Background: Hydrogen sulfide (H₂S) is an endogenous gasotransmitter synthesised in the central nervous system (CNS) primarily by cystathionine β-synthase (CBS) and cystathionine γ-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-naïve 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-naïve 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 µmol/L) compared with healthy controls (0.524 ± 0.272 µmol/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 (R² = 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 (R² = 0.061), consistent with a floor effect. Within the control group alone, the regression was strong (R² = 0.772). No significant associations were found between serum H₂S and any sociodemographic variable in either group. Drug-naïve 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.

The authors have declared no competing interest.

This study did not receive any funding

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Institutional Ethics Committee of North Bengal Medical College, Darjeeling, West Bengal, India gave ethical approval for this work. The approval was granted for the research proposal titled A study on serum level of hydrogen sulphide in patients with Major Depressive Disorder in its meeting held on 26 May 2023. The approval memo number was IEC/NBMC/M-07/069/2023, dated 26 May 2023. The Institutional Ethics Committee of North Bengal Medical College, Darjeeling is registered with the Central Drugs Standard Control Organisation, Ministry of Health, Government of India, under Registration Number ECR/1701/Inst/WB/2022, dated 12 July 2022. Written informed consent was obtained from all participants before enrolment, and all procedures were conducted in accordance with the Declaration of Helsinki.

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Contact — Atrim Das: atrimdasgmail.com / qf25081bristol.ac.uk | Dr. Pritam Datta: kutudatta.13gmail.com

Conflict of interest: The authors declare no conflict of interest.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethical approval: The study was approved by the Institutional Ethics Committee of North Bengal Medical College and Hospital (Ref. No.: [ECR/1701/Inst/WB/22]). All procedures were conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants prior to enrolment.

Data availability: The data that support the findings of this study are available from the corresponding author upon reasonable request.

All data produced in the present study are available upon reasonable request to the authors