Efficacy and acceptability of next step treatment strategies in adults with treatment-resistant major depressive disorder: protocol for systematic review and network meta-analysis

Jan Jacobus Muit*, Philip F P van Eijndhoven, Andrea Cipriani, Iris Dalhuisen, Suzanne van Bronswijk, Toshi A Furukawa, Henricus G Ruhe

*Corresponding author for this work

Research output: Contribution to journal(Systematic) Review article peer-review


INTRODUCTION: For major depression, a one-size-fits-all treatment does not exist. Patients enter a 'trial-and-change' algorithm in which effective therapies are subsequently applied. Unfortunately, an empirically based order of treatments has not yet been determined. There is a magnitude of different treatment strategies while clinical trials only compare a small number of these. Network meta-analyses (NMA) might offer a solution, but so far have been limited in scope and did not account for possible differences in population characteristics that arise with increasing levels of treatment-resistance, potentially violating the transitivity assumption. We; therefore, present a protocol for a systematic review and NMA aiming at summarising and ranking treatments for treatment-resistant depression (TRD) while covering a broad range of therapeutic options and accounting for possible differences in population characteristics at increasing levels of treatment-resistance.

METHODS AND ANALYSIS: Randomised controlled trials will be included that compared next-step pharmacological, neuromodulation or psychological treatments for treatment-resistant depression (TRD; ie, failure to respond to ≥1 adequate antidepressant drug trial(s) in the current episode) to each other or to a control condition. Primary outcomes will be the proportion of patients who responded to (efficacy) and dropped out of (acceptability) the allocated treatment. A random effects NMA will be conducted, synthesising the evidence for each outcome and determining the differential efficacy of treatments. Heterogeneity in treatment nodes will be reduced by considering alternative geometries of the network structure and by conducting a meta-regression examining different levels of TRD. Local and global methods will be applied to evaluate consistency. The Cochrane Risk of Bias 2 tool, Confidence in Network Meta-Analysis and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework will be used to assess risk of bias and certainty.

ETHICS AND DISSEMINATION: This review does not require ethical approval.

Original languageEnglish
Article number056777
Pages (from-to)e056777
Number of pages8
JournalBMJ Open
Issue number4
Publication statusPublished - 18 Apr 2022


  • Adult
  • Antidepressive Agents/therapeutic use
  • Depressive Disorder, Major/drug therapy
  • Depressive Disorder, Treatment-Resistant/drug therapy
  • Humans
  • Meta-Analysis as Topic
  • Network Meta-Analysis
  • Randomized Controlled Trials as Topic
  • Review Literature as Topic
  • adverse events
  • adult psychiatry
  • clinical trials
  • depression & mood disorders

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