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A study published in New England Journal of Medicine (NEJM) looks at maintenance or discontinuation of antidepressants in primary care.
This Roundup accompanied an SMC Briefing.
Dr Sameer Jauhar, Senior Clinical Lecturer in Affective Disorders and Psychosis, Institute of Psychiatry, Psychology and Neuroscience, King’s College, London (IoPPN) and Consultant Psychiatrist, South London and Maudsley NHS Foundation Trust, said:
“This is an important study, published in one of the most prestigious journals in clinical medicine.
“In it the authors address an important question- does staying on antidepressant medication prevent relapse of a depression episode?
“This is relevant as around a third of people with a major depressive episode will have at least one relapse, and antidepressant medication has been shown to be effective in preventing relapse, and is recommended by most National guideline groups for this purpose.
“Although a 2003 Lancet review and meta-analysis suggested antidepressants have an approximate two-fold benefit in preventing relapse, previous studies have not been generalisable to the people seen by GPs, ie the majority of people taking antidepressants for depression.
“This study randomised people to continue on medication or placebo, over a 52 week period. Participants were well enough to consider stopping medication. The antidepressants were those most prescribed in the UK (citalopram, sertraline and fluoxetine), as well as mirtazapine.
“Importantly these were people who had experienced two or more episodes of depression and had been taking antidepressants for more than two years.
“Relapse was the primary outcome, defined on the basis of interview, and symptoms needed to have lasted at least two weeks. Other outcomes included depression and anxiety symptoms, discontinuation/withdrawal symptoms and quality of life.
“These measures and the trial design are conventional, and the authors are to be congratulated on conducting a large multi-centre RCT that is relevant, particularly so for the UK population.
What did they find?
“Of the 478 people enrolled in the trial, the maintenance group had less risk of relapse, by a factor of two over a 52 week period (39% versus 52%), and most other measures eg depression and anxiety were better in those continuing to take antidepressants . Scores on the withdrawal scale were not particularly high for either group (though higher in those stopping medication), indicating that it is unlikely that withdrawal symptoms were mistakenly classified as a relapse of depression.
What do we make of this?
“This data fills the evidence gap for people with major depression who have had relapses, and those providing care for them, replicating the findings from meta-analysis, of a two-fold decrease in risk of relapse if people continue taking these treatments. This does reassure those in the field about the clinical value of offering for people to continue these medicines if they have had a relapsing illness.
“Finally, It is worth noting that relapse still occurred in 39% of those taking antidepressants- we now need to look at how we can decrease this figure, possibly with adjuvant treatments, psychological, social and biological.”
Prof Guy Goodwin, CMO, Compass pathways and Emeritus professor of Psychiatry, University of Oxford, said:
“This is an encouraging study that largely supports how GPs treat patients in the UK with recurrent depression. Thus continuing treatment with SSRIs has a sustained advantage over placebo, which supports the view that antidepressants can work for many people. What is just as important is that patients who wish to discontinue SSRIs can do so without major problems from withdrawal effects. This directly contradicts the many misleading statements from the anti-psychiatry movement that such discontinuation is usually very difficult, much as we know that sometimes it is.”
Prof Sir Simon Wessely, Regius Chair of Psychiatry, King’s College London, said:
“This is a very important study. It mirrors one of the first randomised controlled trials ever undertaken in depression, which found some benefit to staying on antidepressants for at least six months after you had recovered from a depressive illness. Now we know this applies for an even longer period. On the other hand, the other good news is that if you do want to come off antidepressants for whatever reason, this can also be done safely over a couple of months. So now patients taking long term antidepressants can make an even more informed choice than before. Yes you can come off medication, provided it’s done slowly, but there is an small but not insignificant risk of another illness. As ever there is no right answer, but this study provides more information to assist people in making up their minds.”
Dr Eric Ruhe, Associate Professor, Department of Psychiatry and Principal Investigator (PI) in Radboudumc (Nijmegen the Netherlands), said:
“The press release accurately reflects the science. This is a well performed and neatly described study. The authors should be complimented with their endeavour of successful running this trial, which was importantly blinded to reduce placebo and nocebo-effects! With the numbers randomized and the minimization procedure, the authors accounted for confounders adequately.
“There is limited evidence to date about long term antidepressant use, especially which patients can stop their antidepressants and when. This study shows three new things: in a large group of long term users of commonly used antidepressants (also having had more than 2 episodes in their lives) it is possible to stop the antidepressants without having a relapse in the following year. However, if you decide to discontinue the antidepressants the risk of having a relapse in this sample was 56% (i.e. 1 in 2) compared to 39% in patients who continued antidepressants. Thirdly the study showed that even with a discontinuation scheme using alternate day dosing (which is generally not recommended in my country (the Netherlands) because it is presumably increasing pharmacokinetic fluctuations) and commonly available dosing units of antidepressants it is possible to stop the antidepressants. The latter is important information for the debate on how to decrease antidepressants and whether smaller dosage units must be used in all patients or not.
“This study shows it is possible to come off antidepressants after long term use, but that the risk of relapse is substantial and is increased after discontinuation of antidepressants. So trying to get off can be successful, but remaining on antidepressants can be more safe, despite a remaining risk of relapse. Moreover, this study shows that it is feasible in a large group of patients to stop antidepressants with the conventional dosage units, so the use of special smaller dosage units can be restricted to a smaller group of patients who show they cannot discontinue due to more severe discontinuation symptoms. It would be nice to reassess the trial for commonly named risk factors for more severe discontinuation symptoms (if recorded). The question how long one should continue antidepressants cannot be answered with this trial, as this was not tested (and technically, nor was a contrast in duration of antidepressant use incorporated in the design). This is one of the questions of the current OPERA-project (www.OPERA-project.nl).
“Unfortunately paroxetine and venlafaxine were excluded, because of their known antidepressant discontinuation symptoms (and not being a first line antidepressant). Especially the occurrence of discontinuation symptoms with these two drugs might be more problematic and need specific investigation for which a new project has recently been funded (https://www.zonmw.nl/nl/onderzoek-resultaten/geneesmiddelen/programmas/project-detail/goed-gebruik-geneesmiddelen-2020-2023/comparing-antidepressant-ad-tapering-strategies-for-paroxetine-and-venlafaxine-the-taper-ad-trial/).
“Finally, the relevance of research into what drives relapse in so many patients, i.e. what is the underlying pathophysiology of recurrent major depressive disorder (MDD) is stressed by the high number of relapses, even in the group that continues their antidepressants. This more fundamental research might provide clues to more directly target relapse prevention in second/third generation relapse prevention programs (e.g using attention/memory bias modification or cognitive control training).
“In terms of clinical practice, in long term users of antidepressants discontinuation is possible when people wish to, but the risk of having a relapse is increased so alternatives like (preventive) cognitive therapies of mindfulness based cognitive therapy should be offered to reduce relapse risk (as the senior author mentions as well). This trial also informs patients and doctors about the risk of relapse that is increased after stopping the antidepressants, so this information can be incorporated in the shared decision making that patients and their physicians have to go through to decide on whether to discontinue the antidepressant. The elaboration of risk factors for unsuccessful discontinuation or severe discontinuation symptoms would further guide patients and caregivers. The study did not provide evidence based psychotherapies against relapse in the whole sample: (preventive) cognitive therapies of mindfulness based cognitive therapy. We know that the combination of antidepressants with these psychotherapies result in the lowest risk of relapse, but understandably that was not the focus of this study and maybe that would not have changed the difference between the two arms studied here.”
Prof Allan Young, Chair of Mood Disorders and Director of the Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London (IoPPN) & South London and Maudsley NHS Foundation Trust, said:
“This is an important study which adds to our knowledge base about the benefits of antidepressants. It is important to note that participants had experienced two or more episodes of depression and had been treated with antidepressants for at least two years and felt well enough to stop them. The group who stopped antidepressants had a higher relapse rate (into depression) than those who were maintained on medication. Most symptom ratings were worse, on average, in the group who stopped antidepressants. These data suggest that some patients will benefit from continuing antidepressants long term and both clinicians and service users should be aware of this when considering whether to stop antidepressants.”
‘Maintenance or Discontinuation of Antidepressants in Primary Care’ by Gemma Lewis et al. was published in New England Journal of Medicine at 22:00 UK time on Wednesday 29th September.
DOI: 10.1056/NEJMoa2106356
Declared interests
Dr Sameer Jauhar: “Dr Juahar has received honoraria from Sunovian for educational talks given on psychosis, and his employer KCL has received honoraria for educational talks he has given for Lundbeck.”
Prof Guy Goodwin: “Compass pathways is developing psilocybin as an alternative to SSRIs in depression: I have previous advised other companies on the development of a variety of antidepressants.”
Prof Sir Simon Wessely: “I have no COIs to declare.”
Dr Eric Ruhe: My relevant conflicts of interest are that I am involved in research investigating the recurrence of MDD sponsored by the Dutch Brain foundation (SMARD) and ZonMW (OPERA and TAPER-AD).
Prof Allan Young: “Professor Young’s independent research is funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.
ORCiD: orcid.org/0000-0003-2291-6952
Employed by King’s College London; Honorary Consultant SLaM (NHS UK)
Deputy Editor, BJPsych Open
Paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage
Consultant to Johnson & Johnson
Consultant to Livanova
Received honoraria for attending advisory boards and presenting talks at meetings organised by LivaNova. Principal Investigator in the Restore-Life VNS registry study funded by LivaNova.
Principal Investigator on ESKETINTRD3004: “An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression.”
Principal Investigator on “The Effects of Psilocybin on Cognitive Function in Healthy Participants”
Principal Investigator on “The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD)”
UK Chief Investigator for Novartis MDD study MIJ821A12201
Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK). Janssen (UK)
No shareholdings in pharmaceutical companies.”