, Volume 235, Issue 8, pp 2267–2274 | Cite as

Decreased plasma levels of gasotransmitter hydrogen sulfide in patients with schizophrenia: correlation with psychopathology and cognition

  • Jian-wen Xiong
  • Bo Wei
  • Yan-kun Li
  • Jin-qiong Zhan
  • Shu-zhen Jiang
  • Hai-bo Chen
  • Kun Yan
  • Bin YuEmail author
  • Yuan-jian YangEmail author
Original Investigation



Aberrant N-methyl-d-aspartate receptor (NMDAR) function has been implicated in the pathophysiology of schizophrenia. Hydrogen sulfide (H2S) is an endogenous gasotransmitter that regulates NMDAR function. The current study investigated the relationship between plasma H2S levels and both psychopathological and cognitive symptoms in schizophrenia.

Materials and methods

Forty-one patients with schizophrenia and 40 healthy control subjects were recruited in present study. Schizophrenic symptomatology was assessed using the Positive and Negative Syndrome Scale (PANSS). Cognitive function was evaluated with a neuropsychological battery including seven neurocognitive tests. Plasma H2S levels were measured by reversed-phase high-performance liquid chromatography (RP-HPLC).


Patients with schizophrenia performed worse in all of the cognitive tests than the healthy controls except for the visual memory. Plasma H2S levels were significantly lower in patients with schizophrenia relative to healthy control subjects (F = 3.821, p = 0.007). Correlation analysis revealed a significant negative correlation between the H2S levels and the PANSS general scores (r = − 0.413, p = 0.007). Additionally, a positive association was observed between plasma H2S levels and working memory (r = 0.416, p = 0.007), visual memory (r = 0.363, p = 0.020), or executive function (r = 0.344, p = 0.028) in patients. Partial correlation analysis showed that the correlations between the H2S levels and the PANSS general scores, working memory, visual memory, or executive function were still significant when controlling for age, gender, years of education, BMI, duration of illness, and age of onset.


The significant relations observed in the current study between H2S and the general psychopathological as well as cognitive symptoms suggest that decreased H2S is involved in the psychopathology and cognitive deficits of schizophrenia, and it might be a promising peripheral biomarker of schizophrenia.


Schizophrenia Hydrogen sulfide Psychopathology Cognition 



Jian-wen Xiong, Bo Wei, Yan-kun Li, Shu-zhen Jiang, Jin-qiong Zhan, Hai-bo Chen, and Kun Yan were responsible for the clinical data collection and lab experiments. Yuan-jian Yang and Bin Yu were responsible for the study design, statistical analysis, and manuscript preparation. All authors have contributed to and have approved the final manuscript.

Funding information

This study was supported by grants from the National Natural Science Foundation of China (No. 81560232, 81600939 and 81760254), the Natural Science Foundation of Jiangxi Province of China (No. 20151BBG70110 and 20161BAB205193), and the Natural Science Foundation of Hubei Province of China (No. 2014CFB186).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abe K, Kimura H (1996) The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 16:1066–1071CrossRefPubMedGoogle Scholar
  2. Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, Quinlan EM, Nakazawa K (2010) Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 13:76–83CrossRefPubMedGoogle Scholar
  3. Belfrage HF, Frisenette-Fich C, Kjellstrom U (1978) A case of schizophrenic psychosis caused by PCP. Lakartidningen 75:4489PubMedGoogle Scholar
  4. Bubenikova-Valesova V, Horacek J, Vrajova M, Hoschl C (2008) Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci Biobehav Rev 32:1014–1023CrossRefPubMedGoogle Scholar
  5. Chen HB, Wu WN, Wang W, Gu XH, Yu B, Wei B, Yang YJ (2017) Cystathionine-beta-synthase-derived hydrogen sulfide is required for amygdalar long-term potentiation and cued fear memory in rats. Pharmacol Biochem Behav 155:16–23CrossRefPubMedGoogle Scholar
  6. Chen WL, Xie B, Zhang C, Xu KL, Niu YY, Tang XQ, Zhang P, Zou W, Hu B, Tian Y (2013) Antidepressant-like and anxiolytic-like effects of hydrogen sulfide in behavioral models of depression and anxiety. Behav Pharmacol 24(7):590–597CrossRefPubMedGoogle Scholar
  7. Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384CrossRefPubMedGoogle Scholar
  8. Deutsch SI, Mastropaolo J, Schwartz BL, Rosse RB, Morihisa JM (1989) A “glutamatergic hypothesis” of schizophrenia. Rationale for pharmacotherapy with glycine. Clin Neuropharmacol 12:1–13CrossRefPubMedGoogle Scholar
  9. Donatti AF, Soriano RN, Leite-Panissi CR, Branco LG, de Souza AS (2017) Anxiolytic-like effect of hydrogen sulfide (H2S) in rats exposed and re-exposed to the elevated plus-maze and open field tests. Neurosci Lett 642:77–85CrossRefPubMedGoogle Scholar
  10. Guo X, Li J, Wang J, Fan X, Hu M, Shen Y, Chen H, Zhao J (2014) Hippocampal and orbital inferior frontal gray matter volume abnormalities and cognitive deficit in treatment-naive, first-episode patients with schizophrenia. Schizophr Res 152:339–343CrossRefPubMedGoogle Scholar
  11. Hardingham GE, Do KQ (2016) Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis. Nat Rev Neurosci 17:125–134CrossRefPubMedGoogle Scholar
  12. Harrison PJ, Owen MJ (2003) Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 361:417–419CrossRefPubMedGoogle Scholar
  13. He XL, Yan N, Zhang H, Qi YW, Zhu LJ, Liu MJ, Yan Y (2014) Hydrogen sulfide improves spatial memory impairment and decreases production of Abeta in APP/PS1 transgenic mice. Neurochem Int 67:1–8CrossRefPubMedGoogle Scholar
  14. Hosoki R, Matsuki N, Kimura H (1997) The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun 237:527–531CrossRefPubMedGoogle Scholar
  15. Hou XY, Hu ZL, Zhang DZ, Lu W, Zhou J, Wu PF, Guan XL, Han QQ, Deng SL, Zhang H, Chen JG, Wang F (2017) Rapid antidepressant effect of hydrogen sulfide: evidence for activation of mTORC1-TrkB-AMPA receptor pathways. Antioxid Redox Signal 27:472–488CrossRefPubMedGoogle Scholar
  16. Hu LF, Lu M, Hon Wong PT, Bian JS (2011) Hydrogen sulfide: neurophysiology and neuropathology. Antioxid Redox Signal 15:405–419CrossRefPubMedGoogle Scholar
  17. Hu LF, Lu M, Tiong CX, Dawe GS, Hu G, Bian JS (2010) Neuroprotective effects of hydrogen sulfide on Parkinson’s disease rat models. Aging Cell 9:135–146CrossRefPubMedGoogle Scholar
  18. Kimura H (2000) Hydrogen sulfide induces cyclic AMP and modulates the NMDA receptor. Biochem Biophys Res Commun 267:129–133CrossRefPubMedGoogle Scholar
  19. Kimura H (2002) Hydrogen sulfide as a neuromodulator. Mol Neurobiol 26:13–19CrossRefPubMedGoogle Scholar
  20. Kimura H (2011) Hydrogen sulfide: its production, release and functions. Amino Acids 41:113–121CrossRefPubMedGoogle Scholar
  21. Kimura H (2014) Production and physiological effects of hydrogen sulfide. Antioxid Redox Signal 20:783–793CrossRefPubMedPubMedCentralGoogle Scholar
  22. Labrie V, Lipina T, Roder JC (2008) Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia. Psychopharmacology 200:217–230CrossRefPubMedGoogle Scholar
  23. Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25:455–467CrossRefPubMedGoogle Scholar
  24. Li Z, Wang Y, Xie Y, Yang Z, Zhang T (2011) Protective effects of exogenous hydrogen sulfide on neurons of hippocampus in a rat model of brain ischemia. Neurochem Res 36:1840–1849CrossRefPubMedGoogle Scholar
  25. Liu SY, Li D, Zeng HY, Kan LY, Zou W, Zhang P, Gu HF, Tang XQ (2017) Hydrogen sulfide inhibits chronic unpredictable mild stress-induced depressive-like behavior by upregulation of Sirt-1: involvement in suppression of hippocampal endoplasmic reticulum stress. Int J Neuropsychopharmacol 20:867–876CrossRefPubMedPubMedCentralGoogle Scholar
  26. Liu XQ, Jiang P, Huang H, Yan Y (2008) Plasma levels of endogenous hydrogen sulfide and homocysteine in patients with Alzheimer’s disease and vascular dementia and the significance thereof. Zhonghua Yi Xue Za Zhi 88:2246–2249PubMedGoogle Scholar
  27. Palmer BW, Dawes SE, Heaton RK (2009) What do we know about neuropsychological aspects of schizophrenia? Neuropsychol Rev 19:365–384CrossRefPubMedPubMedCentralGoogle Scholar
  28. Peter EA, Shen X, Shah SH, Pardue S, Glawe JD, Zhang WW, Reddy P, Akkus NI, Varma J, Kevil CG (2013) Plasma free H2S levels are elevated in patients with cardiovascular disease. J Am Heart Assoc 2:e000387CrossRefPubMedPubMedCentralGoogle Scholar
  29. Shen X, Pattillo CB, Pardue S, Bir SC, Wang R, Kevil CG (2011) Measurement of plasma hydrogen sulfide in vivo and in vitro. Free Radic Biol Med 50:1021–1031CrossRefPubMedPubMedCentralGoogle Scholar
  30. Tang ZJ, Zou W, Yuan J, Zhang P, Tian Y, Xiao ZF, Li MH, Wei HJ, Tang XQ (2015) Antidepressant-like and anxiolytic-like effects of hydrogen sulfide in streptozotocin-induced diabetic rats through inhibition of hippocampal oxidative stress. Behav Pharmacol 26:427–435CrossRefPubMedGoogle Scholar
  31. Wang CM, Yang YJ, Zhang JT, Liu J, Guan XL, Li MX, Lu HF, Wu PF, Chen JG, Wang F (2015) Regulation of emotional memory by hydrogen sulfide: role of GluN2B-containing NMDA receptor in the amygdala. J Neurochem 132:124–134CrossRefPubMedGoogle Scholar
  32. Xu K, Krystal JH, Ning Y, Chen DC, He H, Wang D, Ke X, Zhang X, Ding Y, Liu Y, Gueorguieva R, Wang Z, Limoncelli D, Pietrzak RH, Petrakis IL, Fan N (2015) Preliminary analysis of positive and negative syndrome scale in ketamine-associated psychosis in comparison with schizophrenia. J Psychiatr Res 61:64–72CrossRefPubMedGoogle Scholar
  33. Yang YJ, Xiong JW, Zhao Y, Zhan JQ, Chen HB, Yan K, Hu MR, Yu B, Wei B (2016a) Increased plasma asymmetric dimethylarginine is associated with cognitive deficits in patients with schizophrenia. Psychiatry Res 246:480–484CrossRefPubMedGoogle Scholar
  34. Yang YJ, Zhao Y, Yu B, Xu GG, Wang W, Zhan JQ, Tang ZY, Wang T, Wei B (2016b) GluN2B-containing NMDA receptors contribute to the beneficial effects of hydrogen sulfide on cognitive and synaptic plasticity deficits in APP/PS1 transgenic mice. Neuroscience 335:170–183CrossRefPubMedGoogle Scholar
  35. Zhang XY, Liang J, Chen DC, Xiu MH, Yang FD, Kosten TA, Kosten TR (2012) Low BDNF is associated with cognitive impairment in chronic patients with schizophrenia. Psychopharmacology 222:277–284CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PsychiatryJiangxi Mental Hospital/Affiliated Mental Hospital of Nanchang UniversityNanchangPeople’s Republic of China
  2. 2.Department of Pharmacology, School of PharmacyHubei University of Science and TechnologyXianningPeople’s Republic of China
  3. 3.Medical Experimental CenterJiangxi Mental Hospital/Affiliated Mental Hospital of Nanchang UniversityNanchangPeople’s Republic of China
  4. 4.Department of PharmacyJiangxi Mental Hospital/Affiliated Mental Hospital of Nanchang UniversityNanchangPeople’s Republic of China

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