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Side effect profile and comparative tolerability of 21 antidepressants in the acute treatment of major depression in adults: protocol for a network meta-analysis
  1. Anneka Tomlinson1,
  2. Orestis Efthimiou2,
  3. Katharine Boaden3,
  4. Emma New3,
  5. Sarah Mather3,
  6. Georgia Salanti2,
  7. Hissei Imai4,
  8. Yusuke Ogawa5,
  9. Aran Tajika6,
  10. Sanae Kishimoto4,
  11. Sino Kikuchi4,
  12. Astrid Chevance7,8,
  13. Toshi A Furukawa4,
  14. Andrea Cipriani1,3
  1. 1 Department of Psychiatry, University of Oxford, Oxford, UK
  2. 2 Institute of Social and Preventive Medicine, Bern, Switzerland
  3. 3 Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford
  4. 4 Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan
  5. 5 Department of Healthcare Epidemiology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  6. 6 Department of Psychiatry, Kyoto University Hospital, Kyoto, Japan
  7. 7 Paris Descartes University, Paris, France
  8. 8 METHODS Team, Center for Research in Epidemiology and Statistics, Sorbonne Paris Cité, Paris, France
  1. Correspondence to Dr Anneka Tomlinson, Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford OX3 7JX, UK; anneka.tomlinson{at}


Introduction We have recently compared all second-generation as well as selected first-generation antidepressants in terms of efficacy and acceptability in the acute treatment of major depression. Here we present a protocol for a network meta-analysis aimed at extending these results, updating the evidence base and comparing all second-generation as well as selected first-generation antidepressants in terms of specific adverse events and tolerability in the acute treatment of major depression in adults.

Methods and analysis We will include all double-blind randomised controlled trials comparing one active drug with another or with placebo in the acute treatment major depression in adults. We will compare the following active agents: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. The main outcomes will include the total number of patients experiencing specific adverse events; experiencing serious adverse events; and experiencing at least one adverse event. Published and unpublished studies will be retrieved through relevant database searches, trial registries and websites; reference selection and data extraction will be completed by at least two independent reviewers. For each outcome we will undertake a network meta-analysis to synthesise all evidence. We will use local and global methods to evaluate consistency. We will perform all analyses in R. We will assess the quality of evidence contributing to network estimates with the Confidence in Network Meta-Analysis web application.

Discussion This work will provide an in- depth analysis and an insight into the specific adverse events of individual antidepressants.

Ethics and dissemination This review does not require ethical approval.

PROSPERO registration number CRD42019128141.

  • adult psychiatry

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  • Contributors AC, AT, OE, GS and TAF drafted the manuscript. All other authors revised, edited and approved the final version of the protocol.

  • Funding This research was funded by the National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre (grant BRC-1215-20005).

  • Disclaimer The views expressed are those of the authors and not necessarily those of the UK National Health Service, the National Institute for Health Research, or the UK Department of Health. The funders had no role in the design and conduct of the study; or approval of the manuscript; and decision to submit the manuscript for publication.

  • Competing interests SK reports grants from the Mental Health Okamoto Memorial Foundation, Pfizer Health Research Foundation and KDDI Foundation outside the submitted work. IH reports lecture fees from Mitsubishi-Tanabe and Yoshitomi. TAF reports personal fees from Meiji, Mitsubishi-Tanabe, MSD and Pfizer and a grant from Mitsubishi-Tanabe, outside the submitted work; TAF has a pending patent 2018-177688. All other authors report no conflict of interest

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

  • Patient consent for publication Not required.