Discriminative performance of serum homocysteine in drug-naïve depression: a case-control study with ROC and regression analysis

Abstract Depression is a multifactorial disorder involving neurochemical, metabolic, and inflammatory dysregulation. Elevated homocysteine, a marker of impaired one-carbon metabolism, has been implicated in neurotoxicity and oxidative stress pathways associated with depressive pathology. This study evaluated serum homocysteine levels and their association with body mass index (BMI) in patients with incident drug naiive depression compared to healthy controls. This case-control study enrolled 200 participants: 100 patients with newly diagnosed depressive disorder (DSM-5 criteria) and 100 age- and sex-matched healthy controls recruited from a tertiary psychiatry centre in South India. Serum homocysteine was measured using standard enzymatic assay and BMI was calculated from standardised anthropometric measurements. Independent samples t-test, Pearson’s correlation, ROC analysis and Binomial logistic regression analyses were performed. Serum homocysteine was significantly higher in depressed patients than controls (35.8 ± 7.04 µmol/L vs. 13.6 ± 2.48 µmol/L; p < 0.001, Cohen’s d = 4.193; 95% CI for difference: 20.66–23.58 µmol/L). BMI was also significantly elevated in the depression group (25.67 ± 4.97 kg/m 2 vs. 21.92 ± 2.96 kg/m 2 . p < 0.001, Cohen’s d = 0.912). A positive homocysteine—BMI correlation was observed in depression( r = 0.42, p < 0.001) but not in controls ( r = 0.04, p = 0.71). ROC analysis yielded an AUC of 1.000 (optimal cutoff: 20.065 µmol/L, sensitivity: 100%, specificity: 100%), reflecting complete distributional separation in this clinical sample. Binary logistic regression analysis showed homocysteine to be a significant predictor of depression(omnibus χ 2 = 277.26, df = 1, p < 0.001; 100% classification accuracy; Nagelkerke R 2 = 1.00), though standard odds ratio estimation was precluded by complete separation. Elevated homocysteine and a group-specific BMI—homocysteine correlation were identified in depressed patients. The AUC of 1.000 reflects complete distributional separation in a tightly controlled institutional sample and requires external validation before clinical application. As folate, vitamin B12, and lifestyle confounders were unmeasured, findings are hypothesis-generating and warrant prospective multicentre validation.