New generation antidepressants for depression in children and adolescents: a network meta-analysis.
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ABSTRACT:
SUBMITTER: Hetrick SE
PROVIDER: S-EPMC8143444 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
Publications
New generation antidepressants for depression in children and adolescents: a network meta-analysis.
Hetrick Sarah E SE McKenzie Joanne E JE Bailey Alan P AP Sharma Vartika V Moller Carl I CI Badcock Paul B PB Cox Georgina R GR Merry Sally N SN Meader Nicholas N
The Cochrane database of systematic reviews 20210524
<h4>Background</h4>Major depressive disorders have a significant impact on children and adolescents, including on educational and vocational outcomes, interpersonal relationships, and physical and mental health and well-being. There is an association between major depressive disorder and suicidal ideation, suicide attempts, and suicide. Antidepressant medication is used in moderate to severe depression; there is now a range of newer generations of these medications.<h4>Objectives</h4>To investig ...[more]
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Project description:INTRODUCTION:Although previous conventional meta-analyses and network meta-analyses have provided some important findings about pharmacological treatments for children and adolescents with depressive disorders in the past decades, several questions still remain unsolved by the aggregate data from those meta-analyses. Individual participant data meta-analysis (IPD-MA) enables exploration of the impacts of individual characteristics on treatment effects, allowing matching of treatments to specific subgroups of patients. We will perform an IPD-MA to assess the efficacy and tolerability of new-generation antidepressants for major depressive disorder in children and adolescents. METHODS AND ANALYSIS:We will systematically search for all double-blind randomised controlled trials (RCTs) that have compared any new-generation antidepressant with placebo for the acute treatment of major depressive disorder in children and adolescents, in the following databases: PubMed, EMBASE, the Cochrane Library, PsycINFO, Web of Science, CINAHL, LILACS and ProQuest Dissertations. We will contact all corresponding authors of included RCTs and ask for their cooperation in this project by providing individual participant data from the original trials. The primary outcomes will include efficacy, measured as the mean change of depression symptoms by Children's Depression Rating Scale Revised (CDRS-R), and tolerability, measured as the proportion of patients who withdrew from the trials early due to adverse effects. The secondary outcomes will include response rates, remission rates, deterioration rate, all-cause discontinuation, suicidal-related outcomes and global functioning outcome. Using the raw de-identified study data, we will use mixed-effects logistic and linear regression models to perform the IPD-MAs. The risk of bias of included studies will be assessed using the Cochrane risk of bias tool. We will also detect the publication bias and effects of non-participation of eligible studies. DISSEMINATION:Ethical approval is not required given that informed consent has already been obtained from the patients by the trial investigators before the included trials were conducted. This study may have considerable implications for practice and help improve patient care. PROSPERO REGISTRATION NUMBER:CRD42016051657.
| S-EPMC5781225 | biostudies-other
Project description: Not available
| S-EPMC8786271 | biostudies-literature
Project description:ObjectivesTo evaluate the effect of different exercise interventions on depressive symptoms in children and adolescents.MethodsRandomized controlled trials (RCT) published until May 2023 were screened in four databases. The Cochrane collaboration tool was used to assess the risk of bias for quality evaluation. Stata 16.0 software was used for both a pairwise meta-analysis and a series of frequentist network meta-analyses (NMA).ResultsA total of 35 RCTs and 5393 participants were included. Aerobic exercise had the most significant effect on depressive symptoms (66.2%), followed by group training (62.5%), resistance exercise (59.0%), and aerobic combined with resistance exercise (57.9%). Furthermore, children and adolescents younger than 15 years showed significant improvement in depressive symptoms (SMD=-0.41, 95% CI (-0.63, -0.19), P < 0.01). The study also found a significant improvement in depression among healthy, obesity, and depressed populations (SMD=-0.25, 95% CI (-0.41, -0.08), P < 0.01); SMD=-0.15, 95% CI (-0.31, -0.00), P < 0.01; SMD=-0.75, 95% CI (-1.32, -0.19), P < 0.01). Additionally, 30 min of exercise had a significant effect (SMD=-0.14, 95% CI (-0,81, -0.01), P < 0.01), and 40-50 min of exercise had the best effect (SMD=-0.17, 95% CI (-0,33, -0.02), P < 0.01). Lastly, exercise frequency of three times per week was significant in children and adolescents (SMD=-0.42, 95% CI (-0,66, -0.18), P < 0.01).ConclusionExercise significantly improves depressive symptoms in children and adolescents, with aerobic exercise having the most significant effect. A 12-week, three-times-a-week, 40-50-minute exercise intervention was found to be more effective in younger children and adolescents.
| S-EPMC10552327 | biostudies-literature
Project description:After more than half a century of modern psychopharmacology, with billions of dollars spent on antidepressants annually world-wide, we lack good evidence to guide our everyday decisions in conducting antidepressant treatment of patients with major depression. First we did not know which antidepressant to use as first line treatment. Second we do not know which dosage we should be aiming at with that antidepressant. Because more than half of the patients with major depression starting treatment do not remit after adequate trial with the first agent, they will need a second line treatment. Dose escalation, augmentation and switching are the three often recommended second line strategies but we do not know which is better than the others. Moreover, we do not know when to start considering this second line treatment.The recently published multiple-treatments meta-analysis of 12 new generation antidepressants has provided some partial answers to the first question. Starting with these findings, this proposed trial aims to establish the optimum 1st line and 2nd line antidepressant treatment strategy among adult patients with a non-psychotic unipolar major depressive episode.SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded, parallel-group, multi-centre randomised controlled trial. Step I is a cluster-randomised trial comparing titration up to the minimum vs maximum of the recommended dose range among patients starting with sertraline. The primary outcome is the change in the Patient Health Questionnaire (PHQ)-9 scores administered by a blinded rater via telephone at week 1 through 3. Step II is an individually randomised trial comparing staying on sertraline, augmentation of sertraline with mirtazapine, and switching to mirtazapine among patients who have not remitted on the first line treatment by week 3. The primary outcome is the change in the PHQ-9 scores at week 4 through 9. Step III represents a continuation phase to Steps I and II and aims to establish longer-term effectiveness and acceptability of the above-examined treatment strategies up to week 25. The trial is supported by the Grant-in-Aid by the Ministry of Health, Labour and Welfare, Japan.SUN(^_^)D promises to be a pragmatic large trial to answer important clinical questions that every clinician treating patients with major depression faces in his/her daily practices concerning its first- and second-line treatments.ClinicalTrials.gov: NCT01109693.
| S-EPMC3120681 | biostudies-literature
Project description:SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded, parallel-group, multicenter pragmatic mega-trial to examine the optimum treatment strategy for the first- and second-line treatments for unipolar major depressive episodes. The trial has three steps and two randomizations. Step I randomization compares the minimum and the maximum dosing strategy for the first-line antidepressant. Step II randomization compares the continuation, augmentation or switching strategy for the second-line antidepressant treatment. Step III is a naturalistic continuation phase. The original protocol was published in 2011, and we hereby report its updated protocol including the statistical analysis plan.We implemented two important changes to the original protocol. One is about the required sample size, reflecting the smaller number of dropouts than had been expected. Another is in the organization of the primary and secondary outcomes in order to make the report of the main trial results as pertinent and interpretable as possible for clinical practices. Due to the complexity of the trial, we plan to report the main results in two separate reports, and this updated protocol and the statistical analysis plan have laid out respective primary and secondary outcomes and their analyses. We will convene the blind interpretation committee before the randomization code is broken.This paper presents the updated protocol and the detailed statistical analysis plan for the SUN(^_^)D trial in order to avoid reporting bias and data-driven results.ClinicalTrials.gov: NCT01109693 (registered on 21 April 2010).
| S-EPMC4606498 | biostudies-literature
Project description:IntroductionDepressive disorders are the most common, burdensome and costly mental disorders. Their treatments have developed through the past decades and we now have more than a dozen new generation antidepressants, while a series of guidelines have been published to provide recommendations over the years. However, there still may exist important gaps in this evidence synthesis and implementation process. Systematic reviews may not have been conducted in the most unbiased, informative and timely manners; guidelines may not have reflected the most up-to-date evidence; clinicians may not have changed their clinical decision-makings in accordance with the relevant evidence. The aim of this study is to examine the gaps between the ideally synthesised evidence, guideline recommendations and real-world clinical practices in the prescription of new generation antidepressants for major depression through the past three decades.Methods and analysisWe will conduct cumulative network meta-analyses (cNMAs) based on the comprehensive systematic review which has identified published and unpublished head-to-head randomised controlled trials comparing the following antidepressants in the acute phase treatment of major depression: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. The primary outcomes will be the proportions of patients who responded (efficacy) and who withdrew from treatment for any reasons (acceptability). We will conduct a random effects cNMA to synthesise evidence and obtain a comprehensive ranking of all new generation antidepressants based on their surface under the cumulative ranking curves. We will identify series of international clinical practice guidelines for the treatment of major depression of adults and summarise their recommendations. We will estimate real-world prescription patterns of antidepressants in the nationally representative samples in USA in the Medical Expenditure Panel Survey. We will compare and evaluate the gaps between the rankings according to cNMAs conducted at 5-year intervals between 1990 and 2015, recommendations in guidelines published in the ensuing 5?years and actual practices thereafter.Ethics and disseminationThis review does not require ethical approval. We will disseminate our findings through publications in peer-reviewed journals and presentations at conferences.Trial registration numberUMIN000031898.
| S-EPMC6303574 | biostudies-literature
Project description:It is often challenging to present the available evidence in a timely and comprehensible manner. We aimed to visualize the evolution of evidence about antidepressants for depression by conducting cumulative network meta-analyses (NMAs) and to examine whether it could have helped the selection of optimal drugs. We built a Shiny web application that performs and presents cumulative NMAs based on R netmeta. We used a comprehensive dataset of double-blind randomized controlled trials of 21 antidepressants in the acute treatment of major depression. The primary outcomes were efficacy (treatment response) and acceptability (all-cause discontinuation), and treatment effects were summarized via odds ratios. We evaluated the confidence in evidence using the CINeMA (Confidence in Network Meta-Analysis) framework for a series of consecutive NMAs. Users can change several conditions for the analysis, such as the period of synthesis, among the others. We present the league tables and two-dimensional plots that combine efficacy, acceptability and level of confidence in the evidence together, for NMAs conducted in 1990, 1995, 2000, 2005, 2010, and 2016. They reveal that through the past four decades, newly approved drugs often showed initially exaggerated results, which tended to diminish and stabilize after approximately a decade. Over the years, the drugs with relative superiority changed dramatically; but as the evidence network grew larger and better connected, the overall confidence improved. The Shiny app visualizes how evidence evolved over years, emphasizing the need for a careful interpretation of relative effects between drugs, especially for the potentially amplified performance of newly approved drugs. HIGHLIGHTS: Network meta-analysis is considered to be a proper way of demonstrating the available evidence, since it allows comparisons between multiple interventions, and has been proved to be statistically powerful. It is challenging to present the voluminous results of NMA in an efficient and comprehendible manner. Evidence evolution based on the relatively new method NMA has not been investigated yet. The results of NMA should not only include the effects but also the confidence in the evidence, which can help interpret the findings appropriately. Effective use of rapidly developing statistical analysis and presentation tools such as Shiny package in R, may facilitate and simplify the visualization of NMA output. We should stay conservative towards new drugs, as their performance was often shown to be exaggerated initially, and it took time to become stable.
| S-EPMC7818396 | biostudies-literature
Project description:IntroductionDepressive disorder is common in children and adolescents, with important consequences and serious impairments in terms of personal and social functioning. While both pharmacological and psychological interventions have been shown to be effective, there is still uncertainty about the balance between these and what treatment strategy should be preferred in clinical practice. Therefore, we aim to compare and rank in a network meta-analysis (NMA) the commonly used psychological, pharmacological and combined interventions for depressive disorder in children and adolescents.Methods and analysisWe will update the literature search of two previous NMAs for the identification of trials of antidepressant and psychotherapy alone for depressive disorder in children and adolescents. For identification of trials of combination interventions, seven databases (PubMed, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science, PsycINFO, CINAHL, LiLACS) will be searched from date of inception. We will also search ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform and check relevant reports on the US Food and Drug Administration website for unpublished data. Building on our previous findings in the field, we will include any commonly prescribed oral antidepressants and any manualised or structured psychotherapies, as well as their combinations. Randomised controlled trials assessing any active intervention against active comparator or pill placebo/psychological controls in acute treatment for depressive disorder in children and adolescents will be included. The primary outcomes will be efficacy (mean change in depressive symptoms), and acceptability of treatment (dropout rate due to any cause). The secondary outcomes will be remission rate, tolerability of treatment (dropouts for adverse events), as well as suicide-related outcomes (suicidal behaviour or ideation). We will perform Bayesian NMAs for all relative outcome measures. Subgroup analyses and sensitivity analyses will be conducted to assess the robustness of the findings.DisseminationThis NMA will provide the most up to date and clinically useful information about the comparative efficacy and acceptability of antidepressants, psychological intervention and their combination in the acute treatment of children and adolescents with depressive disorder. This is the newest NMA and therefore these results are very important in terms of evidence-based medicine. The results will be disseminated through peer-reviewed publication.Protocol registrationPROSPERO CRD42015020841.
| S-EPMC5629731 | biostudies-literature
Project description:ObjectiveTo compare the incidence of adverse events between active and placebo arms of randomized clinical trials in depressive children and adolescents (C&A) with antidepressant treatments, in order to look for similarities in both groups that allow to establish a possible nocebo effect.MethodsSystematic search strategy (January 1974-March 2013) in electronic databases, conference abstracts, and reference list of systematic reviews and included studies to identify parallel randomized placebo-controlled trials of antidepressants in C&A (<19?years) with major depressive disorder, and one or more interventions of any orally administered antidepressant. The pooled adverse events were calculated based on a fixed-effect model and statistical analysis involved the risk ratio (RR) of adverse events, with 95% confidence intervals (95% CI).ResultsSixteen studies were included in the review, of which seven studies with a sample of 1911 patients had data to include in the meta-analysis. There was similar risk for the incidence of adverse events between non-active and active group (global RR 1.04, 95% CI: 0.97-1.11).ConclusionDepressive C&A allocated to placebo or active group had similar risk to develop adverse events. These similarities in both groups are attributed to the nocebo effect. It is of note that defining "nocebo" effects is challenging in clinical populations because adverse effects may be attributed to the intervention or may be manifestation of the disease itself. The inclusion of a no-treatment arm may be warranted. Nocebo effects are likely when adverse events of placebo mimic the adverse events of active treatment, as was the case here.
| S-EPMC4217505 | biostudies-literature
Project description:OBJECTIVES:To investigate whether the conclusion of a recent systematic review and network meta-analysis (Cipriani et al) that antidepressants are more efficacious than placebo for adult depression was supported by the evidence. DESIGN:Reanalysis of a systematic review, with meta-analyses. DATA SOURCES:522 trials (116 477 participants) as reported in the systematic review by Cipriani et al and clinical study reports for 19 of these trials. ANALYSIS:We used the Cochrane Handbook's risk of bias tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to evaluate the risk of bias and the certainty of evidence, respectively. The impact of several study characteristics and publication status was estimated using pairwise subgroup meta-analyses. RESULTS:Several methodological limitations in the evidence base of antidepressants were either unrecognised or underestimated in the systematic review by Cipriani et al. The effect size for antidepressants versus placebo on investigator-rated depression symptom scales was higher in trials with a 'placebo run-in' study design compared with trials without a placebo run-in design (p=0.05). The effect size of antidepressants was higher in published trials compared with unpublished trials (p<0.0001). The outcome data reported by Cipriani et al differed from the clinical study reports in 12 (63%) of 19 trials. The certainty of the evidence for the placebo-controlled comparisons should be very low according to GRADE due to a high risk of bias, indirectness of the evidence and publication bias. The mean difference between antidepressants and placebo on the 17-item Hamilton depression rating scale (range 0-52 points) was 1.97 points (95% CI 1.74 to 2.21). CONCLUSIONS:The evidence does not support definitive conclusions regarding the benefits of antidepressants for depression in adults. It is unclear whether antidepressants are more efficacious than placebo.
| S-EPMC6597641 | biostudies-literature