduct disorder (CD) in particular. Based on this insight, we aim at improving treatment and prevention of aggressive behaviour and work through the optimization of existing treatments and the development of novel pharmacological and non-pharmacological ones. Importantly, we argue that the mechanisms underlying aggressive behaviour can only be sufficiently understood if aggression subtypes are considered, that might have different aetiologies. Based on existing evidence for animal work, a subtyping into impulsive (reactive) and instrumental (proactive, premeditated) is postulated. To achieve its aims and objectives, Aggressotype employs a multi- and interdisciplinary design, connecting across different levels of investigation, and balances work in existing samples with new data collection for optimal use of resources. The project consists of 12 work packages (WPs), including 10 scientific ones, as well as 2 coordinating WPs, one for ethics, training, and dissemination and one for the general management of the project.
WPs 1-6 are preclinical WPs, in which the investigation of mechanisms underlying aggressive behaviour is central. WP1 and WP2 are geared towards identifying the neural circuits contributing to aggression and clarifying differences in neural plasticity and neurochemistry underlying impulsive and instrumental aggression. WP1 uses existing and newly collected data from human samples of individuals with ADHD and CD for this purpose, WP2 investigates these points in mouse models. In WPs 3,4,5, and 6, it is our objective to define the genetic factors and their interaction with the environment involved in aggression, and increase our understanding of the biological pathways through which these factors act. WP3 works with large existing samples on gene identification, WP4 uses zebrafish and mouse as well as cellular models to define biological pathways, in WP5 we use neuroimaging genetics models to investigate how such factors act on the human brain. WP6 performs epigenetic studies in both animals (mouse) and existing human cohorts to clarify the interplay between genetic and environmental contributors to aggressive behaviour.
WPs 7-10 are working towards improving treatment and prevention of aggression in ADHD and CD. In WP7, we work towards predicting aggressive behaviour based on biomarkers using the biological insights gained in WPs 1-6. In WP8, it is our aim to develop a new non-pharmacological treatment for aggressive behaviour based on neurofeedback training. WP9 is testing the effectiveness of existing treatment for ADHD, methylphenidate, on aggressive behaviour in young adult prison inmates, which have been diagnosed with ADHD. WP10 is using the zebrafish model to test novel compounds for their effect on aggressive behaviour, as a first step to develop improved pharmacological treatments.
WP11 has the responsibility for ethical conduct of all studies within the Aggressotype project, covering both studies in humans and in animals. This WP coordinates the dissemination activities of the project, in which we aim to reach different target groups including clinicians, researchers, the general public, but also policy makers. For this, we work in close collaboration with the patient organisation ADHD-Europe. In addition, this WP is responsible for training; in this, we see ourselves as responsible for training a new generation of researchers, which have to be able to work interdisciplinary.
WP12 is responsible for effective management of the Aggressotype project and its activities as well as for the contact with the EU.

Project Results:
In WP1, we accomplished data collection for a study on empathy and a longitudinal study of ADHD families. Analysis of these studies linked callous/unemotional traits to increased alterations in brain structure in ADHD and to an altered reward processing. We also initiated a multicenter study together with the MATRICS Consortium on children with conduct disorder (CD), which is currently proceeding at nine EU sites.
In WP2 (in conjunction with WP4), we tested the behaviour or aggression mouse models, the BALB/cJ mouse and Tph2 knock-outs. MRI and 1H-MRS data of those mouse models showed that white matter integrity as well as biochemical markers of brain integrity were affected in aggressive mice.
In WP3, we performed several different studies to evaluate the validity of existing candidate genes and biological pathways for aggression. In addition, we performed a genome-wide association study of CD. Integration of data across different genetics and genomics approaches has led to interesting novel pathways involved in ADHD and the proposal of a new mouse model for aggression.
WP4, after harmonized protocols for behavioural analysis of aggression in mice across sites, has generated knowledge on aggression-related behaviour for several mouse models based on candidate genes for aggression. Some of the genes have also already been evaluated based on our zebrafish model. For example for Nos1, reduced aggression was observed in both models, and this work is now under review. We also made a start with cell models based on neurons derived from induced pluripotent stem cells. Novel findings about biochemical pathways to aggression have e.g. been obtained for the MAOA gene.
In WP5, we finished data collection and genotyping of additional data sets, and have generated knowledge about genes underlying brain structures (volumes) known to play a role in impulsivity and aggression. In addition, we found gene-sets based on known aggression candidates to be involved in reactive aggression in a gender-specific manner. Studies of several candidate genes are ongoing, complementing the studies in the animal models.
WP6 has extended several human cohorts for gene-environment interaction studies and has developed different assays to induce environmental risk factors in the animal studies. Mouse studies have demonstrated strong influences of environment on effects of aggression genes such as Tph2, 5-htt, and Cdh13. Gene expression profiling and epigenetic studies are tapping into the biochemical mechanisms linked to the behavioural changes.
WP7, responsible for the development of predictive algorithms for aggression, has developed algorithms and formats for data integration. First analyses have been performed using causal modelling, interrogating links between impulsivity, CD symptoms, and substance abuse.
For WP8, we have developed an innovative biofeedback protocol for training of self-regulation. Protocols were optimized and ethics approval has been obtained by most. Inclusion is currently ongoing.
WP9 successfully completed a first methylphenidate trial in prisoners, which showed promising results. Based on this, additional funding was obtained to perform a second, placebo-controlled randomized controlled trial, which is currently recruiting.
After successfully designing its measurement equipment and has establishing standardized protocols 108 potentially aggression-reducing compounds were tested in larval zebrafish. Several promising candidates were further evaluated, with four being taken further from this.
WP11 has been handling ethics affairs in Aggressotype, which is now nearly complete. We are running a well-appreciated training program for our early career scientists, and have developed channels for dissemination of our work. We are actively reaching out to the other 3 EU-funded consortia on aggression.
WP12 is successfully managing Aggressotype, keeping communication optimal through regular meetings and clear reporting schedules.

Potential Impact:
Maladaptive aggression is a commonly observed trait in psychiatric disorders, especially in the paediatric conduct disorders of interest to this project, ADHD and CD. These disorders are the most frequent psychiatric disorders in childhood and adolescence, with over 5% and up to 10% of the population below age 18 years affected (Freitag et al., 2010; Green et al., 2005); more than 5.4 million children and adolescents in the European Union are affected (Ezpeleta et al., 2001). Costs of treatment and direct non-medical health care amount to over 6.2 billion Euro per year for this group. Importantly, the disorders are linked to lifelong serious impairment in social and occupational functioning, as ADHD symptoms persist into adulthood in 65% of cases. Both disorders are strong predictors of antisocial and substance use disorders, which underscores their huge impact on society. Costs associated with the adult outcome of ADHD and CD are at least 10 times higher than those for childhood disorders (Ezpeleta et al., 2001). The victims of aggression and also the executive and judiciary legal systems also are additional targets of societal impact of aggression. When systematically meta-analysing the frequency of psychiatric disorders in adolescent detainees, CD (46-53%) and ADHD (12-18%) were the most frequently observed diagnoses (Colins et al., 2010; Fazel et al., 2008). It can thus be assumed that persistence of CD and ADHD, under negative environmental conditions, opens up a detrimental developmental trajectory leading towards aggression, violence, and crime. Appropriate counteractive measures should ideally be prophylactic in nature, i.e. provided early after definite diagnoses of the disorders. Current behavioural and pharmacological treatment options for ADHD and CD are, however, insufficiently effective in treating aggression and have no proven curative potential.
Designing new, improved treatments requires a deeper understanding of the molecular, cellular and brain-circuit-based underpinnings of aggression than is currently available. Strategies to prevent (escalation of) aggression in those susceptible to it require better markers of susceptibility at the genetic, epigenetic and brain-level, which have not yet been forthcoming.

Aggressotype will yield the following concrete impacts on society and the economy, which at the longer term will reduce aggression impact on society and will reduce the economic burden caused by paediatric conduct disorders:
1. Improve aggression subtype characterization for the benefit of more effective research into underlying mechanisms and enable development of more individualized treatment strategies.
2. Develop flexible predictive algorithms based on combinations of molecular, environmental, neural and/or cognitive/behavioural information allowing a stratification of risk groups for more effective, individualized treatment approaches and prediction of adult outcome.
3. Develop clinically feasible Risk Assessment Charts to be used in routine clinical practice to provide clinicians with a tool to prioritize and stratify child patients for early prevention and intervention programmes.
4. Develop a novel non-pharmacological treatment programme based on neurofeedback, placed strategically at an early time point of disorder manifestation in order to lastingly prevent escalation of aggression.
5. Develop best-practice guidelines for aggression treatment in prison inmates.
6. Provide a model system for the efficient and cost-effective development of more effective pharmacological treatments for paediatric conduct disorder patients at high risk of aggressive behaviour.
7. Identify new leads for more effective pharmacological treatment of aggression and further develop such leads in collaboration with the pharmaceutical industry.

Having the subtyping strategy and interdisciplinary approaches of Aggressotype in place, achieving these goals will be feasible.

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