Comparative efficacy and tolerability of antidepressants for major depression in children and adolescents: a network meta-analysis
Background: Major depressive disorder (MDD) is one of the most common mental disorders among children and adolescents. However, the question of whether to use pharmacological interventions in this population and which drug should be preferred is still matter of controversy. Consequently, we aimed to compare and rank antidepressants and placebo for MDD in young people. Methods: We did a network meta-analysis to synthesise 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Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies’ websites and international registers for published and unpublished double-blind randomised controlled trials up to May 31st 2015, for the acute treatment of MDD in children and adolescents. The primary outcomes were efficacy (change in depressive symptoms) and tolerability (discontinuations due to adverse events). We also examined response rate, all-cause dropouts and suicidality. We assessed the quality of evidence using the GRADE framework. This study is registered with PROSPERO, number CRD42015016023. Findings: We deemed 34 trials eligible, including 5,260 participants and 14 antidepressant treatments. The quality of evidence was rated as very low in the majority of comparisons. For efficacy, only fluoxetine was statistically significantly more effective than placebo (standardised mean difference: -0·50, 95% credible intervals [CrIs] -0·98 to -0·03). In terms of tolerability, fluoxetine was also better than duloxetine and imipramine (odds ratio [OR] 0·31, 95% CrI 0·13 to 0·95 and 0·23, 95% CrI 0·04 to 0·78, respectively), while imipramine, venlafaxine, and duloxetine had more discontinuations due to adverse events than placebo (OR 5·49, 95% CrI 1·96 to 20·86; 3·19, 95% CrI 1·01 to 18·70 and 2·80, 95% CrI 1·20 to 9·42, respectively). In terms of heterogeneity, the global I2 values were 38·63% for efficacy and 0% for tolerability. 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, however patients should be carefully monitored for the risk of increased suicidality.