Abstract
Major depressive disorder is one of the most common mental disorders in children and adolescents. However, whether to use pharmacological interventions in this population and which drug should be preferred are still matters of controversy. Consequently, we aimed to compare and rank antidepressants and placebo for major depressive disorder in young people. We did a network meta-analysis to identify both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to May 31, 2015, for the acute treatment of major depressive disorder in children and adolescents. We included trials of amitriptyline, citalopram, clomipramine, desipramine, duloxetine, escitalopram, fluoxetine, imipramine, mirtazapine, nefazodone, nortriptyline, paroxetine, sertraline, and venlafaxine. Trials recruiting participants with treatment-resistant depression, treatment duration of less than 4 weeks, or an overall sample size of less than ten patients were excluded. We extracted the relevant information from the published reports with a predefined data extraction sheet, and assessed the risk of bias with the Cochrane risk of bias tool. The primary outcomes were efficacy (change in depressive symptoms) and tolerability (discontinuations due to adverse events). We did pair-wise meta-analyses using the random-effects model and then did a random-effects network meta-analysis within a Bayesian framework. We assessed the quality of evidence contributing to each network estimate using the GRADE framework. This study is registered with PROSPERO, number CRD42015016023. We deemed 34 trials eligible, including 5260 participants and 14 antidepressant treatments. The quality of evidence was rated as very low in most comparisons. For efficacy, only fluoxetine was statistically significantly more effective than placebo (standardised mean difference -0·51, 95% credible interval [CrI] -0·99 to -0·03). In terms of tolerability, fluoxetine was also better than duloxetine (odds ratio [OR] 0·31, 95% CrI 0·13 to 0·95) and imipramine (0·23, 0·04 to 0·78). Patients given imipramine, venlafaxine, and duloxetine had more discontinuations due to adverse events than did those given placebo (5·49, 1·96 to 20·86; 3·19, 1·01 to 18·70; and 2·80, 1·20 to 9·42, respectively). In terms of heterogeneity, the global I(2) values were 33·21% for efficacy and 0% for tolerability. When considering the risk-benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents. Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated. National Basic Research Program of China (973 Program).
Highlights
We identified double-blind randomised controlled trials (RCTs) published up to May 31, 2015, comparing any antidepressant with placebo or another active antidepressant as oral monotherapy in the acute treatment of children and adolescents, with a primary diagnosis of Major depressive disorder (MDD) according to standardized diagnostic criteria by searching PubMed, the Cochrane Central Register of Controlled Trials, Web of Science, Embase, CINAHL, PsycINFO, and LiLACS from date of inception
In the network we found some inconsistency for efficacy, which was mainly determined by the loop of fluoxetine-nortriptyline-placebo
We excluded studies in which participants were described as having subsyndromal depressive symptoms, which is a significant proportion of patients seen in real world clinical settings
Summary
87 88 Major depressive disorder (MDD) is common in young people with an estimated point prevalence between 2-3% in school-age children (6-12 years) and 3-9% in adolescents (13-18 years). Compared with adults, children and adolescents with MDD are still under-diagnosed and under-treated, possibly because they tend to present with rather undifferentiated depressive symptoms, e.g., irritability, aggressive behaviors and school refusal. Consequences of depressive episodes in these patients include serious impairments in social functioning, as well as suicidal ideation and attempts. Even though psychological treatments are still considered the first line treatment in many clinical guidelines, antidepressants are widely used in the treatment of depression in children and adolescents and the rate of prescription has increased over time. in 2004, the Food and Drug Administration (FDA) cautioned practitioners on the use of antidepressants in children and adolescents about increased suicide risk. As a consequence, the question of whether to use antidepressant agents for the treatment of MDD in young people and, if so, which antidepressant would be preferred, remains controversial. Previous pairwise meta-analyses have tried to evaluate the magnitude of efficacy of all types of antidepressants and to identify factors associated with treatment efficacy. they have been inconclusive because they were not able to generate clear hierarchies among available treatments, as many antidepressants have not been compared head to head. Previous pairwise meta-analyses have tried to evaluate the magnitude of efficacy of all types of antidepressants and to identify factors associated with treatment efficacy.. We conducted a network meta-analysis to comprehensively compare and rank antidepressants for the acute treatment of MDD in children and adolescents. We searched PubMed, the Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies’ websites and international registers for published and unpublished double-blind randomised controlled trials up to May 31st 2015, for the acute treatment of MDD in children and adolescents. 76 Interpretation: Balancing the risk-benefit profile of antidepressants in the acute treatment of MDD, these drugs do not seem to offer a clear advantage for children and adolescents. Fluoxetine is probably the only antidepressant to consider when a pharmacological treatment is indicated, patients should be carefully monitored for the risk of increased suicidality.
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