Reduced Serum Hydrogen Sulfide Levels in Drug-Naive Patients with MajorDepressive Disorder: A Cross-Sectional Analytical Study from Eastern India

Background: Hydrogen sulfide (H2S) is an endogenous gasotransmitter synthesised in the central nervous system (CNS) primarily by cystathionine {beta}-synthase (CBS) and cystathionine {gamma}-lyase (CSE). Pre-clinical studies consistently implicates H2S deficiency in the pathophysiology of depression through disruption of synaptic plasticity, neuroinflammation, oxidative stress, and brain-derived neurotrophic factor (BDNF) signalling. Yet, we still lack direct clinical evidence quantifying circulating H2S in patients with Major Depressive Disorder (MDD), particularly from South Asian populations. In this study, we measured serum H2S levels in drug-naive patients with MDD and compared them with healthy controls at a tertiary care center in eastern India. We examined the associations between serum H2S and depression severity as assessed by the 17-item Hamilton Depression Rating Scale (HAM-D-17). This institution-based, cross-sectional analytical study was conducted at North Bengal Medical College and Hospital (NBMCH), West Bengal, India, over 12 months. Fifty drug-naive patients fulfilling DSM-5 criteria for MDD and fifty age- and sex-matched healthy controls were enrolled by consecutive sampling. We quantified serum H2S using the spectrophotometric methylene blue method and depression severity was assessed using HAM-D-17. Statistical analyses included independent-samples t-test, chi-square test, and linear regression. Serum H2S was markedly and significantly lower in MDD patients (0.068 {+/-} 0.044 {micro}mol/L) compared with healthy controls (0.524 {+/-} 0.272 {micro}mol/L; p < 0.001), representing an approximately 7.7-fold reduction. HAM-D-17 scores were significantly higher in MDD patients (28.94 {+/-} 12.78) than in controls (3.96 {+/-} 2.31; p < 0.001). Linear regression across the combined cohort revealed a significant negative association between serum H2S and HAM-D score (R{superscript 2} = 0.287; y = 24.64 - 26.84x; p < 0.001), indicating that higher serum H2S was associated with lower depression severity. Within the MDD group alone, the regression was weak (R{superscript 2} = 0.061), consistent with a floor effect. Within the control group alone, the regression was strong (R{superscript 2} = 0.772). No significant associations were found between serum H2S and any sociodemographic variable in either group. Drug-naive MDD patients exhibited substantially reduced serum H2S levels compared with healthy controls, and lower H2S was associated with greater depression severity. These findings provide direct clinical evidence from an Indian population supporting the H2S deficiency hypothesis of depression and suggest that the CBS/CSE-H2S axis may represent a novel biomarker and therapeutic target in MDD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/26352330v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1ce64f6org.highwire.dtl.DTLVardef@1465ca2org.highwire.dtl.DTLVardef@6bba64org.highwire.dtl.DTLVardef@9a1411_HPS_FORMAT_FIGEXP M_FIG C_FIG