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BMJ Open
First- and second-generation antidepressants for depressive
disorders in children, adolescents, and young adults: Study
Protocol for a Systematic Review and Network MetaAnalysis
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Journal:
Manuscript ID:
Article Type:
Date Submitted by the Author:
bmjopen-2015-007768
Protocol
23-Jan-2015
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Complete List of Authors:
BMJ Open
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Zhou, Xinyu; The First Affiliated Hospital of Chongqing Medical University,
Department of Neurology
Bin, Qin; The First Affiliated Hospital of Chongqing Medical University,
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,
Del Giovane, Cinzia; University of Modena and Reggio Emilia, Clinical and
Diagnostic Medicine and Public Health
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
Secondary Subject Heading:
Paediatrics, Pharmacology and therapeutics
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Keywords:
Mental health
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Primary Subject
Heading:
Child & adolescent psychiatry < PSYCHIATRY, Depression & mood
disorders < PSYCHIATRY, CLINICAL PHARMACOLOGY
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
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First- and second-generation antidepressants for depressive disorders in children, adolescents,
and young adults: Study Protocol for a Systematic Review and Network Meta-Analysis
Xinyu Zhou1, Bin Qin1, Craig Whittington2, David Cohen3, Yiyun Liu1, Cinzia Del Giovane4, Kurt D. Michael5, Yuqing
Zhang1, and Peng Xie1
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Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Research Department of Clinical, Educational and Health Psychology, University College London, London, UK
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Department of Child and Adolescent Psychiatry, AP–HP, Hôpital Pitié–Salpétrière, Institut des Systèmes Intelligents et
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de Robotiques (ISIR), Centre National pour la Recherche Scientifique, Université Pierre et Marie Curie, Paris, France
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Department of Diagnostic, Clinical, and Public Health Medicine, University of Modena and Reggio, Emilia, Modena,
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Italy
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Department of Psychology, Appalachian State University, Boone, North Carolina, USA;
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Direct correspondence to:
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Xinyu Zhou and Bin Qin contributed equally to the protocol.
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Peng Xie, MD, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi
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Road, Yuzhong District, Chongqing 400016, China; Tel: +86-023-68485490; Fax: +86-023-68485111;
E-mail: xiepeng973@126.com
Keywords: depression, child, adolescent, antidepressant, network meta-analysis
Word count: 2402.
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ABSTRACT
Introduction: Depressive disorders are the most frequent psychiatric disorders in children, adolescents and young
adults, and have adverse effects on their psychosocial functioning. An increasing number of studies are aimed at its
antidepressants treatment. Questions concerning the efficacy and safety of antidepressants in the treatment of depression
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in children and adolescents led us to integrate the available evidence by network meta-analysis to create hierarchies of
these drugs.
Methods and analysis: The databases with PubMed, Embase, the Cochrane Library, Web of Science, CINAHL,
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LiLACS, and PsycINFO will be searched from 1966 to January 5, 2015. There are no restrictions on language or type of
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publication. Randomized clinical trials assessing first- and second-generation antidepressants against another or placebo
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as acute treatment for depressive disorder in patients with children, adolescent, and young adults (under 25 years of age)
will be included. The primary outcome for efficacy will be change scores in depressive symptoms, as measured by the
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mean change score of depression rating scales (self- or assessor-rated) from baseline to endpoint. The tolerability of
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treatment will be defined as side-effect discontinuation, as defined by the proportion of patients who discontinued
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treatment due to adverse events during the study. We will also assess the secondary outcome for efficacy (response in
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depressive symptoms), acceptability (all-cause discontinuation), and suicide-related outcomes. We will perform the
Bayesian network meta-analyses for all relative outcome measures. Subgroup analyses and sensitivity analyses will be
conducted to assess the robustness of the findings.
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Dissemination: The network meta-analysis will provide useful information on antidepressant treatment for child,
adolescent and young adult depression. The results will be disseminated through peer-reviewed publication or
conference presentations.
Protocol registration: PROSPERO CRD42015016023.
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Strengths and limitations of this study
1. This Bayesian network meta-analysis can integrate direct evidence with indirect evidence from multiple treatment
comparisons to estimate the interrelations across all treatments.
2. We will comprehensively assess the efficacy, tolerability, acceptability, and suicide-related outcomes of first- and
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second-generation antidepressants for depression in children, adolescents and young adults.
3. Several subgroup and sensitivity analyses will address some clinically relevant questions.
4. This method comprehensively synthesizes data to provide a clinically useful summary that can guide treatment
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decisions and guideline development.
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BACKGROUND
The depressive disorder in children and adolescents is a major public health problem, which showed as the fourth most
important disease in the estimation of disease burden.1 The prevalence of experiencing at least one episode of major
depression before adulthood is estimated to be approximately 1% to 2% for children (6–12 years old), 2% to 5% for
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adolescents (13–18 years old), and 14% to 25% in young adults (19–25 years old).2 As with adults, the course of
depressive disorders in children and adolescents is often characterized by frequent recurrence, protracted episodes,
comorbidity with psychiatric disorders.3 The consequences of an untreated major depression in young people are likely
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to be serious impairment in social functioning, e.g. poor school achievement; relational problems with family members
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and peers.4 A report from the American Academy of Child and Adolescent Psychiatry (AACAP) indeed that depression
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is responsible for over 500,000 suicide attempts by children and adolescents a year, and most of them diagnosed with
treatable forms of mental illness.5,6 Thus, early recognition, diagnosis, and treatment of depression in children and
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adolescents is an important strategy for curbing the rising rate of youth suicide seen in many developed and advanced
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developing nations.7
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Since the late 1960 years, first-generation antidepressants, e.g., tricyclic antidepressant drugs (TCAs), have been first
used to treat depressive symptoms in young patients.8 In the U.S., the use of antidepressants in children and adolescents
grew 3- to 10-fold between 1987 and 1996.9 Recently, the efficacy of TCAs has been investigated in at least 13
randomized placebo-controlled studies,10 which showed marginal evidence to support the use of TCAs in the treatment
of depression in only adolescents. However, methodological deficiencies in these studies, including small sample sizes
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and diagnostic heterogeneity, as well as none of trials as being at low risk of bias, restrict statistical inference and
generalizability of the findings. At the same time, cardiovascular effects and overdose-related mortality associated with
TCA use have greatly limited their use in clinical practice. 11,12 Nevertheless, nortriptyline is still approved by the Food
and Drug Administration (FDA) for the treatment of depression in adolescents and adults.13
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In recent decades, new-generation antidepressants, e.g., selective serotonin reuptake inhibitors (SSRIs), have been
wildly used for the treatment of depression in children and adolescents.14The frequency of prescription of SSRIs in
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children and adolescents has progressively increased.15 In European countries, there has been a doubling of SSRI use
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over the 4-year period.16 However, only fluoxetine, a SSRIs antidepressant, was approved by the U.S FDA for treating
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depression in children and adolescents in January 2003.17 At the same year, concerns about the increased risk of suicide
and suicide attempts with SSRIs were first raised.18 In September 2004, the Food and Drug Administration cautioned
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practitioners in the use of antidepressant medications in children and adolescents.19 Similar warnings were issued by
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other health regulatory agencies.20-22 Thus, concerns about this issue have refocused attention on the question of how
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effective antidepressants are with youth depression, the most prominent medication alternative.
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The relative effect sizes between different antidepressant medications in these previous reviews were derived from
indirect comparisons between separate placebo-controlled trials,14,17,23,24 while very few from direct comparisons
between active-controlled trials.25 Moreover, the problem of lumping together different antidepressant drugs would limit
the available effect size of each antidepressant. For these reasons, we employed a network meta-analysis –a
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methodological approach that allows the simultaneous comparison of multiple psychotherapeutic interventions within a
single analysis, while preserving randomization.26 This approach is applied to integrate direct evidence (from studies
directly comparing interventions) with indirect evidence (information about two treatments derived via a common
comparator) from multiple treatment comparisons to estimate the interrelations across all treatments.27 We have
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previously compared the efficacy and acceptability of psychotherapies for depression in children and adolescents28 and
the augmentation agents for treatment-resistant depression in adults29 in this way. The aim of the network meta-analysis
is of randomized controlled studies is to re- analyze systematically the efficacy, tolerability, acceptability and suicide
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risk of both first- and second-generation antidepressants, either against another antidepressant or against a control
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condition, in the treatment of child and adolescent depression.
METHODS
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Criteria for included studies
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Types of studies
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Any prospective randomized controlled trials (RCTs) will be included. When trial with crossover design, the
results will be only included from the first randomization period. However, quasi-randomized trials (e.g., those
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allocating using alternate days of the week) will be excluded. Trials with sample sizes smaller than 10 will be excluded
in the review.
Types of participants
Children, adolescents, and young adults (aged from 6 to 25 when they initially enrolled in the studies) with a primary
diagnosis of current major depressive disorder according to standardized diagnostic interviews, e.g., the Diagnostic and
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Statistical Manual of Mental Disorders (DSM)30-32 or the International Classification of Diseases (ICD)33,34 will be
included. Where patients with adults and youths, the data will be included if data on the depressed youths can be
extracted separately, or obtained from trial authors. We will not excluded trials in which patients with a secondary
diagnosis of comorbid medical or general psychiatric disorders. However, we will exclude studies in which those have a
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diagnosis of resistant depression or psychotic depression.
Types of interventions
RCTs comparing any first- and second- generation antidepressant against another or either placebo for treatment of
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depression in children and adolescents will be included. Trials comparing the same type of antidepressant but at
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different therapeutic dose (fixed or flexible dose) and different treatment duration will be considered as the same node
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in the network analysis. We will exclude studies involving combination therapy (i.e., combination of antidepressants,
combination of antidepressants with psychotherapy, or other non-psychotherapeutic interventions); however, studies
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will be considered as eligible if the concomitant psychotherapy is not predefined in the study.
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Types of outcome measures
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The acute phase will be defined as from 4 to 16 week, and if a study presents data for more than one time period within
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our pre-defined acute phase periods, we will take the 8-week time point. Where depression symptoms are measured
using more than one depression scale in a trial, we will extract data from the depressive scales on the basis of a
hierarchy of rating scales. This hierarchy will be based on psychometric properties and appropriateness for use with
children and adolescents and for consistency of use across trials (the most commonly used tool)14 (see Table 1). The
Children’s Depression Rating Scale (CDRS-R)35 is adapted for children and adolescents from the Hamilton Depression
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Rating Scale (HAMD)36, a tool validated and commonly used in adult populations.37 Both the CDRS-R and HAMD
have good reliability and validity.37 The Beck Depression Inventory (BDI)38/Children’s Depression Inventory (CDI)39
are the most commonly used among depression symptom severity-self rated scales and are ranked the second highest in
the hierarchy.
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1. Overall efficacy
1.1 The primary outcome for efficacy will be change scores in depressive symptoms, as measured by the mean change
score of depression rating scales (self- or assessor-rated) from baseline to endpoint.
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1.2 The secondary outcome for efficacy will be response (or remission) in depressive symptoms, as estimated by the
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proportion of patients who achieved a decrease of a certain percentage or below the threshold in depression rating
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2. Overall tolerability
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The tolerability of treatment will be defined as side-effect discontinuation in this review, as defined by the proportion of
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patients who discontinued treatment due to adverse events during the study.
3. Overall acceptability
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The acceptability of treatment will be defined as all-cause discontinuation, as measured by the proportion of patients
who discontinued treatment (during the delivery of the intervention) up to the post intervention time point.
4. Suicide-related outcomes
We will also assess the suicide-related outcome, as estimated by the proportion of patients with one or more events of
definite suicidal behavior or ideation during the acute treatment phase.41
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Data Sources and Search Strategy
Seven electronic databases (PubMed, Embase, the Cochrane Library, Web of Science, CINAHL, LiLACS, and
PsycINFO) will be searched from 1966 to January 5, 2015 with Medical Subject Headings (MeSH) and text
words： ”depress*” or “dysthymi*” or “mood disorder*” or “affective disorder*” and “selective serotonin reuptake
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inhibitor*” or “SSRIs” or “serotonin norepinephrine reuptake inhibitor*” or “SNRIs” or “citalopram” or “fluoxetine” or
“paroxetine” or “sertraline” or “escitalopram[” or “fluvoxamine” or “venlafaxine” or “duloxetine” or “milnacipran” or
“reboxetine” or “bupropion” or “mirtazapine” or “tricyclic” or “amersergide” or “amineptine” or “amitriptyline” or
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“amoxapine” or “butriptyline” or “chlorpoxiten” or “clomipramine” or “clorimipramine” or “demexiptiline” or
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“desipramine” or “dibenzipin” or “dothiepin” or “doxepin” or “imipramine” or “lofepramine” or “melitracen” or
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“metapramine” or “nortriptyline” or “noxiptiline” or “opipramol” or “protriptyline” or “quinupramine” or “tianeptine”
or “trimipramine” and “adolesc*” or “child*” or “boy*” or “girl*” or “juvenil*” or “minors” or “paediatri*” or
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“pediatri*” or “pubescen*” or “school*” or “student*” or “teen*” or “young” or “youth*”. Also, ClinicalTrials.gov,
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World Health Organization’s trial portal and U.S. Food and Drug Administration (FDA) reports will be reviewed. There
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are no restrictions on language or type of publication. Additional studies will be searched in the reference lists of all
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identified publications including relevant meta-analyses and systematic reviews. All relevant authors and principal
manufacturers will be contacted to supplement incomplete reports of the original papers or to provide new data for
unpublished studies.
Study Selection
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Two reviewers (QB and LYY) will be independently scan citations at the title/abstract level identified from the search
strategies and then obtain potentially relevant studies in full text and determine whether to include them by the same
eligibility criteria. Besides, the references of relevant reviews and included trials will also be checked by the two
reviewers. The reasons for exclusion of trials will be reported in the characteristics of excluded studies tables. Any
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disagreements will be resolved by a third review author (XYZ).
Data Extraction and Risk of bias assessment
Two independent reviewers (YYL, BQ) will independently extract the key study parameters using a standardized data
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abstraction form and assess the risk of bias. The standardized data extraction forms will include the study characteristics
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(e.g., first listed author, publication year, journal, country, institution, and sponsor), patient characteristics (e.g.
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diagnostic criteria for depression, the type of patients, the number of patients, and patients’ baseline), intervention
details (e.g. antidepressant type, dose of antidepressant, the duration of treatment, treatment duration) and outcome
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measures (efficacy, tolerability, acceptability, and suicide-related outcome). The risk of bias in trials will be used by the
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risk of bias tool from the Cochrane Handbook.42 Trials attracting a rating of high risk of bias in one or more domains
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will be considered as ‘high risk’ literature, low risk of bias in all domains as ‘low risk’ literature, and one or more
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unclear risk of bias in each domain as ‘unclear risk’ literature.42 Any disagreements will be resolved by a third review
author (XYZ). Also, we will calculate the inter-rater reliability of the two raters.
Data Synthesis and Analysis
We will perform Bayesian network meta-analysis to compare the relative outcomes of different antidepressants and
placebo with each other from the median of the posterior distribution.26,27 The pooled estimates of standardised mean
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difference (SMD) with 95% credible intervals (CrIs) will be calculated for the continuous outcomes; and odds ratios
(or) with 95% CrIs will be calculated for the categorical outcomes. The SMD is that the difference in means (MD) of
change scores between the two groups divided by the pooled standard deviation (SD) of the measurements, with a
negative SMD value indicates greater symptomatic relief. In the presence of minimally informative priors, CrIs can be
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interpreted similarly to confidence intervals, and at conventional levels of statistical significance a two-sided p <0.05
can be assumed if 95% CrIs do not include 0.42 If means and standard deviations (SDs) are not provided, we will
calculate them from the p-value or other statistical indices as described elsewhere.42,43 Results from intention-to-treat
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analysis (ITT) or modified ITT will be preferred over results from completer analyses, while we will also consider the
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dataset for the means and SDs that are presented in the literature.
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The pooled estimates will be obtained using the Markov Chains Monte Carlo method. Two Markov chains will be run
simultaneously with different arbitrarily chosen initial values. To ensure convergence, trace plots and the Brooks-
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Gelman-Rubin statistic will be assessed.44 Convergence will be found to be adequate after running 50,000 samples for
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both chains. These samples will be then discarded as “burn-in”, and posterior summaries will be based on 100,000
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subsequent simulations. The node splitting method will be used to calculate the inconsistency of the model, which
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separate evidence on a particular comparison into direct and indirect evidence.45 Probability values will be summarized
and reported as surface under the cumulative ranking curve (SUCRA) and rankograms, a simple transformation of the
mean rank used to provide a hierarchy of the treatments and accounts for both the location and the variance of all
relative treatment effects.46 Network meta-analysis will be performed using the WinBUGS software package (version
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1.4.3, MRC Biostatistics Unit, Cambridge, UK) with random effects models for multi-arm trials. The other analyses will
be performed and presented by the Stata 11.0 and R 2.11.1 software packages.
Subgroup analyses
The antidepressants will be coded according to clinical characteristics, risk of bias, and sample size. We will conduct
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the subgroups analyses of data in primary outcome for efficacy. We will performed the following subgroups analyses by
using the meta-regression model and calculated Somer’s D (a correlation coefficient for a dichotomous and an ordinal
variable)47: (i) sex ratio (male-to-female ratio> 1 vs. male-to-female ratio<1); (ii) age group (mean age of less than 13
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vs. mean age of more than or equal 13); (iii) treatment duration (<8 weeks vs. ≥8 weeks); (iv) severity of depressive
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symptom (mild-to-moderate vs. moderate-to-severe); (v) comorbid general psychiatric disorders ( with vs. without
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comorbid); (vi) risk of bias (‘high risk’ literature vs. ‘unclear and low risk’ literature); (viii) sample size (≤100 patients
vs. >100 patients); (ix) company sponsor (with vs. without sponsor); and (x) the type of trials (published literature vs.
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unpublished literature). When the limitation by small number of comparisons for some potential modifiers in carrying
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out subgroup analyses on these variables, we will perform the sensitivity analyses by omitting specific studies from the
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overall analysis.
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Other analyses
We will conduct an additional analysis in Bayesian network model based on including only second-generation
antidepressants in primary efficacy and tolerability outcomes. The funnel plot analyses will be performed to check for
publication bias. Moreover, we will carry out meta-regression analyses to investigate the effect of sponsorship or year
published on outcome estimate.
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Ethics and dissemination
This network meta-analysis does not need ethical approval, as data used here are not individual or private. It will be
published in a peer-reviewed journal. The results will provide a general overview and evidence of efficacy and safety of
antidepressants for depression in children, adolescents and young adults. They will also have implications for clinical
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practice and further research.
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Contributors XZ and BQ conceived the study and drafted the protocol. XZ and PX wrote the first draft of the
manuscript. KDM, CW and DC assisted in protocol design and revision. YL and YZ participated in the search strategy
development. CDG and BQ participated in the design of data synthesis and analysis. All authors have approved the
publication of the protocol
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Funding This work is supported by the National Basic Research Program of China (973 Program) (Grant No.
2009CB918300). The funders had no role in the protocol design; the writing of the protocol; or the decision to submit
the protocol for publication.
Competing interests None.
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Provenance and peer review Not commissioned; externally peer-reviewed.
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Open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution- Non
Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-
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commercially, and license their derivative works on different terms, provided the original work is properly cited and the
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use is non-commercial. See: See: http://creativecommons.org/licenses/by-nc/4.0/
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TABLES
Table 1 Hierarchy of depression symptom severity measurement scales
Hierarchy
Depression symptom severity measurement scales
Abbreviation
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Children’s Depression Rating Scale
CDRS
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Hamilton Depression Rating Scale
HAMD
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Montgomery Asberg Depression Rating Scale
MADRS
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Beck Depression Inventory
BDI
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Children’s Depression Inventory
CDI
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Schedule for Affective Disorders and Schizophrenia for School
K-SADS
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Aged Children
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Mood and Feeling Questionnaire
MFQ
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Reynolds Adolescent Depression Scale
RADS
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Bellevue Index of Depression
BID
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Child Depression Scale
CDS
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Centre for Epidemiologic Studies Depression Scale
CESD
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Child Assessment Schedule
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Child Behavior Checklist-Depression
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CAS
CBCL-D
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46. Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple-
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Comparative efficacy and tolerability of first- and newergeneration antidepressants for depressive disorders in
children and adolescents: Study Protocol for a Systematic
Review and Network Meta-Analysis
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Journal:
Manuscript ID:
Article Type:
bmjopen-2015-007768.R1
Protocol
28-Apr-2015
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Keywords:
Mental health
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Primary Subject
Heading:
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Comparative efficacy and tolerability of first- and newer-generation antidepressants for
depressive disorders in children and adolescents: Study Protocol for a Systematic Review and
Network Meta-Analysis
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ABSTRACT
Introduction: Depressive disorders are among the most common psychiatric disorders in children and adolescents, and
have adverse effects on their psychosocial functioning. Questions concerning the efficacy and safety of antidepressants
in the treatment of depression in children and adolescents led us to integrate the direct and indirect evidence using
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network meta-analysis to create hierarchies of these drugs.
Methods and analysis: Seven databases with PubMed, Embase, the Cochrane Library, Web of Science, CINAHL,
LiLACS, and PsycINFO will be searched from 1966 to December 2013 (updated to January 5, 2015). There are no
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restrictions on language or type of publication. Randomized clinical trials assessing first- and newer-generation
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antidepressants against active comparator or placebo as acute treatment for depressive disorder in children and
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adolescents (under 18 years of age) will be included. The primary outcome for efficacy will be
mean improvement in
depressive symptoms, as measured by the mean change score of a depression rating scale from baseline to post-
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treatment. The tolerability of treatment will be defined as side-effect discontinuation, as defined by the proportion of
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patients who discontinued treatment due to adverse events during the study. We will also assess the secondary outcome
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for efficacy (response rate ), acceptability (all-cause discontinuation), and suicide-related outcomes. We will perform
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the Bayesian network meta-analyses for all relative outcome measures. Subgroup analyses and sensitivity analyses will
be conducted to assess the robustness of the findings.
Dissemination: The network meta-analysis will provide useful information on antidepressant treatment for child and
adolescent depression. The results will be disseminated through peer-reviewed publication or conference presentations.
Protocol registration: PROSPERO CRD42015016023
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newer-generation antidepressants for depression in children and adolescents.
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BACKGROUND
Depressive disorder in children and adolescents is a major public health problem, demonstrated by the disorders ranking
as the third most important in the estimation of disease burden.1 The prevalence of experiencing at least one episode of
major depression before adulthood is estimated to be approximately 1% to 2% for children (6–12 years old), and 2% to
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5% for adolescents (13–18 years old).2 The course of major depression in young people is often characterized by
frequent recurrence, protracted episodes, and comorbid psychiatric disorders.3 The consequences of an untreated
episode of major depression in young people are likely to be serious impairment in social functioning, e.g. poor school
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achievement; relational problems with family members and peers.4 A report from the American Academy of Child and
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Adolescent Psychiatry (AACAP) suggested that depression is responsible for over 500,000 suicide attempts by children
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and adolescents a year, and most of them diagnosed with treatable forms of mental illness.5,6 Thus, early recognition,
diagnosis, and treatment of depression in children and adolescents is an important strategy for curbing the rising rate of
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youth suicide seen in many developed and advanced developing nations.7
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Since the late 1960s, first-generation antidepressants, e.g., tricyclic antidepressant drugs (TCAs), have been used to treat
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depressive symptoms in young patients.8 In the U.S., the use of antidepressants in children and adolescents grew 3- to
10-fold between 1987 and 1996.9 The efficacy of TCAs has been investigated in 13 randomized placebo-controlled
studies,10 which showed marginal evidence to support the use of TCAs in the treatment of depression in only
adolescents. However, methodological deficiencies in these studies, including small sample sizes and diagnostic
heterogeneity, restrict statistical inference and generalizability of the findings. At the same time, cardiovascular effects
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and overdose-related mortality associated with TCA use have greatly limited their utility in clinical practice. 11,12
Nevertheless, nortriptyline is still approved by the Food and Drug Administration (FDA) for the treatment of depression
in adolescents and adults.13
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In recent decades, newer-generation antidepressants, including second generation antidepressants (e.g., selective
serotonin reuptake inhibitors [SSRIs]) and third generation antidepressants (e.g., serotonin-norepinephrine reuptake
inhibitors [SNRIs]), have been widely used for the treatment of depression in children and adolescents.14 The frequency
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of prescription of SSRIs and SNRIs in children and adolescents has progressively increased.15 In European countries,
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there has been a doubling of SSRI use over the 4-year period.16 However, only fluoxetinewas approved by the U.S FDA
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for treating depression in children and adolescents in January 2003.17 In the same year, concerns about the increased
risk of suicide and suicide attempts with SSRIs were first raised.18 In September 2004, the FDA cautioned practitioners
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in the use of antidepressant medications in children and adolescents.19 Similar warnings were issued by other health
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regulatory agencies.20-22 Thus, concerns about this issue have refocused attention on the question of how effective
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antidepressants are with youth depression.
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Nonetheless, there is currently no published meta-analysis combining direct and indirect evidence for the use of
antidepressants on children and adolescents, and it is an important one to perform, given the conflicting results
regarding the efficacy and tolerability of various antidepressants in this age group, and lack of head to head trials of
such drugs.23-25. For these reasons, we will employ a network meta-analysis –a methodological approach that allows the
simultaneous comparison of multiple psychotherapeutic interventions within a single analysis, while preserving
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randomization.26 This approach is will be used to integrate direct evidence (from studies directly comparing
interventions) with indirect evidence (information about two treatments derived via a common comparator) from
multiple treatment comparisons to estimate the interrelations across all treatments.27 We have previously compared the
efficacy and acceptability of psychotherapies for depression in children and adolescents28 and the augmentation agents
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for treatment-resistant depression in adults29 in this way. The aim of the network meta-analysis is of randomized
controlled studies is to re-analyze systematically the efficacy, tolerability, acceptability and suicide risk of both first-
and newer-generation antidepressants, either against active comparator or control condition, in the treatment of child
and adolescent depression.
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METHODS
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Types of studies
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Any prospective randomized controlled trials (RCTs), including cross-over design and cluster-randomized trials
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will be included. However, quasi-randomized trials (e.g., those allocating using alternate days of the week) will be
excluded. Trials with sample sizes smaller than 10 will be excluded in this review.
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Children and adolescents (aged from 6 to 18 when they initially enrolled in the studies) with a primary diagnosis of
current major depressive disorder according to standardized diagnostic interviews, e.g., the Diagnostic and Statistical
Manual of Mental Disorders (DSM)30-32 or the International Classification of Diseases (ICD)33,34 will be included.
Where patients with adults and youths, the data will be included if data on the depressed youths can be extracted
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separately, or obtained from trial authors. We will exclude studies focusing on child or adolescent bipolar disorder, but
will include trials involving patients with comorbid general psychiatric disorders, such as attention-hyperactivity
disorder (ADHD) and anxiety disorder. However, we will not exclude studies in which those have a diagnosis of
psychotic depression, and will examine those patients in a subgroup analysis. But we will exclude studies in which
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those have a diagnosis of treatment-resistant depression, because they always involving augmentation or combination
therapy,
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RCTs comparing any first- and newer- generation antidepressant against active comparator or either placebo for
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treatment of depression in children and adolescents will be included. Trials comparing the same type of antidepressant
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but at different therapeutic dose (fixed or flexible dose) and different treatment duration will be considered as the same
node in the network analysis. We will exclude studies involving combination therapy (i.e., combination of
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antidepressants, combination of antidepressants with psychotherapy, or other non-psychotherapeutic interventions);
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however, studies will be considered as eligible if the concomitant psychotherapy is not predefined in the study.
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The acute phase will be defined as from 4 to 16 week, and if a study presents data beyond 16 weeks or for more
than one time period within our pre-defined acute phase periods, we will take the 8-week or close to 8-week time
point.35 We will exclude trials with treatment duration of less than 4 weeks. . Where depression symptoms are measured
using more than one depression scale in a trial, we will extract data from the depressive scales on the basis of a
hierarchy of rating scales. This hierarchy will be based on psychometric properties and appropriateness for use with
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children and adolescents and for consistency of use across trials (referred from Hetrick SE study)14 (see Table 1). The
Children’s Depression Rating Scale (CDRS-R)36 is adapted for children and adolescents from the Hamilton Depression
Rating Scale (HAMD)37, a tool validated and commonly used in adult populations.38 Both the CDRS-R and HAMD
have good reliability and validity.38 The Beck Depression Inventory (BDI)39/Children’s Depression Inventory (CDI)40
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are the most commonly used among depression symptom severity-self rated scales and are ranked the second highest in
the hierarchy.
1. Overall efficacy
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1.1 The primary outcome for efficacy will be mean improvement in depressive symptoms, as measured by the mean
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change score of depression rating scales (self- or assessor-rated) from baseline to endpoint.
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1.2 The secondary outcome for efficacy will be response (or remission) in depressive symptoms, as estimated by the
proportion of patients who achieved a decrease of a certain percentage (e.g., a reduction of 50% or more) or below the
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published threshold in depression rating score (e.g., CDRS-R ≤28).41 When ‘remission’ is not reported, we will use
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‘response’ if available.
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We will also assess the suicide-related outcome, as estimated by the proportion of patients with one or more events of
definite suicidal behavior or ideation during the acute treatment phase.42
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PsycINFO) will be searched from 1966 to December 2013 (update to January, 2015) with Medical Subject Headings
(MeSH) and text words： ”depress*” or “dysthymi*” or “mood disorder*” or “affective disorder*” and “selective
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serotonin reuptake inhibitor*” or “SSRIs” or “serotonin norepinephrine reuptake inhibitor*” or “SNRIs” or
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“citalopram” or “fluoxetine” or “paroxetine” or “sertraline” or “escitalopram[” or “fluvoxamine” or “venlafaxine” or
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“duloxetine” or “milnacipran” or “reboxetine” or “bupropion” or “mirtazapine” or “tricyclic” or “amersergide” or
“amineptine” or “amitriptyline” or “amoxapine” or “butriptyline” or “chlorpoxiten” or “clomipramine” or
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“clorimipramine” or “demexiptiline” or “desipramine” or “dibenzipin” or “dothiepin” or “doxepin” or “imipramine” or
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“minors” or “paediatri*” or “pediatri*” or “pubescen*” or “school*” or “student*” or “teen*” or “young” or “youth*”.
Also, ClinicalTrials.gov, World Health Organization’s trial portal and U.S. Food and Drug Administration (FDA)
reports will be reviewed. There are no restrictions on language or type of publication. Additional studies will be
searched in the reference lists of all identified publications including relevant meta-analyses and systematic reviews. All
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relevant authors and principal manufacturers will be contacted to supplement incomplete reports of the original papers
or to provide new data for unpublished studies.
Study Selection
Two reviewers (QB and LYY) will independently scan citations at the title/abstract level identified from the search
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Two independent reviewers (YYL, BQ) will independently extract the key study parameters using a standardized data
abstraction form and assess the risk of bias. The standardized data extraction forms will include the study characteristics
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diagnostic criteria for depression, the type of patients, the number of patients, level of depressive symptoms,
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comorbidities, the age of patients, and the gender of patients), intervention details (e.g. antidepressant type, dose of
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antidepressant, and the duration of treatment) and outcome measures (efficacy, tolerability, acceptability, and suiciderelated outcome). The risk of bias in trials will be assessed by the Cochrane risk of bias tool.42 Trials attracting a rating
of high risk of bias in one or more domains will be considered as ‘high risk’, low risk of bias in all domains as ‘low
risk’, and one or more unclear risk of bias in each domain as ‘unclear risk’.42 Any disagreements will be resolved by a
third review author (XYZ). In addition, we will calculate the inter-rater reliability of the two raters.
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We will perform Bayesian network meta-analysis to compare the relative outcomes of different antidepressants and
placebo with each other from the median of the posterior distribution.26,27 The pooled estimates of standardized mean
difference (SMD) with 95% credible intervals (CrIs) will be calculated for the continuous outcomes; and odds ratios
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(or) with 95% CrIs will be calculated for the categorical outcomes. The SMD is that the difference in means (MD) of
change scores between the two groups divided by the pooled standard deviation (SD) of the measurements, with a
negative SMD value indicates greater symptomatic relief. In the presence of minimally informative priors, CrIs can be
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interpreted similarly to confidence intervals, and at conventional levels of statistical significance a two-sided p <0.05
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can be assumed if 95% CrIs do not include 0.42 If means and standard deviations (SDs) are not provided, we will
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calculate them from the p-value or other statistical indices as described elsewhere.43,44 Results from intention-to-treat
analysis (ITT) or modified ITT will be preferred over results from completer analyses, while we will also consider the
dataset for the means and SDs that are presented in the literature.
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be performed and presented by the Stata 11.0 and R 2.11.1 software packages. The quality of evidence for all outcomes
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will be judged using the Grading of Recommendations Assessment, Development and Evaluation working group
methodology. The quality of evidence will be assessed across the domains of risk of bias,
consistency, directness, precision and publication bias. Additional domains may be considered where appropriate.
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change the estimate), low (further research is very likely to have an important impact on our confidence in the estimate
of effect and is likely to change the estimate), or very low (very uncertain about the estimate of effect).
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the subgroups analyses of data in primary outcome for efficacy. We will perform the following subgroups analyses by
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using the meta-regression model and calculate Somer’s D (a correlation coefficient for a dichotomous and an ordinal
variable)48: (i) sex ratio (male-to-female ratio> 1 vs. male-to-female ratio<1); (ii) age group (mean age of less than 13
vs. mean age of more than or equal 13); (iii) treatment duration (<8 weeks vs. ≥8 weeks); (iv) severity of depressive
symptom (mild-to-moderate vs. moderate-to-severe); (v) comorbid general psychiatric disorders ( with vs. without
comorbid); (vi) risk of bias (‘high risk’ literature vs. ‘unclear and low risk’ literature); (viii) sample size (≤100 patients
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vs. >100 patients); (ix) company sponsor (with vs. without sponsor); and (x) the type of trials (published literature vs.
unpublished literature). When the limitation by small number of comparisons for some potential modifiers in carrying
out subgroup analyses on these variables, we will perform the sensitivity analyses by omitting specific studies from the
overall analysis.
Other analyses
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We will conduct an additional analysis in Bayesian network model based on including only newer-generation
antidepressants in primary efficacy and tolerability outcomes. The funnel plot analyses will be performed to check for
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publication bias. Moreover, we will carry out meta-regression analyses to investigate the effect of sponsorship or year
published on outcome estimate.
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antidepressants for depression in children and adolescents. They will also have implications for clinical practice and
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TABLES
Hierarchy
Abbreviation
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CDRS
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HAMD
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MADRS
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BDI
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CDI
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K-SADS
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Aged Children
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MFQ
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RADS
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BID
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CDS
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CESD
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CAS
CBCL-D
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References
1.
Ferrari AJ, Charlson FJ, Norman RE, et al. Burden of depressive disorders by country, sex, age, and year: findings
from the global burden of disease study 2010. PLoS Med. 2013;10:e1001547.
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1989;203-25.
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Adolesc Med 2003;157:17-25.
2013;6:CD002317.
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1991;30:495-8.
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Wilkins, 2003:169-72.
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Psychosom 2003;72:71-9.
medications.
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2008;17:279-301.
2004;23:3105-24.
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35. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation
antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-58.36. Poznanski EO, Mokros HB.
Children's depression rating scale, revised (CDRS-R): manual. Western Psychological Services, 1996.
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2006;101:447-59.
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Section and topic
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Administrative information
Title:
Identification
Update
Registration
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Item No
Checklist item
1a
Comparative efficacy and tolerability of first- and newer-generation
antidepressants for depressive disorders in children and adolescents:
Study Protocol for a Systematic Review and Network
Meta-Analysis
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1b
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Authors:
In accordance with the guidelines, our systematic review protocol
was registered with the International Prospective Register of
Systematic Reviews (PROSPERO) on 19 January 2015 and was last
updated on 28 April, 2015 (registration number CRD42015016023).
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*Corresponding author: Peng Xie
xiepeng973@126.com
Contact
3a
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Author Affiliations
1 Department of Neurology, The First Affiliated Hospital of
Chongqing Medical University, Chongqing, China
2 Research Department of Clinical, Educational and Health
Psychology, University College London, London, UK
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3 Department of Child and Adolescent Psychiatry, AP–HP, Hôpital
Pitié–Salpétrière, Institut des Systèmes Intelligents et de Robotiques
(ISIR), Centre National pour la Recherche Scientifique, Université
Pierre et Marie Curie, Paris, France
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4 Department of Diagnostic, Clinical, and Public Health Medicine,
University of Modena and Reggio, Emilia, Modena, Italy
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5 Department of Psychology, Appalachian State University, Boone,
North Carolina, USA
Contributions
3b
Email: Xinyu Zhou xinyu973@126.com - Bin Qin
bin13457@163.com - Craig Whittington c.whittington@ucl.ac.uk David Cohen david.cohen@psl.ap-hop-paris.fr - Yiyun Liu
lyy525@126.com - Cinzia Del Giovane
cinzia.delgiovane@unimore.it - Kurt D. Michael
michaelkd@appstate.edu - Yuqing Zhang yqzhang216@163.com and Peng Xie xiepeng973@126.com
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XZ and BQ conceived the study and drafted the protocol. XZ and
PX wrote the first draft of the manuscript. KDM, CW and DC
assisted in protocol design and revision. YL and YZ participated in
the search strategy development. CDG and BQ participated in the
design of data synthesis and analysis. All authors have approved the
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Amendments
Support:
Sources
Sponsor
Role of sponsor or funder
Introduction
Rationale
Objectives
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5a
This work is funded by the National Basic Research Program of
China (973 Program) (Grant No. 2009CB918300).
5b
The National Basic Research Program of China funded this work .
5c
China (973 Program) (Grant No. 2009CB918300). The funders had
no role in the protocol design; the writing of the protocol; or the
decision to submit the protocol for publication.
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Methods
Eligibility criteria
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[Comparative efficacy and tolerability of first- and
newer-generation antidepressants for depressive disorders in
children and adolescents: Study Protocol for a Systematic Review
and Network Meta-Analysis]
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The aim of the network meta-analysis is of randomized controlled
studies is to re-analyze systematically the efficacy, tolerability,
acceptability and suicide risk of both first- and newer-generation
antidepressants, either against active comparator or control
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Studies will be selected according to the criteria outlined below.
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Study designs
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Any prospective randomized controlled trials (RCTs), including
cross-over design and cluster-randomized trials will be included.
However, quasi-randomized trials (e.g., those allocating using
alternate days of the week) will be excluded. Trials with sample
sizes smaller than 10 will be excluded in this review.
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Participants
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Children and adolescents (aged from 6 to 18 when they initially
enrolled in the studies) with a primary diagnosis of current major
depressive disorder according to standardized diagnostic interviews,
e.g., the Diagnostic and Statistical Manual of Mental Disorders
(DSM) or the International Classification of Diseases (ICD) will be
included. Where patients with adults and youths, the data will be
included if data on the depressed youths can be extracted separately,
or obtained from trial authors. We will exclude studies focusing on
child or adolescent bipolar disorder, but will include trials involving
patients with comorbid general psychiatric disorders, such as
attention-hyperactivity disorder (ADHD) and anxiety disorder.
However, we will not exclude studies in which those have a
diagnosis of psychotic depression, and will examine those patients
in a subgroup analysis. But we will exclude studies in which those
have a diagnosis of treatment-resistant depression, because they
always involving augmentation or combination therapy,
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Interventions
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RCTs comparing any first- and newer- generation antidepressant
against active comparator or either placebo for treatment of
depression in children and adolescents will be included. Trials
comparing the same type of antidepressant but at different
therapeutic dose (fixed or flexible dose) and different treatment
duration will be considered as the same node in the network
analysis. We will exclude studies involving combination therapy
(i.e., combination of antidepressants, combination of
antidepressants with psychotherapy, or other non-psychotherapeutic
interventions); however, studies will be considered as eligible if the
concomitant psychotherapy is not predefined in the study.
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Outcomes
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The acute phase will be defined as from 4 to 16 week, and if a study
presents data beyond 16 weeks or for more than one time period
within our pre-defined acute phase periods, we will take the 8-week
or close to 8-week time point.35 We will exclude trials with
treatment duration of less than 4 weeks. Where depression
symptoms are measured using more than one depression scale in a
trial, we will extract data from the depressive scales on the basis of
a hierarchy of rating scales. This hierarchy will be based on
psychometric properties and appropriateness for use with children
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and adolescents and for consistency of use across trials (referred
from Hetrick SE study). The Children’s Depression Rating Scale
(CDRS-R) is adapted for children and adolescents from the
Hamilton Depression Rating Scale (HAMD), a tool validated and
commonly used in adult populations. Both the CDRS-R and HAMD
have good reliability and validity. The Beck Depression Inventory
(BDI)/Children’s Depression Inventory (CDI) are the most
commonly used among depression symptom severity-self rated
scales and are ranked the second highest in the hierarchy.
1. Overall efficacy
1.1 The primary outcome for efficacy will be mean improvement in
depressive symptoms, as measured by the mean change score of
depression rating scales (self- or assessor-rated) from baseline to
endpoint.
1.2 The secondary outcome for efficacy will be response (or
remission) in depressive symptoms, as estimated by the proportion
of patients who achieved a decrease of a certain percentage (e.g., a
reduction of 50% or more) or below the published threshold in
depression rating score (e.g., CDRS-R ≤28).41 When ‘remission’ is
not reported, we will use ‘response’ if available.
The tolerability of treatment will be defined as side-effect
discontinuation in this review, as defined by the proportion of
patients who discontinued treatment due to adverse events during
the study.
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The acceptability of treatment will be defined as all-cause
discontinuation, as measured by the proportion of patients who
discontinued treatment (during the delivery of the intervention) up
to the post intervention time point.
We will also assess the suicide-related outcome, as estimated by the
proportion of patients with one or more events of definite suicidal
behavior or ideation during the acute treatment phase.
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Setting
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There will be no restrictions by type of setting.
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Language
There will be no restrictions classification of language.
Information sources
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Seven electronic databases (PubMed, Embase, the Cochrane
Library, Web of Science, CINAHL, LiLACS, and PsycINFO) will
be searched from 1966 to December 2013 (update to January, 2015)
with Medical Subject Headings (MeSH) and text words related to
first- and newer-generation antidepressants for depressive disorders
in children and adolescents. Also, ClinicalTrials.gov, World Health
Organization’s trial portal and U.S. Food and Drug Administration
(FDA) reports will be reviewed. There are no restrictions on
language or type of publication.
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Additional studies will be searched in the reference lists of all
identified publications including relevant meta-analyses and
systematic reviews.
All relevant authors and principal manufacturers will be contacted
to supplement incomplete reports of the original papers or to
provide new data for unpublished studies.
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Search strategy
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Appendix1
Draft EMBASE search-Ovid interface
1. (depress$ or dysthymi$ or (mood disorder$) or (affective
disorder$)).ti,ab.
2. (adolesc$ or child$ or boy$ or girl$ or juvenil$ or minors or
paediatri$ or pediatri$ or pubescen$ or school$ or student$ or
teen$ or young or youth$).ti,ab.
3. (citalopram or fluoxetine or paroxetine or sertraline or
escitalopram or fluvoxamine or venlafaxine or duloxetine or
milnacipran or reboxetine or bupropion or mirtazapine).ti,ab.
4. ((tricyclic drugs) or amersergide or amineptine or amitriptyline or
amoxapine or butriptyline or chlorpoxiten or clomipramine or
clorimipramine or demexiptiline or desipramine or dibenzipin or
dothiepin or doxepin or imipramine or lofepramine or melitracen
or metapramine or nortriptyline or noxiptiline or opipramol or
protriptyline or quinupramine or tianeptine or trimipramine).ti,ab.
5. 1 and 2 and 3 and 4
6. limit 5 to (human and clinical trial)
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Study records:
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Data management
Selection process
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11a
Literature search results will be imported to Endnote 7.0 and the
duplicates will be removed during the study selection process. We
will screening citations based on the inclusion and exclusion
criteria.
11b
Two reviewers will independently scan citations at the title/abstract
level identified from the search strategies and then obtain
potentially relevant studies in full text and determine whether to
include them by the same eligibility criteria. Besides, the references
of relevant reviews and included trials will also be checked by the
two reviewers. The reasons for exclusion of trials will be reported in
the characteristics of excluded studies tables. Any disagreements
will be resolved by a third review author.
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Data collection process
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Two independent reviewers will independently extract the key study
parameters using a standardized data abstraction form. The
standardized data extraction forms will include the study
characteristics, patient characteristics, intervention details and
outcome measures (efficacy, tolerability, acceptability, and
suicide-related outcome). Any disagreements will be resolved by a
third review author. In addition, we will calculate the inter-rater
reliability of the two raters.
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Data items
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We will extract study characteristics (e.g., first listed author,
publication year, journal, country, institution, and sponsor), patient
characteristics (e.g. diagnostic criteria for depression, the type of
patients, the number of patients, level of depressive symptoms,
comorbidities, the age of patients, and the gender of patients),
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intervention details (e.g. antidepressant type, dose of antidepressant,
and the duration of treatment) and outcome measures (efficacy,
tolerability, acceptability, and suicide-related outcome).
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Outcomes and prioritization
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1. Overall efficacy
endpoint.
depression rating score (e.g., CDRS-R ≤28). When ‘remission’ is
the study.
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Risk of bias in individual studies
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The risk of bias in trials will be assessed by the Cochrane risk of
bias tool. Trials attracting a rating of high risk of bias in one or
more domains will be considered as ‘high risk’, low risk of bias in
all domains as ‘low risk’, and one or more unclear risk of bias in
each domain as ‘unclear risk’.
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15a
We will perform Bayesian network meta-analysis to compare the
relative outcomes of different antidepressants and placebo with each
other from the median of the posterior distribution.
15b
The pooled estimates of standardized mean difference (SMD) with
95% credible intervals (CrIs) will be calculated for the continuous
outcomes; and odds ratios (or) with 95% CrIs will be calculated for
the categorical outcomes. The SMD is that the difference in means
(MD) of change scores between the two groups divided by the
pooled standard deviation (SD) of the measurements, with a
negative SMD value indicates greater symptomatic relief. In the
presence of minimally informative priors, CrIs can be interpreted
similarly to confidence intervals, and at conventional levels of
statistical significance a two-sided p <0.05 can be assumed if 95%
CrIs do not include 0. Results from intention-to-treat analysis (ITT)
or modified ITT will be preferred over results from completer
analyses, while we will also consider the dataset for the means and
SDs that are presented in the literature.
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Data synthesis
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15c
The antidepressants will be coded according to clinical
characteristics, risk of bias, and sample size. We will conduct the
subgroups analyses of data in primary outcome for efficacy. We
will perform the following subgroups analyses by using the
meta-regression model and calculate Somer’s D (a correlation
coefficient for a dichotomous and an ordinal variable): (i) sex ratio
(male-to-female ratio> 1 vs. male-to-female ratio<1); (ii) age group
(mean age of less than 13 vs. mean age of more than or equal 13);
(iii) treatment duration (<8 weeks vs. ≥8 weeks); (iv) severity of
depressive symptom (mild-to-moderate vs. moderate-to-severe); (v)
comorbid general psychiatric disorders ( with vs. without
comorbid); (vi) risk of bias (‘high risk’ literature vs. ‘unclear and
low risk’ literature); (viii) sample size (≤100 patients vs. >100
patients); (ix) company sponsor (with vs. without sponsor); and (x)
the type of trials (published literature vs. unpublished literature).
When the limitation by small number of comparisons for some
potential modifiers in carrying out subgroup analyses on these
variables, we will perform the sensitivity analyses by omitting
specific studies from the overall analysis.
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We will conduct an additional analysis in Bayesian network model
based on including only newer-generation antidepressants in
primary efficacy and tolerability outcomes. The funnel plot analyses
will be performed to check for publication bias. Moreover, we will
carry out meta-regression analyses to investigate the effect of
sponsorship or year published on outcome estimate.
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Meta-bias(es)
15d
A systematic narrative synthesis will be provided with information
presented in the text and tables to summarise and explain the
characteristics and findings of the included studies.
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In order to determine whether reporting bias is present, we will
determine whether the protocol of the RCT was published before
recruitment of patients of the study was started. For studies
published after January 2015, we will screen the ClinicalTrials.gov,
World Health Organization’s trial portal and U.S. Food and Drug
Administration. We will evaluate whether selective reporting of
outcomes is present (outcome reporting bias). The potential for
reporting bias will be further explored by funnel plots.
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Confidence in cumulative evidence
17
The quality of evidence for all outcomes will be judged using the
Grading of Recommendations Assessment, Development and
Evaluation working group methodology. The quality of evidence
will be assessed across the domains of risk of bias,
consistency, directness, precision and publication bias. Additional
domains may be considered where appropriate.
Quality will be adjudicated as high (further research is very unlikely
to change our confidence in the estimate of effect),
moderate (further research is likely to have an important impact on
ourconfidence in the estimate of effect and may change the
estimate), low (further research is very likely to have an important
impact on our confidence in the estimate of effect and is likely to
change the estimate), or very low (very uncertain about the estimate
of effect).
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Comparative efficacy and tolerability of first- and newergeneration antidepressant medications for depressive
disorders in children and adolescents: Study Protocol for a
Systematic Review and Network Meta-Analysis
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Journal:
Manuscript ID:
Article Type:
bmjopen-2015-007768.R2
Protocol
29-May-2015
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Primary Subject
Heading:
Mental health
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Keywords:
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Comparative efficacy and tolerability of first- and newer-generation antidepressant
medications for depressive disorders in children and adolescents: Study Protocol for a
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Word count: 2402.
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ABSTRACT
have adverse effects on their psychosocial functioning. Questions concerning the efficacy and safety of antidepressant
medications in the treatment of depression in children and adolescents led us to integrate the direct and indirect
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evidence using network meta-analysis to create hierarchies of these drugs.
LiLACS, and PsycINFO will be searched from 1966 to December 2013 (updated to May, 2015). There are no
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antidepressant medications against active comparator or placebo as acute treatment for depressive disorder in children
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and adolescents (under 18 years of age) will be included. The primary outcome for efficacy will be mean improvement
in depressive symptoms, as measured by the mean change score of a depression rating scale from baseline to post-
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patients who discontinued treatment due to adverse events during the trial. We will also assess the secondary outcome
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for efficacy (response rate), acceptability (all-cause discontinuation), and suicide-related outcomes. We will perform the
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newer-generation antidepressant medications for depression in children and adolescents.
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BACKGROUND
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depressive symptoms in young patients.8 In the U.S., the use of antidepressant medication in children and adolescents
grew 3- to 10-fold between 1987 and 1996.9 The efficacy of TCAs has been investigated in 13 randomized placebocontrolled trials,10 which showed marginal evidence to support the use of TCAs in the treatment of depression in only
adolescents. However, methodological deficiencies in these trials, including small sample sizes and diagnostic
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Nevertheless, the TCA nortriptyline is still approved by the Food and Drug Administration (FDA) for the treatment of
depression in adolescents and adults.13
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antidepressant medications are with youth depression.
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Nonetheless, currently, no published meta-analysis combined direct and indirect evidence for the use of antidepressant
medications on children and adolescents, while it is an important one to perform, given the conflicting results regarding
the efficacy and tolerability of various antidepressant medications in this age group, and lack of head to head trials of
such drugs.23-25. For these reasons, we will employ a network meta-analysis –a methodological approach that allows the
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simultaneous comparison of multiple psychotherapeutic interventions within a single analysis, while preserving
randomization.26 This approach is will be used to integrate direct evidence (from studies directly comparing
interventions) with indirect evidence (information about two treatments derived via a common comparator) from
multiple treatment comparisons to estimate the interrelations across all treatments.27 We have previously compared the
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efficacy and acceptability of psychotherapies for depression in children and adolescents28 and the augmentation agents
for treatment-resistant depression in adults29 in this way. The aim of the network meta-analysis is of randomized
controlled trials is to re-analyze systematically the efficacy, tolerability, acceptability and suicide risk of both first- and
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newer-generation antidepressant medications, either against active comparator or control condition, in the treatment of
child and adolescent depression.
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METHODS
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Types of studies
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Any prospective randomized controlled trials (RCTs), including cross-over design and cluster-randomized trials
will be included. However, quasi-randomized trials (e.g., those allocating using alternate days of the week) will be
excluded. Trials with sample sizes smaller than 10 will be excluded in this review.
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Children and adolescents (aged from 6 to 18 when they initially enrolled in the trials) with a primary diagnosis of
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Where a trial contains a portion of participants who are over 18, we will contact trial authors in order to obtain data
from only those participants within our age range. We will exclude trials focusing on child or adolescent bipolar
disorder, but will include trials involving patients with comorbid general psychiatric disorders, such as attention-
hyperactivity disorder (ADHD), anxiety disorder and substance-related disorder. However, we will not exclude trials in
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which participants have a diagnosis of psychotic depression, and these participants will be considered within a separate
subgroup analysis. But we will exclude trials in which those have a diagnosis of treatment-resistant depression,
because those resistance patients always have different treatment response compared with those patients with non-
resistant depression,
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RCTs comparing any first- and newer- generation antidepressant drug against active comparator or either placebo for
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node in the network analysis. We will exclude trials involving combination therapy (i.e., combination of antidepressant
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interventions); however, trials will be considered as eligible if the concomitant psychotherapy is not predefined in the
study.
The acute phase will be defined as from 4 to 16 weeks, and if a trial presents data beyond 16 weeks or for more than
one time period within our pre-defined acute phase periods, we will take the 8-week or close to 8-week time point.35 We
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will exclude trials with treatment duration of less than 4 weeks. Where depression symptoms are measured using more
than one depression scale in a trial, we will extract data from the depressive scales on the basis of a hierarchy of rating
scales. This hierarchy will be based on psychometric properties and appropriateness for use with children and
adolescents and for consistency of use across trials (referred from Hetrick et al. study)14 (see Table 1). The Children’s
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Depression Rating Scale (CDRS-R)36 is adapted for children and adolescents from the Hamilton Depression Rating
Scale (HAMD)37, a tool validated and commonly used in adult populations.38 Both the CDRS-R and HAMD have good
reliability and validity.38 The Beck Depression Inventory (BDI)39/Children’s Depression Inventory (CDI)40 are the most
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commonly used among depression symptom severity-self rated scales and are ranked the second highest in the hierarchy.
1. Overall efficacy
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1.2 The secondary outcome for efficacy will be response in depressive symptoms, as estimated by the proportion of
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patients who achieved a decrease of a certain percentage (e.g., a reduction of 50% or more) in depression rating score.41
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patients who achieved a below the published threshold in depression rating score (e.g., CDRS-R ≤28).41
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Suicide-related outcomes of dichotomous and continuous will be measured. If data are available, we will extracted the
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number of participants with suicidal behavior/ideation during the acute treatment, as measured on a standardised,
validated and reliable rating scales, or reported cases of suicidality.42 In addition, we will also collect data on suicidal
ideation as a continuous outcome where a standardised, validated and reliable rating scale, such as the Suicidal Ideation
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Questionnaire-Junior High School version (SIQ-JR),43 has been used.
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PsycINFO) will be searched from 1966 to December 2013 (update to May, 2015) with Medical Subject Headings
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“noradrenergic and specific serotonergic antidepressants” or “NaSSA” or “citalopram” or “fluoxetine” or “paroxetine”
or “sertraline” or “escitalopram[” or “fluvoxamine” or “venlafaxine” or “duloxetine” or “milnacipran” or “reboxetine”
or “bupropion” or “mirtazapine” or “tricyclic” or “amersergide” or “amineptine” or “amitriptyline” or “amoxapine” or
“butriptyline” or “chlorpoxiten” or “clomipramine” or “clorimipramine” or “demexiptiline” or “desipramine” or
“dibenzipin” or “dothiepin” or “doxepin” or “imipramine” or “lofepramine” or “melitracen” or “metapramine” or
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“nortriptyline” or “noxiptiline” or “opipramol” or “protriptyline” or “quinupramine” or “tianeptine” or “trimipramine”
and “adolesc*” or “child*” or “boy*” or “girl*” or “juvenil*” or “minors” or “paediatri*” or “pediatri*” or “pubescen*”
or “school*” or “student*” or “teen*” or “young” or “youth*”. Also, ClinicalTrials.gov, World Health Organization’s
trial portal and U.S. Food and Drug Administration (FDA) reports will be reviewed. There are no restrictions on
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language or type of publication. Additional studies will be searched in the reference lists of all identified publications
including relevant meta-analyses and systematic reviews. All relevant authors and principal manufacturers will be
contacted to supplement incomplete reports of the original papers or to provide new data for unpublished trials.
Study Selection
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Two independent reviewers (YYL, BQ) will independently extract the key trial parameters using a standardized data
abstraction form and assess the risk of bias. The standardized data extraction forms will include the trial characteristics
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We will perform Bayesian network meta-analysis to compare the relative outcomes of different antidepressant
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medications and placebo with each other from the median of the posterior distribution.26,27 The pooled estimates of
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standardized mean difference (SMD) with 95% credible intervals (CrIs) will be calculated for the continuous outcomes;
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significance a two-sided p <0.05 can be assumed if 95% CrIs do not include 0. If means and standard deviations (SDs)
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are not provided, we will calculate them from the p-value or other statistical indices as described elsewhere.44,45 Results
from intention-to-treat analysis (ITT) or modified ITT will be preferred over results from completer analyses, while we
will also consider the dataset for the means and SDs that are presented in the literature.
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Subgroup analyses
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The antidepressant medications will be coded according to clinical characteristics, risk of bias, and sample size. We will
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an ordinal variable)49: (i) sex ratio (male-to-female ratio> 1 vs. male-to-female ratio<1); (ii) age group; (iii) treatment
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duration; (iv) severity of depressive symptom (mild-to-moderate vs. moderate-to-severe); (v) comorbid general
psychiatric disorders ( with vs. without comorbid); (vi) risk of bias (‘high risk’ literature vs. ‘unclear and low risk’
literature); (vii) sample size; (viii) company sponsor (with vs. without sponsor); and (ix) the type of trials (published
literature vs. unpublished literature). When the limitation by small number of comparisons for some potential modifiers
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in carrying out subgroup analyses on these variables, we will perform the sensitivity analyses by omitting specific trials
from the overall analysis.
Other analyses
We will conduct an additional analysis in Bayesian network model based on including only newer-generation
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antidepressant medications in primary efficacy and tolerability outcomes. The funnel plot analyses will be performed to
check for publication bias. Moreover, we will carry out meta-regression analyses to investigate the effect of sponsorship
or year published on outcome estimate.
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antidepressant medications for depression in children and adolescents. They will also have implications for clinical
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TABLES
Hierarchy
Abbreviation
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CDRS
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HAMD
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MADRS
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BDI
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CDI
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K-SADS
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Aged Children
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MFQ
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RADS
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BID
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CDS
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CESD
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CAS
CBCL-D
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References
1.
Ferrari AJ, Charlson FJ, Norman RE, et al. Burden of depressive disorders by country, sex, age, and year: findings
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1989;203-25.
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Adolesc Med 2003;157:17-25.
2013;6:CD002317.
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1991;30:495-8.
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Wilkins, 2003:169-72.
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Psychosom 2003;72:71-9.
medications.
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2008;17:279-301.
2004;23:3105-24.
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antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-58.
Services, 1996.
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43. Reynolds WM. Suicidal Ideation Questionnaire-Junior. Odessa, FL: Psychological Assessment Resources, 1987.
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1998;7:434-55.
2006;101:447-59.
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Section and topic
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Administrative information
Title:
Identification
Update
Registration
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Item No
Checklist item
1a
Comparative efficacy and tolerability of first- and newer-generation
antidepressants for depressive disorders in children and adolescents:
Study Protocol for a Systematic Review and Network
Meta-Analysis
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1b
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Authors:
In accordance with the guidelines, our systematic review protocol
was registered with the International Prospective Register of
Systematic Reviews (PROSPERO) on 19 January 2015 and was last
updated on 28 April, 2015 (registration number CRD42015016023).
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*Corresponding author: Peng Xie
xiepeng973@126.com
Contact
3a
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Author Affiliations
1 Department of Neurology, The First Affiliated Hospital of
Chongqing Medical University, Chongqing, China
2 Research Department of Clinical, Educational and Health
Psychology, University College London, London, UK
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3 Department of Child and Adolescent Psychiatry, AP–HP, Hôpital
Pitié–Salpétrière, Institut des Systèmes Intelligents et de Robotiques
(ISIR), Centre National pour la Recherche Scientifique, Université
Pierre et Marie Curie, Paris, France
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4 Department of Diagnostic, Clinical, and Public Health Medicine,
University of Modena and Reggio, Emilia, Modena, Italy
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5 Department of Psychology, Appalachian State University, Boone,
North Carolina, USA
Contributions
3b
Email: Xinyu Zhou xinyu973@126.com - Bin Qin
bin13457@163.com - Craig Whittington c.whittington@ucl.ac.uk David Cohen david.cohen@psl.ap-hop-paris.fr - Yiyun Liu
lyy525@126.com - Cinzia Del Giovane
cinzia.delgiovane@unimore.it - Kurt D. Michael
michaelkd@appstate.edu - Yuqing Zhang yqzhang216@163.com and Peng Xie xiepeng973@126.com
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XZ and BQ conceived the study and drafted the protocol. XZ and
PX wrote the first draft of the manuscript. KDM, CW and DC
assisted in protocol design and revision. YL and YZ participated in
the search strategy development. CDG and BQ participated in the
design of data synthesis and analysis. All authors have approved the
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Amendments
Support:
Sources
Sponsor
Role of sponsor or funder
Introduction
Rationale
Objectives
4
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5a
China (973 Program) (Grant No. 2009CB918300).
5b
The National Basic Research Program of China funded this work .
5c
China (973 Program) (Grant No. 2009CB918300). The funders had
no role in the protocol design; the writing of the protocol; or the
decision to submit the protocol for publication.
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Methods
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[Comparative efficacy and tolerability of first- and
newer-generation antidepressants for depressive disorders in
children and adolescents: Study Protocol for a Systematic Review
and Network Meta-Analysis]
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The aim of the network meta-analysis is of randomized controlled
studies is to re-analyze systematically the efficacy, tolerability,
acceptability and suicide risk of both first- and newer-generation
antidepressants, either against active comparator or control
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Studies will be selected according to the criteria outlined below.
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Study designs
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Any prospective randomized controlled trials (RCTs), including
cross-over design and cluster-randomized trials will be included.
However, quasi-randomized trials (e.g., those allocating using
alternate days of the week) will be excluded. Trials with sample
sizes smaller than 10 will be excluded in this review.
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Participants
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Children and adolescents (aged from 6 to 18 when they initially
enrolled in the studies) with a primary diagnosis of current major
depressive disorder according to standardized diagnostic interviews,
e.g., the Diagnostic and Statistical Manual of Mental Disorders
(DSM) or the International Classification of Diseases (ICD) will be
included. Where patients with adults and youths, the data will be
included if data on the depressed youths can be extracted separately,
or obtained from trial authors. We will exclude studies focusing on
child or adolescent bipolar disorder, but will include trials involving
patients with comorbid general psychiatric disorders, such as
attention-hyperactivity disorder (ADHD) and anxiety disorder.
However, we will not exclude studies in which those have a
diagnosis of psychotic depression, and will examine those patients
in a subgroup analysis. But we will exclude studies in which those
have a diagnosis of treatment-resistant depression, because they
always involving augmentation or combination therapy,
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Interventions
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RCTs comparing any first- and newer- generation antidepressant
against active comparator or either placebo for treatment of
depression in children and adolescents will be included. Trials
comparing the same type of antidepressant but at different
therapeutic dose (fixed or flexible dose) and different treatment
duration will be considered as the same node in the network
analysis. We will exclude studies involving combination therapy
(i.e., combination of antidepressants, combination of
antidepressants with psychotherapy, or other non-psychotherapeutic
interventions); however, studies will be considered as eligible if the
concomitant psychotherapy is not predefined in the study.
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Outcomes
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The acute phase will be defined as from 4 to 16 week, and if a study
presents data beyond 16 weeks or for more than one time period
within our pre-defined acute phase periods, we will take the 8-week
or close to 8-week time point.35 We will exclude trials with
treatment duration of less than 4 weeks. Where depression
symptoms are measured using more than one depression scale in a
trial, we will extract data from the depressive scales on the basis of
a hierarchy of rating scales. This hierarchy will be based on
psychometric properties and appropriateness for use with children
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and adolescents and for consistency of use across trials (referred
from Hetrick SE study). The Children’s Depression Rating Scale
(CDRS-R) is adapted for children and adolescents from the
Hamilton Depression Rating Scale (HAMD), a tool validated and
commonly used in adult populations. Both the CDRS-R and HAMD
have good reliability and validity. The Beck Depression Inventory
(BDI)/Children’s Depression Inventory (CDI) are the most
commonly used among depression symptom severity-self rated
scales and are ranked the second highest in the hierarchy.
1. Overall efficacy
endpoint.
depression rating score (e.g., CDRS-R ≤28).41 When ‘remission’ is
the study.
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Setting
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There will be no restrictions by type of setting.
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Language
There will be no restrictions classification of language.
Information sources
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Seven electronic databases (PubMed, Embase, the Cochrane
Library, Web of Science, CINAHL, LiLACS, and PsycINFO) will
be searched from 1966 to December 2013 (update to January, 2015)
with Medical Subject Headings (MeSH) and text words related to
first- and newer-generation antidepressants for depressive disorders
in children and adolescents. Also, ClinicalTrials.gov, World Health
Organization’s trial portal and U.S. Food and Drug Administration
(FDA) reports will be reviewed. There are no restrictions on
language or type of publication.
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Additional studies will be searched in the reference lists of all
identified publications including relevant meta-analyses and
systematic reviews.
All relevant authors and principal manufacturers will be contacted
to supplement incomplete reports of the original papers or to
provide new data for unpublished studies.
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Search strategy
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Appendix1
Draft EMBASE search-Ovid interface
1. (depress$ or dysthymi$ or (mood disorder$) or (affective
disorder$)).ti,ab.
2. (adolesc$ or child$ or boy$ or girl$ or juvenil$ or minors or
paediatri$ or pediatri$ or pubescen$ or school$ or student$ or
teen$ or young or youth$).ti,ab.
3. (citalopram or fluoxetine or paroxetine or sertraline or
escitalopram or fluvoxamine or venlafaxine or duloxetine or
milnacipran or reboxetine or bupropion or mirtazapine).ti,ab.
4. ((tricyclic drugs) or amersergide or amineptine or amitriptyline or
amoxapine or butriptyline or chlorpoxiten or clomipramine or
clorimipramine or demexiptiline or desipramine or dibenzipin or
dothiepin or doxepin or imipramine or lofepramine or melitracen
or metapramine or nortriptyline or noxiptiline or opipramol or
protriptyline or quinupramine or tianeptine or trimipramine).ti,ab.
5. 1 and 2 and 3 and 4
6. limit 5 to (human and clinical trial)
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Study records:
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Data management
Selection process
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11a
Literature search results will be imported to Endnote 7.0 and the
duplicates will be removed during the study selection process. We
will screening citations based on the inclusion and exclusion
criteria.
11b
Two reviewers will independently scan citations at the title/abstract
level identified from the search strategies and then obtain
potentially relevant studies in full text and determine whether to
include them by the same eligibility criteria. Besides, the references
of relevant reviews and included trials will also be checked by the
two reviewers. The reasons for exclusion of trials will be reported in
the characteristics of excluded studies tables. Any disagreements
will be resolved by a third review author.
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Data collection process
11c
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Two independent reviewers will independently extract the key study
parameters using a standardized data abstraction form. The
standardized data extraction forms will include the study
characteristics, patient characteristics, intervention details and
outcome measures (efficacy, tolerability, acceptability, and
suicide-related outcome). Any disagreements will be resolved by a
third review author. In addition, we will calculate the inter-rater
reliability of the two raters.
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Data items
12
We will extract study characteristics (e.g., first listed author,
publication year, journal, country, institution, and sponsor), patient
characteristics (e.g. diagnostic criteria for depression, the type of
patients, the number of patients, level of depressive symptoms,
comorbidities, the age of patients, and the gender of patients),
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intervention details (e.g. antidepressant type, dose of antidepressant,
and the duration of treatment) and outcome measures (efficacy,
tolerability, acceptability, and suicide-related outcome).
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Outcomes and prioritization
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1. Overall efficacy
endpoint.
depression rating score (e.g., CDRS-R ≤28). When ‘remission’ is
the study.
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Risk of bias in individual studies
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The risk of bias in trials will be assessed by the Cochrane risk of
bias tool. Trials attracting a rating of high risk of bias in one or
more domains will be considered as ‘high risk’, low risk of bias in
all domains as ‘low risk’, and one or more unclear risk of bias in
each domain as ‘unclear risk’.
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15a
We will perform Bayesian network meta-analysis to compare the
relative outcomes of different antidepressants and placebo with each
other from the median of the posterior distribution.
15b
The pooled estimates of standardized mean difference (SMD) with
95% credible intervals (CrIs) will be calculated for the continuous
outcomes; and odds ratios (or) with 95% CrIs will be calculated for
the categorical outcomes. The SMD is that the difference in means
(MD) of change scores between the two groups divided by the
pooled standard deviation (SD) of the measurements, with a
negative SMD value indicates greater symptomatic relief. In the
presence of minimally informative priors, CrIs can be interpreted
similarly to confidence intervals, and at conventional levels of
statistical significance a two-sided p <0.05 can be assumed if 95%
CrIs do not include 0. Results from intention-to-treat analysis (ITT)
or modified ITT will be preferred over results from completer
analyses, while we will also consider the dataset for the means and
SDs that are presented in the literature.
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Data synthesis
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15c
The antidepressants will be coded according to clinical
characteristics, risk of bias, and sample size. We will conduct the
subgroups analyses of data in primary outcome for efficacy. We
will perform the following subgroups analyses by using the
meta-regression model and calculate Somer’s D (a correlation
coefficient for a dichotomous and an ordinal variable): (i) sex ratio
(male-to-female ratio> 1 vs. male-to-female ratio<1); (ii) age group
(mean age of less than 13 vs. mean age of more than or equal 13);
(iii) treatment duration (<8 weeks vs. ≥8 weeks); (iv) severity of
depressive symptom (mild-to-moderate vs. moderate-to-severe); (v)
comorbid general psychiatric disorders ( with vs. without
comorbid); (vi) risk of bias (‘high risk’ literature vs. ‘unclear and
low risk’ literature); (viii) sample size (≤100 patients vs. >100
patients); (ix) company sponsor (with vs. without sponsor); and (x)
the type of trials (published literature vs. unpublished literature).
When the limitation by small number of comparisons for some
potential modifiers in carrying out subgroup analyses on these
variables, we will perform the sensitivity analyses by omitting
specific studies from the overall analysis.
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We will conduct an additional analysis in Bayesian network model
based on including only newer-generation antidepressants in
primary efficacy and tolerability outcomes. The funnel plot analyses
will be performed to check for publication bias. Moreover, we will
carry out meta-regression analyses to investigate the effect of
sponsorship or year published on outcome estimate.
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Meta-bias(es)
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A systematic narrative synthesis will be provided with information
presented in the text and tables to summarise and explain the
characteristics and findings of the included studies.
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In order to determine whether reporting bias is present, we will
determine whether the protocol of the RCT was published before
recruitment of patients of the study was started. For studies
published after January 2015, we will screen the ClinicalTrials.gov,
World Health Organization’s trial portal and U.S. Food and Drug
Administration. We will evaluate whether selective reporting of
outcomes is present (outcome reporting bias). The potential for
reporting bias will be further explored by funnel plots.
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Confidence in cumulative evidence
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The quality of evidence for all outcomes will be judged using the
Grading of Recommendations Assessment, Development and
Evaluation working group methodology. The quality of evidence
will be assessed across the domains of risk of bias,
consistency, directness, precision and publication bias. Additional
domains may be considered where appropriate.
Quality will be adjudicated as high (further research is very unlikely
to change our confidence in the estimate of effect),
moderate (further research is likely to have an important impact on
ourconfidence in the estimate of effect and may change the
estimate), low (further research is very likely to have an important
impact on our confidence in the estimate of effect and is likely to
change the estimate), or very low (very uncertain about the estimate
of effect).
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Comparative efficacy and tolerability of first- and newergeneration antidepressant medications for depressive
disorders in children and adolescents: Study Protocol for a
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Journal:
Manuscript ID:
Article Type:
bmjopen-2015-007768.R3
Protocol
06-Aug-2015
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Keywords:
Mental health
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Primary Subject
Heading:
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Comparative efficacy and tolerability of first- and newer-generation antidepressant
medications for depressive disorders in children and adolescents: Study Protocol for a
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Word count: 2585.
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ABSTRACT
have adverse effects on their psychosocial functioning. Questions concerning the efficacy and safety of antidepressant
medications in the treatment of depression in children and adolescents led us to integrate the direct and indirect
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evidence using network meta-analysis to create hierarchies of these drugs.
LiLACS, and PsycINFO will be searched from 1966 to December 2013 (updated to May, 2015). There are no
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antidepressant medications against active comparator or placebo as acute treatment for depressive disorder in children
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and adolescents (under 18 years of age) will be included. The primary outcome for efficacy will be mean improvement
in depressive symptoms, as measured by the mean change score of a depression rating scale from baseline to post-
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patients who discontinued treatment due to adverse events during the trial. We will also assess the secondary outcome
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for efficacy (response rate), acceptability (all-cause discontinuation), and suicide-related outcomes. We will perform the
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newer-generation antidepressant medications for depression in children and adolescents.
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BACKGROUND
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depressive symptoms in young patients.8 In the U.S., the use of antidepressant medication in children and adolescents
grew 3- to 10-fold between 1987 and 1996.9 The efficacy of TCAs has been investigated in 13 randomized placebocontrolled trials,10 which showed marginal evidence to support the use of TCAs in the treatment of depression in only
adolescents. However, methodological deficiencies in these trials, including small sample sizes and diagnostic
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Nevertheless, the TCA nortriptyline is still approved by the Food and Drug Administration (FDA) for the treatment of
depression in adolescents and adults.13
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antidepressant medications are with youth depression.
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Nonetheless, currently, no published meta-analysis has combined direct and indirect evidence for the use of
antidepressant medications on children and adolescents, while it is an important one to perform, given the conflicting
results regarding the efficacy and tolerability of various antidepressant medications in this age group, and lack of head
to head trials of such drugs.23-25. For these reasons, we will employ a network meta-analysis –a methodological
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approach that allows the simultaneous comparison of multiple psychotherapeutic interventions within a single analysis,
while preserving randomization.26 This approach is will be used to integrate direct evidence (from studies directly
comparing interventions) with indirect evidence (information about two treatments derived via a common comparator)
from multiple treatment comparisons to estimate the interrelations across all treatments.27 We have previously compared
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the efficacy and acceptability of psychotherapies for depression in children and adolescents28 and the augmentation
agents for treatment-resistant depression in adults29 in this way. The aim of the network meta-analysis is of randomized
controlled trials is to re-analyze systematically the efficacy, tolerability, acceptability and suicide risk of both first- and
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newer-generation antidepressant medications, either against active comparator or control condition, in the treatment of
child and adolescent depression.
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METHODS
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Types of studies
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Any prospective randomized controlled trials (RCTs), including cross-over design and cluster-randomized trials will be
included. However, quasi-randomized trials (e.g., those allocating using alternate days of the week) will be excluded.
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Trials with sample sizes smaller than 10 will be excluded in this review.
Children and adolescents (aged from 6 to 18 when they initially enrolled in the trials) with a primary diagnosis of
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Where a trial contains a portion of participants who are over 18, we will contact trial authors in order to obtain data
from only those participants within our age range. We will exclude trials focusing on child or adolescent bipolar
disorder, but will include trials involving patients with comorbid general psychiatric disorders, such as attention-
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hyperactivity disorder (ADHD), anxiety disorder and substance-related disorder. However, we will not exclude trials in
which participants have a diagnosis of psychotic depression, and these participants will be considered within a separate
subgroup analysis. But we will exclude trials in which those have a diagnosis of treatment-resistant depression,
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because those resistance patients tend to have different treatment response compared with those patients with non-
resistant depression.
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RCTs comparing any first- and newer- generation antidepressant drug against active comparator or either placebo for
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node in the network analysis. We will exclude trials involving combination therapy (i.e., combination of antidepressant
medications, combination of antidepressant medication with psychotherapy, or other non-psychotherapeutic
interventions); however, trials will be considered as eligible if the concomitant psychotherapy is not predefined in the
study.
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The acute phase will be defined as from 4 to 16 weeks, and if a trial presents data beyond 16 weeks or for more than
one time period within our pre-defined acute phase periods, we will take the 8-week or close to 8-week time point.35 We
will exclude trials with treatment duration of less than 4 weeks. Where depression symptoms are measured using more
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than one depression scale in a trial, we will extract data from the depressive scales on the basis of a hierarchy of rating
scales. This hierarchy will be based on psychometric properties and appropriateness for use with children and
adolescents and for consistency of use across trials (referred from Hetrick et al. study)14 (see Table 1). The Children’s
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Depression Rating Scale (CDRS-R)36 is adapted for children and adolescents from the Hamilton Depression Rating
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Scale (HAMD)37, a tool validated and commonly used in adult populations.38 Both the CDRS-R and HAMD have good
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reliability and validity.38 The Beck Depression Inventory (BDI)39/Children’s Depression Inventory (CDI)40 are the most
commonly used among depression symptom severity-self rated scales and are ranked the second highest in the hierarchy.
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1. Overall efficacy
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1.2 The secondary outcome for efficacy will be response in depressive symptoms, as estimated by the proportion of
patients who achieved a decrease of a certain percentage (e.g., a reduction of 50% or more) in depression rating score.41
When ‘response’ is not reported, we will use ‘remission’ if available. The remission will be defined as the proportion of
patients who achieved a below the published threshold in depression rating score (e.g., CDRS-R ≤28).41
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Suicide-related dichotomous and continuous outcomes will be measured. If data are available, we will extracted the
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number of participants with suicide-related events (combined suicidal ideation and suicidal behavior) during the acute
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treatment, as measured on a standardised, validated and reliable rating scales, or reported cases of suicidality.42 In
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addition, we will also collect data on suicidal ideation as a continuous outcome where a standardised, validated and
reliable rating scale, such as the Suicidal Ideation Questionnaire-Junior High School version (SIQ-JR),43 has been used.
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PsycINFO) will be searched from 1966 to December 2013 (update to May, 2015) with Medical Subject Headings
“noradrenergic and specific serotonergic antidepressants” or “NaSSA” or “citalopram” or “fluoxetine” or “paroxetine”
or “sertraline” or “escitalopram[” or “fluvoxamine” or “venlafaxine” or “duloxetine” or “milnacipran” or “reboxetine”
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or “bupropion” or “mirtazapine” or “tricyclic” or “amersergide” or “amineptine” or “amitriptyline” or “amoxapine” or
“butriptyline” or “chlorpoxiten” or “clomipramine” or “clorimipramine” or “demexiptiline” or “desipramine” or
“dibenzipin” or “dothiepin” or “doxepin” or “imipramine” or “lofepramine” or “melitracen” or “metapramine” or
“nortriptyline” or “noxiptiline” or “opipramol” or “protriptyline” or “quinupramine” or “tianeptine” or “trimipramine”
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and “adolesc*” or “child*” or “boy*” or “girl*” or “juvenil*” or “minors” or “paediatri*” or “pediatri*” or “pubescen*”
or “school*” or “student*” or “teen*” or “young” or “youth*”. Also, ClinicalTrials.gov, World Health Organization’s
trial portal and U.S. Food and Drug Administration (FDA) reports will be reviewed. There are no restrictions on
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language or type of publication. Additional studies will be searched in the reference lists of all identified publications
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including relevant meta-analyses and systematic reviews. All relevant authors and principal manufacturers will be
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contacted to supplement incomplete reports of the original papers or to provide new data for unpublished trials.
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Study Selection
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Two independent reviewers (YYL, BQ) will independently extract the key trial parameters using a standardized data
abstraction form and assess the risk of bias. The standardized data extraction forms will include the trial characteristics
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We will perform Bayesian network meta-analysis to compare the relative outcomes of different antidepressant
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medications and placebo with each other from the median of the posterior distribution.26,27 The pooled estimates of
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standardized mean difference (SMD) with 95% credible intervals (CrIs) will be calculated for the continuous outcomes;
and odds ratios (or) with 95% CrIs will be calculated for the categorical outcomes. The SMD is that the difference in
means (MD) of change scores between the two groups divided by the pooled standard deviation (SD) of the
measurements, with a negative SMD value indicates greater symptomatic relief. In the presence of minimally
informative priors, CrIs can be interpreted similarly to confidence intervals, and at conventional levels of statistical
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significance a two-sided p <0.05 can be assumed if 95% CrIs do not include 0. If means and standard deviations (SDs)
are not provided, we will calculate them from the p-value or other statistical indices as described elsewhere.44,45 Results
from intention-to-treat analysis (ITT) or modified ITT will be preferred over results from completer analyses, while we
will also consider the dataset for the means and SDs that are presented in the literature.
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simultaneously with different arbitrarily chosen initial values. To ensure convergence, trace plots and the BrooksGelman-Rubin statistic will be assessed.46 Convergence will be found to be adequate after running 50,000 samples for
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Subgroup analyses
The antidepressant medications will be coded according to clinical characteristics, risk of bias, and sample size. We will
conduct the subgroups analyses of data in primary outcome for efficacy. We will perform the following subgroups
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analyses by using the meta-regression model and calculate Somer’s D (a correlation coefficient for a dichotomous and
an ordinal variable)49: (i) sex ratio (male-to-female ratio> 1 vs. male-to-female ratio<1); (ii) age group; (iii) treatment
duration; (iv) severity of depressive symptom (mild-to-moderate vs. moderate-to-severe); (v) comorbid general
psychiatric disorders ( with vs. without comorbid); (vi) risk of bias (‘high risk’ literature vs. ‘unclear and low risk’
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literature); (vii) sample size; (viii) company sponsor (with vs. without sponsor); and (ix) the type of trials (published
literature vs. unpublished literature). When the limitation by small number of comparisons for some potential modifiers
in carrying out subgroup analyses on these variables, we will perform the sensitivity analyses by omitting specific trials
from the overall analysis.
Other analyses
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The funnel plot analyses will be performed to check for publication bias. Moreover, we will carry out meta-regression
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analyses to investigate the effect of sponsorship or year published on outcome estimate.
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antidepressant medications for depression in children and adolescents. They will also have implications for clinical
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TABLES
Hierarchy
Abbreviation
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CDRS
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HAMD
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MADRS
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BDI
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CDI
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K-SADS
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Aged Children
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MFQ
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RADS
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BID
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CDS
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CESD
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CAS
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Comparative efficacy and tolerability of
first-generation and newer-generation
antidepressant medications for depressive
disorders in children and adolescents: study
protocol for a systematic review and network
meta-analysis
Xinyu Zhou, Bin Qin, Craig Whittington, David Cohen, Yiyun Liu, Cinzia Del
Giovane, Kurt D Michael, Yuqing Zhang and Peng Xie
BMJ Open 2015 5:
doi: 10.1136/bmjopen-2015-007768
Updated information and services can be found at:
http://bmjopen.bmj.com/content/5/9/e007768
These include:
References
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http://bmjopen.bmj.com/content/5/9/e007768#BIBL
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