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Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis
  1. Klaus Munkholm,
  2. Asger Sand Paludan-Müller,
  3. Kim Boesen
  1. Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark
  1. Correspondence to Dr Klaus Munkholm; km{at}


Objectives To investigate whether the conclusion of a recent systematic review and network meta-analysis (Cipriani et al) that antidepressants are more efficacious than placebo for adult depression was supported by the evidence.

Design Reanalysis of a systematic review, with meta-analyses.

Data sources 522 trials (116 477 participants) as reported in the systematic review by Cipriani et al and clinical study reports for 19 of these trials.

Analysis We used the Cochrane Handbook’s risk of bias tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to evaluate the risk of bias and the certainty of evidence, respectively. The impact of several study characteristics and publication status was estimated using pairwise subgroup meta-analyses.

Results Several methodological limitations in the evidence base of antidepressants were either unrecognised or underestimated in the systematic review by Cipriani et al. The effect size for antidepressants versus placebo on investigator-rated depression symptom scales was higher in trials with a ‘placebo run-in’ study design compared with trials without a placebo run-in design (p=0.05). The effect size of antidepressants was higher in published trials compared with unpublished trials (p<0.0001). The outcome data reported by Cipriani et al differed from the clinical study reports in 12 (63%) of 19 trials. The certainty of the evidence for the placebo-controlled comparisons should be very low according to GRADE due to a high risk of bias, indirectness of the evidence and publication bias. The mean difference between antidepressants and placebo on the 17-item Hamilton depression rating scale (range 0–52 points) was 1.97 points (95% CI 1.74 to 2.21).

Conclusions The evidence does not support definitive conclusions regarding the benefits of antidepressants for depression in adults. It is unclear whether antidepressants are more efficacious than placebo.

  • adult psychiatry

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  • Contributors KM, ASP-M and KB contributed to the conception and design of the study. KM performed the meta-analyses. KM, ASP-M and KB analysed and interpreted the data, drafted and critically revised the manuscript and approved the final version to be published. All authors had full access to all the data and take responsibility for the integrity of the data and the accuracy of the data analysis.

  • Funding The study was funded by the Nordic Cochrane Centre. The research was designed, conducted, analysed and interpreted by the authors entirely independently of the funding source.

  • Competing interests None declared.

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

  • Data sharing statement All data files and the code for the statistical analyses are available from the Open Science Framework database (

  • Patient consent for publication Not required.