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Comparative efficacy and acceptability of antidepressants in the long-term treatment of major depression: protocol for a systematic review and networkmeta-analysis
  1. Kiyomi Shinohara1,
  2. Orestis Efthimiou2,
  3. Edoardo G Ostinelli3,
  4. Anneka Tomlinson4,
  5. John R Geddes4,5,
  6. Andrew A Nierenberg6,
  7. Henricus G Ruhe7,
  8. Toshi A Furukawa1,
  9. Andrea Cipriani4,5
  1. 1 Departments of Health Promotion and Human Behavior and of Clinical Epidemiology, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan
  2. 2 Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
  3. 3 University of Milan, Milano, Lombardia, Italy
  4. 4 Department of Psychiatry, University of Oxford, Oxford, UK
  5. 5 Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK
  6. 6 Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA
  7. 7 Department of Psychiatry, Radboud University, Nijmegen, the Netherlands
  1. Correspondence to Dr Kiyomi Shinohara; kiyomi.wb3{at}


Introduction Pharmacotherapy plays an important role in the treatment of major depression. At the initiation of antidepressant treatment, both improvement of symptoms in the short term and relapse prevention in the long term should be taken into account. However, there is insufficient evidence regarding the efficacy and the acceptability of continuation/maintenance treatments and the relative efficacy/acceptability of antidepressants.

Objective We will conduct a pairwise meta-analysis and a network meta-analysis (NMA) to examine the relative efficacy, tolerability and acceptability of antidepressants in the long-term treatment of major depression.

Methods and analysis We will include double-blind randomised controlled trials comparing any of the following antidepressants, which we included in our previous NMA of the acute treatment for major depression, with placebo or with another active drug for long-term treatment of major depression: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. Our primary outcomes will be sustained response and all-cause dropouts. We will include four types of designs that are used to investigate long-term treatment. We will conduct two main analyses. First, we will conduct a pairwise meta-analysis comparing all antidepressants versus placebo to investigate whether continuing antidepressants after achieving a positive response in the acute-phase treatment is beneficial and/or safe. Second, we will conduct an NMA to examine the comparative efficacy and acceptability of the drugs. We will use a novel approach that will combine the results of acute-phase treatment NMA with long-term treatment studies to include all related designs in the NMA. We will ensure the validity of combining different designs and our new approach by checking the distribution of important effect modifiers and consistency of network.

Ethics and dissemination This study did not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal.

PROSPERO registration number CRD42018114561; Pre-results.

  • depression
  • antidepressants
  • long-term treatment
  • network meta-analysis
  • relapse prevention

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  • Contributors KS, AT, AC, TAF and OE designed this study and drafted the protocol. AC developed the search strategies. KS, EGO, AT, TAF and AC independently screened potential studies and extracted data from the included studies, assessed the risk of bias and summarised the evidence. JRG, AAN and HGR arbitrated in cases of disagreement and ensured the absence of errors. OE performed the statistical analysis. All authors approved the publication of this protocol.

  • Funding This study was supported in part by JSPS Grant-in-Aid for Scientific Research (Grant Number 17K19808) to TAF. Andrea Cipriani is supported by the National Institute for Health Research (NIHR) Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP-2017-08- ST2-006) and by the NIHR Oxford Health Biomedical Research Centre (grant BRC-1215-20005). The views expressed are those of the authors and are not necessarily those of the UK National Health Service, the NIHR or the UK Department of Health. The funders had no role in developing the protocol.

  • Competing interests None declared.

  • Ethics approval We will disseminate our findings by publishing in a peer-reviewed journal.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Not required.