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Aggression aetiology unveiled, new treatments on the way

The biological foundation of aggression is a much-discussed issue, but our understanding of the mechanisms underlying it is still very limited. The AGGRESSOTYPE project sought to bridge this gap in order to help predict aggression and, ultimately, to explore new treatment options.
Aggression aetiology unveiled, new treatments on the way
The dawn of human civilisation has made aggression – a common trait of all animals looking to predate or defend themselves – a deviant behaviour that can lead to maladjustment, social impairment and crime. The real question for psychiatrists, however, is twofold: How do our genes impact a patient’s tendency to show maladaptive aggressive behaviour, and how can the better understanding of its aetiology lead to better prediction and treatment.

Funding under the five-year AGGRESSOTYPE (Aggression subtyping for improved insight and treatment innovation in psychiatric disorders) project, which will end in October 2018, is helping answer these questions. Barbara Franke, Professor of Molecular Psychiatry at the Radboud University Medical Centre and project coordinator, discusses its results so far.

There are some treatments available for patients with ADHD or conduct disorder. Would you say that those treatments are completely ineffective?

So far, options for treatment are really limited, with behavioural training and a small set of psychopharmacological agents which, whilst in general use, are often insufficiently effective. We argue that this is due to an insufficient understanding of the biological mechanisms underlying aggression.

How did you aim to tackle this issue?

Aggression aetiology is highly heterogeneous: given its different evolutionary roles in survival, different pathways towards aggression exist. In AGGRESSOTYPE, we took information from animal research as our starting point for subdividing aggressive behaviour. We found that two different types of maladaptive aggressive behaviour can be distinguished: impulsive, reactive aggression – where a person overreacts to perceived threats or internal frustrations – and proactive aggression – where aggression is used as a tool to reach a goal. It is known that different brain circuits support these different types of aggression. We subsequently also found differences in the genetic contribution to the aggression subtypes.

Can you tell us more about the research process involved and your main findings related to the mechanisms underlying aggression?

We investigated the mechanisms underlying aggression subtypes at multiple levels. The first three levels consisted of: molecular genetic studies to find new candidate genes for aggression with a breakdown per subtype and gender; identifying alterations of gene regulation through epigenetics studies and direct analysis of gene-expression; and using neurons derived from human-induced pluripotent stem cells (iPSCs) to identify alterations in carriers of genetic mutations linked to increased (impulsive) aggression. We found alterations linked to aggression and its subtypes at all those levels. In the latter in vitro model system, we could actually show alterations in the communication of neuronal cells.

The other investigated levels include: the effect of aggression genes and genes for impulsivity disorders on the brain (we found subtle changes in total brain size which were in part accompanied by changes in the maturation of connections in the brain during early development); the study of aggression genes in zebrafish and mice which enabled us to identify underlying molecular pathways; and studies of brain circuits that are differentially involved in reactive and proactive forms of aggression. Finally, we conducted studies of populations at risk. One of our most notable findings was that people prone to proactive aggression will often be seen resorting to reactive aggression as well, whilst the reactive subtype exists without proactive aggression.

What would you say were the most innovative aspects of your approach?

There are several novel and highly interesting aspects to our work. For me, the most important one is the strong integration across different disciplines. This allows findings to be translated from molecular identification to testing in animal and cell model systems within a single project, for example. We have very interesting data to show from this, such as the identification of a new candidate gene for aggression, RBFOX1. We are currently studying this candidate in more detail, also using mouse and zebrafish as models.

The project also focused on treatment. How did you proceed to find potential candidates?

Treatment is a second very important pillar of our project. We have been looking into new avenues for both non-pharmacological and pharmacological treatment.

As for the first, we are studying biofeedback as a potential new option for preventing aggravation of aggressive tendencies. We teach children to regulate their brain activity while viewing emotional scenes. The study is still ongoing, but pilots look promising.

For pharmacological treatment, we have been looking into the use of methylphenidate, the most frequently used ADHD medication, for treatment of aggressive behaviour in young prisoners with ADHD. This open label trial was a huge success, and we are now following up with a randomised controlled trial. In addition, we employ multiple activities to make sure that prisoners are provided with appropriate diagnostic services and medication, where necessary. We have started training prisoner mental health professionals, and we are planning to extend the programme across Europe. In many of those activities, we are supported by the European patient organisations for ADHD, represented by ADHD-Europe.

To innovate in pharmacological treatment, we developed a medium high-throughput screen for juvenile zebrafish together with the SME ViewPoint. This has recently been commercialised. Using our automated screen, we have identified several promising compounds, which we have characterised in much detail.

What are your follow-up plans?

We are looking into different ways to extend funding for our work. Collaboration among most AGGRESSOTYPE researchers has been ongoing for more than 11 years as part of the International Multicenter Persistent ADHD Collaboration (IMpACT), and is also supported by an ECNP Network (ADHD across the lifespan).

We recently obtained an EU grant to investigate the role of nutrition and the microbiome in impulsive and aggressive behaviour (Eat2beNICE, led by Dr Alejandro Arias Vasquez), under which we can continue some aspects of our work in AGGRESSOTYPE. Importantly, we have also built close collaboration with the three other EU-funded consortia on aggression and conduct disorder, FemNAT-CD, MATRICS and ACTION, with whom we are organising workshops, symposia and conferences, as well as Special Issues in different scientific journals.

Biological research of aggression has been a neglected issue for a long time, and it was highly commendable for the European Commission to award four projects with funding to work on this subject, which has such important implications for society. We hope that future EU calls will provide opportunities to continue the work started among our consortia in the years to come.

For more information, please see:
Project website

Source: Interview from Research*eu magazine n. 76

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