Microbiome and tryptophan metabolomics analysis in adolescent depression: roles of the gut microbiota in the regulation of tryptophan-derived neurotransmitters and behaviors in human and mice.

BACKGROUND: Adolescent depression is becoming one of the major public health concerns, because of its increased prevalence and risk of significant functional impairment and suicidality. Clinical depression commonly emerges in adolescence; therefore, the prevention and intervention of depression at this stage is crucial. Recent evidence supports the importance of the gut microbiota (GM) in the modulation of multiple functions associated with depression through the gut-brain axis (GBA). However, the underlying mechanisms remain poorly understood. Therefore, in the current study, we aimed to screen the microbiota out from healthy and depressive adolescents, delineate the association of the targeted microbiota and the adolescent depression, address the salutary effects of the targeted microbiota on anti-depressive behaviors in mice involving the metabolism of the tryptophan (Trp)-derived neurotransmitters along the GBA. RESULTS: Here, we found the gut microbiota from healthy adolescent volunteers, first diagnosis patients of adolescent depression, and sertraline interveners after first diagnosis displayed significant difference, the relative abundance of Faecalibacterium, Roseburia, Collinsella, Blautia, Phascolarctobacterium, Lachnospiraceae-unclassified decreased in adolescent depressive patients, while restored after sertraline treatment. Of note, the Roseburia abundance exhibited a high efficiency in predicting adolescent depression. Intriguingly, transplantation of the fecal microbiota from healthy adolescent volunteers to the chronic restraint stress (CRS)-induced adolescent depressed mice significantly ameliorated mouse depressive behaviors, in which the Roseburia exerted critical roles, since its effective colonization in the mouse colon resulted in remarkably increased 5-HT level and reciprocally decreased kynurenine (Kyn) toxic metabolites quinolinic acid (Quin) and 3-hydroxykynurenine (3-HK) levels in both the mouse brain and colon. The specific roles of the Roseburia were further validated by the target bacteria transplantation mouse model, Roseburia intestinalis (Ri.) was gavaged to mice and importantly, it dramatically ameliorated CRS-induced mouse depressive behaviors, increased 5-HT levels in the brain and colon via promoting tryptophan hydroxylase-2 (TPH2) or -1 (TPH1) expression. Reciprocally, Ri. markedly restrained the limit-step enzyme responsible for kynurenine (indoleamine2,3-dioxygenase 1, IDO1) and quinolinic acid (3-hydroxyanthranilic acid 3,4-dioxygenase, 3HAO) generation, thereby decreased Kyn and Quin levels. Additionally, Ri. administration exerted a pivotal role in the protection of CRS-induced synaptic loss, microglial activation, and astrocyte maintenance. CONCLUSIONS: This study is the first to delineate the beneficial effects of Ri. on adolescent depression by balancing Trp-derived neurotransmitter metabolism and improving synaptogenesis and glial maintenance, which may yield novel insights into the microbial markers and therapeutic strategies of GBA in adolescent depression. Video Abstract.

Identification of adolescent patients with depression via assessment of the niacin skin flushing response.

BACKGROUND: Depressive disorder (DD) affects approximately 20 % of adolescents worldwide, but it is underdiagnosed due to the lack of objective biomarkers. Niacin skin flushing response (NSFR) is an objective and noninvasive biomarker of adult depression; however, its effectiveness has not been assessed in adolescents. METHODS: This study included 198 adolescents with 50 % healthy controls (HC). Linear mixed-effects model and multiple linear regression analyses were performed to assess differences in NSFR between the DD and HC groups. Logistic regression models based on NSFR were constructed, and the area under curve (AUC) was calculated to evaluate the performance of models. Spearman correlations were calculated to assess the relationships between NSFR and disease duration and hormone levels associated with puberty. RESULTS: Adolescents with DD displayed significantly attenuated and delayed NSFR compared to HC. NSFR effectively distinguished DD patients from HC with AUC values of 0.719 (sensitivity = 0.844) and 0.721 (sensitivity = 0.829) determined in the discovery and validation sets, respectively. Within the DD group, the maximum degree of NSFR was negatively correlated with the disease duration (r = -0.28, p = 0.011), and the overall degree of NSFR was positively associated with prolactin (r = 0.29, p = 0.039) and thyroxine (r = 0.29, p = 0.027) levels. LIMITATIONS: Future investigations will be necessary to confirm our results in an independent sample set. CONCLUSIONS: This study provides the first evidence of the utility of NSFR as an objective auxiliary diagnostic biomarker for adolescent depression. It provides new clues to understand the pathophysiology of the disease, and helps promote precise diagnosis, treatment, and prognostic evaluation of adolescent depression.

Analysis of the status of drug treatment in 746 inpatients with early-onset schizophrenia in China: a retrospective study.

BACKGROUND: There is limited evidence on the use of antipsychotics in patients with early-onset schizophrenia, which lags significantly behind the studies on adult patients' medication and has a large disparity from actual clinical needs. Hence, this study aims to analyse the status of the drug use and its changes for patients with early-onset schizophrenia in our ward and to provide references on clinical medications for children and adolescents with schizophrenia. METHODS: The distribution of antipsychotics on the day of discharge and their changes over time were retrospectively analysed in our inpatient department from March 2012 to July 2019. Descriptive statistical methods and χ2 tests were carried out. RESULTS: A total of 746 inpatients with early-onset schizophrenia were included. Among them, 99.3% of patients were prescribed atypical antipsychotic drugs, with 5.5% of patients prescribed typical antipsychotic drugs. The top five most commonly used antipsychotics were aripiprazole, olanzapine, risperidone, paliperidone and clozapine. Olanzapine and risperidone were used more frequently in men (P < 0.01), whereas aripiprazole was used less frequently (P < 0.01). Olanzapine and paliperidone were used more frequently in patients with adolescent-onset schizophrenia (AOS) (P < 0.05), and risperidone was used more frequently in patients with child-onset schizophrenia (COS) (P < 0.01). Multiple antipsychotics during hospitalization were prescribed in 23.1% of patients. The combination of aripiprazole and olanzapine was the most common in the AOS group, and the combination of risperidone and clozapine was the most common in the COS group. Before and after approval by the competent Chinese authorities, the use of paliperidone and aripiprazole tended to be stable. CONCLUSION: Atypical antipsychotics have been increasingly valued and used clinically. The consideration of medications for patients with early-onset schizophrenia needs to include factors such as age, sex, and severity of illness, metabolism and cognitive function at baseline.

Comparison of clinical characteristics and treatment efficacy in childhood-onset schizophrenia and adolescent-onset schizophrenia in mainland China: A retrospective study.

AIM: The comparative study of childhood-onset schizophrenia (COS) and adolescent-onset schizophrenia (AOS) is scarce. This study aimed to examine the differences in clinical presentations and treatment efficacy between COS and AOS and further analyse the factors affecting the efficacy of early-onset schizophrenia (EOS). METHODS: A total of 582 electronic medical records of inpatients with EOS (216 COS and 366 AOS inpatients) between 2012 and 2019 were retrospectively analysed. The positive and negative syndrome scale (PANSS) was used to assess psychotic symptoms. Logistic regression analysis was performed to analyse the predictors of efficacy. RESULTS: The mean age of onset of EOS was 12.87 ± 2.19 years. The importance of better diagnosing COS appeared in a longer illness course, more frequently insidious onset, less frequent delusions, more severe negative symptoms and bizarre behaviours than AOS. Besides, COS had more frequent visual hallucinations and impulsive behaviours than AOS. After hospitalization, the improvement rate of psychotic symptoms in COS and AOS were 38.3% and 47.8%, respectively. The difference of efficacy between the two groups was statistically significant. Days of hospitalization, age of onset, presence of flat affect, PANSS total and negative score at admission were predictors of treatment efficacy in EOS individuals. CONCLUSIONS: COS inpatients suffer more obvious negative symptoms, bizarre behaviours, visual hallucinations and impulsive behaviours and worse efficacy than AOS inpatients. The severity of negative symptoms and age of onset seem the most noteworthy predictors of efficacy. These findings highlight the importance of early detection and early intervention.

Autism spectrum disorder as early neurodevelopmental disorder: evidence from the brain imaging abnormalities in 2-3 years old toddlers.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that occurs within the first 3 years of life, which is marked by social skills and communication deficits along with stereotyped repetitive behavior. Although great efforts have been made to clarify the underlying neuroanatomical abnormalities and brain-behavior relationships in adolescents and adults with ASD, literature is still limited in information about the neurobiology of ASD in the early age of life. Brain images of 50 toddlers with ASD and 28 age, gender, and developmental quotient matched toddlers with developmental delay (DD) (control group) between ages 2 and 3 years were captured using combined magnetic resonance-based structural imaging and diffusion tensor imaging (DTI). Structural magnetic resonance imaging was applied to assess overall gray matter (GM) and white matter (WM) volumes, and regional alterations were assessed by voxel-based morphometry. DTI was used to investigate the white matter tract integrity. Compared with DD, significant increases were observed in ASD, primarily in global GM and WM volumes and in right superior temporal gyrus regional GM and WM volumes. Higher fractional anisotropy value was also observed in the corpus callosum, posterior cingulate cortex, and limbic lobes of ASD. The converging findings of structural and white matter abnormalities in ASD suggest that alterations in neural-anatomy of different brain regions may be involved in behavioral and cognitive deficits associated with ASD, especially in an early age of 2-3 years old toddlers.