The cycle of relapse and remission in major depressive disorder can lead to people being prescribed antidepressant medication for many years as a preventative strategy (Kato et al., 2021; Ross et al., 2019). Many people would prefer not to be on lifelong medication (Gibson et al., 2016; Read et al., 2014), but fear relapsing if they discontinue (Bowers et al., 2020; Bosman et al., 2016). Long-term antidepressant medication can have unwanted side effects including sexual dysfunction and weight gain (Gafoor et al., 2018). Another important factor to consider is that abrupt discontinuation of antidepressants can lead to withdrawal syndrome which can be difficult to distinguish from relapse (Davies and Read, 2019). Slowly tapering the dose can reduce the risk of this syndrome developing (Davies and Read, 2019).
Once an individual has been in remission for 6 months, the National Institute for Clinical Excellence (NICE) lays out three pathways for those at high risk of relapse or with a history of recurrent depression:
- Maintenance treatment;
- Augmentation with another medication; or
- Psychological intervention to prevent relapse.
Previous meta-analyses have shown that tapering antidepressants and undergoing a psychological intervention (referred to as the sequential model) is as effective at preventing relapse as maintenance antidepressant medication (Guidi et al., 2016; Guidi and Fava, 2021).
A recent review by Josefien Breedvelt and colleagues published in JAMA Psychiatry had three main study objectives and outcomes:
- Time to relapse and relapse incidence at 15 months;
- Risk factors for relapse, including age, age at onset of depression, relationship status, educational attainment, sex, number of previous depressive episodes, number of therapy sessions attended, months in remission, presence of a comorbid psychiatric disorder, and residual depressive symptoms at study baseline; and
- Associations between baseline patient characteristics and time to relapse and relapse incidence at 15 months.
The authors conducted a meta-analysis using individual participant data (IPDMA) with evidence compiled according to the standard PRISMA guidelines. They carried out a systematic search of the literature, using PubMed, Embase, PsycInfo, and Cochrane Library to identify four relevant papers: (Bockting et al., 2015; Kuyken et al., 2015; Kuyken et al., 2008; and Segal et al., 2010).
The authors included studies of adults 18-65 years old, fully or partially remitted from depression for 6 months at baseline. They included randomised controlled trials (RCT) which compared two relapse prevention strategies: maintenance antidepressants vs. tapering antidepressant dosage for 1-6 months undergoing 8 weeks of either preventative cognitive therapy or mindfulness-based cognitive behavioural therapy.
No significant differences were seen in relapse incidence or time to relapse in the tapering medication and psychological intervention group compared with the maintenance antidepressants group during 15 months follow-up.
Three risk factors associated with a higher risk relapse were found across both groups:
- Overall, younger age at onset (p 0.001)
- Shorter duration of remission (0.003)
- Higher levels of residual depressive symptoms at baseline (<0.001)
There was no association between any individual baseline characteristic and increased risk of relapse in either group (maintenance antidepressants versus tapering medication and psychological intervention).
The authors’ main “take-home message” was that clinicians should feel confident in recommending antidepressant tapering and psychological intervention, even to patients whose high levels of residual depressive symptoms or a high number of prior episodes puts them at an increased risk of relapse.
Regardless of treatment condition, the authors indicated that the greater residual symptoms that patients had, and the more prior relapses they had, the greater chance they had of relapse.
Strengths and limitations
By using data collected on each individual participant in the study, which has been harmonised to create one large pool of participant data, the results provided additional baseline information than the aggregate meta-analyses using summary data previously published in this area.
Moreover, 15 months is a naturalistic duration for follow-up data on relapse incidence. All randomised controlled trials used an independent researcher to assess depressive symptoms, who were blinded to the treatment condition. An independent statistician supervised the evidence synthesis.
An ever-present limitation in psychological treatment trials is the lack of blinding to treatment conditions, which introduces a high risk of bias. Participants would have been aware of receiving psychological therapy or not. Those in the medication maintenance condition who did not, might have been disappointed to have not been given the opportunity to come off their medication with support, which could have increased the likelihood of relapse in this group. Related to this, there was no mention of participant preference into which group they were randomised. We know that patient preference affects drop-out rates and may impact treatment efficacy through altered participant engagement with treatment (Dunlop et al., 2017; Kappelmann et al., 2020).
The type and dosage of antidepressants were not reported in the trials. This is very relevant information, as some treatments may be more protective against relapse, and others more difficult to taper and discontinue. Thus, there may have been over-reporting of relapses in the antidepressant discontinuation group, as withdrawal syndrome is difficult to distinguish from relapse.
One should not generalise that all psychological therapies are protective against depressive relapse. Indeed, only mindfulness-based cognitive therapy (MBCT) was found to be protective against relapse in this study; whilst preventative cognitive therapy was not as powerful (although the numbers were small in this sample).
Lastly, Marloes Huijbers wrote comments below the original article in JAMA Psychiatry, (Breedvelt et al., 2021), pointing out that only a proportion of patients in the antidepressant tapering group had discontinued their medication at 6 months as planned: 60% of patients halved their dose at 6 months in the preventative cognitive therapy trial (Bockting et al., 2018) and in the PREVENT study (mindfulness-based cognitive behavioural therapy), the discontinuation rate was between 58% and 75% (Kuyken et al., 2015). If patients were still on antidepressants beyond 6 months, then this may have been preventative of relapse in this condition. We do not know the number of medication-free individuals, and how many relapses there were in this group.
This is a meta-analysis of (mostly) other people’s studies and as the authors acknowledge “it was not possible to include all variables of interest because some were inconsistently reported and infrequently collected”.
Implications for practice
The authors of this paper set out to “inform future personalised medicine research, advance shared decision making”. Unfortunately, they were not able to find much evidence to further stratify the population by individualised risk factors for relapse.
It is encouraging news that even patients at high-risk of depressive relapse might feel some confidence in tapering their antidepressants whilst simultaneously receiving an evidence-based psychological intervention that focuses on relapse prevention, such as mindfulness-based cognitive therapy. However, these are not conclusive results, and researchers have a long way to go in understanding the individual risk factors in depressive relapse.
Drawing attention to the lack of clinical distinction between withdrawal syndrome and relapse during antidepressant tapering may encourage further research in this area. It seems vital to support patients to “stay the distance” needed to experience subsequent mood improvement after the withdrawal effects wear off. This could improve drop-out rates in tapering groups of studies, and reduce the resumption of antidepressant treatment in the clinic.
Statement of interests
Breedvelt, J. J. F., Warren, F. C., Segal, Z., Kuyken, W., and Bockting, C. L. (2021). Continuation of Antidepressants vs Sequential Psychological Interventions to Prevent Relapse in Depression: An Individual Participant Data Meta-analysis. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2021.0823.
Bockting, C. L. H., Klein, N. S., Elgersma, H. J., van Rijsbergen, G. D., Slofstra, C., Ormel, J., et al. (2018). Effectiveness of preventive cognitive therapy while tapering antidepressants versus maintenance antidepressant treatment versus their combination in prevention of depressive relapse or recurrence (DRD study): a three-group, multicentre, randomised controlled trial. The lancet. Psychiatry 5, 401–410. doi:10.1016/S2215-0366(18)30100-7.
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