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Comparative efficacy and acceptability of first-generation and second-generation antidepressants in the acute treatment of major depression: protocol for a network meta-analysis
  1. Toshi A Furukawa1,
  2. Georgia Salanti2,3,4,
  3. Lauren Z Atkinson5,
  4. Stefan Leucht6,
  5. Henricus G Ruhe7,8,
  6. Erick H Turner9,10,
  7. Anna Chaimani4,
  8. Yusuke Ogawa1,
  9. Nozomi Takeshima1,
  10. Yu Hayasaka1,
  11. Hissei Imai1,
  12. Kiyomi Shinohara1,
  13. Aya Suganuma1,
  14. Norio Watanabe1,
  15. Sarah Stockton5,
  16. John R Geddes5,11,
  17. Andrea Cipriani5,11
  1. 1Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan
  2. 2Department of Clinical Research, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
  3. 3Institute of Primary Health Care (BIHAM), University of Bern, Switzerland
  4. 4Department of Hygiene and Epidemiology, University of Ioannina, Ioannina, Greece
  5. 5Department of Psychiatry, University of Oxford, Oxford, UK
  6. 6Department of Psychiatry and Psychotherapy, TU- Munich, Munchen, Germany
  7. 7Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  8. 8University Center for Psychiatry, University of Groningen, Groningen, The Netherlands
  9. 9Behavioral Health and Neurosciences Division, VA Portland Health Care System, Portland, Oregon, USA
  10. 10Departments of Psychiatry and Pharmacology, Oregon Health & Science University, Portland, Oregon, USA
  11. 11Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK
  1. Correspondence to Professor Andrea Cipriani;{at}


Introduction Many antidepressants are indicated for the treatment of major depression. Two network meta-analyses have provided the most comprehensive assessments to date, accounting for both direct and indirect comparisons; however, these reported conflicting interpretation of results. Here, we present a protocol for a systematic review and network meta-analysis aimed at updating the evidence base and comparing all second-generation as well as selected first-generation antidepressants in terms of efficacy and acceptability in the acute treatment of major depression.

Methods and analysis We will include all randomised controlled trials reported as double-blind and comparing one active drug with another or with placebo in the acute phase treatment of major depression in adults. We are interested in comparing 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 be the proportion of patients who responded to or dropped out of the allocated treatment. Published and unpublished studies will be sought through relevant database searches, trial registries and websites; all reference selection and data extraction will be conducted by at least two independent reviewers. We will conduct a random effects network meta-analysis to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. To rank the various treatments for each outcome, we will use the surface under the cumulative ranking curve and the mean ranks. We will employ local as well as global methods to evaluate consistency. We will fit our model in a Bayesian framework using OpenBUGS, and produce results and various checks in Stata and R. We will also assess the quality of evidence contributing to network estimates of the main outcomes with the GRADE framework.

Ethics and dissemination This review does not require ethical approval.

PROSPERO registration number CRD42012002291.

  • Major depression
  • Systematic review
  • Network meta-analysis
  • Antidepressants

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