Sex differences in the association between Hcy levels and cognitive deficits among individuals with first-episode and drug-naive major depressive disorder

<title>Abstract</title> Objective Previous studies have shown that elevated homocysteine (Hcy) levels are associated with cognitive deficits in first-episode and drug-naïve individuals with major depressive disorder (MDD). However, research on sex differences in this context is limited. This study aimed to evaluate sex differences in the association between Hcy levels and cognitive deficits among individuals with first-episode and drug-naïve MDD. Methods We recruited 85 MDD patients and 100 healthy controls. The MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognitive function, and serum Hcy levels were measured in all participants. Clinical features were evaluated using the Hamilton Depression Rating Scale (HAMD), the Hamilton Anxiety Rating Scale (HAMA) and the Positive and Negative Syndrome Scale (PANSS). Results Hcy levels were significantly higher in male patients with MDD than in female patients (F = 6.772, <italic>p</italic> = 0.001). In male patients, higher Hcy levels were found to be positively correlated with the severity of positive symptoms (r = 0.477, <italic>p</italic> = 0.010) and negatively correlated with working memory (WM) scores (r=-0.409, <italic>p</italic> = 0.031). Additionally, multivariate regression analyses revealed that Hcy levels were independent predictors of WM scores (beta = 0.46, t = 2.75, <italic>p</italic> = 0.010) and positive symptoms (beta = 0.46, t = 2.80, <italic>p</italic> = 0.009). Conclusions These findings highlight sex differences in the associations of Hcy with cognitive deficits and positive psychotic symptoms. In particular, male patients are more susceptible to Hcy-related symptom exacerbation. These results support the potential of Hcy as a biomarker for cognitive deficits and positive psychotic symptoms and provides a target for therapeutic intervention in male patients with MDD.