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Original Investigation
May 19, 2021

Continuation of Antidepressants vs Sequential Psychological Interventions to Prevent Relapse in Depression: An Individual Participant Data Meta-analysis

Author Affiliations
  • 1Department of Psychiatry, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  • 2Institute of Health Research, College of Medicine and Health, University of Exeter, Exeter, United Kingdom
  • 3Department of Clinical Psychological Science, University of Toronto Scarborough, Toronto, Ontario, Canada
  • 4Department of Psychiatry, University of Oxford, Oxford, United Kingdom
  • 5Department of Psychiatry, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
JAMA Psychiatry. 2021;78(8):868-875. doi:10.1001/jamapsychiatry.2021.0823
Key Points

Question  Can a psychological intervention be an alternative to antidepressant medication?

Findings  This individual participant data meta-analysis of 4 trials that included 714 participants found no evidence of a difference in relapse risk associated with a psychological intervention during and/or after tapering antidepressant medication vs continuing antidepressant monotherapy during 15 months of follow-up and no associations of differential treatment with relapse across potential risk factors for relapse.

Meaning  This individual participant data meta-analysis suggests that delivering a psychological intervention while a patient undergoes antidepressant tapering may be an alternative to long-term use of antidepressants in the treatment of recurrent depression.


Importance  Depression frequently recurs. To prevent relapse, antidepressant medication is often taken in the long term. Sequentially delivering a psychological intervention while undergoing tapering of antidepressant medication might be an alternative to long-term antidepressant use. However, evidence is lacking on which patients may benefit from tapering antidepressant medication while receiving a psychological intervention and which should continue the antidepressant therapy. A meta-analysis of individual patient data with more power and precision than individual randomized clinical trials or a standard meta-analysis is warranted.

Objectives  To compare the associations between use of a psychological intervention during and/or after antidepressant tapering vs antidepressant use alone on the risk of relapse of depression and estimate associations of individual clinical factors with relapse.

Data Sources  PubMed, the Cochrane Library, Embase, and PsycInfo were last searched on January 23, 2021. Requests for individual participant data from included randomized clinical trials (RCTs) were sent.

Study Selection  Randomized clinical trials that compared use of a psychological intervention while tapering antidepressant medication with antidepressant monotherapy were included. Patients had to be in full or partial remission from depression. Two independent assessors conducted screening and study selection.

Data Extraction and Synthesis  Of 15 792 screened studies, 236 full-text articles were retrieved, and 4 RCTs that provided individual participant data were included.

Main Outcomes and Measures  Time to relapse and relapse status over 15 months measured via a blinded assessor using a diagnostic clinical interview.

Results  Individual data from 714 participants (mean [SD] age, 49.2 [11.5] years; 522 [73.1%] female) from 4 RCTs that compared preventive cognitive therapy or mindfulness-based cognitive therapy during and/or after antidepressant tapering vs antidepressant monotherapy were available. Two-stage random-effects meta-analysis found no significant difference in time to depressive relapse between use of a psychological intervention during tapering of antidepressant medication vs antidepressant therapy alone (hazard ratio [HR], 0.86; 95% CI, 0.60-1.23). Younger age at onset (HR, 0.98; 95% CI, 0.97-0.99), shorter duration of remission (HR, 0.99; 95% CI, 0.98-1.00), and higher levels of residual depressive symptoms at baseline (HR, 1.07; 95% CI, 1.04-1.10) were associated with a higher overall risk of relapse. None of the included moderators were associated with risk of relapse.

Conclusions and Relevance  The findings of this individual participant data meta-analysis suggest that regardless of the clinical factors included in these studies, the sequential delivery of a psychological intervention during and/or after tapering may be an effective relapse prevention strategy instead of long-term use of antidepressants. These results could be used to inform shared decision-making in clinical practice.

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    1 Comment for this article
    Continuation of Antidepressants vs Sequential Psychological Interventions to Prevent Relapse in Depression. Are we sure enough?
    Marloes Huijbers, PhD | Radboud University Medical Center, Nijmegen, the Netherlands
    An individual patient data meta-analysis (IPDMA) by Breedvelt et al. [1] compared the relative efficacy of antidepressant medication (ADM) versus psychological interventions while tapering ADM, for preventing relapse in recurrent depression. Four trials including 714 patients were reported, one comparing preventive cognitive therapy (PCT/tapering) with continued ADM and three comparing mindfulness-based cognitive therapy (MBCT/tapering) with continued ADM. There was insufficient evidence for a difference in risk of relapse over 15 months. The authors concluded that sequential delivery of psychological interventions during or after tapering ADM may be an alternative to continued ADM. In absence of moderating variables, the authors suggested that this may apply to all patients.

    First, despite the merits and promising implications of this IPDMA, it seems crucial to also consider combination treatment to optimize shared-decision making. There is evidence that combining PCT with mADM is more effective than PCT/tapering (HR=0.54, 95% CI 0.33–0.87) and mADM alone (HR=0.59, 95% CI 0.38–0.94).[2] Similarly, combining MBCT with mADM seems more effective than MBCT/tapering (HR=1.59, 95% CI 1.10–2.31) to prevent relapse.[3]

    Second, discontinuation is challenging [4] exemplified by protocol violations in the abovementioned studies. With PCT/tapering, only 60% of patients achieved halving their dose at 6 months. Data on full discontinuation were not reported.[2] With MBCT, full discontinuation might be achieved by only 53%.3 In the PREVENT trial, data were reported only for 176/212 patients who attended ≥4 MBCT sessions, of whom 124 (71%) discontinued fully.[5] Thus, the discontinuation rate for the entire MBCT/tapering group in that trial is estimated between 58% and 75%. Consequently, intention-to-treat analyses will favor a null-finding. Per-protocol analysis including only those who actually completed discontinuation would provide more realistic estimates within this sample. Then still, the null-finding should be substantiated by explicit quantification, e.g. with Bayes factor. Furthermore, to answer the research question whether psychological interventions can substitute continued ADM, a non-inferiority design would be more suitable. Additionally, the role of discontinuation could be assessed in Cox-models using medication use as a time-dependent covariate.

    In sum, the combination of PCT or MBCT with continued or partially [4] discontinued ADM may be the most suitable treatment for some patients. Methodological improvements to the reported IPDMA are necessary before concluding that psychological interventions may be an alternative to continued ADM. Moreover, aside from possible preventive psychological interventions, more comprehensive and practical tapering support tools should be available to patients and doctors who are interested in discontinuing ADM.

    Authors: Marloes J. Huijbers, PhD, Henricus G. Ruhé, MD, PhD, Dirk Geurts, MD, PhD, Anne E.M. Speckens. MD, PhD.

    1. Breedvelt JJ, Warren FC, Segal Z, Kuyken W, Bockting CL. JAMA psychiatry 2021.
    2. Bockting CL, Klein NS, Elgersma HJ, et al. The Lancet Psychiatry 2018; 5(5): 401-10.
    3. Huijbers MJ, Spinhoven P, Spijker J, et al. British Journal of Psychiatry 2016; 208(4): 366-73.
    4. Huijbers MJ, Wentink C, Simons E, Spijker J, Speckens A. BMJ open 2020; 10(11): e039053.
    5. Kuyken W, Hayes R, Barrett B, et al. Lancet 2015; 386(9988): 63-73.
    CONFLICT OF INTEREST: MH is employed by the Radboud University Medical Center, Center for Mindfulness, as a researcher and mindfulness teacher. HGR is a psychiatrist and assistant professor at the Radboud University Medical Center, Psychiatry Dept. He received a grant from ZonMW in 2020 for a study on tapering antidepressants (grant nr 10140021910006). DEMG is consultant psychiatrist and assistant professor at the Radboud University Medical Center, Psychiatry Dept., without competing interests. AEMS is director of the Radboud University Medical Center, Center for Mindfulness, and received a grant in 2015 from the Dutch Health Care Insurers Innovation Foundation (No 3.048) for a cluster randomised controlled trial of Discontinuation of Antidepressant Medication in Primary Care Supported by Monitoring Plus Mindfulness-based Cognitive Therapy Versus Monitoring Alone.