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Psychopharmacology

, 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 Yu
  • Yuan-jian Yang
Original Investigation

Abstract

Objective

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).

Results

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.

Conclusion

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.

Keywords

Schizophrenia Hydrogen sulfide Psychopathology Cognition 

Introduction

The glutamate hypothesis of schizophrenia assumes that hypofunction of N-methyl-d-aspartate receptor (NMDAR) is involved in the etiopathogenesis of schizophrenia (Bubenikova-Valesova et al. 2008; Coyle 2006; Deutsch et al. 1989). This theory is supported by the evidence that blockade of NMDARs by antagonists such as phencyclidine and ketamine would cause a psychotic reaction that resembles schizophrenia symptoms in healthy human subjects and reinstate pre-existing symptoms in stabilized patients with schizophrenia (Belfrage et al. 1978; Lahti et al. 2001; Xu et al. 2015). Genetically engineered mouse strains that carry mutations in NMDAR subunit-encoding genes displayed phenotypes that were similar to schizophrenia (Belforte et al. 2010; Labrie et al. 2008).

Hydrogen sulfide (H2S) is a colorless, water soluble gas with the smell of rotten eggs. It was known to be a toxic gas for hundreds of years. However, accumulating evidence shows that H2S also serves as an endogenous gasotransmitter (Abe and Kimura 1996; Chen et al. 2017; Hosoki et al. 1997; Wang et al. 2015) and it has been considered as the third gasotransmitter alongside nitric oxide (NO) and carbon monoxide (CO) because it plays an important regulatory role in multiple physiological and pathological processes in mammals (Hu et al. 2011; Kimura 2014). Endogenous H2S is largely generated from l-cysteine and homocysteine by the enzyme cystathionine-β-synthase (CBS) in the brain and the enzyme cystathionine-γ-lyase (CSE) in the peripheral tissues (Kimura 2011, 2014). H2S produces a variety of biological effects in the central nervous system, including anti-inflammatory, anti-oxidation, anti-apoptosis, and neuroprotection (Hu et al. 2011). Furthermore, it is revealed to be a novel neuromodulator in the brain (Abe and Kimura 1996; Kimura 2002). A large number of studies have shown that dysfunction of H2S signaling contributes to the pathogenesis of many neuropsychiatric diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), cerebral ischemia, and depression (Hou et al. 2017; Hu et al. 2010; Li et al. 2011; Yang et al. 2016b). However, whether there is any relationship between H2S signaling and the psychopathological symptoms and cognitive deficits in schizophrenia remains unknown.

The influences of H2S on NMDAR function were first studied by Abe and Kimura (1996). They showed that physiological concentrations of H2S could enhance the function of NMDARs and facilitate the induction of LTP in the hippocampus. We found that exogenous treatment with H2S could promote the function of NMDARs in amygdalar neurons and improve cued fear memory and amygdalar LTP in normal rats (Wang et al. 2015). Furthermore, we found that inhibiting the generation of endogenous H2S resulted in a reduction in NMDAR-mediated synaptic response in the thalamo-lateral amygdala pathway, and treatment with H2S donor restored the function of NMDARs (Chen et al. 2017). In the view of the important regulatory role of H2S in NMDAR function and hypofunction of NMDARs in the etiopathogenesis of schizophrenia, we hypothesized that H2S might be involved in the pathophysiology of schizophrenia. We therefore tested this hypothesis by investigating whether (1) plasma H2S level was altered in patients with schizophrenia and (2) there were any relationships between the altered H2S levels and both psychopathological and cognitive symptoms in these patients.

Methods

Subjects

Forty-one patients with schizophrenia (male/female = 22/19) were recruited from Jiangxi Mental Hospital, a Nanchang city-owned psychiatric hospital. The diagnosis of schizophrenia was confirmed by two psychiatrists based on the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). The exclusion criteria included any additional axis I or axis II DSM-IV diagnosis, current pregnancy, autoimmune, allergic, or neoplastic diseases and other physical disorders including cardiac or cerebral infarction within the past 3 months. All these recruited patients had not taken any antipsychotic drug for at least 3 months before entering this study. Forty healthy controls (male/female = 18/22), matched with the patients by age, gender, education years, and body mass index (BMI), were recruited from the local community. Subject presented a personal or family history of psychiatric disorder was ruled out among the control group.

The research was carried out in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board at Jiangxi Mental Hospital. A written informed consent was obtained from each subject, or his or her legal guardians.

Clinical assessments

The Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of psychopathology of patients. To ensure consistency and reliability of rating across the study, three psychiatrists who participated in this study simultaneously attended a training session in the use of the PANSS before the study began. After training, the inter-observer correlation coefficient for the PANSS total score was greater than 0.80.

The cognitive functions of participants were evaluated by a comprehensive battery of neurocognitive tests that are widely used in China (Guo et al. 2014; Yang et al. 2016a). The clinical reliability and validity of these tests have been examined in Chinese populations. Seven tests were involved in the battery:
  • The trail making test part A (TMT-A): this is a timed paper-and-pencil test. In brief, the participant draws a line to connect consecutively numbered circles placed irregularly on a sheet of paper as fast as possible while they still need to maintain accuracy. The time required to complete the test serves as the measured outcome.

  • Brief assessment of cognition in schizophrenia (BACS) symbol coding: 133 digit-symbol pairs are involved in this test. The participant is required to copy the corresponding symbol for a given number as fast as possible and the number of correct symbols listed within 120 s was measured in the test.

  • The Wechsler memory scale-3rd edition spatial span (WMS-III spatial span): ten cubes are irregularly spaced on a board. The participant must remember the order in which an administrator points to a series of cubes in both the forward and reverse order. Two trials of different combinations are given at each level. The number of correctly recalled trials in each condition is used for the outcome measure.

  • The brief visual-spatial memory test-revised (BVMT-R): reproducing six geometric figures from memory are involved in this test. These figures are displayed three times for 10 s each time and the participant is required to draw as many figures as possible in the correct locations on a page in the response booklet. The performance is measured by the total number of correctly recalled figures.

  • The Hopkins verbal learning test-revised (HVLT-R): this is an oral test in which a list of 12 words from three taxonomic categories is presented, and the participant is required to recall as many words as possible. This test contains three learning trials and a delayed recall (25–30 min delay) trial. The performance is measured by the total number of correctly recalled words.

  • The Stroop color-word test (SCWT): this test contains three parts: word page (the names of colors printed in black ink), color page (rows of Xs printed in colored ink), and word-color page (the words from the first page are printed in the colors from the second page, but the word meanings and ink colors are mismatched). Each trial contains 100 items, and the participant is asked to read as quickly as possible in 45 s intervals. The number of correct names is recorded for every trial.

  • Continuous performance test-identical pairs (CPT-IP): in this task, trials of 2, 3, and 4 digit numbers are flashed briefly on a computer monitor and participant is asked to click the mouse when the same number appears consecutively. The total number of possible hits is 90, the total number of possible false alarms is also 90, and total number of possible random responses is 270.

These seven tests were grouped into six cognitive domains: processing speed (TMT-A, BACS-symbol coding), working memory (WMS-III spatial span), visual memory (BVMT-R), verbal learning (HVLT-R), executive function (the Stroop color-word test), and attention (CPT-IP).

Plasma H2S measurement

Blood samples were obtained from patients with an overnight fasting. Whole blood was collected into tubes with EDTA and the tubes were centrifuged at 3000 rpm for 5 min at temperature of 4 °C. The plasma was separated, aliquoted, and stored at − 80 °C before use.

Plasma H2S levels were analyzed using a monobromobimane method coupled with reversed-phase high-performance liquid chromatography (RP-HPLC) (Peter et al. 2013; Shen et al. 2011). Briefly, plasma free H2S was measured by RP-HPLC after derivatization with excess monobromobimane (MBB) to form stable sulfide dibimane derivative. Thirty microliters of plasma sample was pipetted and mixed with 70 μL of 100 mM Tris-HCl buffer (pH 9.5, 0.1 mM DTPA), followed by addition of 50 μL of 10 mM MBB. Thirty minutes later, the reaction was stopped by adding 50 μL of 200 mM 5-sulfosalicylic acid. Then, the sample was centrifuged and the supernatant was analyzed using an Agilent 1220 HPLC system (Agilent Technologies, Santa Clara, CA, USA) and an Agilent ZORBAX Eclipse XDB-C18 column. Plasma H2S levels were quantified based on sulfide dibimane standard curves.

Statistical analysis

To compare the demographic and clinical variables, we used Student’s t test or analysis of variance (ANOVA) for continuous variables and chi-squared for categorical variables. Since the H2S variables were normally distributed in patient and control groups (the Kolmogorov-Smirnov one-sample test; both p > 0.05), one-way ANOVA was used to test the difference of H2S between two groups. Whenever the ANOVA was significant, analysis of covariance (ANCOVA) was also performed to test the effect of age, gender, years of education, and BMI by using these variables as covariates. The correlation between variables was assessed by Pearson’s product moment method. Then, partial correlation analysis was performed to assess the relationships between H2S levels and the psychotic symptoms or cognitive deficits controlling for clinical variables including age, gender, years of education, BMI, duration of illness, and age of onset. Statistical Product and Service Solutions (SPSS) 18.0 software was used to do all statistical analyses. The level of significance was set at p < 0.05.

To calculate the cognitive domain scores, all test raw scores were first converted to standardized z scores by setting the sample mean of each measure to 0 and the standard deviation to 1. For domains with more than one cognitive test, summary scores were determined by calculating the mean of the z scores for the measures that comprised the domain, then converting the mean to a z score with a mean of 0 and a standard deviation of 1.

Results

Demographic and clinical characteristics and cognitive performance

Table 1 shows the clinical demographic data of patients and healthy controls. No significant difference was found in gender, age, years of education, and BMI between two groups (all p > 0.05). Table 2 presents the results of cognitive function tests in patients with schizophrenia and healthy individuals. Patients with schizophrenia performed worse in all of the cognitive tests than the normal controls (all p < 0.05). The significant differences still existed when adjusting for age, gender, years of education, and BMI except for the BVMT-R score (p = 0.091).
Table 1

Demographic and clinical data between patients and normal control subjects

 

Healthy controls (n = 40)

Patients with schizophrenia (n = 41)

F or X2

p

Sex, M/F

18/20

22/19

0.312

0.655

Age (years)

34.5 ± 9.9

31.3 ± 8.6

3.001

0.089

Education (years)

11.5 ± 4.9

10.3 ± 5.2

0.876

0.353

BMI (kg/m2)

20.9 ± 2.0

21.6 ± 2.2

1.607

0.210

Age of onset (years)

24.7 ± 6.4

Duration of illness (years)

6.1 ± 5.0

PANSS total score

80.6 ± 11.6

 Positive subscale

22.7 ± 4.2

 Negative subscale

13.7 ± 4.4

 General psychopathology subscale

44.2 ± 6.3

BMI body mass index, PANSS Positive and Negative Syndrome Scale

Table 2

Comparison of cognitive function between two groups

 

Healthy controls (n = 40)

Patients with schizophrenia (n = 41)

F

p

Adjusted F

p

TMT-A

38.8 ± 8.7

74.2 ± 29.6

39.198

< 0.001

8.375

< 0.001

BACS-SC

65.7 ± 5.9

34.0 ± 14.4

124.762

< 0.001

30.540

< 0.001

WMS-III-SS

17.8 ± 2.5

14.3 ± 3.1

7.119

0.010

2.506

0.041

HVLT-R

26.8 ± 4.7

18.4 ± 5.9

28.790

< 0.001

7.828

< 0.001

BVMT-R

27.7 ± 11.2

20.4 ± 4.6

8.311

0.006

2.021

0.091

Stroop color-word test

 Word raw score

86.2 ± 9.1

54.6 ± 15.9

88.664

< 0.001

20.298

< 0.001

 Color raw score

50.8 ± 8.9

36.3 ± 15.1

19.833

< 0.001

5.346

< 0.001

 Color-word raw score

36.5 ± 7.8

21.5 ± 14.4

27.987

< 0.001

5.733

< 0.001

CPT-IP

3.3 ± 1.0

1.4 ± 0.9

57.954

< 0.001

12.427

< 0.001

TMT-A trail making task part A, BACS-SC brief assessment of cognition in schizophrenia-symbol coding, CPT-IP continuous performance test-identical pairs, WMS-III-SS the Wechsler memory scale-3rd edition-spatial span, HVLT-R the Hopkins verbal learning test-revised, BVMT-R brief visual-spatial memory test-revised

Adjusted F indicates the F value controlled for age, gender, years of education, and BMI

Plasma H2S levels in patients and healthy controls

Plasma H2S levels in patient and control groups are shown in Table 3 and Fig. 1. There was a significant difference between patient and control groups in plasma H2S levels (0.78 ± 0.14 vs. 0.93 ± 0.21 μmol/L; F = 15.164, p < 0.001). When gender, age, and BMI were added as potentially confounding covariate terms, the differences between the patients and controls remained significant (F = 3.821, p = 0.007). No significant difference was observed between male and female in both groups (p > 0.05).
Table 3

Plasma H2S levels in patient and control groups

 

Healthy controls (n = 40)

Patients with schizophrenia

(n = 41)

F

p

Adjusted F

p

H2S level (μmol/L)

0.93 ± 0.21

0.78 ± 0.14

15.164

< 0.001

3.821

0.007

Male

Female

p

Male

Female

p

    

0.94 ± 0.22

0.92 ± 0.20

0.797

0.78 ± 0.16

0.77 ± 0.12

0.773

    

Adjusted F indicates the F value controlled for age, gender, and BMI

Fig. 1

This figure presents a scattergram of plasma H2S levels from patients with schizophrenia (n = 41) and from control subjects (n = 40). The sample means are indicated by the black bars. **p < 0.01

Within the normal controls, no significant correlation was observed between H2S levels and gender, age, and BMI. Within the patient group, no significant correlation was noted between H2S levels and any demographic parameters, including gender, age, BMI, age of onset of psychosis, and duration of illness (all p > 0.05).

Relationship between H2S levels and psychopathological symptoms in schizophrenia

Correlation analysis revealed a significant negative association between plasma H2S levels and the PANSS general scores in patients with schizophrenia (r = − 0.413, p = 0.007) (Fig. 2A). No significant difference was found between plasma H2S and the PANSS total scores (r = − 0.120), the positive scores (r = − 0.251), or the negative scores (r = − 0.187) (all p > 0.05). Partial correlation analysis showed that the correlation between H2S levels and the PANSS general scores was still significant when controlling for age, gender, years of education, BMI, duration of illness, and age of onset (r = − 0.397, p = 0.017).
Fig. 2

The correlation between plasma H2S levels and PANSS general psychopathology scores (A), working memory index (B), visual memory index (C), or executive function index (D1–3) in patients with schizophrenia

Correlation between H2S levels and cognitive symptoms in schizophrenia

The cognitive tests were grouped into six domains: processing speed (TMT-A, BACS-symbol coding), working memory (WMS-III spatial span), visual memory (BVMT-R), verbal learning (HVLT-R), executive function (the Stroop color-word test), and attention (CPT-IP). Then, correlations between plasma H2S levels and cognitive performances in both patients and healthy controls were tested.

For the healthy individuals, plasma H2S levels were not associated with any index of the cognitive tests (all p > 0.05). For the patient groups, correlation analysis revealed a significant positive association of plasma H2S levels with the working memory index (r = 0.416, p = 0.007), the visual memory index (r = 0.363, p = 0.020), or the executive function index (r = 0.344, p = 0.028) (Fig. 2B–D). There was no significant association between plasma H2S and the processing speed index (r = − 0.069), the verbal learning index (r = 0.089), or the attention index (r = 0.224) (all p > 0.05). Partial correlation analysis revealed that the correlations between H2S levels and the working memory (r = 0.432, p = 0.008), visual memory (r = 0.391, p = 0.018), or executive function (r = 0.386, p = 0.020) were still significant when controlling for age, gender, years of education, BMI, duration of illness, and age of onset.

Discussion

Our results revealed that (1) plasma H2S levels were significantly decreased in patients with schizophrenia than in healthy control subjects; (2) there was a significant negative correlation between H2S levels and the PANSS general scores in patients; and (3) plasma H2S levels were positively associated with working memory, visual memory, and executive function in patients with schizophrenia. To our knowledge, this is the first study concerning the role of H2S signaling in the pathophysiology of schizophrenia.

H2S has been identified as an endogenous modulator in the central nervous system (Kimura 2002). It can promote astrocytic glutamate uptake, upregulate the expression of γ-aminobutyric acid B (GABAB) receptor subunits, increase intracellular [Ca2+], and regulate intracellular pH value in neurons, astrocytes, and microglia (Hu et al. 2011). H2S is also a regulator for NMDAR function. For instance, it selectively stimulates NMDAR-mediated currents via activating adenylyl cyclase and the subsequent cyclic adenosine monophosphate/protein kinase A (PKA) cascades (Abe and Kimura 1996; Kimura 2000); inhibition of endogenous H2S production causes a reduction of NMDAR-mediated synaptic response in the amygdalar neurons (Chen et al. 2017). Hypofunction of NMDARs has been implicated in the pathogenesis of schizophrenia. Genes that are linked to the susceptibility to develop schizophrenia are relevant to proteins or molecules that modulate the function of NMDARs (Hardingham and Do 2016; Harrison and Owen 2003). Our finding showed that plasma H2S levels were significantly decreased in patients with schizophrenia and H2S levels were associated with the psychopathological symptoms and cognitive deficits in patients. Given the important regulatory role of H2S in NMDAR function and NMDAR hypofunction in schizophrenia, these results indicate that H2S might also be implicated in the pathophysiology of schizophrenia. However, it is worth mentioning that the differences in H2S between patients and controls could be attributed to schizophrenia itself or other confounding factors, such as the effects of antipsychotic medication. In our present study, the recruited patients had not taken any antipsychotic drug for at least 3 months before entering this study. In combination with the finding that decreased plasma H2S was associated with the severity of psychopathological and cognitive symptoms in patients, we thus postulate that the group difference in H2S is more likely to be related to the illness per se, rather than a phenomenon secondary to medication treatment. However, future studies are required to test this hypothesis by measuring H2S in first-episode and drug-naive patients with schizophrenia.

The current study observed a significantly negative relationship between plasma H2S levels and the PANSS general scores, suggesting that patients with lower H2S levels would be more likely to have severe general psychopathological symptoms. Anxiety and depression are included in the PANSS general subscale. Previous studies have demonstrated a role for H2S in anxiety and depression. For example, H2S can produce anxiolytic-like effects in rats exposed to the elevated plus maze (Chen et al. 2013; Donatti et al. 2017) and inhibit depressive-like behaviors in rats exposed to chronic unpredictable mild stress (Hou et al. 2017; Liu et al. 2017). Treatment with H2S could alleviate depressive-like behaviors of streptozotocin-induced diabetic rats in the forced swimming and tail suspension tests and reduce their anxiety-like behaviors in the elevated plus maze test (Tang et al. 2015). Therefore, we postulate that the negative correlation observed between H2S and general psychopathological symptoms in schizophrenia in the present study might be due to the influence of abnormal H2S on anxiety and depression. However, this explanation is quite speculative. Interaction between H2S and other items of the general psychopathology scale in schizophrenia needs to be explored in further investigations.

Cognitive deficits are a core feature of schizophrenia. Multi-faceted cognitive impairments including processing speed, attention, working memory, verbal learning, visual memory, and executive function were reported in schizophrenia (Palmer et al. 2009). In agreement with the previous studies (Guo et al. 2014; Yang et al. 2016a; Zhang et al. 2012), our results showed that patients with schizophrenia performed worse in processing speed, working memory, visual memory, executive function, and attention than the normal controls. H2S plays an important role in the regulation of cognitive function. Treatment with H2S improved cued fear memory and amygdalar synaptic plasticity in rats by enhancing the function of NMDARs (Wang et al. 2015), while blocking endogenous H2S production caused impairments of NMDAR-dependent amygdalar LTP and memory (Chen et al. 2017). Furthermore, H2S levels were decreased in the brains of model animals for neurodegenerative disorders such as AD and brain ischemia, and administration of H2S alleviated the cognitive impairments in these animals (He et al. 2014; Li et al. 2011; Yang et al. 2016b). Liu et al. (2008) reported that plasma H2S levels in AD patients were much lower than those of normal controls, and the plasma H2S concentration was negatively correlated the severity of AD. Our present study revealed that plasma H2S levels were decreased in patients with schizophrenia, and H2S levels were positively associated with working memory, visual memory, and executive function in patients, suggesting that dysregulation of H2S signaling is relevant to cognitive deficits in schizophrenia.

Correlation analysis revealed that there were significant correlations between H2S levels and the PANSS general scores, working memory, visual memory, or executive function in patients with schizophrenia. Partial correlation analysis showed that the correlations between H2S levels and these indexes were still significant when controlling for age, gender, years of education, BMI, duration of illness, and age of onset. These results suggest that altered H2S is probably involved in the pathophysiological process of schizophrenia. However, whether decreased H2S levels in schizophrenia are just an epiphenomenon or are related to the pathomechanism of the disorder still cannot be established because this is a cross-sectional study and other factors including medication and secondary effects of chronic illness cannot be excluded completely at this stage. Further research using animal experiments or longitudinal and prospective study is needed to address these possibilities.

The present study has some limitations. Firstly, although we found a close correlation between decreased plasma H2S and the severity of psychopathological and cognitive symptoms in patients with schizophrenia, the exact mechanisms through which H2S affects schizophrenia-related behaviors are still unknown. Further research using animal experiments is needed to reveal the action mechanisms of H2S signaling in schizophrenia. Second, we measured H2S levels only in plasma, but not in cerebral spinal fluid (CSF). Although H2S can diffuse rapidly across cell membranes and blood-brain barrier, it is still uncertain whether peripheral H2S reflects similar change in the central nervous system. Third, the sample size was relatively small. Further large-scale clinical studies are needed.

In summary, our results showed that the levels of plasma H2S were decreased in Chinese patients with schizophrenia and plasma H2S levels were significantly correlated with the general psychopathological or cognitive symptoms of the patients, suggesting that decreased H2S is probably involved in the psychopathology and cognitive deficits of schizophrenia. However, these findings remain preliminary. More studies in larger patient samples and in people at risk of psychosis (before psychosis onset and during antipsychotic-naive early psychosis) would be needed in the future for the following purposes: (a) H2S appears associated with schizophrenia and the reproducibility of this finding should be confirmed in other patient cohorts; (b) studies that measure H2S before onset of psychosis could indicate whether decreases in H2S precede expression of frank psychosis; (c) studies examining H2S in antipsychotic naive patients could confirm this reduction is not secondary to medication effects.

Notes

Contribution

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.

References

  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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