by Thomas Wagner-Nagy (concentris research management GmbH)
Attention deficit hyperactivity disorder (ADHD) is a mental health condition that rarely occurs alone. More than 80 percent of adult ADHD patients suffer from a comorbid disorder, meaning there is at least one additional disease co-occuring with the primary disease.
In the case of ADHD, two common comorbid conditions are obesity and major depressive disorder. Therefore, the risk for comorbid obesity and major depressive disorder is increased in adolescents and adults with ADHD. Moreover, a disturbed circadian rhythm and altered sleep are key features of ADHD.
Bright light therapy, a so-called chronobiological modification, improves the day-night (circadian) rhythm and is an established therapy for major depression in adolescents and adults. Exercise prevents and reduces obesity in adolescents and adults along with improving depressive symptoms.
While these non-pharmacologic treatments are known to modulate dopaminergic transmission (DA) and circadian rhythm (CIRCA), two key mechanisms regulating mental wellbeing, no study has assessed their effect on ADHD and its comorbidities in an experimental setting yet. PROUD is therefore the first large scale, multicentre study to systematically evaluate the role of DA and CIRCA and scrutinize their potential relevance for developing disease biomarkers and thus obtaining measurable indicators for predicting and treating these ADHD comorbidities.
“The idea here is to employ non-pharmacological methods to improve patients’ lives. There is a well-established drug treatment for ADHD with stimulants – methylphenidate being the most famous one. However, that is only one step and we want to make use of the knowledge that sports on the one hand and bright light therapy on the other hand showed promising initial data to improve patients’ lives with ADHD”, says CoCA project coordinator Andreas Reif, Chair of the Department of Psychiatry, Psychosomatic Medicine and Psychotherapy at the University Hospital Frankfurt in Germany.
“So we put that into a clinical study where we compared treatment as usual with add-on sports therapy or add-on bright light therapy. Over this ten-week trial, we will see whether this affects not only ADHD symptoms but overall health symptoms like depressive symptoms or weight.”
Need a watchdog or motivator? There’s an app for that
Just how do you motivate obese patients to exercise regularly? “It’s very hard to get up and do sports on a daily basis”, says Reif. “We thought about how we can empower our patients to adhere to the study protocol. In order to do that, we have developed a mobile health application, the mHealth App.”
The mHealth App was specifically developed for the PROUD Study with the aim of keeping the patients motivated. “We achieve this by showing them videos of exercise, sending reminders as well as a daily feedback and summary on their achievements”, trial coordinator Jutta Mayer explains.
The study has started with its first participants at the University Hospital of Frankfurt in late March 2017. The CoCA team expects first results and insights by the end of 2017.
This post has also been submitted as a press-release to announce the start of the PROUD trial.
A short while ago, three of our professors were in the media, featuring an article and a TV-documentary about ADHD. Professor Andreas Reif wrote an elegant piece for the Frankfurter Algemeine – a German national newspaper – explaining the biology of ADHD and the need for treatment [see also this recent post on Andreas Reif’s recent appearances in German Media]. Around the same time, professors Barbara Franke and Phillip Asherson appeared in a documentary in which Britisch comedian Rory Bremner went on a personal mission to discover the science of ADHD. As not everyone can read German, and the BBC show is unfortunately only viewable inside the UK, I’ll tell you about the highlights of both pieces.
Do you know the stories by Heinrich Hoffman (1845)? The psychiatrist who wrote a children’s book about naughty children. One of the stories is about Fidgety Philip – or Zappelphilip in German – a boy who can’t sit still and as a result pulls down the tablecloth including everything that’s on top of it, smashing all the table’s contents on the floor. Both Andreas Reif and Rory Bremner mention Fidgety Philip, as the characteristics of this boy resemble several symptoms of ADHD: fidgetiness, restlessness and impulsivity. This example illustrates that ADHD is not a new or modern day phenomenon.
Interestingly, it’s not just the behaviour of people with ADHD that is restless. As Rory Bremner describes it “the music in my brain is [..] pounding and rapid and switching”. This ‘busy brain’ is often described by people with ADHD. And this makes it logical to expect that you should be able to see this with an MRI-scanner – a machine that allows researchers to measure brain activity. Unfortunately, reality is not so simple. Despite a lot of research on people with ADHD and their brain activity, we still can’t diagnose ADHD by using a brain scan. As professor Katya Rubia explains to Rory Bremner, differences in the brains of people with ADHD, compared to those without ADHD, can be seen when you average over large groups (see figure below). For instance, children with ADHD have smaller brain structures in the frontal parts and in deeper areas of the brain (the basal ganglia). These regions are also known to be less activated in children with ADHD, when they need to inhibit a response. As an example, in the documentary Rory Bremner finds it very difficult to inhibit his comments about Katya Rubia’s accent and beauty. This could be due to under activation of his frontal brain and basal ganglia. However, the MRI findings are only based on averages, and can be very different for individual people. Just like that you can’t tell if someone is a man or a women just by measuring their length – even though men on average are taller than women – you can’t tell if someone has ADHD by just looking at their brains.
Fruit flies and ginger bread men
So why does someone have ADHD? Are you born with ADHD? Is it the fault of your parents? Or should we blame society? Extensive research has shown that there is a strong genetic component to ADHD. This means that you inherit the risk for developing ADHD from your parents – even when they don’t raise you, as for instance in the case of adoption. Professor Andreas Reif describes that there are hundreds or even thousands of genes that can contribute to ADHD. Each single gene by itself will not cause ADHD, but together they contribute to the risk for ADHD. The situation with the genes is therefore similar as to that of the brain scans: no gene test can prove that you have ADHD as there is too much variation between individuals. So why should we put time and money in investigating the genetics of ADHD?
For one thing, if we understand which combination of genes contributes to a high risk for developing ADHD, screening could help in early detection of those at risk. For instance, ADHD is known to often co-occur with other disorders, such as depression, substance abuse or obesity. If we know who is at risk of developing such a secondary disorder, the person can be informed about the importance of behavioural adaptations that reduce this risk, such as regular exercise in the case of obesity. Another reason is that better understanding of causal mechanisms can aid in developing new treatments for ADHD.
In order to study these causal mechanisms, professor Barbara Franke uses fruit flies (drosophila melanogaster). With these flies she can investigate which gene is associated with which specific aspect of ADHD, such as hyperactivity or inattention. In the documentary Barbara Franke shows Rory Bremner how she releases fruit flies in a specially designed maze. At the end of the maze, the fruit flies can find food. The more often they go through the maze, the better they learn the route. But while the flies go through the maze, they are being distracted by a light which they should ignore. For this experiment, some fruit flies have undergone modifications of genes that we suspect to pose risk for ADHD. And it turns out that the ADHD-like flies are more distracted by the lights than the ‘normal’ flies. In this way, we can find out which genes cause increased distractibility.
But it’s not just genes that contribute to ADHD. Although genes explain about 80% of ADHD, environmental influences, such as preterm birth or toxins during pregnancy also contribute to the risk for ADHD [i.e. see this recent post by Stephen Faraone)]. In the documentary, Peter Hill shows Rory Bremner how genetic and environmental factors can contribute to slightly different appearances – also called phenotypes – by baking gingerbread men. Peter and Rory bake several of these cookies, but with slight differences in the ingredients and procedure. One gingerbread man for instance is baked less long, which translates to environmental. The other gingerbread men lack eggs, contain less flour, or have no ginger. These are exemplary of the genetic influences of ADHD. All in all, the gingerbread men still look like gingerbread men – and probably are just as tasty – but knowledge about what happened in the preparation and baking process can help understand why they are different.
Medication & treatment
As mentioned earlier, ultimately we hope that a better understanding of ADHD enables better treatment. At the moment, psychostimulant medication, such as Ritalin and Concerta, is the most widely used form of treatment. As Andreas Reif explains, methylphenidate (which is the active substance in Ritalin) increases the availability of dopamine and noradrenaline in the brain. These two substances are necessary for a wide range of cognitive tasks, including learning, paying attention and inhibiting responses. In people with ADHD there seems to be too little dopamine available, which is why they benefit from this medication. Rory Bremner tries it for the first time in the documentary, just before he gives a comedy show. He describes the effect as “It’s a bit like someone switched my brain from techno radio 1 to classic fm”. However, as professor Phillip Asherson tell us, although this medication can help you to focus, some people will feel more nervous or restless. In that case, the medication doesn’t work for them.
Alternative forms of treatment are also being tested, such as neurofeedback. Friederike Blume from Tübingen shows Rory Bremner how she uses EEG (measuring electric signals in the brain by using a device that looks like a swim cap) combined with virtual reality in order to train people to improve their neural signals. Similar to going to the gym, regular neurofeedback training may help to improve brain functioning and hence reduce symptoms.
And what happens when ADHD is left untreated? In some cases, not so much. Rory Bremner was never diagnosed with ADHD, even though in the documentary he finds out that he does have all the symptoms of ADHD. For a comedian as himself, an impulsive and associative mind is very beneficial. However, for others, untreated ADHD can cause big problems. About 30% of the offenders in prison has ADHD, and most of them have not received treatment. As most of these offences concern impulsive offences, such as spraying graffiti, medication can help to prevent such behaviour.
So, what have we learned?
All in all, both the documentary and the newspaper article give us an idea of what the research on ADHD is all about: from fruit flies to brain scans, researchers are trying to discover the biology of ADHD. As Andreas Reif puts it, better knowledge and diagnostics of ADHD, in all stages of life, can greatly improve detecting and treating ADHD. And this can greatly improve quality of life of those with ADHD. That’s what inspires us to do the research.
Enlightened, energised and slightly sunburned – that’s how I left the General Assembly (GA)-meeting of CoCA. This meeting took place from 19 – 22 March in Barcelona. After the kick-off meeting last year, this was the second time that all researchers came together and shared their findings, expertise and problems concerning the research on comorbid conditions of ADHD (CoCA). The meeting made clear that despite everyone’s different backgrounds, nationalities and expertise, we’re all working towards the same goal: reducing the burden of comorbid conditions in ADHD.
In 2 days I had listened to updates from researchers, talked about the latest findings and struggles in the various research groups, and informed the CoCA group about the progress we had made in the dissemination and valorisation workpackage. My ears were spinning, my throat was dry and my brain was tired, but the meeting had been a great success. Let me summarise my personal highlights from this meeting.
Comorbid conditions in ADHD are prevalent, and costly
The first epidemiological findings of CoCA are currently being written up. Very large databases from Sweden, Germany and Estonia have been studied to investigate the prevalence and costs of comorbid conditions in ADHD. The results will likely make a strong case that comorbid conditions in ADHD are very common, and that better treatment of these conditions is expected to reduce societal costs. You can expect some interesting and important papers to appear this or next year.
What has already been published in the past year is for instance this paper on the genetic overlap between ADHD and bipolar disorder (Van Hulzen et al. 2016).
The first intervention studies with patients have started
Other CoCA researchers have been working hard to get the first intervention studies up and running. In Frankfurt am Main, the first participants have started in the PROUD-trials (see this recent blog post). Using both bright-light therapy and regular physical exercises, we hope that symptoms of depression and obesity in adolescents and adults with ADHD will decrease. This same study will also run in Nijmegen (NL), London (UK) and Barcelona (SP). So no results yet, but exciting things are coming up!
CoCA researchers are actively disseminating and communicating the project
On the dissemination and communication side, which I’m personally involved in, things are moving forward as well. I was very happy to hear from many different researchers how they are informing children, adults, patients, health care professionals and other parties about the work that we are doing. In Spain for instance, researchers go to schools to inform pupils about ADHD and comorbid conditions. And in Germany, health care professionals are informed about the co-occurrence of depression, substance abuse and obesity with ADHD. We are also closely collaborating with the ADHD patient organisation ADHD-Europe, who are a great help in disseminating our messages to ADHD patients and their families.
Additionally, this blog is receiving an increasing number of visitors and followers. Although still somewhat hesitant, the CoCA researchers themselves start to get excited about writing posts for this blog. And after I gave a workshop on ‘how to write a blogpost’ at this meeting, I expect that many more posts will appear in the next months.
Philips is interested in our project and gave us useful advice
Besides the research findings and publications that CoCA will generate, we want the project to have additional societal impact. For instance, that the tools of our intervention study that we are now testing could be further developed by a company. We had therefore invited someone from Philips to join our meeting, listen to what we’re doing and give feedback from an industrial perspective. I learned for instance that when at Philips a new product is developed, they always first ask what problem they are solving, and for whom. Seems pretty obvious, right? But it’s a good thing to keep in mind also when designing studies.
The weather was perfect
Let’s be honest, the weather in Barcelona was another highlight. Although most of the meetings were indoors, lunch and tea breaks allowed us to enjoy the Spanish sun. And if you’re coming from Northern Europe, this is a welcome treat after a long and dark winter. I would vote to have next year’s meeting in a sunny place again!
So now the real work starts. With the first results coming out, dissemination activities can really start taking place. We have also come up with the idea to make tip-sheets about CoCA that every member can use for dissemination. This way, our activities will be more coordinated and combined.
Keep following this blog for updates on CoCA (and the other consortia), as well as our new Twitter account @mindgap_psy
Usually on this blog, scientists write about ADHD. But now, let’s listen to someone who has ADHD. And who can explain very well, and on rhyme, what it’s like to have ADHD. Watch Bryn Travers’ video here:
ADHD Europe – the European patient organisation for people with ADHD – has launched a declaration on behalf of teenagers with ADHD. The declaration states that adult services in all European countries should offer suitable care for teenagers with ADHD who transition into adulthood, and to adults who are newly diagnosed. Andrea Bilbow is the president of the ADHD Europe organisation. I asked her about the importance of this declaration, and what she thinks that the consequences of the declaration will be.
Why was this declaration to urgently needed?
“Well it’s a bit of a long story that goes back 20 years. We started as organisations to raise awareness for ADHD in children, and to organise good services for these children. In most European countries there now are good services for children with ADHD.”
“However, these children are all becoming adults. For many young people across Europe as soon as they reach 18 years of age, they find that transition to adult services is very poor. In many cases treatment is withdrawn altogether leaving them vulnerable and at risk. And for those fortunate enough to receive the medication that they need for ADHD in adulthood, the medication is no longer reimbursed. This puts a huge burden on families who often have two or more children with ADHD and who do not have the resources to pay for the medication. Only in one or two countries in Europe are there official adult licences for the medication needed by adults with ADHD. Besides medication, young adults with ADHD do not have access to the services for ADHD in adult clinics, while they were receiving help in children’s services.”
Why is it so important that adults with ADHD receive suitable care?
“18 is a very vulnerable age. It’s the age when adolescents move up to Higher Education or start with their first jobs. Having ADHD, these young people are vulnerable to substance abuse, academic failure, job loss, becoming homeless or even crime. Furthermore, many of them will be starting to drive. Studies have shown that a significant number of young people with untreated ADHD will be involved in car accidents.”
“For years the EU has been trying to address the problem of school dropout in Europe, without success. Having medication for ADHD continue to be reimbursable and proper services for young adults with ADHD available would go a long way to reduce the number of young people who abandon education. So it is very, very important that they receive proper treatment and support. It’s probably one of the most important things you can do for this age group.”
People can now sign the declaration to show their support. What do you think will happen next?
“Well first of all, it’s amazing to see how much support we are receiving. The Declaration has been launched for only a week and already we have more than 500 signatures. More importantly, these signatures come from all over the world. But it also shows that what this declaration states is very much needed. Clearly, 18+ people across Europe are really struggling.”
“First, we will let this run for a couple of months to see how many signatures we can receive. We encourage professionals to also show their support: professors, doctors, medics, researchers, teachers, police. Anybody who has any stake in improving the lives of people with mental health problems. Once we have gathered this support, we will encourage the member countries to take it to their MEPs and try to get the required number of MEPs to sign the declaration in order for it to be discussed in the European Parliament. That is our mission. We will try to find out why in some countries they don’t want psychiatrists to diagnose and treat adults with ADHD. This is a human right that’s being breached.”
The Declaration also shows the importance of research on ADHD. The CoCA project for example will investigate the societal costs of ADHD and comorbid disorders. Such data can assist in persuading governments about the importance of providing suitable care for those – children and adults- with ADHD.