Project description:Children and adolescents with major depressive disorder (MDD) appear to be more responsive to placebo than adults in randomized placebo-controlled trials (RCTs) of second and newer generation antidepressants (SNG-AD). Previous meta-analyses obtained conflicting results regarding modifiers. We aimed to conduct a meta-analytical evaluation of placebo response rates based on both clinician-rating and self-rating scales. Based on the most recent and comprehensive study on adult data, we tested whether the placebo response rates in children and adolescents with MDD also increase with study duration and number of study sites. We searched systematically for published RCTs of SNG-AD in children and/or adolescents (last update: September 2017) in public domain electronic databases and additionally for documented studies in clinical trial databases. The log-transformed odds of placebo response were meta-analytically analyzed. The primary and secondary outcomes were placebo response rates at the end of treatment based on clinician-rating and self-rating scales, respectively. To examine the impact of study duration and number of study sites on placebo response rates, we performed simple meta-regression analyses. We selected other potential modifiers of placebo response based on significance in at least one previous pediatric meta-analysis and on theoretical considerations to perform explorative analyses. We applied sensitivity analyses with placebo response rates closest to week 8 to compare our data with those reported for adults. We identified 24 placebo-controlled trials (2229 patients in the placebo arms). The clinician-rated placebo response rates ranged from 22 to 62% with a pooled response rate of 45% (95% CI 41-50%). The number of study sites was a significant modifier in the simple meta-regression analysis [odds ratio (OR) 1.01, 95% CI 1.01-1.02, p?=?0.0003, k?=?24) with more study sites linked to a higher placebo response. Study duration was not significantly associated with the placebo response rate. The explorative simple analyses revealed that publication year may be an additional modifier. However, in the explorative multivariable analysis including the number of study sites and the publication year only the number of study sites reached a p value???0.05. The self-rated placebo response rates ranged from 1 to 68% with a pooled response rate of 26% (95% CI 10-54%) (k?=?6; n?=?396). This meta-analysis confirms a high pooled placebo response rate in children and adolescents based on clinician ratings, which exceeds that observed in the most recent meta-analysis of placebo effects in adults (36%; 95% CI 35-37%) published in 2016. However, and similar to findings in adults, the pooled response rates based on self-ratings were substantially lower. In accordance with previous meta-analyses, we corroborated the number of study sites as significant modifier. In comparison to the recent adult meta-analysis, the substantially lower number of pediatric studies entails a reduced power to detect modifiers. Future studies should provide more precise and homogenous information to support discovery of potential modifiers and consider no-treatment-if ethically permissible-to allow differentiation between placebo and spontaneous remission rates. If these differ, practicing clinicians should facilitate placebo effects as an addition to the verum effect to maximize benefits. Further research is required to explain the discrepant response rates between clinician and self-ratings.

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.

Project description:ObjectiveGuidelines for the prescription of antidepressants for Depressive Disorders (DD) have been in place for a long time. However, there is a lack of systematic information on the prescribing behavior of antidepressants in evidence-based clinical practice in psychopharmacotherapy of depressive disorders. This may suggest a lack of implementation of clinical guidelines by clinicians. Existing literature mainly focuses on specific issues or medications. To provide general information on the prescribing behavior of antidepressants for depressive disorders, a systematic review of available studies since 2013 was conducted.Methods and materialsTo ensure a structured and systematic approach for the literature search and subsequent review process, the PRISMA guidelines for systematic reviews were followed. Major medical and health and psychological databases were used for the literature search. These included Ebsco Host, OVID, PubMed, Science Direct, Scopus, and Web of Science. The online application "Covidence" was employed to manage the titles collected and the full articles retrieved from the initial literature search. Upon finalizing the list of selected studies, data extraction was then conducted using a build-in function of the Covidence platform with the required information pre-set on a template for data extraction. The extracted information was tabulated and summarized in a table.ResultsForty-one studies were identified after an extensive search of the literature following the PRISMA guidelines. Of these, 37 quantitative studies providing useful information were systematically reviewed and information extracted. There was a high level of heterogeneity among these studies with different foci or characteristics. Most studies were conducted in or utilized data obtained from hospital and primary healthcare settings. SSRIs were the most commonly prescribed type of antidepressant in the past decade, particularly among younger patients. Among these studies, antidepressants were mainly prescribed by psychiatrists with some by other physicians and general practitioners. This might reflect differences in legislation regarding professional requirements for prescribers or clinical practices.ConclusionsA few themes that would be considered important in terms of the effect of prescription behavior on depression, specifically children/adolescents, special target populations, and off-label prescription. The results highlighted the need for more studies on a community-based approach and the role of GPs in the treatment of DD.

Project description:ImportanceLittle evidence exists on neurological adverse events (movement disorders and seizures) that occur during adjuvant use of antipsychotics with antidepressants, especially in children and adolescents.ObjectiveTo assess the association between neurological adverse events (movement disorders, including parkinsonism, dystonia, extrapyramidal symptoms, chorea, and tic, and seizures) and the adjuvant use of antipsychotics in children and adolescents with depression.Design, setting, and participantsA retrospective cohort study using the Health Insurance Review and Assessment claims database in Korea between 2008 and 2018. The study population was children and adolescents aged 2 to 18 years with depression who began treatment with antidepressants between January 1, 2010, and December 31, 2018. Data were analyzed between December 9, 2020, and December 10, 2021.ExposureTime-varying exposure to antidepressants, antipsychotics, and concomitant use of antidepressants and antipsychotics. Concomitant use was further subdivided according to the antipsychotic treatment status (dose and agent).Main outcomes and measuresThe extended Cox proportional hazards regression model, with adjustment for sex, age, health insurance type, psychiatric comorbidities, psychiatric hospitalization, and comedication with other psychotropic drugs, was used to estimate adjusted hazard ratios (aHRs) and 95% CIs for the associations of movement disorders and seizures with use of antidepressants and antipsychotics.ResultsA total of 9890 patients were included in the study: 9541 (mean [SD] age, 14.8 [2.8] years; 4956 [51.9%] female) and 7731 (mean [SD] age, 14.9 [2.7] years; 4150 [53.7%] female) met the inclusion criteria for movement disorders and seizures, respectively. For movement disorders, associations were found between concomitant use (aHR, 3.68; 95% CI, 3.06-4.44) and antipsychotic-only use (aHR, 3.84; 95% CI, 3.03-4.87) compared with antidepressant-only use, but their CIs overlapped. The associations with seizure were similar (concomitant use: aHR, 2.06; 95% CI, 1.66-2.55; antipsychotic-only use: aHR, 2.05; 95% CI, 1.53-2.75). With concomitant use, the aHRs gradually increased with increasing doses of antipsychotics. Haloperidol had the highest aHR, 7.15 (95% CI, 3.89-10.00) for movement disorders. The highest aHR for seizure was observed with quetiapine (aHR, 2.36; 95% CI, 1.55-3.59), followed by aripiprazole (aHR, 2.05; 95% CI, 1.52-2.77).Conclusions and relevanceIn this cohort study, adjunctive antipsychotics with antidepressants were associated with movement disorders and seizures compared with antidepressant monotherapy in children and adolescents with depression. These results suggest that careful consideration of the risk-benefit profile of the antipsychotic use as adjuvant therapy in this population is needed.

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.

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Newer generation antidepressants for depressive disorders in children and adolescents.

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