• Research into depression

    The patient in the spotlight

    Decades of depression research have yet to result in a definitive treatment. But RUG scientists are changing course. ‘What we’re doing now is really cool.’
    in short

    People who are depressed struggle for weeks, months or even years with feelings of gloom, feeling worthless or thinking about death. They live in a ‘never-ending funeral procession’.

    Forty years of research has shown that there is a strong genetic component to depression. It also involves neurotransmitters in the brain, and the brain processes emotional information differently. A definitive treatment, however, is still a long way off.

    Researchers at the RUG have decided to try a different approach. For years, they focused on large groups of patients, but now, they will be studying individuals. ‘We want to know what makes you tick.’

    Claudi Bockting and Marie-José van Tol are working on preventative therapy. In some patients, eight one-hour sessions is enough to prevent a relapse. With the help of fMRI scans, Van Tol wants to find out who these patients are.

    Marieke Wichers and Harriëtte Riese are focusing on the individual patients. They measure patients’ moods and activities several times a day. This will allow them to see what influences someone’s moods and whether a possible change is coming.

    Robert Schoevers focuses on experimental therapy for patients who do not benefit from conventional treatment.

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    Reading time: 15 minutes (2,676 words)

    We are not even supposed to call it a disease. Diseases have causes, and so far, no one has succeeded in exactly pinpointing how depression works. So we call it a disorder, in spite of the fact that 19 per cent of people suffer from a depression at some point in their lives, or – as one patient describes it – have to ‘live in a never-ending funeral procession’.

    You already suffer from a depression when you have been gloomy for two weeks and are not taking any pleasure in what you do. And then there are the additional symptoms, such as feeling worthless, having trouble focusing, insomnia, thinking about death a lot, and a whole host of other things so severe that they dramatically interfere with your everyday life.

    Suicidal thoughts

    Two weeks might seem doable, but unfortunately, most depressed people do not suffer from the disorder for a couple of weeks, but rather for months or years. Weeks and months where everything around you looks bleak, useless – worthless. You struggle with suicidal thoughts, are constantly bone tired and there is nothing, absolutely nothing, that you enjoy anymore. And then there are the calls from those around you, saying, ‘come on’, ‘don’t be such a wuss’. They call you lazy or unmotivated because ‘we all feel a little down sometimes.’

    Even worse news: people who have suffered from a depression once run a high risk of relapsing. If you have been depressed three times, that chance is 90 per cent. And in spite of the millions spent on research each year, no one knows exactly how it works just yet.

    ‘After 40 years of research, we still don’t know very much’, says Claudi Bockting, professor of clinical psychology. ‘Even now, only half the people respond well to therapy, and that is not enough. We have to make a switch in the way we think about this: what are our methods and basic assumptions, and what is depression, actually?’

    Biological component

    There are things we do know, however. There are large studies such as the NESDA study http://www.nesda.nl/ – the Netherlands Study of Depression and Anxiety, which the RUG participates in – that has been following 3,000 people suffering from anxiety and depression for the past nine years, and TRAILS https://www.trails.nl/, which has been studying adolescents for ten years, as well as dozens of smaller studies, all of which have shown that there is a strong biological component. It is partly the ‘fault’ of someone’s genes, we know now: you are more at risk if depression runs in your family. Another insight we have gained is that there is often something wrong with the neurotransmitters in your brain, and depressed patients often have a higher level of the stress hormone cortisol.

    We also know that a depressed person’s brain handles emotional information differently. That inability to see that the sun is shining? You can see it happening in the brain. The amygdala, the part of the brain that causes the instinctual fight-or-flight signal, appears to be more sensitive than it is in healthy people, which causes you to interpret small, unpleasant situations – such as someone not saying hello on the street – negatively. On top of that, the frontal lobe – which houses an area that checks and, if necessary, puts that first instinctive reaction into perspective – just does not work as well as it should.


    Unfortunately, no one knows whether that hyperactive amygdala is the cause of the depression, or its effect. Or maybe they are just indelibly linked. No one knows which adolescents with ‘risky’ genes will actually develop a depression and which ones will not. A toxic mix of countless factors causes depression. ‘There is only one thing that all the studies have in common’, says Bockting. ‘Misery. And that is very unfortunate, because you can’t arm yourself against misery. It overwhelms you.’

    ‘You can’t arm yourself against misery’

    And when it happens to you, when you were already vulnerable and in the clutches of depression, it is really hard to get rid of it. Because the treatment is like using a sledgehammer to crack nuts. Antidepressants work – for some patients. Cognitive therapy works – for some patients. But which therapy? And which patient? And what are the odds the patient will relapse? Can you safely release them back in the world?

    ‘It’s my dream’, says Marie-José van Tol, who does fMRI research into how emotional information is processed in the brain, ‘that a patient goes to their doctor with symptoms and they can simply run a few tests. That they can find out the exact problem, and which treatment matches it best.’

    Is this naive? You might think so given the current situation, but the Groningen researchers are remarkably positive when they talk about the future. Because – and pretty much all of them feel this way – not only should they change tack, they already have. For years, they focused on large groups of patients, but now, they will be studying individuals. ‘We want to know what makes you tick.’

    Preventing relapse

    So far, the results from exploratory studies are promising. Bockting herself, for example, developed a preventative therapy that should help patients in preventing a relapse. Consisting of eight one-hour sessions, the therapy course is surprisingly short, but the treatment can help patients for up to ten years. ‘During the therapy, we make people aware of their negative bias’, says Bockting. ‘And then we teach them to adjust it.’

    Depression diagnosis

    Together with experience expert Selma Parmentier, Robert Schoevers wrote the book Diagnose depressie. Psychiater en patiënt over de dagelijkse werkelijkheid, de behandeling en de toekomst. There are quite a few books about depression, but this one is a truly valuable addition.

    Schoevers writes about every aspect of the subject, from causes to possible hospitalisation, in a clear, nuanced style. However, the diary fragments, poignantly written by Palmentier, are what makes this book truly special. They describe her struggle with depression in a poignant, personal way.

    It’s a matter of retraining, consciously letting the realistic convictions take the place of the negative thoughts. The training also makes them more aware of their positive feelings, so these can serve as a resource when things are not going well. ‘Finally, they make their own prevention plan by figuring out what does and doesn’t work for them’, says Bockting.

    This approach clearly works. And Bockting is working hard to bring the therapy closer to the patients through online self-help training http://www.doorbreek-depressie.nl/ and apps. The time is ripe, she thinks. The technical possibilities and the knowledge are converging.

    Emotional images

    Yet Bockting’s prevention therapy does not work for everyone, meaning that hundreds of patients are – once again – left disappointed at the end of their treatment. Marie-José van Tol is researching how to prevent this http://depressiestudie.com/. ‘We think the patients whose amygdala and frontal lobe don’t work together properly benefit from this’, she says.

    Van Tol presents her test subjects – healthy but with a history of depression – with emotional images while they lie in an fMRI machine. ‘Cheerful pictures of families in the sun, birthday parties and fields of flowers, or, conversely, grim photos: crying children, an intubated baby, someone with a gun to their head.’

    Then, she measures their brain activity, once when the patients are watching the images ‘normally’, and once when they have been instructed to ‘manipulate’ the feeling they get ‘by thinking to themselves, ‘it’s only a movie’, van Tol explains. ‘Or: ‘I’m sure everything turned out fine’.’ Next, she offers some of the ex-patients cognitive therapy. After that, they have to go into the machine one more time.


    The study is expected to show that in some of the depressed patients, the frontal lobe – which should start working to put these images into perspective – is not properly doing its job of subduing them, says Van Tol. She thinks – and hopes – that this is the same group of patients who will benefit from preventative therapy.

    And because it is impossible to put every patient in an fMRI machine in order to decide on the right course of therapy, she is also doing some additional research. She watches to see how the eye’s pupil responds to emotional information. ‘When you see something difficult or horrible, your pupil enlarges’, she says. ‘But when you subdue the information, it gets smaller.’

    ‘The research we’re doing right now is really cool’

    Once you know how to transform information like that into a test about how the frontal lobe is functioning, that is a procedure that a general practitioner would be able to do.

    Diary technique

    Another exciting development is the one Harriëtte Riese is working on. For years, she worked on the NESDA study, where patients sometimes had to fill in questionnaires about their moods. ‘They would ask questions like, how are you feeling today?’, she explains. ‘But they didn’t take into account the fluctuations during the day. And those definitely exist.’ This is why there currently exists a study where 400 NESDA participants have to write down their moods five times a day, for two weeks.

    But, thought Riese, you can also use the NESDA diary technique on a single patient. ‘That gives us a wealth of information that connects moods to different events and activities during a day.’ And this is possible nowadays, once again thanks to the technique of cell phones, powerful computers, and complex software.

    By putting the data into a diagram, you can not only see exactly how a patient feels over the course of the day, but also which factors this is connected to. ‘You can see that if you take a walk right now that, even if you don’t feel like it, you’ll probably feel better in three hours’, says Riese. ‘The practitioner gains insight, but is also able to give feedback to the patient. And that is really cool.’

    One size does not fit all

    She has only conducted one pilot study with her method, but she feels the results are promising. ‘This makes me so happy’, she says. ‘This provides the opportunity for personalised diagnostics and intervention, which we sorely need. When it comes to depression, one size does not fit all.’

    Researcher seeks test subjects

    Would you like to aid research into depression? For her research into information processing in depressed people, Marie-José van Tol and her colleague Rozemarijn van Kleef need test subjects – both healthy and with a history of depression – who want to take a test in the fRMI machine. Compensation is 25 euros for the healthy group, and a total of 75 euros (for three sessions) for the ex-patients. More information at depressiestudie.com

    Marieke Wichers is also looking for people to help her. She is looking for people who want to reduce their antidepressants and monitor their emotions over the course of four months. Maximum compensation for full participation is 250 euros. Anyone interested can contact Evelien Snippe at 050 3612054, or send an e-mail to [email protected].

    Groningen is bursting with researchers, she says. Researchers are looking to collaborate with practitioners and colleagues from other fields. One building over, for example, we can find psychiatrist Richard Schoevers. He focuses on experimental treatment for patients who absolutely do not respond to therapy, such as TMS (transcranial magnetic stimulation) or therapy in which he tries to reset someone’s biological clock with the use of sleep deprivation and light therapy.

    When severely depressed patients do not benefit from earlier treatment, they sometimes also get electroshock therapy. There is also an on-going trial involving ketamine, originally a narcotic and currently better known as the party drug K, which seems to help some people. In addition, Schoevers is studying the benefits of early recognition and prevention of the first symptoms. He believes that paying more attention to bullying at school, or pressure at work, and tackling that in a timely fashion can prevent a lot of misery.

    Two million euros

    Across the hall is Marieke Wichers’ office. She has been studying depression for 15 years, but was becoming dissatisfied with the subject. ‘I would find things, like how in depressed people a certain substance has an elevation of so many percentage points. I was beginning to wonder what the point of all that was. Depression is so very complex, there are so many factors that influence each other. How on earth were we going to uncover all of this?’

    But then, a revolutionary idea struck her, for which she recently was awarded a research grant of no less than two million euros. Wichers approaches depression as a complex dynamic system. Ecosystems, ant colonies, the climate – they are all systems with numerous interconnected factors that can undergo transitions at any time: from a warm climate to an ice age, for example.

    In 2009, Marten Scheffer from Wageningen wrote an article in Nature about how those sudden transitions actually have warning signs to announce themselves, even before any actual change takes place. ‘During a brainstorming session with colleagues, we thought: could that apply to depression as well? We can see sudden recovery and sudden relapse, so what if there are small signals there for us to detect as well?’


    Wichers went looking for those signals described by Scheffer, except she applied them to patients’ emotions. Autocorrelation, for example, which is a fancy word that means ‘figuring out’ a feeling. ‘This is where that negative feeling – about a meeting, for example – influences anything that comes after.’ It means that your system is having trouble being reset.

    ‘We no longer compare the patients to someone else, but to themselves’

    Another signal is variability: when someone is really happy one moment but intensely sad the next. And then there is the concept of connectivity: one emotion triggers the next. ‘Like dominoes’, says Wichers. ‘Discomfort triggers anxiety, the anxiety triggers gloom, and so on and so forth.’

    Wichers utilised repeated, daily measurements to test the idea. It turned out that in a test group where she had tried to find these signals over the course of five days, the people who had experienced a switch a year later indeed exhibited warning signs. ‘So that was an indication, although we’d only looked at the difference between people instead of the development within one person.’

    Dynamic system

    That is when Wichers ran into a fellow researcher – who himself had a history of depressive episodes – who wanted to scale back his antidepressant use and wanted to know what effect that would have on the possibility of a relapse. He wrote down his emotions ten times a day and when Wichers studied those measurements, she found exactly what she had been hoping for: warning signals that the patient had not noticed himself, that preceded a serious relapse.

    Over the next few years, Wichers will be working on this new approach. She will do a series of approximately 100 extensive case studies – with a lot of measurements per test subject – in order to replicate the first study and gain insight into whether depression can really be understood as a dynamic system. It also means that there is a practical application: perhaps it can be used to predict when something is going to change, which will enable you to intervene.


    So what do all these studies have in common? ‘We no longer compare patients to other people, but to themselves’, says Wichers.

    ‘We’re going from a few measurements in several patients to a lot of measurements in just one’, says Riese. ‘It used to be that these case studies were considered bad research, not science. But now, hopefully we can use them to really make a difference.’

    And: ‘We have to take what we learned from the groups and reduce it to a single patient’, says Schoevers.

    Bockting is hopeful as well, although she will always be strict on herself. ‘I’ll always be a clinician, and I judge myself on how well I’m able to implement better treatment’, she says. ‘But now is the time. The zooming in that we’re doing is a promise.’

    More about depression

    This article is part of trio of stories about depression. Be sure to read the other two pieces from this series:

    Studying with depression – former RUG student Evi* reveals how a serious depression pushed her to the brink of death.

    First aid for depression – where can you go as a RUG student if you are suffering from depression?