Researchers can predict the risk of relapsing into depression after stopping antidepressant medication


In a study supported by the Swiss National Science Foundation, researchers have shown that it is possible to predict the risk of relapsing into depression after stopping antidepressant medication. People who relapse take longer to decide how much effort to invest for a reward.

Depressive disorder is a major public health problem with an unpredictable course.

It often recurs, with episodes of depression interspersed with periods of remission.

Many studies have shown that in order to reduce the risk of relapse, treatment should continue even after symptoms have disappeared.

Unfortunately, this does not seem to have any effect on the risk of subsequent relapse after the drugs have been discontinued.

“It is estimated that 30% of patients relapse within six months of withdrawal. That’s a very high rate.

And doctors currently have no reliable tools for estimating this risk”, says Isabel Berwian, psychologist.

In a longitudinal study funded by the Swiss National Science Foundation (SNSF) and published in the journal JAMA Psychiatry, Isabel Berwian, now postdoc at the Translational Neuromodeling Unit at the University of Zurich and ETH Zurich, has now shown that observing the way people in remission make choices helps to predict the risk of depression relapse.

Looking at motivation

To conduct this study, Quentin Huys – at the time researcher in computational psychiatry as well as a psychiatrist and psychotherapist – and his team recruited patients who had experienced recurrent or severe depression and were in remission, i.e. with no or almost no symptoms but still undergoing treatment.

Independent of the study, these patients had already decided to stop taking antidepressants. Each participant was given a task to measure his or her willingness to exert effort based on different levels of reward.

This type of task was chosen because the scientific literature shows that a characteristic feature of depression is low willingness to exert the effort required to receive a reward.

The researchers wished to go further and investigate whether this might be an indicator of potential relapse.

Data from 123 patients and 66 healthy controls was collected between July 2015 and January 2019 in both Zurich and Berlin. All of the people who had experienced depression completed the task twice: once before the medication was stopped and a second time either before or after discontinuation.

All subjects were also followed for 6 months after the study to monitor them for relapse. Analysis of the results showed that the decision time was longer in patients (mean 1.77 seconds) than in controls (mean 1.61 seconds) and, among patients, even longer in those who relapsed after tapering (mean 1.95 seconds).

The researchers could show that decision time correctly indicates a future relapse for 2 out of 3 people.

Stay in bed or get up?

A computational model was used to understand the mechanisms involved in the task.

The model showed that the nature of the choice (small effort for a small reward or larger effort for a larger reward) made it possible to differentiate between formerly depressed people and healthy people: the former more often chose the option that required the least effort.

The researchers believe that in these people, depression may in fact persist, but asymptomatically.

The model also showed that people in remission are more sensitive to effort. Isabel Berwian explains the finding this way:

“Imagine that one evening you are already in bed. Some friends invite you to go into town to have ice cream. A healthy person would probably get up and go out. A person who is suffering from a depressive episode would be more likely to stay in bed. Even if it’s something the person enjoys doing, it just seems like too much trouble.”

The model showed that the nature of the choice (small effort for a small reward or larger effort for a larger reward) made it possible to differentiate between formerly depressed people and healthy people: the former more often chose the option that required the least effort.

Although the study found that the time it takes people to decide is predictive of the risk of depressive relapse, it’s too early to apply the finding in practice.

“This indicator is promising, but at this stage we cannot claim to have found ‘the’ solution.

The results need to be validated on a larger sample, because ours was relatively small”, says Isabel Berwian.

That poses a challenge for researchers as it’s difficult to find patients for these kinds of studies. Quentin Huys – now an associate professor at University College London – and his team are also working on other potential indicators of depression relapse.

For example, they are examining whether brain activity differs between people who have had depression and healthy people while they are watching a sad movie.

The study was carried out at the Translational Neuromodeling Unit at the University of Zurich and ETH Zurich and at the University Psychiatric Clinic, Zurich, in collaboration with the Charité University Hospital, Berlin. The SNSF project funding scheme enables scientists to independently conduct research projects with topics and goals of their own choice.

Inflate a balloon, win points

To measure decision time, the study participants were asked to complete a task.

The task consisted of tapping a key on a computer keyboard to obtain a certain number of virtual points. The participants had five seconds to choose between two alternatives: exerting little effort by tapping the key 20 times to gain one point, or exerting more effort by tapping the key 100 times for three to seven points, depending on the trial.

Once participants had made their decision, they had 40 seconds to tap the key the number of times required to inflate a virtual balloon.

The balloon burst when the number of taps was reached. Each participant performed the task 60 times.

Antidepressant use continues to rise. Between 2003 and 2013, antidepressant prescription numbers have doubled in western countries [1], and have been rising with 3% per year in the Netherlands [2].

Despite being effective for some patients in reducing symptoms of depression and anxiety and reducing the risk of depressive relapse [3] antidepressants may also have side effects such as sleep disturbance, weight gain, sexual dysfunction and gastrointestinal bleeding [45]. In addition, they sometimes even go along with more serious adverse events, such as falls, attempted suicide or self harm, stroke and epilepsy [6].

Consequently, current primary care guidelines advise to consider discontinuation of antidepressants 6 months after remission of a depression or 6–12 months after remission of an anxiety disorder. Patients with recurrent depression are advised to discontinue medication after 1–2 years.

It is generally recommended to taper slowly, with guidelines suggesting a 50% dose reduction every 2 weeks while monitoring side effects and deploying relapse prevention strategies [7].

The pace of tapering seems important as it appears to influence the risk of relapse in patients with depressive disorder [8].

However, the steady rise of antidepressant use seems to be explained mainly by an increase in long-term users [9]. In the UK and US, 50–65% of patients treated with antidepressants continue to use them for more than 2 years [1012].

After starting antidepressant medication almost 30% of the patients become chronic users, defined as the consecutive use of any antidepressant for at least 12 months [13]. Despite the general guidelines on tapering antidepressants in primary care, actually discussing and initiating discontinuation appears to be challenging [1415].

Stopping antidepressant medication might be hampered by the presence of physical or psychological withdrawal symptoms, including headache, dizziness, electric-shock sensations, sleep disturbance, anxiety and mood swings.

These symptoms may easily be misidentified as signs of impending relapse [16]. In addition, earlier unsuccessful attempts to discontinue may provoke further fears for withdrawal symptoms and relapse.

Previous research in a sample of 146 inappropriate long-term antidepressant users from 45 general practices in the Netherlands showed that a multidisciplinary, patient tailored advice to discontinue antidepressant medication was rejected in 48% of the cases. The proportion of successful antidepressant discontinuation following this multidisciplinary advice was only 6% [17].

To protect against depressive relapse after the acute phase of depression several psychotherapeutic treatment strategies have evolved [18]. This way alternatives for patients not wanting to maintain antidepressants seem available.

Mindfulness Based Cognitive Therapy (MBCT) is one of these approaches of relapse prevention, it is an innovative psychological approach for relapse/recurrence prevention in recurrent depression developed by Segal, Williams & Teasdale [19].

It is an 8-week group-based treatment that integrates elements from mindfulness-based stress reduction (MBSR) [20] and cognitive–behavioural therapy (CBT) [21]. A recent meta-analysis showed that MBCT appears efficacious as a treatment for relapse prevention for those with recurrent depression. MBCT reduces the risk of depressive relapse/recurrence compared with the current mainstay approach, maintenance antidepressants [22].

As MBCT appears to be a viable alternative to antidepressant medication it is possible that mindfulness could provide patients support in the de-identification of thoughts and allowing of uncomfortable physical and mental symptoms, and also help them to deal with possible withdrawal effects.

There is some evidence that MBCT might be useful in supporting tapering of antidepressant medication. Two randomized controlled trials in the UK, offering recurrently depressed patients MBCT with additional tapering support, show successful tapering of Antidepressant Medication (ADM) in 75% [23] and 71% of participants [24].

However, results from a study conducted in the Netherlands were less promising. Only 53% of the patients allocated to the group who received MBCT and tapering support succeeded in tapering their antidepressants [25].

Remarkably, there was a relatively large number of “cross-overs” in this trial, as 12% of patients who were asked to continue their medication after MBCT actually discontinued their antidepressant medication successfully.

This latter trial showed that tapering was not necessarily easy even after MBCT, but that the perspective of the patient (e.g. preferences, motives, previous experiences with withdrawal) may have played a significant role.

The authors suggested that MBCT for tapering ADM might need to be offered in homogeneous groups of patients who are eager to withdraw from their medication and that it should be specifically tailored to address effects of discontinuation within the mindfulness framework.

Therefore, the aim of this study is to investigate the effectiveness of the combination of supported protocolized discontinuation (SPD) and mindfulness-based cognitive therapy (MBCT) in comparison with SPD alone in successfully discontinuing long-term use of antidepressants in primary care. SPD is carried out by the GP and mental health assistant (MHA).

The function of the MHA (POH-GGZ in Dutch this is an abbreviation for Practice Support Professional for Mental Health Care) was installed in the Netherlands in 2008 to support GPs in diagnosing, treating and referring patients with mental health problems. In 2016 in the Netherlands 81% of all GP’s have arranged a MHA in their practice.

Our main hypothesis is that long-term users of antidepressants in primary care receiving SPD + MBCT will more often successfully discontinue their medication within a period of 6 months than patients receiving SPD alone.

Our secondary hypotheses are that, in comparison with patients receiving SPD alone, patients who receive SPD + MBCT will have a lower rate of relapse/recurrence of a depressive or anxiety disorder, a lower rate of restarting medication, suffer less from withdrawal symptoms, report less depression, anxiety, and ruminative brooding, and more mindfulness skills, self-compassion and psychological wellbeing over the 12 months follow-up period.


Both patients and professionals seem to call for appropriate tools and information to better support the process of discontinuing antidepressant medication. In the current study we will address this gap by devising a protocol for shared decision making and the accompanying materials (i.e. information brochure, decision aid, and tapering protocol). This may serve a structured and comprehensive way to approach discontinuation.

One of the strengths of this study is its inclusive sampling strategy, allowing all patients with long-term ADM use to consider tapering and participation. Rather than a priori precluding patients with a certain level of symptomatology, for example with depressive or anxiety disorder, we used a shared decision making approach (including topics related to psychological functioning and effectiveness of antidepressant medication) to define the final RCT population.

The decision to taper an antidepressant seems multifaceted, and probably does not solely depend on the level of symptoms. Another advantage of this strategy is that rather than tapering, patients and their GPs might consider switching to a different medication if that seems more appropriate.

In addition this will be the first study that will directly compare MBCT to facilitate discontinuation as an add-on to support in general practice, with support alone. This study will provide more information about the entire process of discontinuation of antidepressants in a population of long-term users in general practices, including the views and preferences of GPs and patients with regard to discontinuation, the value of using psycho-education material about tapering, and the possible value of MBCT to support the process.



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