BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-007768 on 9 September 2015. Downloaded from First- and second-generation antidepressants for depressive disorders in children, adolescents, and young adults: Study Protocol for a Systematic Review and Network Meta- Analysis For peer review only Journal: BMJ Open Manuscript ID: bmjopen-2015-007768 Article Type: Protocol Date Submitted by the Author: 23-Jan-2015 Complete List of Authors: Zhou, Xinyu; The First Affiliated Hospital of Chongqing Medical University, Department of Neurology Bin, Qin; The First Affiliated Hospital of Chongqing Medical University, Department of Neurology Whittington, Craig; UCL, Clinical, Educational and Health Psychology Cohen, David; AP–HP, Hôpital Pitié–Salpétrière, Institut des Systèmes Intelligents et de Robotiques (ISIR), Centre National pour la Recherche Scientifique, Université Pierre et Marie Curie, Department of Child and Adolescent Psychiatry Liu, Yiyun; The First Affiliated Hospital of Chongqing Medical University, Department of Neurology Del Giovane, Cinzia; University of Modena and Reggio Emilia, Clinical and Diagnostic Medicine and Public Health http://bmjopen.bmj.com/ Michael, Kurt; Appalachian State University, Department of Psychology Zhang, Yuqing; The First Affiliated Hospital of Chongqing Medical University, Department of Neurology Xie, Peng; The First Affiliated Hospital of Chongqing Medical University, Department of Neuropsychiatry <b>Primary Subject Mental health Heading</b>: on September 23, 2021 by guest. Protected copyright. Secondary Subject Heading: Paediatrics, Pharmacology and therapeutics Child & adolescent psychiatry < PSYCHIATRY, Depression & mood Keywords: disorders < PSYCHIATRY, CLINICAL PHARMACOLOGY For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-007768 on 9 September 2015. Downloaded from 1 2 3 4 5 First- and second-generation antidepressants for depressive disorders in children, adolescents, 6 7 8 and young adults: Study Protocol for a Systematic Review and Network Meta-Analysis 9 10 1 1 2 3 1 4 5 11 Xinyu Zhou , Bin Qin , Craig Whittington , David Cohen , Yiyun Liu , Cinzia Del Giovane , Kurt D. Michael , Yuqing 12 13 Zhang1, and Peng Xie1 14 15 For peer review only 16 1Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China 17 18 19 2 Research Department of Clinical, Educational and Health Psychology, University College London, London, UK 20 21 22 3 Department of Child and Adolescent Psychiatry, AP–HP, Hôpital Pitié–Salpétrière, Institut des Systèmes Intelligents et 23 24 25 de Robotiques (ISIR), Centre National pour la Recherche Scientifique, Université Pierre et Marie Curie, Paris, France 26 27 28 4Department of Diagnostic, Clinical, and Public Health Medicine, University of Modena and Reggio, Emilia, Modena, 29 30 31 Italy 32 33 5 34 Department of Psychology, Appalachian State University, Boone, North Carolina, USA; http://bmjopen.bmj.com/ 35 36 37 Xinyu Zhou and Bin Qin contributed equally to the protocol. 38 39 40 Direct correspondence to: 41 42 on September 23, 2021 by guest. Protected copyright. Peng Xie, MD, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi 43 44 45 Road, Yuzhong District, Chongqing 400016, China; Tel: +86-023-68485490; Fax: +86-023-68485111; 46 47 48 E-mail: [email protected] 49 50 51 Keywords: depression, child, adolescent, antidepressant, network meta-analysis 52 53 54 Word count: 2402. 55 56 57 58 59 60 1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 21 BMJ Open: first published as 10.1136/bmjopen-2015-007768 on 9 September 2015. Downloaded from 1 2 3 4 5 ABSTRACT 6 7 8 Introduction: Depressive disorders are the most frequent psychiatric disorders in children, adolescents and young 9 10 11 adults, and have adverse effects on their psychosocial functioning. An increasing number of studies are aimed at its 12 13 antidepressants treatment. Questions concerning the efficacy and safety of antidepressants in the treatment of depression 14 15 For peer review only 16 in children and adolescents led us to integrate the available evidence by network meta-analysis to create hierarchies of 17 18 19 these drugs. 20 21 22 Methods and analysis: The databases with PubMed, Embase, the Cochrane Library, Web of Science, CINAHL, 23 24 25 LiLACS, and PsycINFO will be searched from 1966 to January 5, 2015. There are no restrictions on language or type of 26 27 28 publication. Randomized clinical trials assessing first- and second-generation antidepressants against another or placebo 29 30 31 as acute treatment for depressive disorder in patients with children, adolescent, and young adults (under 25 years of age) 32 33 34 will be included. The primary outcome for efficacy will be change scores in depressive symptoms, as measured by the http://bmjopen.bmj.com/ 35 36 37 mean change score of depression rating scales (self- or assessor-rated) from baseline to endpoint. The tolerability of 38 39 40 treatment will be defined as side-effect discontinuation, as defined by the proportion of patients who discontinued 41 42 on September 23, 2021 by guest. Protected copyright. treatment due to adverse events during the study. We will also assess the secondary outcome for efficacy (response in 43 44 45 depressive symptoms), acceptability (all-cause discontinuation), and suicide-related outcomes. We will perform the 46 47 48 Bayesian network meta-analyses for all relative outcome measures. Subgroup analyses and sensitivity analyses will be 49 50 51 conducted to assess the robustness of the findings. 52 53 54 55 56 57 58 59 60 2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-007768 on 9 September 2015. Downloaded from 1 2 3 4 5 Dissemination: The network meta-analysis will provide useful information on antidepressant treatment for child, 6 7 8 adolescent and young adult depression. The results will be disseminated through peer-reviewed publication or 9 10 11 conference presentations. 12 13 Protocol registration: PROSPERO CRD42015016023. 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 23, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 21 BMJ Open: first published as 10.1136/bmjopen-2015-007768 on 9 September 2015. Downloaded from 1 2 3 4 5 Strengths and limitations of this study 6 7 8 1. This Bayesian network meta-analysis can integrate direct evidence with indirect evidence from multiple treatment 9 10 11 comparisons to estimate the interrelations across all treatments. 12 13 2. We will comprehensively assess the efficacy, tolerability, acceptability, and suicide-related outcomes of first- and 14 15 For peer review only 16 second-generation antidepressants for depression in children, adolescents and young adults. 17 18 19 3. Several subgroup and sensitivity analyses will address some clinically relevant questions. 20 21 22 4. This method comprehensively synthesizes data to provide a clinically useful summary that can guide treatment 23 24 25 decisions and guideline development. 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on September 23, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 4 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-007768 on 9 September 2015. Downloaded from 1 2 3 4 5 BACKGROUND 6 7 8 The depressive disorder in children and adolescents is a major public health problem, which showed as the fourth most 9 10 1 11 important disease in the estimation of disease burden. The prevalence of experiencing at least one episode of major 12 13 depression before adulthood is estimated to be approximately 1% to 2% for children (6–12 years old), 2% to 5% for 14 15 For peer review only 16 adolescents (13–18 years old), and 14% to 25% in young adults (19–25 years old).2 As with adults, the course of 17 18 19 depressive disorders in children and adolescents is often characterized by frequent recurrence, protracted episodes, 20 21 22 comorbidity with psychiatric disorders.3 The consequences of an untreated major depression in young people are likely 23 24 25 to be serious impairment in social functioning, e.g. poor school achievement; relational problems with family members 26 27 28 and peers.4 A report from the American Academy of Child and Adolescent Psychiatry (AACAP) indeed that depression 29 30 31 is responsible for over 500,000 suicide attempts by children and adolescents a year, and most of them diagnosed with 32 33 5,6 34 treatable forms of mental illness. Thus, early recognition, diagnosis, and treatment of depression in children and http://bmjopen.bmj.com/ 35 36 37 adolescents is an important strategy for curbing the rising rate of youth suicide seen in many developed and advanced 38 39 7 40 developing nations. 41 42 on September 23, 2021 by guest. Protected copyright. 43 44 45 Since the late 1960 years, first-generation antidepressants, e.g., tricyclic antidepressant drugs (TCAs), have been first 46 47 48 used to treat depressive symptoms in young patients.8 In the U.S., the use of antidepressants in children and adolescents 49 50 51 grew 3- to 10-fold between 1987 and 1996.9 Recently, the efficacy of TCAs has been investigated in at least 13 52 53 54 randomized placebo-controlled studies,10 which showed marginal evidence to support the use of TCAs in the treatment 55 56 57 of depression in only adolescents.