Clinical Study And Plasma Metabolomics Of Depression In Children And Adolescents

Background: Major depressive disorder(MDD) is one of the most common mental disorders among children and adolescents, and accounts for the greatest burden of disease in this age group. Due to the atypical presentation and the high frequency of comorbidities, many cases of child and adolescent depression remain undetected, and do not receive the treatments they need. Thus, Youths with depression experience serious impairment in social functioning, as well as suicide attempts and behaviors.There are two categories among the treatments of MDD in children and adolescents, e.g., psychotherapy and pharmacotherapy. However, a series of questions of which category of treatment should be chosen in this population and which psychological program or drug should be preferred are still matter of controversy. Previous meta-analyses of treatments for child and adolescent depression were limited with the small number of trials and direct comparisons between two treatments, and thus they usually inconclusive because they could not generate clear hierarchies among available treatments, as many treaments have not been compared head to head.Objective: In the present part of study, we aime to conduct two network meta-analyses, a new approach that integrates direct and indirect evidence from randomized controlled studies and allows the simultaneous comparison of multiple treatments within a single analysis, to estimate the comparative efficacy and acceptability/tolerability of psychotherapies or pharmacotherapies separately.Methods: In the network meta-analysis of psychotherapies for depression in children and adolescents, eight databases, including Pub Med, Cochrane, Web of Science, EMBASE, Psyc INFO, CINAHL, LILACS, and Pro Quest Dissertations were searched from January 1, 1966 to July 1, 2014. Also, Clinical Trials.gov, the World Health Organization’s trial portal and U.S. Food and Drug Administration(FDA) reports were reviewed. The primary outcome was efficacy at post-treatment, as measured by mean change scores in depressive symptoms(self- or assessor-rated) from baseline to post-treatment. The secondary outcome was efficacy at follow-up, as measured by mean change scores in depressive symptoms from baseline to the end of follow-up. The acceptability of treatment was operationally defined as all-cause discontinuation, as measured by the proportion of patients who discontinued treatment up to the post-intervention time point.In the network meta-analysis of antidepressants for major depression in children and adolescents, we also searched Pub Med, Cochrane, Web of Science, Embase, CINAHL, Psyc INFO, Li LACS, regulatory agencies’ websites and international registers for published and unpublished randomised controlled trials up to May 31 st 2015, for the acute treatment of MDD in children and adolescents. The primary outcomes were efficacy(change in depressive symptoms) and tolerability(discontinuations due to adverse events). We also examined response rate, all-cause dropouts and suicidality.Results: In the network meta-analysis of psychotherapies for depression in children and adolescents, 52 studies(3,805 participants) of 9 psychotherapies and 4 control conditions were indentified. At post-treatment, only interpersonal therapy(IPT) and cognitive-behavioral therapy(CBT) were significantly more effective than most control conditions(standardized mean differences, SMDs ranged from-0.47 to-0.96). Also, IPT and CBT were more beneficial than play therapy. Only psychodynamic therapy and play therapy were not significantly superior to waitlist. At follow-up, IPT and CBT were significantly more effective than most control conditions(SMDs ranged from-0.26 to-1.05), although only IPT retained this superiority at both short-term and long-term follow-up. In addition, IPT and CBT were more beneficial than problem-solving therapy. Waitlist was significantly inferior to other control conditions. With regard to acceptability, IPT and problem-solving therapy had significantly fewer all-cause discontinuations than cognitive therapy and CBT(ORs ranged from 0.06 to 0.33).In the network meta-analysis of antidepressants for major depression in children and adolescents, we deemed 34 trials eligible, including 5,260 participants and 14 antidepressant treatments. For efficacy, only fluoxetine was statistically significantly more effective than placebo(standardised mean difference:-0.50, 95% credible intervals [Cr Is]-0.98 to-0.03). In terms of tolerability, fluoxetine was also better than duloxetine and imipramine(odds ratio [OR] 0.31, 95% Cr I 0.13 to 0.95 and 0.23, 95% Cr I 0.04 to 0.78, respectively), while imipramine, venlafaxine, and duloxetine had more discontinuations due to adverse events than placebo(OR 5.49, 95% Cr I 1.96 to 20.86; 3.19, 95% Cr I 1.01 to 18.70 and 2.80, 95% Cr I 1.20 to 9.42, respectively).Conclusions: For psychotherapies, IPT and CBT should be considered as the best available psychotherapies for depression in children and adolescents. However, several alternative psychotherapies are understudied in this age group. Waitlist may inflate the effect of psychotherapies, so that psychological placebo or treatment-as-usual may be preferable as a control condition in psychotherapy trials. For pharmacotherapies, balancing the risk-benefit profile of antidepressants in the acute treatment of MDD, the included drugs do not seem to offer a clear advantage for children and adolescents except for fluoxetine, which is probably the only antidepressant to consider when a pharmacological treatment is indicated, however patients should be carefully monitored for the risk of increased suicidality.Background: Major depressive disorder(MDD) is a frequent affective disturbance disease, depression in young people has significant developmental implications, and accounts for the greatest burden of disease in this age group. Though abundant of preclinical and clinical studies associated with the pathophysiology of depression in children and adolescents have been reported, and many mechanism hypotheses have been raised, the underlying molecular mechanisms are still essentially unknown. In addition, the current diagnosis of depression in children and adolescents mainly relies on the clinical symptoms of the patient, which is subjective. Therefore, metabonomics study of plasma for depression in children and adolescents is needed to explore the pathogenesis of depression, identify objective biomarkers and promote the diagnosis of depression from subjective to combination of subjective and objective.Objective: 1. To identify biomarkers in plasma samples from depressed children and adolescents and healthy controls based on a non-targeted metabolomics approach. 2. To performe function analysis of these biomarkers and investigate the potential pathophysiology of depression in children and adolescents.Methods:1. 89 depressed children and adolescents(drug-na?ve MDD, n = 54; drug-treatment MDD, n = 35) with Hamilton Depression Scale(HAMD) value greater than 17 or Children’s Depression Rating Scale(CDRS) value greater than 40 and 89 matched healthy controls were enrolled. 2. An ultra-high-performance liquid chromatography equipped with quadrupole time-offlight mass spectrometry-based(UPLC-Q-TOF/MS) non-targeted metabolomics approach was used to compare the plasma metabolic profiles among the 54 drug-na?ve depressed subjects, 35 drug-treatment depressed subjects and 89 matched healthy controls in order to identify biomarkers for depression in children and adolescents. 3. Kyoto Encyclopedia of Genes and Genomes(KEGG) was used to identify the significantly perturbed metabolic pathways based on the functional analysis of the differentially expressed metabolites among the groups.Results : 1. In the analysis of demographic characteristics, the drug-na?ve depressed children and adolescents had a significant statistical difference in the gender composition compared with healthy controls(p = 0.005) or drug-treatment depressed children and adolescents(p = 0.002). Howerver, no significant statistical differences in the age and body mass index(BMI) were found among the three groups. 2. Multivariate statistical analysis(PLS-DA) showed that there was a significant metabolic differences between drug-na?ve depressed children and adolescents and healthy controls, as well as the drug-treatment depressed children and adolescents. A total of 37 different metabolites were identified in drug-na?ve depressed children and adolescents compared to healthy controls, and a total of 10 different metabolites were identified compared to drug-treatment depressed children and adolescents. 3. Function analysis showed that the identified 37 metabolites were involved in lipid metabolism and energy metabolism.Conclusion: In this study, ultra-high-performance liquid chromatography equipped with quadrupole time-offlight mass spectrometry(UPLC-Q-TOF/MS) non-targeted metabolomics approach was used for the first time to identified the metabolic changes in the depressed children and adolescents. The results indicated that the lipid metabolism and energy metabolism play an important role in the pathogenesis of depression in children and adolescents, which provides useful insights into the pathogenesis of depression in children and adolescents.