ANTLER
Research type
Research Study
Full title
A Phase IV double blind multi-site, individually randomised parallel group controlled trial investigating the use of citalopram, sertraline, fluoxetine and mirtazapine in preventing relapse in patients in primary care who are taking long term maintenance antidepressants but now feel well enough to consider stopping medication.
IRAS ID
192573
Contact name
Glyn Lewis
Contact email
Sponsor organisation
PRIMENT Clinical Trials Unit
Eudract number
2015-004210-26
ISRCTN Number
ISRCTN15969819
Research summary
Research Summary
The dramatic rise in antidepressant prescription in the UK is a major cause of concern. The evidence suggests that up to 45%, of the individuals on long term prescription are well and taking it to prevent relapse. However, there is currently poor evidence for the effectiveness of long term maintenance antidepressants if someone has been taking them for more than 9 months.
The research question is:
“What is the clinical and cost-effectiveness in UK primary care of continuing on long term maintenance antidepressants compared to a placebo in preventing relapse of depression in those who have taken antidepressants for more than 9 months and who are now well enough to consider stopping maintenance treatment?”
The study will provide a valid and generalizable estimate of the clinical and cost-effectiveness of long term maintenance treatment with antidepressants in UK primary care. The relevant population is those people who are taking long term maintenance antidepressants and now feel well enough to consider stopping medication.
We will carry out an individually randomised parallel group controlled trial that will compare (1) continuing with the following antidepressant medication (citalopram 20mg, sertraline 100mg, fluoxetine 20mg or mirtazapine 30mg) with (2) replacement of the medication with a placebo after a tapering period. We will follow up participants for 12 months. Our primary outcome will be time to depressive relapse. We will also examine secondary outcomes and perform a cost-effectiveness analysis based upon results of the trial.Summary of Results
10.3310/hta25690.
Has the registry been updated to include summary results?: Yes
If yes - please enter the URL to summary results: doi: 10.3310/hta25690.
If no - why not?:
Did you follow your dissemination plan submitted in the IRAS application form (Q A51)?: Yes
If yes, describe or provide URLs to disseminated materials: N Engl J Med 2021; 385:1257-1267
DOI: 10.1056/NEJMoa2106356
If pending, date when dissemination is expected:
If no, explain why you didn't follow it:
Have participants been informed of the results of the study?: Yes
If yes, describe and/or provide URLs to materials shared and how they were shared: Participants received a letter informing them of the results being published in the peer-reviewed journal. The letter also included the following press release:
Long-term antidepressant use is effective, but many people can come off them safely - new research September 29, 2021 10.08pm BST The number of prescriptions written for antidepressants in wealthy countries has doubled in the past 20 years. This increase is mostly due to people staying on antidepressants for a long time. There are now many people who have been on these drugs for several years and feel fairly well but are unsure whether they still benefit from taking them.
Many people who have had depression continue to take antidepressants for years for fear that if they stop, they might have a relapse. Most studies of antidepressants and relapse have been done in people taking the medication for less than eight months. We wanted to know whether antidepressant treatment was still effective when people have been taking the pills for several years.
Our study, published in the New England Journal of Medicine, found that remaining on antidepressants long-term reduced the risk of a relapse, but many people were able to come off them safely.
Our study recruited 478 people who had been receiving long-term antidepressant treatment, 70% of whom had been taking antidepressants for more than three years. All the patients had a history of at least two episodes of depression, had been taking their antidepressants for a minimum of nine months, and felt well enough to consider stopping the pills.
All patients, from 150 GP surgeries in England, were interviewed by a researcher, and we excluded those who had symptoms of depression that met the criteria for a clinical diagnosis. We recruited people who were taking the most commonly prescribed antidepressants - sertraline, citalopram and fluoxetine. These are all selective serotonin reuptake inhibitors (SSRIs) that increase serotonin levels in the brain. We also included mirtazapine, a newer antidepressant that has been increasing in use in the UK.
We randomly allocated people to one of two groups: half of the study participants stopped taking their antidepressant medication and half continued. The group who stopped their medication were given reduced doses of their antidepressants for up to two months until they were on placebo only. The other group continued with the same dose of the antidepressant they were already receiving.
Neither researchers nor patients knew which group people were allocated to. This type of "double-blind study" helps to reduce bias. After the study started, we collected data from participants at intervals of six, 12, 26, 39 and 52 weeks after they started the trial.Over the following year, 56% of people who stopped taking their antidepressants experienced a relapse, compared with 39% of people who kept taking them. So, remaining on antidepressants is appropriate for many people receiving long-term treatment from their GP. We didn't find any evidence that the antidepressants in our study had serious side-effects.Remaining on antidepressants did not guarantee wellbeing in our study - 39% of people who continued with their regular dose had a relapse within a year. The decision to remain on long-term treatment is offset by any potential side-effects and many people prefer not to take medication for many years.
No relapse in 44% of participants
In our study, many people were able to come off their antidepressants safely without a relapse. In the group who stopped their antidepressants, 44% did not relapse after a full year. Even among those who did relapse after stopping, only half chose to return to an antidepressant prescribed by their GP.
Many patients might decide to stop their antidepressants, in consultation with their doctor, knowing there might be a risk of relapse. If people who want to discontinue their antidepressants are regularly monitored by their GP, it may be possible to prevent relapses with different treatments, such as talk therapy. For example, studies have shown that mindfulness based cognitive therapy is effective at preventing relapse. Alternatives to antidepressants include talk therapy. Blurryme/Shutterstock There has been uncertainty about the extent to which people experience withdrawal symptoms after they stop taking antidepressants. In our study, people who stopped their antidepressants after reducing the dose over two months were more likely to experience withdrawal symptoms, such as irritability and difficulty in concentrating, than those who continued treatment. Yet, by the end of the study, a year later, 59% of the discontinuation group were not taking antidepressants.
Our study only provides information about the average probability of relapse. We do not yet know why some people are able to come off their antidepressants and some cannot. Further research may help us to predict who can stop antidepressants safely.
Our study provides an estimate of the risk of relapse if someone carries on with long-term antidepressants or decides to stop them. These findings will help doctors and patients to make an informed decision together on whether or not to stop long-term antidepressant treatment.REC name
East of England - Cambridge South Research Ethics Committee
REC reference
16/EE/0032
Date of REC Opinion
29 Mar 2016
REC opinion
Further Information Favourable Opinion