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Interview with Andreas Reif
Andreas Reif

 

This is the third in our series of interviews with key people in the field, looking at their work and what it says about the future of applied neuroscience. We hope you enjoy it.

Andreas Reif heads the department of Psychiatry, Psychosomatic Medicine and Psychotherapy at University Hospital Frankfurt, Germany. With a deep involvement in ECNP’s ADHD network, and the many projects it encompasses, he described how such collaborations came about and why a broad approach can be helpful in answering psychiatry’s big questions.

Your research is centred on a number of disorders, including anxiety, ADHD, and bipolar disorder. How do these connect together in your work, not least in the sense of them sharing common elements?
The basic ideas behind my research interests are two different phenomena – disease trajectories and prediction – which are however quite intertwined.

Anxiety, for me, is somewhat of an overarching principle here, and something that can be a precursor to – and comorbid to – many other disorders. My research interests mainly encompass ADHD and mood disorders, with key questions: how do these disorders develop over the lifespan? How do they interact, and what is the level of comorbidity?

The genetics of these highly heritable disorders is of course one starting point, because genetics is something that doesn’t change. Then however, this genetic makeup, familial environment and other environments interact to shape disease cause and trajectories. The big question is: how is this reflected on the pathophysiological level? This is one of the core research questions we have.

To address these questions, we not only do gene x environment studies, but we also use neuroimaging to see how systems are modified. We use rodent models, because there we can experimentally test environmental influences on a given genetic background; this translational aspect is also heavily involved in this type of research.

The other area that interests me is the use of predictive biomarkers, in the sense of personalised medicine, and also by using machine learning approaches (and similar methods) to predict the course of disease, treatment response, and in differential diagnosis. Of course, this is related to how the disease develops, so these two questions are actually quite close together from the lifespan perspective.

You have worked extensively on the nitric oxide (NO) synthase gene. What is your latest understanding of the role of this gene and its involvement in the CNS?
I have worked on this for almost 20 years, so it is my ‘pet gene’, so to speak! There is a lot known about NO in cell systems and in the rodent brain, but not as much in the human brain, especially in mental disorders. So its precise role in human disease is not that well known.

The gene NO synthase type 1 – the neuronal isoform – is the enzyme that produces NO in your brain. It does so everywhere across the brain. It is a very widespread system, interacting with a lot of other systems.

The problem is that the whole system is very tightly regulated and very complex, so it is not easy to disentangle the different roles of NO. Its role in the hippocampus is totally different from its role in, say, the striatum; those two systems are not interconnected at all. Each NO molecule is like a small guerrilla warrior that receives its chain of commands from upstream activators, but it is not linked to other NO synthase-producing regions of the brain. It is not orchestrated like, for example, the serotonin system, where you have the Raphe nucleus that produces serotonin which is then distributed everywhere in the brain.

One of our starting points was that NO has many roles in physiology as well as pathophysiology. Thereby, it can contribute to several disorders, and actually independently.

Our key interests were first the role of NO in impulsivity, and NO synthase in the striatum likely has a role here; the other thing we considered was the role of NO in cognition and schizophrenia, and that likely is hippocampal and cortical NO.

This shows that one and the same molecule may have very different effects depending on which brain region you look at, and which molecular cascades you are looking at. To come this long way from gene to molecule, to molecular network, to cellular network, to the systems level, to be able to look at behaviour and ultimately disease – this we are trying to do paradigmatically in NO synthase. We are not there yet: we have some pieces of this very complex puzzle, but it is still far from being finished.

You are on the ECNP Workshop Committee. The ECNP Workshop on Neuropsychopharmacology for Junior Scientists in Europe has just taken place in Nice, and this year’s theme was ‘The flip side of the brain’, on the topic of glial cells. What goes into the choice of theme?
Glial cells had long been on our list, so this was overdue. The role of glial cells in neuropsychiatric disorders is undisputed; however, many people don’t know that much about them. We tend to talk about neurons, and we hardly talk about glial cells – although they are as exciting.

We, i.e. the Workshop Committee, meet at least twice a year to discuss which speakers to invite, the variable topic, etc. We try to find topics that are emerging, that are timely, interesting and rapidly moving, that perhaps have not been given much room in previous workshops, and that bring a different angle on our view on psychiatric disorders. This also makes the workshop attractive for a broad range of researchers.

You also co-chair the ECNP ADHD Network with Barbara Franke. A number of projects are running under this banner; could you describe their progress?
The ADHD Network has quite a long history. It came from an unfunded research consortium, the so-called IMpACT (International Multicentre Persistent ADHD CollaboraTion) consortium1. This was a loose research collaboration for European centres in Bergen (Norway), Nijmegen (Netherlands), Barcelona (Spain), London (UK), and Germany (where Klaus-Peter Lesch and myself headed). We also involved Stephen Farone from SUNY Upstate (USA) and later on Claiton Bau from Porte Alegre (Brazil).

We joined forces in order to work on the genetic basis of adult ADHD: we wrote a couple of papers, collaborated nicely, exchanged samples, developed common phenotyping protocols, and so forth. We also worked on joint grants, and we were quite successful in doing so. We obtained an FP7 grant called Agressotype2, which is on sub-phenotyping aggression and trajectories towards aggressive behaviour. We also have a European Training Network (ETN) funded project called MiND, which is a training network on ADHD and autism.

Quite recently, we obtained funding for the CoCA (Co-morbid Conditions of ADHD) project. We study the cause of comorbidities to ADHD and their genetic underpinning, and whether we can modify that at all (a website will be up soon at www.coca-project.eu).

Also, as one further offspring of the IMpACT network, we thought an ECNP Network would be highly helpful to enable us to interact and to have a joint platform where we can prepare grant proposals (such as the CoCA consortium, which was the first outcome from that). The ECNP Network has helped us to be visible within the ECNP community, to be present at the conferences, to foster and stimulate discussions and interactions. This is what we wanted to have with this network, and it is a very good way of doing so.

Beyond that, we have thought: how can we effectively work together using new ways? One of the things we are about to implement within the frame of the Network is a web-based phenotyping protocol, which we have translated into all languages of participating centres. This was done with an ECNP grant. With this we can reassess a lot of old patients as well as new patients, who we have already enrolled, in order to really harmonise all of our databases and increase leverage on the data we already have.

You will be presenting at the upcoming ECNP Congress on ADHD throughout the lifespan – a topic which we have seen has grown considerably in importance. What are the research directions here, in terms of understanding more fully pathogenetic mechanisms at play within the patient population that could inform treatment?
The numbers around persistence into adulthood are somewhat debated – the most corroborated one is, still, that of Stephen Faraone’s meta-analysis, which says that 15% of children with ADHD have full syndromal persistence of ADHD, while roughly half of them continuing to have some symptoms into adulthood which do not constitute full-blown disease. That adds up to 35% in which the disease fully remits.

The big question is: what predisposes you to end up in each group? Is it that the persistent group is a genetically distinct group, or is that a group with a higher genetic load? Is there a genetic predisposition towards it? Is it the level of comorbidity, or is it environment – early (prenatal) environment, or the life course during childhood and adolescence?

To be honest, up to now we understand very little of these questions. But we have not been asking these research questions for long. ADHD as a persistent, adult condition has only been acknowledged for about 20 years. And so there is very little prospective data on who might persist and who would remit, and especially much less data on the mechanisms underlying this.

So the first big question is: what mechanisms are involved? Are there distinct diagnostic subgroups that predispose to persistence? By the way, I don’t think these are separate diseases, but there are probably modifying factors that lead to persistence or remittance.

If we know that, how then can we prevent it? I am still a clinically working psychiatrist, and to me this is the most interesting question of all. How can we help these children so that they remit, and ideally without any treatment necessary in their adult life?

My second clinical focus is bipolar disorder and here, again, the same questions come up: which patients will go on to which course – high or low disease load, or, who will go to a more manic-driven or depressive-driven phenotype? How can we enable early detection (and ideally, prevention) of deleterious courses? We have the same big questions here.

Andreas Reif will speak at the 29th ECNP Congress in Vienna (17-20 September 2016) in session S.28 - Developmental aspects and top-down regulation in ADHD.


References
1. International Multi-centre persistent ADHD CollaboraTion (IMpACT). http://www.impactadhdgenomics.com
2. Aggressotype. http://www.aggressotype.eu
3. Mastering skills in the training Network for attention deficit hyperactivity and autism spectrum Disorders (MiND). http://www.mind-project.eu

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