Antidepressants for depressive disorder in children and adolescents: a database of randomised controlled trials

Antidepressants for depressive disorder in children and adolescents: a database of randomised... Background: In recent years, whether, when and how to use antidepressants to treat depressive disorder in children and adolescents has been hotly debated. Relevant evidence on this topic has increased rapidly. In this paper, we present the construction and content of a database of randomised controlled trials of antidepressants to treat depressive disorder in children and adolescents. This database can be freely accessed via our website and will be regularly updated. Description: Major bibliographic databases (PubMed, the Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO and LiLACS), international trial registers and regulatory agencies’ websites were systematically searched for published and unpublished studies up to April 30, 2017. We included randomised controlled trials in which the efficacy or tolerability of any oral antidepressant was compared with that of a control group or any other treatment. In total, 7377 citations from bibliographical databases and 3289 from international trial registers and regulatory agencies’ websites were identified. Of these, 53 trials were eligible for inclusion in the final database. Selected data were extracted from each study, including characteristics of the participants (the study population, setting, diagnostic criteria, type of depression, age, sex, and comorbidity), characteristics of the treatment conditions (the treatment conditions, general information, and detail of pharmacotherapy and psychotherapy) and study characteristics (the sponsor, country, number of sites, blinding method, sample size, treatment duration, depression scales, other scales, and primary outcome measure used, and side-effect monitoring method). Moreover, the risk of bias for each trial were assessed. Conclusion: This database provides information on nearly all randomised controlled trials of antidepressants in children and adolescents. By using this database, researchers can improve research efficiency, avoid inadvertent errors and easily focus on the targeted subgroups in which they are interested. For authors of subsequent reviews, they could only use this database to insure that they have completed a comprehensive review, rather than relied solely on the data from this database. We expect this database could help to promote research on evidence-based practice in the treatment of depressive disorder in children and adolescents. The database could be freely accessed in our website: http://xiepengteam.cn/research/evidence-based-medicine. Keywords: Depressive disorder, Children, Adolescents, Antidepressants, Randomised controlled trials, Database, Meta-analysis, Systematic review * Correspondence: xiepeng973@126.com Yuqing Zhang and Xinyu Zhou contributed equally to this work. Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China Chongqing Key Laboratory for Cerebrovascular Disease Research, Yongchuan Hospital of Chongqing Medical University, Chongqing, China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhang et al. BMC Psychiatry (2018) 18:162 Page 2 of 7 Background inception to April 31, 2017. The following words and Depressive disorder is common in children and adoles- Medical Subject Headings (MeSH) were searched with a cents. Untreated episodes of depressive disorder in these filter for clinical trials: (depress* or dysthymi* or mood groups frequently result in serious impairments in terms disorder* or affective disorder*) AND (adolesc* or child* of personal and social functioning [1, 2]. Although some or boy* or girl* or juvenil* or minors or paediatri* or psychological treatments are demonstrated efficacious pediatri* or pubescen* or school* or student* or teen* or [3–5], many young people cannot access this kind of young or youth*) AND (antidepressant* or selective treatment soon enough [6]. For this reason, antidepres- serotonin reuptake inhibitor* or SSRI or SSRIs or citalo- sants are widely used in children and adolescents, with pram or fluoxetine or paroxetine or sertraline or escita- the prescription of these drugs continuing to increase in lopram or fluvoxamine or serotonin norepinephrine recent years [7]. reuptake inhibitor* or SNRI or SNRIs or venlafaxine or In the past 20 years, the number of trials and review duloxetine or milnacipran or reboxetine or bupropion or articles investigating the efficacy and tolerability of anti- noradrenergic and specific serotonergic antidepressant* depressants in the treatment of depressive disorder in or NaSSA or NaSSAs or mirtazapine or nefazodone or children and adolescents has increased rapidly. Most of trazodone or TCA or TCAs or tricyclic or amersergide the meta-analyses of this work have focused on one spe- or amineptine or amitriptyline or amoxapine or butriptyline cific subgroup of studies, such as a specific class of anti- or chlorpoxiten or clomipramine or clorimipramine or depressants [8–11], a specific population [12–14]ora demexiptiline or desipramine or dibenzepin or dothiepin or specific mode of therapy [15–17]. A recent network doxepin or imipramine or lofepramine or melitracen or meta-analysis in which the authors participated found a metapramine or nortriptyline or noxiptiline or opipramol surprising result that the risk–benefit profile of 14 in- or protriptyline or quinupramine or tianeptine or trimipra- cluded antidepressants in the acute treatment of depres- mine). No restrictions were set on language. In addition, sion did not seem to offer a clear advantage of using international trial registers and a regulatory agency’sweb- these drugs for children and adolescents [18]. However, site (US Food and Drug Administration (FDA)) were this result was limited by the low quality of evidence for searched for published and unpublished studies. most of the comparisons and influenced by potential We began the project and conducted the original moderators (e.g., the implementation deficits among searches for several subgroups of studies in December studies [19]). Thus, the questions of whether antidepres- 2013. We then conducted another search with more sants are effective and safe for children and adolescents comprehensive search terms (listed above) for all studies with depressive disorder and which is the most suitable on May 31, 2015. We updated the search on April 30, drug for different subgroups among these populations 2017. Table 1 presents the number of citations identified remain uncertain. It is vital for us to constantly update from each bibliographic database and trial register. In the evidence and consolidate our knowledge in this field total, 7377 citations were identified from the bibliographic to better support clinical decisions. databases, and 3289 were identified from the international Our group is engaged in research on evidence-based trial registers and the FDA website. Further, relevant medicine for depression in children and adolescents. In the principal manufacturers (e.g. GlaxoSmithKline, Lilly, past 5 years, we have built a database of all randomised Organon, Forest Pharmaceuticals, Bristol-Myers Squibb) controlled trials (RCTs) of antidepressants in children and were contacted, and some relevant journals and confer- adolescents with depressive disorder. Using subgroups ence proceedings were manually searched. Additional of studies in this database, we have published five relevant studies were obtained by scanning the reference meta-analyses focusing on different topic [10–12, 14, 18]. lists of relevant systematic reviews, meta-analyses and In this paper, we present the method and process of estab- eligible trials [20]. lishing the database and briefly introduce the characteris- tics of the included studies. Other researchers can easily Inclusion of studies access the dataset and use it for further analysis. The For the database, we selected the studies in which (1) database can be freely accessed in our website: http:// children and adolescents (aged 6–18 years at initial trial xiepengteam.cn/research/evidence-based-medicine. enrolment) were included, (2) a primary diagnosis of current depressive disorder was confirmed by standar- Construction and content dised diagnostic interviews based on international classi- Identification and selection of studies fications (e.g. the Diagnostic and Statistical Manual of We conducted a comprehensive search of seven elec- Mental Disorders, and the International Classification of tronic databases (PubMed, the Cochrane Library, Web Diseases [21–25]), (3) the efficacy or tolerability of an of Science, Embase, CINAHL, PsycINFO and LiLACS) oral antidepressant or combined therapy (pharmacother- for RCTs published from the date of each database’s apy plus psychotherapy) was compared with that of a Zhang et al. BMC Psychiatry (2018) 18:162 Page 3 of 7 Table 1 Number of abstracts identified at each search Databases and Trial registers: Titles and abstracts First search Published before May 2015 Updated May 2015–April 2017 Databases PubMed 364 341 Cochrane 1556 209 Web of Science 1743 406 Embase 638 284 CINAHL 172 31 PsychInfo 1277 288 LILACS 44 24 Total (databases) 5794 1583 Trial registers Australia (ANZCTR) 108 15 China (ChiCTR) 12 2 USA (ClinicalTrials.gov) 214 15 Japan (UMIN-CTR) 56 10 Netherlands (Trial Register) 14 3 UN (ISRCTN) 110 9 World Health Organization (ICTRP) 1003 154 USA Food and Drug Administration (FDA) 992 572 Total (trial registers) 2509 780 control condition or any other treatment, and (4) a com- Next, 33 records were reviewed in detail. Finally, three eli- pletely randomised design was adopted. gible publications from trial registers and the FDA website Antidepressants can be divided into several classes, for were included. Additionally, we obtained further studies example, tricyclic antidepressants (TCAs), selective sero- from inquiries to pharmaceutical companies. In total, 50 tonin reuptake inhibitors (SSRIs), serotonin–norepin- publications (reporting the results of 53 RCTs) were in- ephrine reuptake inhibitors (SNRIs), and noradrenergic cluded in the final database. All disagreements between and specific serotonergic antidepressants (NaSSAs). In reviewers in the screening process were resolved through this database, RCTs comparing any antidepressant with discussion with a senior reviewer (PX or XZ) in the team. an active comparator or placebo for the treatment of de- Figure 1 presents a flowchart illustrating the screening pressive disorder in children and adolescents were in- process in detail. cluded, regardless of the class of drug, dose range and treatment duration. Trials including participants with Data extraction any psychiatric comorbidity or physical disease were also At least two reviewers independently extracted the key pa- selected for inclusion. rameters from each included study using a standardised data abstraction form. Any disagreements were resolved Screening process through discussion with a senior reviewer (PX or XZ) in We identified 7377 potentially relevant studies from the the team. Although different meta-analyses focus on dif- bibliographic databases. After removing 2128 duplicate ferent characteristics, we summarised and extracted the records, 5249 titles and abstracts were reviewed by two following important items for each trial: independent reviewers. Of these, 5020 studies were ex- cluded because they did not meet the inclusion criterion. Characteristics of participants The full text of the remaining 229 articles was reviewed. From these, 46 articles were deemed eligible, and 183 were  Population: In this column, the targeted population, excluded from the final database. In terms of international such as children (aged 6–12 years) or adolescents trial registers and the FDA website, 3289 citations were (aged 13–18 years) in general, adolescents with initially identified. Two independent reviewers independ- treatment-resistant depression or adolescents with ently scanned the titles, and 3256 studies were excluded. substance use disorder, is described in each trial. Zhang et al. BMC Psychiatry (2018) 18:162 Page 4 of 7 Fig. 1 Process of literature search and study selection. RCT = randomised controlled trial Setting: This column indicates whether outpatients psychotherapy, combined therapy or control or inpatients were recruited for the study. condition. In the ‘N baseline’ column, we report the Diagnostic criteria: Here, we report the diagnostic number of participants randomly assigned to each criteria used for the diagnosis of depressive disorder condition. in children and adolescents.  Pharmacotherapy: In these columns, we describe the Type of depression: In this column, we describe the name, class (such as SSRI, SNRI, TCA or NaSSA) types of depression included (major depressive and dose range of the antidepressants used in the disorder, dysthymic disorder, depressive disorder not condition of pharmacotherapy or combined therapy. otherwise specified, minor depression, etc.) and the  Psychotherapy: In these columns, we describe the proportion of patients with each type in the study. characteristics of the psychotherapies used in the Age: Participants’ age is reported here, with the condition of psychotherapy or combined therapy. range and mean presented in two columns. The ‘Type’ column refers to the type of Sex: Here, we report the proportion of participants psychotherapy (cognitive behaviour therapy, who are female. interpersonal therapy, family therapy, etc.) [3]. The Comorbidity: This column describes the types of ‘Format’ column indicates the format used in the psychiatric comorbidity of participants, and if psychotherapy (e.g. individual therapy, group available, the proportion of participants in each therapy, bibliotherapy or Internet-assisted therapy). comorbidity is also reported. In the ‘Number of sessions’ column, we report the number of psychotherapy sessions. Characteristics of treatment conditions Study characteristics Conditions: Here, we briefly describe all the conditions examined in each trial. This column  Sponsor: Here, we indicate the sponsor of the trial, provides an overall impression of the group which may include pharmaceutical industries and assignment in each trial. non-profit organisations. General: Here, for each trial, we describe the general  Country: In this column, we report the country information about every condition included. In the where the trial was conducted. ‘Type’ column, we describe the general types of  Number of sites: This column report the number of conditions, such as pharmacotherapy, sites in each trial. Zhang et al. BMC Psychiatry (2018) 18:162 Page 5 of 7 Blinding: The blinding method used in each trial is efficacy or tolerability of an intervention involving any indicated in this column, including ‘Double-blind’, antidepressant with that of a control group or any other ‘Single-blind’ and ‘Non-blind’. treatment. Using this database, other researchers can not Sample size: This column refers to the total number only save a large amount of time through the searching, of randomly assigned participants in each trial. screening and checking publications from various re- Treatment duration: In this column, the total sources that we have done, but also avoid inadvertent treatment duration is reported. If a trial conducted omissions and overlaps with existing studies. In addition, extension treatment, we also indicate the acute this database will make it convenient for other reviewers treatment duration. to re-analyse the results from previous meta-analyses in- Depression scales: In this column, we report the dependently; this will increase the transparency and reli- main depression measurement scales that the study ability of the methods used in research by different used to measure depressive symptom severity. review teams. Other scales: Here, we report other important scales In addition, this database describes the characteristics used in each trial. of studies, participants and interventions in detail. This Primary outcome measure: This column indicates will allow other researchers to quickly get a comprehen- what was used as the primary outcome measure in sive overview of the existing evidence regarding pharma- each trial. cotherapy for depressive disorder in children and Side-effect monitoring: In this column, the method adolescents. It will also help scholars to focus on the of side-effect monitoring in each trial is briefly specific subgroups they interested, such as studies in descript as ‘spontaneous’, ‘unstructured’, ‘structured’, which patients with similar characteristics, interventions and ‘measured with ...’. with same types or classes, and outcomes with same measurements. By pooling these similar studies, more We did not include the original quantitative values of targeted systematic reviews and meta-analyses, with less the measures or the effect sizes in this database, because mistakes and incorrect estimations, will be produced. different meta-analyses may require different statistical This will finally promote the optimisation of clinical de- approaches and the corresponding datasets. Our main cision making. purpose was not to extract all data from each study, but Furthermore, the risk of bias of included trials has rather to provide a comprehensive overview and tell been assessed within Cochrane risk of bias tool. How- other researchers what they can do. Thus, we only re- ever, it is important to note that the methodology of ported the kind of measures used in each trial. RCTs progressed over time, resulting that the quality of trial in this database varied dramatically from early TCA Risk of bias assessment trials to more recent SSRI trials. Thus, researchers using Two investigators independently assessed the risk of bias this database should not simply group poor quality stud- of included trials using the Cochrane risk of bias tool ies and make poor quality conclusions. Reasonable sub- [26]. The risk of bias was rated as ‘L’(low risk), ‘U’(un- group analyses, meta-regression or sensitive analyses clear risk) or ‘H’(high risk) within the following items: according to risk of bias and publication year are sug- sequence generation, allocation concealment, blinding of gested. In addition, the interpretation of such results participants and personnel, blinding of outcome asses- should be in caution. sors, incomplete outcome data, selective outcome Considering that this field has attracted a great deal of reporting and other sources of bias. As it is usually not attention and that relevant studies have increased rapidly possible to perform blindness for participants and in recent years, we will continue to update this database personnel in psychotherapy trials, this term was rated as by keep searching the seven major literature databases, high risk in all these trials. It is noted that the risk of the major international trial registers and FDA reports. bias tool could not cover each aspect of bias, which may In addition, we will continue to retrieve reference lists of include the information about who the investigators the relevant studies and contact manufacturers for in- were and their specific expertise, how selected, how dustry data. The update time will be between May and trained, how monitored over the course of the study for July in each year. And the update results will be reported maintaining quality in recruitment, retention, etc. These in our website. Moreover, we will continue to search and are also an important area of bias but usually hard to check potentially eligible studies that were omitted in assess. previous searches. Utility Discussion This database includes nearly all RCTs of depressive dis- In 2004, the US FDA cautioned that the use of antide- order in children and adolescents that compare the pressants in children and adolescents may be associated Zhang et al. BMC Psychiatry (2018) 18:162 Page 6 of 7 with increased risk for suicidality [27]. In addition, a re- complete and accurate. Thus, if anyone found a mistake cent network meta-analysis found that most antidepres- or an omitted study that meets our inclusion criteria, sants may ineffective for children and adolescents with please contact us via email: xiepeng973@126.com. Finally, depressive disorder [18]. Therefore, whether antidepres- it is possible that some caveats indicated in this paper will sants are effective and safe for the treatment of depres- not be applicable in the future, and some future problems sion in children and adolescents has caused great will be identified in the updated literature. Therefore, we concern in the recent years. However, from limited num- will continue to update the caveats in our website: http:// ber and poor quality of the current evidence, we could xiepengteam.cn/research/evidence-based-medicine. not draw a reliable conclusion. Thus, a constantly up- dated database, which collected and will continue to col- Conclusions lect all relevant RCTs in this field, will be helpful for us The present database collects nearly all randomised con- to find this answer in the future. trolled trials of antidepressants for treating depressive dis- This paper presented the construction method and order in children and adolescents. By using the process of a free online database of RCTs of antidepres- comprehensive and well maintained database, researchers sants for treating depressive disorder in children and ad- can improve research efficiency, avoid inadvertent errors olescents. The content and utility of this database were and easily focus on their interested subgroups. This data- also described. By using this database, researchers could base will help to promote the performance of high-quality quickly find the evidence regarding their interested anti- evidence-based studies in this field, as well as the opti- depressants. It is noted that the purpose of this paper misation of clinical decisions on antidepressants for chil- was not to analyse the studies included in this database, dren and adolescents with depressive disorder. but rather to provide a description of what is currently Abbreviations the most comprehensive resource of RCTs in this field NaSSAs: Noradrenergic and specific serotonergic antidepressants; and to illustrate what this resource can do. RCT: Randomised controlled trial; SNRIs: Serotonin–norepinephrine reuptake Similar databases, such as the Cuijpers et al. database inhibitors; SSRIs: Selective serotonin reuptake inhibitors; TCAs: Tricyclic antidepressants of psychological treatment for adults with depression [28] and the Christensen et al. database of psychosocial Funding interventions for suicidal ideation, plans and attempts This study was supported by the National Key Research and Development [29], have been highly cited and have effectively stimu- Program of China (Grant no. 2017YFA0505700). lated an increase in the quantity and quality of relevant Availability of data and materials reviews. Therefore, we have reason to believe that the This database can be freely accessed via our website: http://xiepengteam.cn/ database described in the present paper will also be use- research/evidence-based-medicine. ful for future research. Authors’ contributions The database does have some limitations. First, there YZ, XZ and PX conceived and designed the project. YZ and XZ drafted the is also a sizable study of antidepressants and psychother- paper, supervised the data extraction, and participated in the data analysis apy for anxiety disorder and obsessive-compulsive dis- and interpretation of results. JP, HZ, LY and LL conducted the search, selected the studies and extracted the data up to 2015. CZ, SY and XJ order (OCD). However, we only included the literature participated in the processes of update searching, data collection and of antidepressants and part of psychotherapies for de- verification. YZ, LY, XZ and PX assessed the risk of bias. All authors read and pressive disorder. Therefore, this database is only part of approved the final version of the manuscript. the antidepressant and psychotherapy picture for intern- Ethics approval and consent to participate alizing conditions. Second, this database only collected Not applicable. the original RCT reports. Whereas some RCTs can de- rive numerous papers that tell more comprehensive stor- Competing interests The authors declare that they have no competing interests. ies of these studies, the original RCT reports are only a limited section of these depression literatures. Third, al- though we attempted to retrieve all available published Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published and unpublished studies that were eligible for this data- maps and institutional affiliations. base, we cannot rule out the possibility that some stud- ies are still missing. Fourth, it is possible that some Author details Department of Neurology, Yongchuan Hospital of Chongqing Medical characteristics of interest to other researchers are not in- University, Chongqing, China. Chongqing Key Laboratory for cluded in the current version of the database. Thus, we Cerebrovascular Disease Research, Yongchuan Hospital of Chongqing will continuously review and expand the content of this Medical University, Chongqing, China. Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. database. We sincerely welcome suggestions from other Department of Neurology, The First Affiliated Hospital of Chongqing reviewers. Fifth, although we have tried to avoid errors, Medical University, 1 Youyi Road, Yuzhong District, Chongqing 400016, we cannot be certain that all of the data are entirely China. Zhang et al. BMC Psychiatry (2018) 18:162 Page 7 of 7 Received: 19 May 2017 Accepted: 15 May 2018 22. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-III-R). 3rd ed. Washington, DC: American Psychiatric Association; 1987. 23. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-IV). 4th ed. 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American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-III). 3rd ed. Washington, DC: American Psychiatric Association; 1980. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Psychiatry Springer Journals

Antidepressants for depressive disorder in children and adolescents: a database of randomised controlled trials

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Abstract

Background: In recent years, whether, when and how to use antidepressants to treat depressive disorder in children and adolescents has been hotly debated. Relevant evidence on this topic has increased rapidly. In this paper, we present the construction and content of a database of randomised controlled trials of antidepressants to treat depressive disorder in children and adolescents. This database can be freely accessed via our website and will be regularly updated. Description: Major bibliographic databases (PubMed, the Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO and LiLACS), international trial registers and regulatory agencies’ websites were systematically searched for published and unpublished studies up to April 30, 2017. We included randomised controlled trials in which the efficacy or tolerability of any oral antidepressant was compared with that of a control group or any other treatment. In total, 7377 citations from bibliographical databases and 3289 from international trial registers and regulatory agencies’ websites were identified. Of these, 53 trials were eligible for inclusion in the final database. Selected data were extracted from each study, including characteristics of the participants (the study population, setting, diagnostic criteria, type of depression, age, sex, and comorbidity), characteristics of the treatment conditions (the treatment conditions, general information, and detail of pharmacotherapy and psychotherapy) and study characteristics (the sponsor, country, number of sites, blinding method, sample size, treatment duration, depression scales, other scales, and primary outcome measure used, and side-effect monitoring method). Moreover, the risk of bias for each trial were assessed. Conclusion: This database provides information on nearly all randomised controlled trials of antidepressants in children and adolescents. By using this database, researchers can improve research efficiency, avoid inadvertent errors and easily focus on the targeted subgroups in which they are interested. For authors of subsequent reviews, they could only use this database to insure that they have completed a comprehensive review, rather than relied solely on the data from this database. We expect this database could help to promote research on evidence-based practice in the treatment of depressive disorder in children and adolescents. The database could be freely accessed in our website: http://xiepengteam.cn/research/evidence-based-medicine. Keywords: Depressive disorder, Children, Adolescents, Antidepressants, Randomised controlled trials, Database, Meta-analysis, Systematic review * Correspondence: xiepeng973@126.com Yuqing Zhang and Xinyu Zhou contributed equally to this work. Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China Chongqing Key Laboratory for Cerebrovascular Disease Research, Yongchuan Hospital of Chongqing Medical University, Chongqing, China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhang et al. BMC Psychiatry (2018) 18:162 Page 2 of 7 Background inception to April 31, 2017. The following words and Depressive disorder is common in children and adoles- Medical Subject Headings (MeSH) were searched with a cents. Untreated episodes of depressive disorder in these filter for clinical trials: (depress* or dysthymi* or mood groups frequently result in serious impairments in terms disorder* or affective disorder*) AND (adolesc* or child* of personal and social functioning [1, 2]. Although some or boy* or girl* or juvenil* or minors or paediatri* or psychological treatments are demonstrated efficacious pediatri* or pubescen* or school* or student* or teen* or [3–5], many young people cannot access this kind of young or youth*) AND (antidepressant* or selective treatment soon enough [6]. For this reason, antidepres- serotonin reuptake inhibitor* or SSRI or SSRIs or citalo- sants are widely used in children and adolescents, with pram or fluoxetine or paroxetine or sertraline or escita- the prescription of these drugs continuing to increase in lopram or fluvoxamine or serotonin norepinephrine recent years [7]. reuptake inhibitor* or SNRI or SNRIs or venlafaxine or In the past 20 years, the number of trials and review duloxetine or milnacipran or reboxetine or bupropion or articles investigating the efficacy and tolerability of anti- noradrenergic and specific serotonergic antidepressant* depressants in the treatment of depressive disorder in or NaSSA or NaSSAs or mirtazapine or nefazodone or children and adolescents has increased rapidly. Most of trazodone or TCA or TCAs or tricyclic or amersergide the meta-analyses of this work have focused on one spe- or amineptine or amitriptyline or amoxapine or butriptyline cific subgroup of studies, such as a specific class of anti- or chlorpoxiten or clomipramine or clorimipramine or depressants [8–11], a specific population [12–14]ora demexiptiline or desipramine or dibenzepin or dothiepin or specific mode of therapy [15–17]. A recent network doxepin or imipramine or lofepramine or melitracen or meta-analysis in which the authors participated found a metapramine or nortriptyline or noxiptiline or opipramol surprising result that the risk–benefit profile of 14 in- or protriptyline or quinupramine or tianeptine or trimipra- cluded antidepressants in the acute treatment of depres- mine). No restrictions were set on language. In addition, sion did not seem to offer a clear advantage of using international trial registers and a regulatory agency’sweb- these drugs for children and adolescents [18]. However, site (US Food and Drug Administration (FDA)) were this result was limited by the low quality of evidence for searched for published and unpublished studies. most of the comparisons and influenced by potential We began the project and conducted the original moderators (e.g., the implementation deficits among searches for several subgroups of studies in December studies [19]). Thus, the questions of whether antidepres- 2013. We then conducted another search with more sants are effective and safe for children and adolescents comprehensive search terms (listed above) for all studies with depressive disorder and which is the most suitable on May 31, 2015. We updated the search on April 30, drug for different subgroups among these populations 2017. Table 1 presents the number of citations identified remain uncertain. It is vital for us to constantly update from each bibliographic database and trial register. In the evidence and consolidate our knowledge in this field total, 7377 citations were identified from the bibliographic to better support clinical decisions. databases, and 3289 were identified from the international Our group is engaged in research on evidence-based trial registers and the FDA website. Further, relevant medicine for depression in children and adolescents. In the principal manufacturers (e.g. GlaxoSmithKline, Lilly, past 5 years, we have built a database of all randomised Organon, Forest Pharmaceuticals, Bristol-Myers Squibb) controlled trials (RCTs) of antidepressants in children and were contacted, and some relevant journals and confer- adolescents with depressive disorder. Using subgroups ence proceedings were manually searched. Additional of studies in this database, we have published five relevant studies were obtained by scanning the reference meta-analyses focusing on different topic [10–12, 14, 18]. lists of relevant systematic reviews, meta-analyses and In this paper, we present the method and process of estab- eligible trials [20]. lishing the database and briefly introduce the characteris- tics of the included studies. Other researchers can easily Inclusion of studies access the dataset and use it for further analysis. The For the database, we selected the studies in which (1) database can be freely accessed in our website: http:// children and adolescents (aged 6–18 years at initial trial xiepengteam.cn/research/evidence-based-medicine. enrolment) were included, (2) a primary diagnosis of current depressive disorder was confirmed by standar- Construction and content dised diagnostic interviews based on international classi- Identification and selection of studies fications (e.g. the Diagnostic and Statistical Manual of We conducted a comprehensive search of seven elec- Mental Disorders, and the International Classification of tronic databases (PubMed, the Cochrane Library, Web Diseases [21–25]), (3) the efficacy or tolerability of an of Science, Embase, CINAHL, PsycINFO and LiLACS) oral antidepressant or combined therapy (pharmacother- for RCTs published from the date of each database’s apy plus psychotherapy) was compared with that of a Zhang et al. BMC Psychiatry (2018) 18:162 Page 3 of 7 Table 1 Number of abstracts identified at each search Databases and Trial registers: Titles and abstracts First search Published before May 2015 Updated May 2015–April 2017 Databases PubMed 364 341 Cochrane 1556 209 Web of Science 1743 406 Embase 638 284 CINAHL 172 31 PsychInfo 1277 288 LILACS 44 24 Total (databases) 5794 1583 Trial registers Australia (ANZCTR) 108 15 China (ChiCTR) 12 2 USA (ClinicalTrials.gov) 214 15 Japan (UMIN-CTR) 56 10 Netherlands (Trial Register) 14 3 UN (ISRCTN) 110 9 World Health Organization (ICTRP) 1003 154 USA Food and Drug Administration (FDA) 992 572 Total (trial registers) 2509 780 control condition or any other treatment, and (4) a com- Next, 33 records were reviewed in detail. Finally, three eli- pletely randomised design was adopted. gible publications from trial registers and the FDA website Antidepressants can be divided into several classes, for were included. Additionally, we obtained further studies example, tricyclic antidepressants (TCAs), selective sero- from inquiries to pharmaceutical companies. In total, 50 tonin reuptake inhibitors (SSRIs), serotonin–norepin- publications (reporting the results of 53 RCTs) were in- ephrine reuptake inhibitors (SNRIs), and noradrenergic cluded in the final database. All disagreements between and specific serotonergic antidepressants (NaSSAs). In reviewers in the screening process were resolved through this database, RCTs comparing any antidepressant with discussion with a senior reviewer (PX or XZ) in the team. an active comparator or placebo for the treatment of de- Figure 1 presents a flowchart illustrating the screening pressive disorder in children and adolescents were in- process in detail. cluded, regardless of the class of drug, dose range and treatment duration. Trials including participants with Data extraction any psychiatric comorbidity or physical disease were also At least two reviewers independently extracted the key pa- selected for inclusion. rameters from each included study using a standardised data abstraction form. Any disagreements were resolved Screening process through discussion with a senior reviewer (PX or XZ) in We identified 7377 potentially relevant studies from the the team. Although different meta-analyses focus on dif- bibliographic databases. After removing 2128 duplicate ferent characteristics, we summarised and extracted the records, 5249 titles and abstracts were reviewed by two following important items for each trial: independent reviewers. Of these, 5020 studies were ex- cluded because they did not meet the inclusion criterion. Characteristics of participants The full text of the remaining 229 articles was reviewed. From these, 46 articles were deemed eligible, and 183 were  Population: In this column, the targeted population, excluded from the final database. In terms of international such as children (aged 6–12 years) or adolescents trial registers and the FDA website, 3289 citations were (aged 13–18 years) in general, adolescents with initially identified. Two independent reviewers independ- treatment-resistant depression or adolescents with ently scanned the titles, and 3256 studies were excluded. substance use disorder, is described in each trial. Zhang et al. BMC Psychiatry (2018) 18:162 Page 4 of 7 Fig. 1 Process of literature search and study selection. RCT = randomised controlled trial Setting: This column indicates whether outpatients psychotherapy, combined therapy or control or inpatients were recruited for the study. condition. In the ‘N baseline’ column, we report the Diagnostic criteria: Here, we report the diagnostic number of participants randomly assigned to each criteria used for the diagnosis of depressive disorder condition. in children and adolescents.  Pharmacotherapy: In these columns, we describe the Type of depression: In this column, we describe the name, class (such as SSRI, SNRI, TCA or NaSSA) types of depression included (major depressive and dose range of the antidepressants used in the disorder, dysthymic disorder, depressive disorder not condition of pharmacotherapy or combined therapy. otherwise specified, minor depression, etc.) and the  Psychotherapy: In these columns, we describe the proportion of patients with each type in the study. characteristics of the psychotherapies used in the Age: Participants’ age is reported here, with the condition of psychotherapy or combined therapy. range and mean presented in two columns. The ‘Type’ column refers to the type of Sex: Here, we report the proportion of participants psychotherapy (cognitive behaviour therapy, who are female. interpersonal therapy, family therapy, etc.) [3]. The Comorbidity: This column describes the types of ‘Format’ column indicates the format used in the psychiatric comorbidity of participants, and if psychotherapy (e.g. individual therapy, group available, the proportion of participants in each therapy, bibliotherapy or Internet-assisted therapy). comorbidity is also reported. In the ‘Number of sessions’ column, we report the number of psychotherapy sessions. Characteristics of treatment conditions Study characteristics Conditions: Here, we briefly describe all the conditions examined in each trial. This column  Sponsor: Here, we indicate the sponsor of the trial, provides an overall impression of the group which may include pharmaceutical industries and assignment in each trial. non-profit organisations. General: Here, for each trial, we describe the general  Country: In this column, we report the country information about every condition included. In the where the trial was conducted. ‘Type’ column, we describe the general types of  Number of sites: This column report the number of conditions, such as pharmacotherapy, sites in each trial. Zhang et al. BMC Psychiatry (2018) 18:162 Page 5 of 7 Blinding: The blinding method used in each trial is efficacy or tolerability of an intervention involving any indicated in this column, including ‘Double-blind’, antidepressant with that of a control group or any other ‘Single-blind’ and ‘Non-blind’. treatment. Using this database, other researchers can not Sample size: This column refers to the total number only save a large amount of time through the searching, of randomly assigned participants in each trial. screening and checking publications from various re- Treatment duration: In this column, the total sources that we have done, but also avoid inadvertent treatment duration is reported. If a trial conducted omissions and overlaps with existing studies. In addition, extension treatment, we also indicate the acute this database will make it convenient for other reviewers treatment duration. to re-analyse the results from previous meta-analyses in- Depression scales: In this column, we report the dependently; this will increase the transparency and reli- main depression measurement scales that the study ability of the methods used in research by different used to measure depressive symptom severity. review teams. Other scales: Here, we report other important scales In addition, this database describes the characteristics used in each trial. of studies, participants and interventions in detail. This Primary outcome measure: This column indicates will allow other researchers to quickly get a comprehen- what was used as the primary outcome measure in sive overview of the existing evidence regarding pharma- each trial. cotherapy for depressive disorder in children and Side-effect monitoring: In this column, the method adolescents. It will also help scholars to focus on the of side-effect monitoring in each trial is briefly specific subgroups they interested, such as studies in descript as ‘spontaneous’, ‘unstructured’, ‘structured’, which patients with similar characteristics, interventions and ‘measured with ...’. with same types or classes, and outcomes with same measurements. By pooling these similar studies, more We did not include the original quantitative values of targeted systematic reviews and meta-analyses, with less the measures or the effect sizes in this database, because mistakes and incorrect estimations, will be produced. different meta-analyses may require different statistical This will finally promote the optimisation of clinical de- approaches and the corresponding datasets. Our main cision making. purpose was not to extract all data from each study, but Furthermore, the risk of bias of included trials has rather to provide a comprehensive overview and tell been assessed within Cochrane risk of bias tool. How- other researchers what they can do. Thus, we only re- ever, it is important to note that the methodology of ported the kind of measures used in each trial. RCTs progressed over time, resulting that the quality of trial in this database varied dramatically from early TCA Risk of bias assessment trials to more recent SSRI trials. Thus, researchers using Two investigators independently assessed the risk of bias this database should not simply group poor quality stud- of included trials using the Cochrane risk of bias tool ies and make poor quality conclusions. Reasonable sub- [26]. The risk of bias was rated as ‘L’(low risk), ‘U’(un- group analyses, meta-regression or sensitive analyses clear risk) or ‘H’(high risk) within the following items: according to risk of bias and publication year are sug- sequence generation, allocation concealment, blinding of gested. In addition, the interpretation of such results participants and personnel, blinding of outcome asses- should be in caution. sors, incomplete outcome data, selective outcome Considering that this field has attracted a great deal of reporting and other sources of bias. As it is usually not attention and that relevant studies have increased rapidly possible to perform blindness for participants and in recent years, we will continue to update this database personnel in psychotherapy trials, this term was rated as by keep searching the seven major literature databases, high risk in all these trials. It is noted that the risk of the major international trial registers and FDA reports. bias tool could not cover each aspect of bias, which may In addition, we will continue to retrieve reference lists of include the information about who the investigators the relevant studies and contact manufacturers for in- were and their specific expertise, how selected, how dustry data. The update time will be between May and trained, how monitored over the course of the study for July in each year. And the update results will be reported maintaining quality in recruitment, retention, etc. These in our website. Moreover, we will continue to search and are also an important area of bias but usually hard to check potentially eligible studies that were omitted in assess. previous searches. Utility Discussion This database includes nearly all RCTs of depressive dis- In 2004, the US FDA cautioned that the use of antide- order in children and adolescents that compare the pressants in children and adolescents may be associated Zhang et al. BMC Psychiatry (2018) 18:162 Page 6 of 7 with increased risk for suicidality [27]. In addition, a re- complete and accurate. Thus, if anyone found a mistake cent network meta-analysis found that most antidepres- or an omitted study that meets our inclusion criteria, sants may ineffective for children and adolescents with please contact us via email: xiepeng973@126.com. Finally, depressive disorder [18]. Therefore, whether antidepres- it is possible that some caveats indicated in this paper will sants are effective and safe for the treatment of depres- not be applicable in the future, and some future problems sion in children and adolescents has caused great will be identified in the updated literature. Therefore, we concern in the recent years. However, from limited num- will continue to update the caveats in our website: http:// ber and poor quality of the current evidence, we could xiepengteam.cn/research/evidence-based-medicine. not draw a reliable conclusion. Thus, a constantly up- dated database, which collected and will continue to col- Conclusions lect all relevant RCTs in this field, will be helpful for us The present database collects nearly all randomised con- to find this answer in the future. trolled trials of antidepressants for treating depressive dis- This paper presented the construction method and order in children and adolescents. By using the process of a free online database of RCTs of antidepres- comprehensive and well maintained database, researchers sants for treating depressive disorder in children and ad- can improve research efficiency, avoid inadvertent errors olescents. The content and utility of this database were and easily focus on their interested subgroups. This data- also described. By using this database, researchers could base will help to promote the performance of high-quality quickly find the evidence regarding their interested anti- evidence-based studies in this field, as well as the opti- depressants. It is noted that the purpose of this paper misation of clinical decisions on antidepressants for chil- was not to analyse the studies included in this database, dren and adolescents with depressive disorder. but rather to provide a description of what is currently Abbreviations the most comprehensive resource of RCTs in this field NaSSAs: Noradrenergic and specific serotonergic antidepressants; and to illustrate what this resource can do. RCT: Randomised controlled trial; SNRIs: Serotonin–norepinephrine reuptake Similar databases, such as the Cuijpers et al. database inhibitors; SSRIs: Selective serotonin reuptake inhibitors; TCAs: Tricyclic antidepressants of psychological treatment for adults with depression [28] and the Christensen et al. database of psychosocial Funding interventions for suicidal ideation, plans and attempts This study was supported by the National Key Research and Development [29], have been highly cited and have effectively stimu- Program of China (Grant no. 2017YFA0505700). lated an increase in the quantity and quality of relevant Availability of data and materials reviews. Therefore, we have reason to believe that the This database can be freely accessed via our website: http://xiepengteam.cn/ database described in the present paper will also be use- research/evidence-based-medicine. ful for future research. Authors’ contributions The database does have some limitations. First, there YZ, XZ and PX conceived and designed the project. YZ and XZ drafted the is also a sizable study of antidepressants and psychother- paper, supervised the data extraction, and participated in the data analysis apy for anxiety disorder and obsessive-compulsive dis- and interpretation of results. JP, HZ, LY and LL conducted the search, selected the studies and extracted the data up to 2015. CZ, SY and XJ order (OCD). However, we only included the literature participated in the processes of update searching, data collection and of antidepressants and part of psychotherapies for de- verification. YZ, LY, XZ and PX assessed the risk of bias. All authors read and pressive disorder. Therefore, this database is only part of approved the final version of the manuscript. the antidepressant and psychotherapy picture for intern- Ethics approval and consent to participate alizing conditions. Second, this database only collected Not applicable. the original RCT reports. Whereas some RCTs can de- rive numerous papers that tell more comprehensive stor- Competing interests The authors declare that they have no competing interests. ies of these studies, the original RCT reports are only a limited section of these depression literatures. Third, al- though we attempted to retrieve all available published Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published and unpublished studies that were eligible for this data- maps and institutional affiliations. base, we cannot rule out the possibility that some stud- ies are still missing. Fourth, it is possible that some Author details Department of Neurology, Yongchuan Hospital of Chongqing Medical characteristics of interest to other researchers are not in- University, Chongqing, China. Chongqing Key Laboratory for cluded in the current version of the database. 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BMC PsychiatrySpringer Journals

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