HPLC Analysis of Plasma H₂S Reveals Insights into Cognitive Improvement in Schizophrenia

Hydrogen sulfide (H₂S) is a chemical in the brain that helps control how brain cells communicate. When it doesn’t work, it is linked to the thinking and memory problems often experienced by people with schizophrenia. Fortunately, newer medications for schizophrenia can help improve these mental skills. Recently, researchers conducted a study to see if these newer drugs boost brain function by changing how H₂S works in the body. To find out, they used a specialized laboratory test to measure the levels of this chemical in the patients' blood. Plasma H₂S levels were determined using high-performance liquid chromatography (HPLC). A paper based on this research was published in Frontiers in Psychology.¹

Why Is H₂S Important in Matters Related to the Brain?

H₂S has been recognized as the third gaseous signaling molecule following nitric oxide (NO) and carbon monoxide (CO) and plays a key role in regulating various physiological processes in both the brain and peripheral systems.^2-4H₂S produced in the brain plays a vital role in helping our brain cells communicate and adapt, which is crucial for learning and memory. It also helps reduce inflammation, which can protect the brain against diseases that cause cognitive decline over time.^5-7When the brain's H₂S system does not work correctly, it can lead to memory and thinking problems. This breakdown is linked to several serious brain conditions, including Alzheimer's disease, Parkinson's disease, and strokes.⁸

How Was This Study Conducted, and What Was Learned?

The study was conducted with 25 schizophrenia patients with acute exacerbation who completed follow-up, as well as 28 healthy controls were included in this study. Psychopathological symptoms and cognitive function were assessed using the Positive and Negative Syndrome Scale (PANSS) and a neuropsychological test battery, respectively. The researchers found that compared with normal controls, schizophrenia patients exhibited poorer cognitive function and lower plasma H₂S levels at baseline (p < 0.05). After two months of atypical antipsychotic treatment, the patients showed significant improvements in processing speed, working memory, visuospatial memory, attention, and executive function (all p < 0.01). At the same time, plasma H₂S levels in patients after treatment were significantly elevated compared to baseline (0.918 ± 0.036 vs. 0.712 ± 0.023 µmol/L; t = 6.807, p < 0.001). Correlation analysis revealed that the increase in H₂S was significantly associated with improvements in working memory (r = 0.291, p = 0.005) and visuospatial memory (r = 0.227, p = 0.016).¹

“Our findings,” wrote the authors of the paper,¹ “demonstrated that cognitive improvement in patients with schizophrenia after treatment with atypical antipsychotics is correlated with an increase of plasma H₂S levels, suggesting that H₂S signaling is involved in the pathophysiological process of cognitive impairment in schizophrenia.”

While the results are promising, the researchers pointed out a few limitations to keep in mind¹:

• It was a small, focused study: The researchers observed a relatively small group of people, so larger studies are needed to confirm if these findings easily apply to the general public.
• They measured blood, not brain fluid: The chemical levels were tested using the patients' blood. While this chemical moves easily throughout the body, scientists can't be completely sure that the blood levels perfectly match the levels directly inside the brain.
• Connection doesn't prove cause: They found a clear link between higher levels of the chemical and better memory and thinking. However, they can't yet prove that the chemical directly causes the improvement.
• Other chemicals are involved: Similar chemicals in the body also affect how we think. Future studies should measure all of these related chemicals together to get a complete picture of what is happening in the brain.

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References

1. Huang, Y. C.; Li, Y. H.; Li, L. et al. Changes in Plasma Hydrogen Sulfide Are Associated with Cognitive Improvements in Schizophrenia Patients Treated with Atypical Antipsychotics. Front Psychiatry 2026, 17, 1789058. DOI: 10.3389/fpsyt.2026.1789058
2. Kimura, H. Hydrogen Sulfide as a Neuromodulator. Mol Neurobiol. 2002, 26 (1), 13-19. DOI: 10.1385/MN:26:1:013
3. Tripathi, S. J.; Chakraborty, S.; Miller, E. et al. Hydrogen Sulfide Signalling in Neurodegenerative Diseases. Br J Pharmacol. 2026, 183 (1), 83-100. DOI: 10.1111/bph.16170
4. Fatima, G.; Mahdi, A. A.; Alhmadi, H. B. et al. Unveiling Hydrogen Sulfide: A New Frontier in Neuroprotection and Neuromodulation. Indian J Clin Biochem. 2025, 40 (4), 540-550. DOI: 10.1007/s12291-024-01278-w
5. Kimura, H. Hydrogen Sulfide: Its Production, Release and Functions. Amino Acids 2011, 41 (1), 113-121. DOI: 10.1007/s00726-010-0510-x
6. Chen, H. B.; Wu, W. N.; Wang, W. et al. Cystathionine-β-Synthase-Derived Hydrogen Sulfide is Required for Amygdalar Long-Term Potentiation and Cued Fear Memory in Rats. Pharmacol Biochem Behav. 2017, 155, 16-23. DOI: 10.1016/j.pbb.2017.03.002
7. Li, Y. L.; Wu, P. F.; Chen, J. G. et al. Activity-Dependent Sulfhydration Signal Controls N-Methyl-D-Aspartate Subtype Glutamate Receptor-Dependent Synaptic Plasticity via Increasing d-Serine Availability. Antioxid Redox Signal. 2017, 27 (7), 398-414. DOI: 10.1089/ars.2016.6936
8. Wei, H. J.; Tan, H. Y.; Cao, J. P. et al. Therapeutic Importance of Hydrogen Sulfide in Cognitive Impairment Diseases. Brain Res. 2025, 1856, 149547. DOI: 10.1016/j.brainres.2025.149547