Beneficial and harmful effects of antidepressants versus placebo, ‘active placebo’, or no intervention for adults with major depressive disorder: a protocol for a systematic review of published and unpublished data with meta-analyses and trial sequential analyses

Abstract

Background Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide. Antidepressants are frequently used to treat major depressive disorder. It has been shown repeatedly that antidepressants seem to reduce depressive symptoms with a statistically significant effect, but the clinical importance of the effect sizes seems questionable. Both beneficial and harmful effects of antidepressants have not previously been sufficiently assessed. The main objective of this review will be to evaluate the beneficial and harmful effects of antidepressants versus placebo, ‘active placebo’, or no intervention for adults with major depressive disorder. Methods/design A systematic review with meta-analysis will be reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), bias will be assessed with the Cochrane Risk of Bias tool-version 2 (ROB2), our eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, Trial Sequential Analysis will be conducted to control for random errors, and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. To identify relevant trials, we will search both for published and unpublished trials in major medical databases from their inception to the present. Clinical study reports will be obtained from regulatory authorities and pharmaceutical companies. Two review authors will independently screen the results of the literature searches, extract data, and perform risk of bias assessment. We will include any published or unpublished randomised clinical trial comparing one or more antidepressants with placebo, ‘active placebo’, or no intervention for adults with major depressive disorder. The following active agents will be included: agomelatine, amineptine, amitriptyline, bupropion, butriptyline, cianopramine, citalopram, clomipramine, dapoxetine, demexiptiline, desipramine, desvenlafaxine, dibenzepin, dosulepin, dothiepin, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, iprindole, levomilnacipran, lofepramine, maprotiline, melitracen, metapramine, milnacipran, mirtazapine, nefazodone, nortriptyline, noxiptiline, opipramol, paroxetine, protriptyline, quinupramine, reboxetine, sertraline, trazodone, tianeptine, trimipramine, venlafaxine, vilazodone, and vortioxetine. Primary outcomes will be depressive symptoms, serious adverse events, and quality of life. Secondary outcomes will be suicide or suicide attempt, suicidal ideation, and non-serious adverse events. Discussion As antidepressants are commonly used to treat major depressive disorder in adults, a systematic review evaluating their beneficial and harmful effects is urgently needed. This review will inform best practice in treatment and clinical research of this highly prevalent and burdensome disorder. Systematic review registration PROSPERO CRD42020220279

The risks of adverse events with venlafaxine and mirtazapine versus ‘active placebo’, placebo, or no intervention for adults with major depressive disorder: a protocol for two separate systematic reviews with meta-analysis and Trial Sequential Analysis

“…Our systematic reviews will take risks of bias (systematic errors), play of chance (random errors), and certainty of the evidence into consideration. The systematic reviews will be conducted as part of a larger project investigating the beneficial and harmful effects of all antidepressants for major depressive disorder [ 29 ]. In addition to these systematic reviews, we will also publish separate systematic reviews for selective serotonin reuptake inhibitors, duloxetine [ 30 ], and tricyclic antidepressants [ 31 ].…”

Tricyclic antidepressants versus ‘active placebo’, placebo or no intervention for adults with major depressive disorder: a protocol for a systematic review with meta-analysis and Trial Sequential Analysis

“…Our systematic review will take bias risk (systematic errors), play of chance (random errors) and certainty of the findings into consideration. This systematic review will be conducted as part of a larger project investigating the beneficial and harmful effects of all antidepressants for major depressive disorder [ 27 ]. In addition to this systematic review, we will also publish separate systematic reviews for selective serotonin reuptake inhibitors, duloxetine [ 28 ], venlafaxine and mirtazapine [ 27 ].…”

“…This systematic review will be conducted as part of a larger project investigating the beneficial and harmful effects of all antidepressants for major depressive disorder [ 27 ]. In addition to this systematic review, we will also publish separate systematic reviews for selective serotonin reuptake inhibitors, duloxetine [ 28 ], venlafaxine and mirtazapine [ 27 ]. These systematic reviews will ultimately provide data for a systematic review investigating the effects of all antidepressants for major depressive disorder [ 27 ].…”

“…In addition to this systematic review, we will also publish separate systematic reviews for selective serotonin reuptake inhibitors, duloxetine [ 28 ], venlafaxine and mirtazapine [ 27 ]. These systematic reviews will ultimately provide data for a systematic review investigating the effects of all antidepressants for major depressive disorder [ 27 ]. We chose to publish the present protocol and systematic review separately to investigate the effects of tricyclic antidepressants in more detail (i.e.…”

“…We chose to publish the present protocol and systematic review separately to investigate the effects of tricyclic antidepressants in more detail (i.e. more outcomes) [ 27 ].…”