[Gender differences in acylcarnitine metabolism among patients with depression disorder]

Depression is a complex mental disorder whose disease burden has become a major global public health issue. Sex is an important factor influencing susceptibility to depression, but the underlying mechanisms remain unclear. Previous studies have demonstrated a significant association between depression and acylcarnitine metabolism; however, systematic comparisons of acylcarnitine metabolic profiles between male and female patients with depression remain limited. This study aims to investigate sex differences in plasma acylcarnitine metabolic characteristics in first-episode, drug-naïve patients with depression, analyze the relationships between specific acylcarnitines and depression susceptibility and severity in different sexes, and explore the potential biological mechanisms underlying sex differences in depression from a metabolomics perspective.

Plasma samples from first-episode, drug-naïve patients with depression and healthy controls collected in a clinical trial conducted between 2017 and 2020 were analyzed for carnitine levels. A total of 100 patients with first-episode, drug-naïve depression and 50 healthy controls were included. A two-step analytical strategy combining qualitative identification using ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF MS) and targeted quantification using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to systematically detect plasma acylcarnitine metabolic profiles. Two-way analysis of variance (ANOVA) or the Scheirer-Ray-Hare test was used to examine the effects of depression diagnosis and sex differences on acylcarnitine levels. Multivariate linear regression analysis was further conducted to determine the associations between acylcarnitines, sex, depression susceptibility, and severity.

A total of 33 acylcarnitines and free carnitine were detected in plasma. After preliminary analysis and screening, 8 acylcarnitines showed significant sex differences. Further multivariate linear regression analysis incorporating baseline characteristics revealed that acetylcarnitine C2:0 (β=0.910, P=0.023), valerylcarnitine C5:0 (β=-0.020, P=0.012), and undecylenoylcarnitine C11:1 (β=-3.322, P=0.008) were significantly associated with sex. When baseline characteristics and sex-differentiated acylcarnitines were included as independent variables and scale scores were used as dependent variables in multivariate linear regression models, C11:1 showed a significant positive correlation with Beck Depression Inventory (BDI) scores (β=0.817, P=0.036). C12:1-OH (β=0.774, P=0.034) was positively correlated with Hamilton Anxiety Scale (HAMA) scores, whereas C4:0 (β=-44.616, P=0.028) and C13:1 (β=-1.344, P=0.022) were negatively correlated with HAMA scores (P<0.05).

This study demonstrated significant sex differences in acylcarnitine metabolism in patients with first-episode depression. Among them, C2:0, C5:0, and C11:1 were key metabolites independently regulated by sex. C4:0, C11:1, C12:1-OH, and C13:1 were closely associated with depression susceptibility and anxiety severity. These findings suggest that dysregulation of mitochondrial fatty acid β-oxidation pathways may represent an important biological basis for sex differences in depression and provide new directions for precision classification and sex-specific diagnostic and therapeutic strategies for depression.