Vitamin D has been associated with depression, potentially via anti-inflammatory mechanisms, yet data are scarce, particularly in adolescence. We investigated (1) whether lower vitamin D status is associated with greater depression severity and (2) whether this association is statistically moderated by inflammation in patients of a child and adolescent psychiatry department. At admission, fasting morning venous blood was drawn. Serum vitamin D (25-hydroxy-cholecalciferol (25(OH)D)) and C-reactive protein (CRP) were analysed in all participants (n 465 (64·7 %♀; 11·3-18·9 years)). In a subsample (n 177), we additionally measured tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and interleukin (IL)-1β, IL-6, IL-8 and IL-10. Depression severity was assessed by the Beck Depression Inventory II (BDI-II) (n 450), the Diagnostic System for Mental Disorders in Childhood and Adolescence via self-assessment (DISYPS Self) (n 441) and parent-assessment (DISYPS Proxy) (n 422). Overall, 43·2 % (n 201) were at risk for vitamin D deficiency (< 30 nmol/l), and 73·5-83·2 % - depending on assessment tool - showed at least mild depression. Linear regression revealed an inverse association between 25(OH)D and BDI-II in both crude and CRP-adjusted full-sample models. Logistic regressions showed a robust inverse association between 25(OH)D and DISYPS Proxy, but not for DISYPS Self. Although 25(OH)D was inversely correlated with some pro-inflammatory markers, neither their inclusion in regression models nor formal mediation analyses supported inflammation as a mediator of the vitamin D-depression association. Overall, our results suggest that vitamin D relates modestly to both depression and inflammation in adolescence. However, based on the measured parameters, we cannot confirm that anti-inflammatory effects are the link between vitamin D and depression.

Mutations that impair the function of the melanocortin 4 receptor (MC4R) cause severe obesity in both heterozygous and homozygous carriers. However, recent findings indicate that individuals with this form of monogenic obesity may be unexpectedly protected against dyslipidemia and cardiovascular diseases.

The relationship between leptin levels and psychiatric disorders has been studied more extensively in adults than in children and adolescents. However, the results are conflicting. We investigated serum leptin levels in children and adolescents (11 to 18.9 years) with psychiatric disorders (n = 363). Absolute and relative (body-mass-index (BMI)-, sex- and pubertal-stage-adjusted z-scores using reference values of healthy children and adolescents) leptin levels of different patient groups according to diagnosis were compared. The association between leptin levels and depression (Beck Depression Inventory-II) and anxiety (Child Behavior Checklist and Youth Self Report) was examined using regression analysis. Leptin z-scores were higher in patients with psychiatric disorders than in healthy controls (median 1.50, p < .001). While global tests suggested differences in leptin z-scores between patients with different psychiatric disorders, these differences could not be attributed to diagnosis groups in post-hoc pairwise comparisons. Absolute leptin levels differed between psychiatric disorders (p < .001). Patients with anorexia nervosa (AN) had the lowest levels, and patients with mood disorders had higher leptin levels than patients with mental disorders other than mood disorders, anxiety or AN. Neither absolute nor relative leptin levels were related to depressive or anxiety symptoms in regression models adjusted for sex and BMI. Significantly elevated BMI-, sex- and puberty-stage-adjusted leptin levels were observed in children and adolescents with psychiatric disorders compared to a reference sample. Further controlled studies are needed to confirm and explain this finding. No relationship was found between absolute or relative leptin levels and symptoms of depression or anxiety.

Studies in adults suggest antidepressant effects of vitamin D, possibly via anti-inflammatory pathways, but evidence in youth is lacking. In the first randomized controlled trial (RCT) in depressed, vitamin D-deficient adolescents (DRKS00009758), symptom reduction emerged in only one of three outcomes. This secondary analysis investigates whether baseline inflammatory status modifies the effect of vitamin D. Data from 92 participants (78.3

Abstract Adolescence is a vulnerable period for the emergence of mental health problems. Adrenarche, an early stage of pubertal development marked by rising adrenal androgens, particularly dehydroepiandrosterone (DHEA), may influence emotional and behavioral development. However, longitudinal evidence linking early-adolescent endocrine influences to adolescent psychopathology remains limited. Using data from the Adolescent Brain Cognitive Development (ABCD) Study (up to N = 11 696), we analyzed whether salivary DHEA during early adolescence predicted later externalizing and internalizing symptoms during adolescence. Early-adolescent hormone levels were averaged across baseline and 1-year follow-up (age range = 8.9–12.4 years). Outcomes were measured via the Child Behavior Checklist (CBCL) at the 2-, 3-, and 4-year follow-ups (up to = 14.08 ± 0.68 years). Sex-stratified linear mixed models adjusted for age, race/ethnicity, BMI and physical activity. In males, higher DHEA levels were linked to fewer externalizing symptoms across follow-ups (e.g., β = –0.07 SD change of CBCL per SD-change of log-transformed DHEA levels (95% CI [–0.10, –0.04] at 3-year) and fewer internalizing symptoms at 3-year and 4-year follow-ups. Higher early-adolescent DHEA in males also reduced the probability of externalizing symptoms to reach clinical thresholds across follow-ups (e.g., adjusted Risk Ratio = 0.81 to reach clinical threshold for CBCL externalizing per SD increase in log-transformed DHEA; 95% CI [0.70, 0.93] at 3-year). In females, no hormone–symptom associations emerged. Sex-by-DHEA interaction effects tended to increase across follow-up years for both symptom domains. These findings suggest that early-adolescent adrenal endocrine influences may contribute to the development of sex-specific vulnerability during adolescence. Future studies should consider adrenarche as a sensitive period for hormonal effects on mental health.

Endocannabinoid (eCB) signaling has been implicated in the physiological and affective responses to endurance exercise, including phenomena such as the runner’s high. However, although humans have the capacity to run for several hours and even days, evidence regarding eCB signaling is largely limited to exercise bouts shorter than 60 min. Consequently, the temporal dynamics of eCB signaling during prolonged running and the accompanying acute affective responses remain unclear. This study investigated eCB signaling during long-distance running and following a 45-minute break. Two studies were conducted: In Study 1, 19 trained runners completed both a marathon and a duration-matched walking session, with repeated blood sampling every 14 km during the marathon and after a 45-minute recovery. In Study 2, 36 ultramarathon runners completed races of 100 km, 160 km, or 230 km and provided blood samples before and after their respective races. Plasma concentrations of anandamide (AEA), 2-arachidonoylglycerol (2-AG), 1-AG, arachidonic acid (AA), and palmitoylethanolamide (PEA) were quantified by a standardized liquid chromatography/multiple reaction monitoring assay. Euphoria, anxiety, and pain were assessed as core features of the runner’s high using visual analog scales. AEA increased progressively throughout the marathon and remained elevated after 45 min, whereas walking elicited only modest changes. In line, after all ultramarathon distances AEA levels were increased compared with baseline. By contrast, an increase in 2-AG during exercise was observed only in the regular marathon, where concentrations rose significantly during the later stages of running and into early recovery. Elevated post-race 2-AG levels were also observed following all ultramarathon distances, consistent with a delayed, recovery-related response. Marathon running was associated with higher euphoria and lower anxiety than walking, while pain increased after 28 km of running. Ultramarathon running increased pain, reduced anxiety, and did not significantly alter euphoria post-exercise. Together, these findings show robust, time-dependent changes in circulating eCB concentrations during and after prolonged endurance running, as well as gradual increases in AEA during walking. These eCB dynamics occurred alongside acute affective changes during sustained endurance exercise.

Abstract Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (GFAP) are biomarkers of neuroaxonal and astrocytic damage but remain understudied in adolescent psychiatric populations. This study investigated sNfL and GFAP levels in 412 adolescents diagnosed with anorexia nervosa (AN) ( n = 52), depression ( n = 237), and other psychiatric disorders ( n = 123). We assessed their diagnostic utility, correlation with disease severity, and longitudinal changes during AN treatment. Biomarkers were measured using Single Molecule Array technology, with Z-scores derived from reference datasets. Compared to population norms, both biomarkers were elevated in AN (sNfL: 1.15 ± 1.17; GFAP: 1.50 ± 0.84) and in depression (sNfL: 0.34 ± 1.10; GFAP: 0.58 ± 1.00). Patients with AN showed significantly higher biomarker levels than those with depression or other psychiatric disorders; importantly, this distinction remained evident in sensitivity analyses restricted to underweight individuals with depression. In AN, sNfL levels correlated with baseline weight loss (β = −0.45, R² = 0.20) and declined significantly during treatment, while GFAP changes were less pronounced. Neither marker correlated with depressive symptom severity. Bootstrapped ROC analyses showed moderate-to-good discriminatory power (AUCs 0.70–0.84) for distinguishing AN from depression. These findings suggest that neuroaxonal and astrocytic stress is a component of adolescent psychopathology, particularly in AN. sNfL appears sensitive to starvation-related neurobiological changes, with levels normalizing alongside weight restoration. GFAP showed similar but less robust trends. Accordingly, the observed biomarker changes reflect more than underweight alone, supporting a potential role in differential diagnosis and treatment monitoring.

Eating disorders—including anorexia nervosa (AN), bulimia nervosa and binge-eating disorder—are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. Here we conducted a genomic meta-analysis of case–control studies of binge-eating behavior (BE; 39,279 cases, 1,227,436 controls), alongside analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six BE-associated loci, including loci associated with a higher body mass index and impulse-control behaviors. AN genome-wide association studies yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry studies. BE and AN exhibited similar positive genetic correlations with psychiatric disorders but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with body mass index. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries. This research identified six areas in the genome that are associated with binge eating, and eight areas that are associated with anorexia nervosa, in people of European ancestry. Binge eating has both shared and distinct genetic features compared with anorexia nervosa.

Objective:To examine whether screen time predicts interindividual variability regarding pubertal development across adolescence. Study design:This longitudinal cohort study included 10786 participants (47.9% female) from the Adolescent Brain Cognitive Development (ABCD) study. First, associations were examined between average daily screen time (hours/day, parent-reported Screen Time Survey) at baseline (mean age = 9.91 ± 0.63 years) and pubertal timing, derived from Pubertal Development Scale (PDS) scores through 4-year follow-up (mean age = 14.08 ± 0.68 years) and standardized by age and sex. Second, associations were examined between screen time groups (very low: 0-1.29 h/day; low: 1.29-2.07 h/day; moderate: 2.07-2.86 h/day; high: 2.86-4.0 h/day; very high: 4.00-12.43 h/day) and age at mid-puberty, defined as the age at first parent report of Pubertal Development Scale (PDS) category at least 3. Results:In linear mixed models adjusting for age, sex, race/ethnicity, socioeconomic status, BMI, and physical activity, higher log-transformed screen time at baseline was associated with more advanced pubertal timing at 1-, 2- and 3- year follow-ups, with the strongest effect observed at year 2 (standardized ß=0.07 [95%-CI, 0.05 to 0.10]). The associations were more pronounced in girls. The group of participants with very high screen time reached mid-puberty 2.47 months earlier [adjusted effect size, 95%-CI, -3.38 to -1.56) than participants with very low screen time. Conclusion:These findings suggest that screen time in late childhood is linked with earlier pubertal development and highlight its relevance for parental guidance on preadolescents' screen media use.

Sex-specific differences in liver gene expression have previously been reported in humans and rodents. Clinically, female-to-male liver transplants are known to be associated with adverse post-transplantation outcomes. However, the underlying molecular mechanisms remain largely unknown. Sex-specific gene expression differences may be involved in the post-transplantation outcomes. Here, we analyse sex-specific differences in liver gene expression of Lewis rats on a genome-wide scale. In total, 543 genes exhibited a differential gene expression between male (n = 4) and female (n = 4) rats, with the largest difference found for the transcript ENSRNOG00000009273.7 (log2FC = 10.69, p < 2.2*10− 308). Genes downregulated (n = 272) in males were enriched for cholesterol homeostasis and late oestrogen response. We further analysed inter- and intra-sex gene expression differences in three individual liver sections to evaluate liver heterogeneity. Although several genes exhibited a sex-specific expression in all three liver sections (n = 240), distinct expression patterns within each individual section were determined. Variations between sections were even evident within the same sex with male liver sections revealing more differentially expressed genes (male n = 40, female n = 11). Consequently, studies investigating liver-specific gene expressions should consider this intrahepatic heterogeneity to avoid introducing potential biases. Subsequent studies ought to explore gene expression differences between the sexes pre- and post-transplantation, particularly regarding a female-to-male transplants.

Anorexia nervosa (AN) is a mental disorder marked by a significantly low body weight. Differentially methylated CpG sites have been reported to be involved in body weight regulation. Methylation pattern may change during considerable weight gain by in-patient treatment. Consequently, we aimed to (1) replicate the hypomethylation at the NR1H3 gene locus (identified in our previous epigenome-wide association study) in independent study groups of 189 female patients with AN and 67 healthy-lean female controls, and (2) identify regions associated with large weight gain associated DNA methylation changes in three patients with AN through whole-genome bisulfite sequencing in CD14+ cells. In the replication study, no evidence was observed for hypomethylation at the investigated 15 CpG sites of the NR1H3 locus. Relying on two analysis tools (camel, metilene) to identify differentially methylated regions (DMRs), subtle methylation differences concordant between both tools were detected only when the usual threshold of camel was lowered. Then, eight regions were selected exemplarily for technical replication with deep bisulfite sequencing in the same three patients with AN. None of the regions could be confirmed. Summarising, we could not confirm hypomethylation at NR1H3 and could not detect methylation differences in patients with AN between admission and weight gain at discharge.

Eating disorders -including anorexia nervosa (AN), bulimia nervosa, and binge eating disorder-are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. We conducted the first genomic meta-analysis of binge eating behaviour (BE; 39,279 cases, 1,227,436 controls), alongside new analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six loci associated with BE, including loci associated with higher body mass index (BMI) and impulse-control behaviours. AN GWAS yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry cohorts. BE and AN exhibited similar positive genetic correlations with psychiatric disorders, but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with BMI. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries.

Variations in circadian rhythm-related genes influence the individual chronotype. Here, we hypothesize that the peak of clock gene expression at 7 a.m. differs between young adults with a late chronotype and young adults with an early chronotype. Participants of the Chronotype and Nutrition nutritional trial (ChroNu study) were selected for their chronotype assessed by the Munich Chronotype questionnaire (MCTQ) and actigraphy. Total RNA was isolated from CD14+ monocytes of participants at 7 a.m. on the run-in day. Expression levels of seven clock genes (PER1, PER2, PER3, NR1D1, NR1D2, CRY1 and CRISPLD2) of individuals with early (n = 11) or late chronotypes (n = 19) were analysed by reverse transcription quantitative polymerase chain reaction. Difference in expression levels was tested by Mann Whitney-U test. The relative expression levels of the selected genes were not significantly different between individuals with early and late chronotypes (all p > 0.07). Contrary to expectation, clock gene expression levels at 7 a.m. was similar in individuals with early and late chronotypes. Further studies on larger sample sizes with multiple sampling time points should elucidate whether gene expression is altered at other day times underscoring the biological difference between individuals with early or late chronotypes.

Zusammenfassung: In Deutschland sind mittlerweile genetische Untersuchungen Teil einer leitliniengerechten diagnostischen Abklärung bei Patientinnen und Patienten mit Intelligenzminderung. Auch bei weiteren kinder- und jugendpsychiatrischen Störungsbildern sollte die Veranlassung genetischer Diagnostik in Erwägung gezogen werden, insbesondere wenn zusätzliche somatische Auffälligkeiten (z. B. angeborene Fehlbildungen, Epilepsie) oder Auffälligkeiten in den Wachstumsparametern (z. B. Mikro- oder Makrozephalie) vorliegen. Derzeit stellen unter anderem der noch geringe praktische Erfahrungsschatz kinder- und jugendpsychiatrisch tätiger Kolleginnen und Kollegen und der wenig praktizierte Austausch mit Ärzten/Ärztinnen in der Humangenetik eine Herausforderung hinsichtlich der konkreten Umsetzung einer humangenetischen Untersuchung und Beratung dar. Zusätzlich sind die aktuellen Finanzierungsmöglichkeiten der genetischen Diagnostik für den klinischen Alltag der Kinder- und Jugendpsychiatrie und -psychotherapie (KJPP) wenig geeignet. Die vorliegende Arbeit ist als Orientierungshilfe für Ärztinnen und Ärzte der KJPP gedacht, welche eine leitliniengerechte genetische Diagnostik in ihren klinischen Alltag integrieren möchten. Sie fokussiert sich auf den Prozess der Veranlassung genetischer Diagnostik nach der Indikationsstellung, von der Patientenaufklärung bis hin zum Erhalt des Ergebnisses der Untersuchungen und seiner Vermittlung an die Betroffenen.

Off-label treatment of a 17-year-old female patient with anorexia nervosa (AN), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and non-suicidal self-injury (NSSI) with human recombinant leptin (metreleptin) for two dosing periods of 15 and seven days was associated with self- and clinician-rated improvements of eating disorder related psychopathology, OCD, depression, and NSSI. These intermittent improvements occurred despite the patient having high endogenous serum leptin levels ranging up to the 99th centile adjusted for sex, Tanner stage and body mass index (BMI; kg/m²) upon initiation of dosing. The results further extend the hypothesized effects of metreleptin on AN and comorbid psychopathology to patients with adjusted leptin levels in the normal to high range. We hypothesize that for unknown reasons the clinical symptomatology of a subgroup of patients with AN persists despite attainment of endogenous leptin levels well above those characteristic of the state of starvation, potentially entailing a prolonged entrapment in the eating disorder. An insight into the mechanisms underlying this distinct type of leptin resistance may help to promote recovery of such affected patients. Placebo controlled randomized clinical trials are required to assess if and to what extent short and medium term metreleptin treatment indeed improves recovery.

BACKGROUND:Preexisting epidemiological studies suggest that early pubertal development in males is associated with externalizing (e.g. conduct problems, risky behavior, and aggression) and internalizing (e.g. depression and anxiety) traits and disorders. However, due to problems inherent to observational studies, especially of residual confounding, it remains unclear whether these associations are causal. Mendelian randomization (MR) studies take advantage of the random allocation of genes at conception and can establish causal relationships. METHODS:In this study, N = 76 independent genetic variants for male puberty timing (MPT) were derived from a large genome-wide association study (GWAS) on 205,354 participants and used as an instrumental variable in MR studies on 17 externalizing and internalizing traits and psychopathologies utilizing outcome GWAS with 16,400-1,045,957 participants. RESULTS:In these MR studies, earlier MPT was significantly associated with higher scores for the overarching phenotype of 'Externalizing Traits' (b = -0.03, 95% CI [-0.06, -0.01]). However, this effect was likely driven by an earlier age at first sexual contact (b = -0.17, 95% CI [-0.21, -0.13]), without evidence for an effect on further externalizing phenotypes. Regarding internalizing phenotypes, earlier MPT was associated with higher levels of the 'Depressed Affect' subdomain of neuroticism (b = -0.04, 95% CI [-0.07, -0.01]). Late MPT was related to higher scores of internalizing traits in early life (b = 0.04, 95% CI [0.01, 0.08]). CONCLUSIONS:This comprehensive MR study supports a causal effect of MPT on specific traits and behaviors. However, no evidence for an effect of MPT on long-term clinical outcomes (depression, anxiety disorders, alcohol dependency, cannabis abuse) was found.