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Antidepressants are prescribed for the treatment of a number of psychiatric disorders in children and adolescents, however there is still controversy about whether they should be used in this population. This meta-review aimed to assess the effects of antidepressants for the acute treatment of attention-deficit/hyperactivity disorder (ADHD), anxiety disorders (ADs), autistic spectrum disorder (ASD), enuresis, major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD) in children and adolescents. Efficacy was measured as response to treatment (either as mean overall change in symptoms or as a dichotomous outcome) and tolerability was measured as the proportion of patients discontinuing treatment due to adverse events. Suicidality was measured as suicidal ideation, behavior (including suicide attempts) and completed suicide. PubMed, EMBASE, and Web of Science were systematically searched (until 31 October 2019) for existing systematic reviews and/or meta-analyses of double-blind randomized controlled trials. The quality of the included reviews was appraised using AMSTAR-2. Our meta-review included nine systematic reviews/meta-analyses (2 on ADHD; 1 on AD; 2 on ASD; 1 on enuresis; 1 on MDD, 1 on OCD and 1 on PTSD). In terms of efficacy this review found that, compared to placebo: fluoxetine was more efficacious in the treatment of MDD, fluvoxamine and paroxetine were better in the treatment of AD; fluoxetine and sertraline were more efficacious in the treatment of OCD; bupropion and desipramine improved clinician and teacher-rated ADHD symptoms; clomipramine and tianeptine were superior on some of the core symptoms of ASD; and no antidepressant was more efficacious for PTSD and enuresis. With regard to tolerability: imipramine, venlafaxine, and duloxetine were less well tolerated in MDD; no differences were found for any of the antidepressants in the treatment of anxiety disorders (ADs), ADHD, and PTSD; tianeptine and citalopram, but not clomipramine, were less well tolerated in children and adolescents with ASD. For suicidal behavior/ideation, venlafaxine (in MDD) and paroxetine (in AD) were associated with a significantly increased risk; by contrast, sertraline (in AD) was associated with a reduced risk. The majority of included systematic reviews/meta-analyses were rated as being of high or moderate in quality by the AMSTAR-2 critical appraisal tool (one and five, respectively). One included study was of low quality and two were of critically low quality. Compared to placebo, selected antidepressants can be efficacious in the acute treatment of some common psychiatric disorders, although statistically significant differences do not always translate into clinically significant results. Little information was available about tolerability of antidepressants in RCTs of OCD and in the treatment of ADHD, ASD, MDD, and PTSD. There is a paucity of data on suicidal ideation/behavior, but paroxetine may increase the risk of suicidality in the treatment of AD and venlafaxine for MDD. Findings from this review must be considered in light of potential limitations, such as the lack of comparative information about many antidepressants, the short-term outcomes and the quality of the available evidence., (Copyright © 2020 Boaden, Tomlinson, Cortese and Cipriani.)

Introduction: We have recently compared all second-generation as well as selected first-generation antidepressants in terms of efficacy and acceptability in the acute treatment of major depression. Here we present a protocol for a network meta-analysis aimed at extending these results, updating the evidence base and comparing all second-generation as well as selected first-generation antidepressants in terms of specific adverse events and tolerability in the acute treatment of major depression in adults., Methods and Analysis: We will include all double-blind randomised controlled trials comparing one active drug with another or with placebo in the acute treatment major depression in adults. We will compare the following active agents: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. The main outcomes will include the total number of patients experiencing specific adverse events; experiencing serious adverse events; and experiencing at least one adverse event. Published and unpublished studies will be retrieved through relevant database searches, trial registries and websites; reference selection and data extraction will be completed by at least two independent reviewers. For each outcome we will undertake a network meta-analysis to synthesise all evidence. We will use local and global methods to evaluate consistency. We will perform all analyses in R. We will assess the quality of evidence contributing to network estimates with the Confidence in Network Meta-Analysis web application., Discussion: This work will provide an in- depth analysis and an insight into the specific adverse events of individual antidepressants., Ethics and Dissemination: This review does not require ethical approval., Prospero Registration Number: CRD42019128141., Competing Interests: Competing interests: SK reports grants from the Mental Health Okamoto Memorial Foundation, Pfizer Health Research Foundation and KDDI Foundation outside the submitted work. IH reports lecture fees from Mitsubishi-Tanabe and Yoshitomi. TAF reports personal fees from Meiji, Mitsubishi-Tanabe, MSD and Pfizer and a grant from Mitsubishi-Tanabe, outside the submitted work; TAF has a pending patent 2018-177688. All other authors report no conflict of interest, (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)