To evaluate the success rate of different antidepressants in addressing depression among teenagers, while also offering substantiation for the efficacy and tolerability of these treatments in this demographic. Participants were adolescents aged 6–18 years diagnosed with major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) , Chinese Classification of Mental Disorders (CCMD-3) or equivalent diagnostic criteria (e.g., Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition(DSM-4) , International Classification of Diseases, Tenth/Eleventh Revision(ICD10/11) ) . We conducted a systematic search of major databases (PubMed, Cochrane Library, and Web of Science) for randomized controlled trials (RCTs) published up to October 2024. The search strategy included the following keywords: “Depression,” “Depressive Disorders,” “Emotional Disorders,” “adolescent,” “young adult, ” “minors,” “fluoxetine,” “sertraline,” “paroxetine,” “agomelatine,” “vilazodone,” “escitalopram,” and “venlafaxine.” Our network meta-analysis(NMA) included 15 RCTs involving 12,258 participants. The included studies were assessed using the Cochrane risk of bias tool. The majority of studies had low risk of bias in terms of randomization and allocation concealment, while some studies had unclear implementation of blinding or outcome assessment. The NMA results showed that in several major indicators Children’s Depression Rating Scale-Revised (CDRS-R) , Clinical Global Impression-Severity (CGI-S) and Children’s Global Assessment Scale (CGAS) , agomelatine (MD = -0.34, 95 % CI = -0.59, -0.09), fluoxetine (MD = -0.31, 95 % CI = -0.42, -0.21), sertraline (MD = -0.27, 95 % CI = -0.47, -0.06) were significantly better than placebo in improving CDRS-R. In terms of CGI-S, sertraline (MD = -4.39, 95 % CI = -4.77, -4.01) was more effective. In contrast to the placebo, escitalopram (MD = 2.08,95 % CI = 1.33,2.84) was more effective in CGAS; Surface Under the Cumulative Ranking Curve (SUCRA) values showed that escitalopram (96.1 % and 86.4 %) could achieve better therapeutic effects in CGAS and Clinical Global Impressions-Improvement (CGI-I) , and agomelatine (86.4 %) was more effective in improving CDRS-R scores than other drugs. Sertraline (100 %) appears to be the most likely strategy to decelerate the increase in CGI-I scores. The effectiveness of paroxetine (99.9%) in the management of Montgomery-Asberg Depression Rating Scale (MADRS) was significantly better than that of several other drugs. For symptom severity scales, agomelatine (CDRS-R: SUCRA 86.4%) and paroxetine (MADRS: SUCRA 99.9%) demonstrated the greatest efficacy. For functional improvement, escitalopram ranked highest on CGAS (SUCRA 96.1%). Sertraline showed superiority in clinician-rated severity (CGI-S: SUCRA 100%) and improvement (CGI-I: SUCRA 80.2%). Clinical decisions should prioritize escitalopram for functional recovery and sertraline for severe cases requiring rapid symptom reduction. PROSPERO registration number: CRD42024609880.

INTRODUCTION: Systemic inflammation and lipid metabolism disturbances are important hallmarks of the onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to explore the association of lymphocyte-high-density lipoprotein-cholesterol ratio (LHR), monocyte-HDL-C ratio (MHR), neutrophil-HDL-C ratio (NHR), and platelet-HDL-C ratio (PHR) with MASLD and significant liver fibrosis using NHANES 2017–2020 data. METHODS: LHR, MHR, NHR, and PHR were calculated based on complete blood count parameters and serum HDL-C. MASLD and liver fibrosis were diagnosed based on transient elastography. Multivariate logistic regression analyses were used to explore these associations, and receiver operating characteristic was used to compare the predictive power of these markers. RESULTS: A total of 8,341 participants were included, and the prevalence of MASLD and significant liver fibrosis was 45.1% and 11.57%, respectively. In fully adjusted models, log-transformed LHR, MHR, NHR, and PHR were positively associated with the odds of MASLD (odds ratio 1.853, 1.685, 1.470, and 1.879, respectively) and significant liver fibrosis (odds ratio 1.570, 1.425, 1.396, and 1.384, respectively) (all P < 0.05). Most of these associations were nonlinear, and significant positive correlations existed only after their respective inflection points. The association of LHR with significant liver fibrosis was more pronounced in men. Receiver operating characteristic analysis showed that LHR/NHR was superior in predicting MASLD, whereas MHR/NHR distinguished significant liver fibrosis better than other markers. DISCUSSION: LHR, MHR, NHR, and PHR were independently associated with MASLD and liver fibrosis in US adults and may serve as emerging predictors. Future cohort studies are needed to confirm these findings and explore clinical predictive value.

Importance: Metabolic dysfunction‐associated steatotic liver disease (MASLD) is caused by dysregulated lipid metabolism, inflammation, and mitochondrial dysfunction. Given the rising burden of MASLD in children and adolescents, identifying experimentally tractable mechanisms relevant to pediatric diseases is of considerable interest. Tryptophan hydroxylase‐1 (TPH1), the rate‐limiting enzyme for peripheral serotonin synthesis, has been implicated in metabolic disorders, but its hepatic role in MASLD remains unclear. Objective: To investigate whether Tph1 suppression alleviates lipid accumulation, mitochondrial dysfunction, and hepatocyte injury through changes associated with Parkin‐mediated mitophagy. Methods: MASLD was induced in young adult male C57BL/6J mice by a 12‐week high‐fat diet (HFD). At HFD onset, mice received a single tail‐vein injection of liver‐tropic AAV8‐shTph1 or the control AAV8. The HFD feeding was continued for 12 weeks until the end of the experiment. Hepatic histology, serum biochemistry, oxidative stress, inflammatory responses, apoptosis, and mitochondrial function were also evaluated. Mechanistic studies were conducted in palmitic acid/oleic acid‐treated AML12 hepatocytes using siRNA targeting Tph1 and Parkin . Results: Hepatic TPH1 expression was elevated in MASLD mice. Tph1 knockdown alleviated diet‐induced steatosis, reduced serum triglycerides, total cholesterol, low‐density lipoprotein cholesterol, and transaminase levels, suppressed oxidative stress, and attenuated inflammatory and fibrotic markers. Tph1 silencing decreased hepatocyte apoptosis and restored mitochondrial function. Transmission electron microscopy and fractionated Western blotting analyses revealed increased Parkin‐associated mitophagy. In AML12 cells, siTph1 reduced lipid accumulation and apoptosis, whereas co‐silencing Parkin partially reversed these effects. Interpretation: Hepatic TPH1 is associated with MASLD progression and impaired Parkin‐mediated mitophagy. Tph1 suppression may represent a potential therapeutic strategy for experimental MASLD, with possible translational relevance to pediatric MASLD, though direct clinical validation is still needed.