Glucuronic acid (GlcA) is crucial in the glucuronidation pathway, facilitating the metabolism and elimination of various substances and drugs. Recent studies have noted elevated GlcA levels in patients with schizophrenia (SCZ) compared with healthy individuals. However, it remains unclear whether this elevation contributes to SCZ pathophysiology or results from medication effects.

This study investigated the relationship between peripheral GlcA levels and clinical characteristics in patients with SCZ and assess whether these associations persist independently of psychotropic medication effects to provide insight into the potential role of GlcA in the pathophysiology of SCZ.

Plasma GlcA levels were analysed in 218 patients with SCZ, examining their association with clinical features. The correlation between GlcA levels and symptom severity, assessed using the Positive and Negative Syndrome Scale (PANSS), was analysed in 35 patients. In addition, multiple regression analysis was conducted to adjust for age and psychotropic medication effects.

Significant correlations were observed between GlcA levels and PANSS scores for negative symptoms, general psychopathology and total scores. After adjustment for age and psychotropic medications, significant correlations between GlcA levels and PANSS scores persisted for negative symptoms (adjusted β [95% CI], 13.926 [2.369, 25.483]) and general psychopathology (adjusted β [95% CI], 19.437 [3.884, 34.990]), while the total score was no longer significant (adjusted β [95% CI], 34.054 [–0.517, 68.626]).

Elevated GlcA levels in patients with SCZ are associated with specific symptom severity irrespective of the medication dose, suggesting a potential role of GlcA in SCZ pathophysiology.

Schools are central places for adolescent social lives, which is a major factor greatly affecting adolescent mental health; school climate (i.e. quality of the school social environments) can be a proximal social determinant for adolescent mental health. Supportive school environments may serve as a protective factor during crises like COVID-19, which disrupt social lives and worsen adolescent mental health. This is the first study examining whether the pandemic effects differed based on the levels of school climate on depressive symptoms (DS) and psychotic experiences (PEs) among adolescents.

School climate (score range: 0–28), DS (0–26), and PEs (0–5) were self-reported in a population-based cohort (Tokyo Teen Cohort; N = 3171) at four timepoints (10y, 12y, 14y, and 16y) before and during COVID-19. COVID-19 occurred midway through the 16y survey, allowing us to examine its impact and interaction effect with school climate while accounting for within-person changes over time using mixed-effects models.

Significant interaction effects were found on DS (unstandardized coefficient [B] = −0.166, 95% confidence interval [CI] −0.225 to −0.107) and PEs (B = −0.020, 95% CI −0.028 to −0.012). The pandemic effects were not significant for adolescents with high school climate scores (around the 80th percentile or higher), although the pandemic significantly worsened these outcomes among the overall sample.

The negative mental health effects of the pandemic were significantly mitigated among adolescents experiencing a supportive school climate. A positive school climate can protect adolescent mental health during challenging social conditions, such as pandemics.

Little information is available on the association between gender nonconformity during adolescence and subsequent mental health. While the distress related to gender nonconformity may be socially produced rather than attributed to individual-level factors, further research is needed to better understand the role of psychosocial factors in this context.

We analyzed data from the Tokyo Teen Cohort, obtained through random sampling of adolescents born between 2002 and 2004. We used inverse probability weighting to examine the association of gender nonconformity at ages 12 and 14 as a time-varying variable with subsequent mental health at age 16, while accounting for time-fixed and time-varying confounders. Furthermore, we used a weighting approach to investigate the mediating role of modifiable psychosocial factors in this association, addressing exposure-mediator and mediator–mediator interactions.

A total of 3171 participants were analyzed. Persistent gender nonconforming behavior at ages 12 and 14 was associated with subsequent depression (β = 2.02, 95% confidence interval [CI] 0.85 to 3.19) and psychotic experiences (β = 0.33, 95% CI 0.14 to 0.52) at age 16. The results remained robust in sensitivity analyses. Approximately 30% of the association between gender nonconformity and depression was consistently mediated by a set of psychosocial factors, namely loneliness, bullying victimization, and relationships with mother, father, and friends.

Persistent gender nonconformity during adolescence is associated with subsequent mental health. Psychosocial factors play a vital mediating role in this association, highlighting the essential need for social intervention and change to reduce stigmatization and ameliorate mental health challenges.