A Meeting of MiNDs

On Friday 1st June the MiND EU project hosted a successful patient information evening in collaboration with ADHD-Europe, the ADANA Foundation and Dr Toni Ramos-Quiroga at Vall d’Hebron Hospital in Barcelona. Anyone with an interest in research into Autism and ADHD were warmly invited to view posters and presentations on the latest developments from the MiND project and our collaborators.

Patient evening blog 1

The world of science is often seen as having a mind of its own, which does not often engage with the community. However, the MiND project would like to change this perception! We hosted a patient information evening to discuss our work on ASD and ADHD with the public, with the aim to share our knowledge of these disorders and to promote inquisitive minds.

The presentations were opened by Dr. Toni Ramos-Quiroga and Andrea Bilbow OBE, President of ADHD Europe. Although our speakers varied in their backgrounds, they are all active in genetics and psychiatric research, with a passion to improve our understanding of ADHD and ASD.

Professor Bru Cormand, who leads a Neurogenetics Research Group at the University of Barcelona, talked about the genetics of Autism and ADHD and the role of the environment in the development of these disorders. Professor Cormand explained that we share more than 99% of our genome with any other human being, so it is the remaining 1% which makes the differences among individuals, both in health and disease. Biomedical researchers look into this fraction of the genome to find the causes of many diseases. These genes are instructions for producing proteins, some of which are involved in the communication process between neurons in our brain. It is important that we study these genes because the connectivity between neurons is crucial. When this mechanism is impaired, due to alterations in certain genes, the result is often a  psychiatric condition like ADHD or ASD.

Professor Cormand also explained how we can use family studies to understand ASD and ADHD. From this type of research we now know that genetic factors play a very important role both in ADHD and in ASD, with a share of more than 70%. The rest possibly corresponds to environmental risk factors, such as prenatal or birth complications. Other external factors, like vaccines, do not contribute to these disorders. To date, we have been able to identify several contributor genes for both ASD and ADHD. Professor Cormand eloquently described our genome as a ‘crystal ball’ “if correctly asked, it can provide information about things that will take place in the future. Our health and our disease is, to a great extent, written in the genes… but they can also help us to find ways for improvement”.

Further research in this area will be highly beneficial for patients in the future for several reasons:

  1. They provide basic knowledge on the causes of the disorders, which can be useful in diagnosis or even for prognosis (anticipation of future complications).
  2. It points at potential therapeutic targets, i.e. proteins that can be targeted with drugs.
  3. The genetic profile of an individual can predict response to a treatment or side effects, if any.

However, we still need some time to complete the full genetic landscape before we fully understand these disorders!

Dr Alejandro Arias-Vasquez, an associate professor in genetic epidemiology informed attendees of an exciting, up and coming area of research: the microbiome and its role in ADHD. Through research we have learned which are “good” and “bad” foods that influence the risk of being obese, having diabetes, or suffering from cardiovascular disease.  However, we are also beginning to learn that what people eat can also affect the way the brain works, although these mechanisms are currently unclear.

So far research has shown that there is convincing evidence of a sizeable impact – both harmful and protective – of nutrition components on behaviors such as impulsivity and compulsivity. Currently, the experts do not know how big the impact (effect size) of these non-pharmacological interventions is, which raises questions such as:

  • Can people improve our overall brain functioning by improving diet and lifestyle?
  • Can we replace medication used for treating psychiatric disease with specific diets?
  • Shall we complement pharmacological treatment with specific diets to improve behavior?

Dr Arias-Vasquez hopes to answer these questions by leading a new research consortium called Eat2beNICE. This project will study different diets and nutritional supplements in children and adults. It is anticipated that this research will create new evidence-based approaches for making recommendations about nutrition and its links to changing behavior. This could mean that specific dietary changes could be one or part of the treatment options for ASD and ADHD in the future.

Patient evening blog 2

Dr Laura Gisbert explained her research as a psychiatrist at Vall d’Hebron. Currently, Dr Gisbert is involved with many research projects (that take place in her clinic). In particular, there are two clinical trials testing out medications for ASD and ADHD: Vasopressin for adults with ASD and Guanfacine for children with ADHD. Dr Gisbert explained that two main approaches are used to develop pharmacological agents for ASD. One is re-purposing treatments from other psychiatric disorders that have symptoms in common with ASD. The second approach is to target the neurobiological processes underlying ASD. Although there have been studies of medications that reduce ASD symptoms, by targeting specific circuits in the brain, there is still a lack of clear evidence to recommend the routine use of any of these medications for the moment. Similarly in ADHD, more research is needed to find effective medications with fewer side effects. Not all patients can tolerate stimulant medications that are often prescribed for ADHD, and therefore alternatives need to be found. Furthermore, this medications that can simultaneously improve symptoms of frequently co-occuring disorders such as ASD, would also be advantageous to patients. It is hoped that the clinical trials taking place at Val d’Hebron will contribute to this work, in order to improve treatment strategies for patients with ASD and/or ADHD.

These presentations were highly engaging as demonstrated by our audiences need for a long Q&A session with our speakers on various topics from treatment strategies to genetics.

Patient evening blog 3

Attendees were also highly interested in the poster presentations given by the MiND early stage researchers (Viola Palladino, Niall Mortimer, Anu Shivalikanjli, Joanna Szopinska-Tokov, Sara Boxhoorn and Francesca Waddington). These posters represented the diverse range of topics studied within the MiND project, which include the gut microbiome in ADHD, the genetics of ADHD, stem cell research, how we measure attention in ASD and ADHD and the relationship between these two disorders. These also proved to be very thought-provoking with many discussions between members of the public and our researchers.

The MiND project is proud that our event was so insightful and to have elicited such a great response!

If you would like to find out more about our research see
mind-project.eu
Eat2beNice

Patient evening blog 4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

How sports might help in adult ADHD

A recent case in our outpatient clinic gave me an interesting insight into the link between professional sports and adult ADHD. An US-American football player who was quite impulsive presented for a diagnostic assessment. He had a history of childhood ADHD but never received stimulant treatment because his mother felt that she was able to cope by providing a structured environment. While he was not very successful in obtaining an economy degree during college, he earns nowadays money playing in foreign American football leagues. He is now 35 years old and started to think about what to do after his career ends and how his ADHD would affect future plans. He clearly fulfilled most diagnostic criteria but was not too handicapped in everyday life. Obviously, he found the perfect niche for a hyperactive adult with a high degree of impulsivity: American football. During the diagnostic assessment, he had to do a commercial continuous performance test which tests both attention as well as hyperactivity over 20 min. While his attention was not to bad, his activity during the tests was one of the highest scores we saw so far in our outpatient clinic. When talking to him about his test results, he commented that this result is typical for his adult life: professional sports taught him how to deal with his inattention and consecutive frustration. So while his ADHD was manifesting in lots of micro movements he nevertheless was able not to loose motivation and to sustain a certain degree of attention until the end of this test. So after having seen this patient, I wondered what evidence we have so far to recommend sports training in adult ADHD. Obviously, we might think of three good reasons for sports in general and in adult ADHD patients.

First, people showing a high degree of restlessness, will just enjoy sports and fitness training because it helps them to reduce their restlessness.

Second, the neurotransmitter dopamine plays a decisive role in mediating all effects in adult ADHD. There is this elegant rat experiment (by Kim et al. 2011) about the effect of a treadmill exercise on the dopamine system. Spontaneous hypertensive rats, a special breed which shows signs of hyperactivity and is considered to be an ADHD model, were given methylphenidate or treadmill exercise. While the improvement due to MPH is not surprising, treadmill exercise impacted on expression of BDNF, a marker for neuroplasticity, in the striatum and the substantia nigra.

Apart from these direct neurochemical effects, some sports training teaches how to handle frustrating challenges and not to give up early. While this is a trivial statement for every ambitious sportsmen, there are only few scientific or clinical studies in sports psychology which assessed this statement systematically and almost none for adult ADHD (please correct me if I’m wrong).

Inspired by my patient’s story, I became curious whether frustration handling could be a way of how adult ADHD patients might learn to cope with their disease. Maybe some readers have own thoughts about this?

Reference:

Kim, H., Heo, H. I., Kim, D. H., Ko, I. G., Lee, S. S., Kim, S. E., … Kim, C. J. (2011). Treadmill exercise and methylphenidate ameliorate symptoms of attention deficit/hyperactivity disorder through enhancing dopamine synthesis and brain-derived neurotrophic factor expression in spontaneous hypertensive rats. Neuroscience Letters. https://doi.org/10.1016/j.neulet.2011.08.052

Oliver Grimm is a senior psychiatrist at the University Hospital Frankfurt where he is responsible for the adult ADHD outpatient clinic and is involved in the CoCA-project ( www.coca-project.eu ).

Exciting findings on ADHD comorbidities shared on 3rd meeting of CoCA researchers in Dublin

A few weeks ago, researches from all over Europe (and some even from the USA) gathered in Dublin to discuss the progress of the CoCA project. This project, investigating the prevalence and causal factors of ADHD comorbidities, is now almost half way. Time for an update on what’s happening. 

CoCA Dublin
All attendees of CoCA’s 3rd general assembly meeting in Dublin

ADHD is a risk factor for developing other (psychiatric) disorders

One of CoCA’s aims is to estimate the prevalence of comorbid disorders that occur together with ADHD. By using very large data registries from Norway, Sweden, Denmark and Estonia we can estimate the risk of developing a psychiatric comorbidity when a person has ADHD. For instance, last month a paper was published based on data from Norway, stating that the prevalence of anxiety, depression, bipolar and personality disorders, schizophrenia and substance use disorders is 4 to 9 times higher in adults with ADHD compared to adults without ADHD [1]. Interesting differences between men and women were also observed in this study. Such that depression is much more prevalent in women with ADHD, compared to women without, while in men substance use disorders are more common together with ADHD.

ADHD does not only co-occur with other psychiatric disorders, but also with obesity. Earlier last year, we published a study based on the Swedish national registry, where it was observed that ADHD and being overweight or having obesity share familial risk factors [2]. In other words, when you have a sibling who is overweight or has obesity, you are more likely to have ADHD compared to similar people who do not have overweight siblings.

The data from these registries can not only be used to estimate prevalence, but also to predict the risk someone has to develop other disorders. Our partners in the USA are using advanced machine learning tools to predict within the ADHD population who will develop comorbid disorders. Using the Swedish registry data they have found that having an ADHD diagnosis combined with a high number of injuries before the age of 12 predicts a comorbid substance use disorder at a later age. High risk taking behavior could mediate this association, and may therefore be a trait to investigate further and monitor in young people with ADHD. These data are now being further investigated and have not yet been published.

Publications on other registries and data will come out soon, so keep your eye on this blog for more information on the co-occurrence of (psychiatric) disorders in persons with ADHD.

ADHD and (psychiatric) comorbidities share genetic variants

When you know that ADHD often co-occurs with other disorders, the next question is to understand how and why. Our geneticists are trying to map the genetic overlap between the different disorders and identify shared genetic risks. Much of the work is still ongoing, but you can expect some exciting findings to be published very soon. What I can already share is the recent publication on how polygenic risk scores of ADHD overlap with other disorders and traits [3]. Polygenic risk scores (PRS) were calculated based on 12 genetic loci that are associated with ADHD based on earlier studies. In other words, the more risk variants you have on these loci, the higher your risk is for ADHD. Using the UK Biobank data, the researchers found that ADHD PRS were associated with higher body mass index, neuroticism, anxiety, depression, alcohol and nicotine use, risk taking and lower general cognitive ability (verbal-numerical reasoning). This suggests that the genes that contribute to ADHD are also involved in other traits and disorders that are often observed in people with ADHD. More knowledge on these genetic factors is expected from the studies that are now being conducted.

Searching for new treatment possibilities for ADHD and comorbid disorders

At the moment, there are no good treatments for obesity and substance use disorders, and there is little progress in the development of medication for ADHD in combination with depression. Within the CoCA project we are therefore investigating new treatment possibilities. In Frankfurt, Barcelona and London the first people with ADHD have received bright light therapy and physical exercise training to reduce symptoms of depression (the PROUD study). In Nijmegen this study will soon start as well. Meanwhile in Rostock (Germany), the circadian rhythm of participants with ADHD and other disorders is being measured. And in Frankfurt researchers are investigating the effects of dopamine agonists and antagonists on the reward system in the brain.

CoCA researchers in Norway have been searching the literature for new druggable targets for ADHD and comorbid disorders. A publication on many promising druggable genes can be expected soon. The first group of targets will be tested in an animal models.

Collaborations with patient organisations

Two representatives of ADHD patient organisations also joined our meeting: Andrea Bilbow from ADHD Europe, who is a partner in the CoCA project, and Ken Kilbride from ADHD Ireland. It was good to have these experts with us, and discuss with them how we can best translate our research findings to the people who should benefit from these findings. In Ireland for instance, there is very little knowledge about adult ADHD amongst health care professionals. It is therefore essential that our knowledge is also transferred to them, so that they can provide better care.

With the help of Andrea and Ken, we came up with a lot of new ideas for ADHD Awareness Month. During the entire month of October we aim to generate more awareness about. We will specifically target schools, such as universities and German Berufschule to inform both pupils and teachers about how to recognise ADHD and comorbidities, in adolescence and adulthood.

What’s next?

With the project being almost half way, we feel that we’re progressing very well (and our external advisor Jim Swanson – who attend the meeting as well – agrees!). In the coming year, we expect many exciting publications to appear and we will organise several symposia on international scientific conferences to share with you what we’ve found. By collaborating with patient organisations across Europe we will also share our knowledge with patients, family members, health care professionals and teachers. You can follow all of our progress on this blog!

This blog was written by Jeanette Mostert. Jeanette is dissemination manager of the CoCA project.

Further reading

1: Solberg, Halmøy, Engeland, Igland, HAavik & Kungsøyr (2018) Gender differences in psychiatric comorbidity: a population‐based study of 40 000 adults with attention deficit hyperactivity disorder. Acat Psychiatria Scandinavia, 137 (3): 176 – 186. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838558/

2: Chen, Kuja-Halkola, Sjölander, Serlachius, Cortese, Farone, Almgvist & Larsson (2017) Shared familial risk factors between attention-deficit/hyperactivity disorder and overweight/obesity – a population-based familial coaggregation study in Sweden. Journal of child psychology and psychiatry, 58 (6): 711-718. https://www.ncbi.nlm.nih.gov/pubmed/28121008

3: Du Rietz, Coleman, Glanville, Wan Choi, O’Reilly & Kuntsi (2018) Association of Polygenic Risk for AttentionDeficit/Hyperactivity Disorder With Co-occurring Traits and Disorders. Biological Psychiary CNNI, in press. https://www.sciencedirect.com/science/article/pii/S2451902217302318?via%3Dihub

 

 

Do genes explain the overlap between ADHD and other conditions, such as cognitive functioning, obesity, mood disorders and substance use?

ADHD is a heritable disorder, which means that genes contribute to the risk for getting the disorder. There are hundreds or even thousands of genes that contribute to ADHD, and while each single gene itself will not cause ADHD, together they contribute to the risk. But it is important to note that genes are not everything – environmental influences, such as preterm birth or exposures during pregnancy, may also contribute to the risk for ADHD.

 

Individuals with ADHD sometimes have other co-occurring conditions, such as mood disorders, obesity and substance abuse. This has led to the important research question of why do these conditions often co-occur with ADHD. Are there shared risk factors?

Comorbidity

We know that people with ADHD not only tend to have a family history of ADHD, but they also are more likely to have siblings or parents with certain other co-occurring traits and disorders. This suggests that there are overlapping familial risk factors – which could be genes – between ADHD and other conditions.

 

A very large and recent genetic study that examined thousands of common genetic markers across our DNA, identified for the first time several genes that underlie risk for ADHD2. This information allowed us to investigate the genetic overlap between ADHD and other disorders using actual genetic data. In our new paper published in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging3, we selected a bunch of genetic markers that most strongly underlie risk for ADHD, identified in the previous genetic study, and tested if they showed an overlap with other traits and disorders that often co-occur with ADHD. We tested this on a very large sample of 135,000 people in the UK. We found that some of the genetic risk factors were shared between ADHD and co-occurring conditions in the general population, specifically – atypical cognitive functioning, higher body mass index, neurotic behaviour, anxiety, depression, risk-taking behaviour, smoking and alcohol use.

 

Our study findings suggest that genes do, at least to some extent, explain the overlap between ADHD and co-occurring conditions. These genetic factors contribute to cognitive functioning, body mass index, mood symptoms and substance use in the general population.

 

The aim of this research is to further our understanding of ADHD and co-occurring traits and disorders. A better understanding of why ADHD often co-occurs with other conditions may help in the development of new treatments. Also, if we know how to predict which individuals with ADHD are at risk for other co-occurring disorders, we will be in a better position to offer early interventions that could prevent such further problems from developing.

 

Ebba Du Rietz and Jonna Kuntsi

 

References:

  1. Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, Sklar P. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005; 57:1313–1323. doi: 10.1016/j.biopsych.2004.11.024.
  2. Demontis D, Walters RK, Martin J, et al. Discovery of the first genome-wide significant risk loci for ADHD. bioRxiv 145581. 2017. doi: https://doi.org/10.1101/145581.
  3. Du Rietz E, Coleman J, Glanville K, Wan Choi S, O’Reilly PF, Kuntsi J. Association of polygenic risk for attention-deficit/hyperactivity disorder with co-occurring traits and disorders. Biol Psychiatry: CNNI. In press. doi: https://doi.org/10.1016/j.bpsc.2017.11.013

 

ADHD and school failure

Patient involvement is essential in health care, as well as in medical research.

For this purpose, our research group at the University of Bergen is collaborating with a board of ADHD patient representatives. The panel is committed to provide suggestions for future research topics and feedback on our work. During a recent meeting, panel members were asked what they considered the most urgent (research) needs in this field.

Much to our surprise, all four panel members expressed almost univocal messages: “You must fix the school system”. “There is too little knowledge about ADHD among teachers”. “Schools either ignore our problems, or offer too little assistance, too late “.

Perhaps these complaints shouldn’t be that surprising? After all, ADHD symptoms typically appear in school settings. Whether an ADHD condition is formally diagnosed during childhood, or the diagnosis is made retrospectively in adults, most people with an ADHD diagnosis will tell that they had negative experiences during school and many also suffered from academic failure.

The connection between learning difficulties, ADHD symptoms and dropping out of school are obvious also in genetic studies. In fact, this connection inspired us to perform a molecular genetic study, where large scale data collected about the genetics of educational attainment (EA) was coupled to a genome wide association (GWA) studies on ADHD genetics. Taking advantage of this connection, this design was able to boost the statistical power of the ADHD GWA study.

Until recently, genome wide studies on ADHD have been small and failed to provide reliable genome wide significant association signals. When a conditional false discovery rate method was applied to GWA data on ADHD educational data, to identify ADHD-associated loci and loci overlapping between ADHD and EA, we identified five ADHD-associated loci, three of these being shared between ADHD and EA. These five novel loci associated with ADHD confirm that there is a shared genetic basis between ADHD and EA and may increase our understanding of the genetic risk architecture of ADHD .

http://www.jaacap.com/article/S0890-8567(17)31863-4/abstract

From this study, we have learned: (1) the importance of patients and society being engaged our work, (2) that there is a strong connection between ADHD and failed educational attainment and (3) that this connection can be used to find ADHD susceptibility genes.

Finally , as our patients have explained; this is not only about persons with ADHD failing at school, but also about a school system failing to adapt their teaching to persons with ADHD-related problems. This is obviously also a field in need of future research and interventions.

Jan Haavik is professor at the department of Biomedicine of the University of Bergen in Norway. He is involved in the CoCA and Aggressotype projects.

Adult ADHD and gender differences in psychiatric comorbidity

Interestingly, ADHD symptoms are usually different in girls and boys during childhood. Girls show less hyperactivity and this may lead to later identification and later treatment. Could this affect the development of other psychiatric disorders in adulthood? This was the big question behind a study examining differences in mental health among men and women with ADHD.

Previous studies have tried to figure out differences among men and women with ADHD in the risk of psychiatric comorbidities. Our study is the first to actually show such differences.

In our study, we linked information from four large national registries in Norway, and identified 40,000 adults with ADHD, which is 2.4% of the adult population. We compared them with the remaining population of 1.6 million Norwegian adult inhabitants without ADHD. The psychiatric disorders we studied were anxiety, bipolar, depression, personality disorder, schizophrenia spectrum (schizophrenia) and substance use disorders (SUD).

Both men and women with ADHD were 4-9 more likely to be diagnosed with these psychiatric disorders compared with the remaining population. We also found that there were significant differences in risk of a psychiatric diagnosis between men and women with ADHD.

Figure_colour_Acta_Psych_Scand_160917_title

Women with ADHD were significantly more often diagnosed with anxiety, depression, bipolar and personality disorder than men, while men with ADHD had more schizophrenia and SUD.

We also found that a considerable proportion of anxiety, bipolar disorder, depression, schizophrenia, SUD and personality disorders in the population could be explained by an underlying ADHD. About 6 percent of depression and 13 percent of bipolar disorders in women could be related to ADHD.

What clinicians need to know is that when treating adults with ADHD, they should be aware of these gender-specific psychiatric comorbidities, in order to both detect the conditions and offer early treatment if diagnosed. Importantly, clinicians should also be aware of a possible underlying ADHD when adults present with symptoms of other psychiatric disorders.

It is also important to identify children and adolescents with ADHD at earlier stages in order to reduce the risk of future psychiatric comorbidity. This may be particularly important in girls and women with ADHD, who often have a lower degree of hyperactivity and are therefore at an increased risk of being undiagnosed in childhood. This could result in a higher risk of developing other psychiatric disorders as a possible consequence as they grow older.

This study was done at Stiftelsen Kristian Gerhard Jebsen Center for research on Neuropsychiatric disorders, University of Bergen, Norway, and published OnlineOpen in Acta Psychiatrica Scandinavica, December 2017, with the title: “Gender Differences in Psychiatric Comorbidity: A Population-based Study of 40,000 Adults with Attention-Deficit Hyperactivity Disorder”

http://onlinelibrary.wiley.com/doi/10.1111/acps.12845/abstract;jsessionid=9377E31A46561F6810527AC39EC90981.f02t04