Background Major depressive disorder causes a great burden on patients and societies. Venlafaxine and mirtazapine
are commonly prescribed as second-line treatment for patients with major depressive disorder worldwide. Previous
systematic reviews have concluded that venlafaxine and mirtazapine reduce depressive symptoms, but the efects
seem small and may not be important to the average patient. Moreover, previous reviews have not systematically
assessed the occurrence of adverse events. Therefore, we aim to investigate the risks of adverse events with venlafaxine or mirtazapine versus ‘active placebo’, placebo, or no intervention for adults with major depressive disorder in two
separate systematic reviews.
Methods This is a protocol for two systematic reviews with meta-analysis and Trial Sequential Analysis. The assessments of the efects of venlafaxine or mirtazapine will be reported in two separate reviews. The protocol is reported
as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols, risk of bias will
be assessed with the Cochrane risk-of-bias tool version 2, clinical signifcance will be assessed using our eight-step
procedure, and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment,
Development and Evaluation approach. We will search for published and unpublished trials in major medical databases and trial registers. Two review authors will independently screen the results from the literature searches, extract
data, and assess risk of bias. We will include published or unpublished randomised clinical trial comparing venlafaxine
or mirtazapine with ‘active placebo’, placebo, or no intervention for adults with major depressive disorder. The primary
outcomes will be suicides or suicide attempts, serious adverse events, and non-serious adverse events. Exploratory outcomes will include depressive symptoms, quality of life, and individual adverse events. If feasible, we will assess the
intervention efects using random-efects and fxed-efect meta-analyses.
Discussion Venlafaxine and mirtazapine are frequently used as second-line treatment of major depressive disorder
worldwide. There is a need for a thorough systematic review to provide the necessary background for weighing
the benefts against the harms. This review will ultimately inform best practice in the treatment of major depressive
disorder.