Elevated homocysteine and non-suicidal self-injury in adolescent depression: possible sex-specific clinical associations

Non-suicidal self-injury (NSSI) has become increasingly prevalent among adolescents with major depressive disorder (MDD), yet its underlying biological mechanisms remain poorly understood. This study investigated the association between serum homocysteine and NSSI in adolescents with MDD, with emphasis on sex-specific effects. This retrospective study enrolled 141 adolescents with MDD, categorized into NSSI ( n = 57) and Non-NSSI (NNSSI, n = 84) groups. Serum homocysteine was measured from fasting samples at admission. Clinical symptoms were assessed using the Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA). Analysis of covariance compared homocysteine between groups. Partial correlation and hierarchical regression analyses examined associations between homocysteine and clinical symptoms, evaluating sex moderation effects. Homocysteine was significantly elevated in the NSSI versus NNSSI group (14.57 ± 7.31 vs. 11.70 ± 2.77 µmol/L, P = 0.001). In the NNSSI group, homocysteine negatively correlated with diurnal variation ( r = −0.232, P = 0.034). Hierarchical regression revealed distinct sex moderation patterns across groups. In the NNSSI group, significant sex-by-homocysteine interactions were identified for sleep disturbance (β = 0.376, P = 0.013) and somatic symptoms (β = 0.127, P = 0.019). In the NSSI group, interaction effects appeared only for diurnal variation (β = 0.056, P = 0.034). Elevated homocysteine may serve as a potential biological marker for NSSI in adolescents with MDD. Associations between homocysteine and clinical symptoms may exhibit sex-specific patterns that differed markedly between NSSI and NNSSI groups.