Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis.
BACKGROUND
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.


METHODS
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Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to May 31, 2015, for the acute treatment of major depressive disorder in children and adolescents.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.


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
National Basic Research Program of China (973 Program).
Department of Psychiatry, University of Oxford, Oxford, UK. Electronic address: andrea.cipriani@psych.ox.ac.uk.
Andrea
A
Cipriani
Department of Neurology and Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China.
Xinyu
X
Zhou
Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.
Cinzia
C
Del Giovane
Orygen, The National Centre of Excellence in Youth Mental Health, University of Melbourne, Melbourne, VIC, Australia.
Sarah E
SE
Hetrick
Department of Neurology and Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China.
Bin
B
Qin
Doctor Evidence, Santa Monica, CA, USA.
Craig
C
Whittington
Division of Neuroscience, School of Medicine, University of Dundee, Dundee, UK; Department of Paediatrics, and Department of Psychiatry, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.
David
D
Coghill
Department of Neurology and Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China.
Yuqing
Y
Zhang
Discipline of Psychiatry, Sydney Medical School, Concord West, NSW, Australia.
Philip
P
Hazell
Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.
Stefan
S
Leucht
Department of Clinical, Neuro- and Developmental Psychology, VU University Amsterdam, Amsterdam, Netherlands.
Pim
P
Cuijpers
Department of Neurology and Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China.
Juncai
J
Pu
Department of Child and Adolescent Psychiatry, Hôpital Pitié-Salpétrière, Institut des Systèmes Intelligents et Robotiques, Université Pierre et Marie Curie, Paris, France.
David
D
Cohen
Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Arun V
AV
Ravindran
Department of Neurology and Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China.
Yiyun
Y
Liu
Department of Psychology, Appalachian State University, Boone, NC, USA.
Kurt D
KD
Michael
Department of Neurology and Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China.
Lining
L
Yang
Department of Neurology and Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China.
Lanxiang
L
Liu
Department of Neurology and Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia. Electronic address: xiepeng973@126.com.
Peng
P
Xie
D000293:Adolescent; D000639:Amitriptyline / Q000008:administration & dosage / Q000009:adverse effects; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D001499:Bayes Theorem; D002648:Child; D015283:Citalopram / Q000008:administration & dosage / Q000009:adverse effects; D002997:Clomipramine / Q000008:administration & dosage / Q000009:adverse effects; D015986:Confounding Factors, Epidemiologic; D003865:Major Depressive Disorder / Q000188:drug therapy*; D003891:Desipramine / Q000008:administration & dosage / Q000009:adverse effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D000068736:Duloxetine Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects; D019317:Evidence-Based Medicine; D005473:Fluoxetine / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007099:Imipramine / Q000008:administration & dosage / Q000009:adverse effects; D008803:Mianserin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000078785:Mirtazapine; D009661:Nortriptyline / Q000008:administration & dosage / Q000009:adverse effects; D017374:Paroxetine / Q000008:administration & dosage / Q000009:adverse effects; D010879:Piperazines; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D020280:Sertraline / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects; D000069470:Venlafaxine Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects
D000928:Antidepressive Agents; D010879:Piperazines; D014230:Triazoles; D005473:Fluoxetine; D015283:Citalopram; D000639:Amitriptyline; D008803:Mianserin; D017374:Paroxetine; C051752:nefazodone; D000069470:Venlafaxine Hydrochloride; D000068736:Duloxetine Hydrochloride; D000078785:Mirtazapine; D009661:Nortriptyline; D002997:Clomipramine; D007099:Imipramine; D020280:Sertraline; D003891:Desipramine