Evidence synthesis, practice guidelines and real-world prescriptions of new generation antidepressants in the treatment of depression: a protocol for cumulative network meta-analyses and meta-epidemiological study.

INTRODUCTION: Depressive disorders are the most common, burdensome and costly mental disorders. Their treatments have developed through the past decades and we now have more than a dozen new generation antidepressants, while a series of guidelines have been published to provide recommendations over the years. However, there still may exist important gaps in this evidence synthesis and implementation process. Systematic reviews may not have been conducted in the most unbiased, informative and timely manners; guidelines may not have reflected the most up-to-date evidence; clinicians may not have changed their clinical decision-makings in accordance with the relevant evidence. The aim of this study is to examine the gaps between the ideally synthesised evidence, guideline recommendations and real-world clinical practices in the prescription of new generation antidepressants for major depression through the past three decades.

METHODS AND ANALYSIS: We will conduct cumulative network meta-analyses (cNMAs) based on the comprehensive systematic review which has identified published and unpublished head-to-head randomised controlled trials comparing the following antidepressants in the acute phase treatment of major depression: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. The primary outcomes will be the proportions of patients who responded (efficacy) and who withdrew from treatment for any reasons (acceptability). We will conduct a random effects cNMA to synthesise evidence and obtain a comprehensive ranking of all new generation antidepressants based on their surface under the cumulative ranking curves. We will identify series of international clinical practice guidelines for the treatment of major depression of adults and summarise their recommendations. We will estimate real-world prescription patterns of antidepressants in the nationally representative samples in USA in the Medical Expenditure Panel Survey. We will compare and evaluate the gaps between the rankings according to cNMAs conducted at 5-year intervals between 1990 and 2015, recommendations in guidelines published in the ensuing 5 years and actual practices thereafter.

ETHICS AND DISSEMINATION: This review does not require ethical approval. We will disseminate our findings through publications in peer-reviewed journals and presentations at conferences.

TRIAL REGISTRATION NUMBER: UMIN000031898.