Glutathione levels and activities of glutathione metabolism enzymes in patients with schizophrenia: A systematic review and meta-analysis

Abstract

Background:

Glutathione is among the important antioxidants to prevent oxidative stress. However, the relationships between abnormality in the glutathione system and pathophysiology of schizophrenia remain uncertain due to inconsistent findings on glutathione levels and/or glutathione-related enzyme activities in patients with schizophrenia.

Methods:

A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies, in which three metabolite levels (glutathione, glutathione disulfide, and total glutathione (glutathione+glutathione disulfide)) and five enzyme activities (glutathione peroxidase, glutathione reductase, glutamate-cysteine ligase, glutathione synthetase, and glutathione S-transferase) were measured with any techniques in both patients with schizophrenia and healthy controls, were included. Standardized mean differences were calculated to determine the group differences in the glutathione levels with a random-effects model.

Results:

We identified 41, 9, 15, 38, and seven studies which examined glutathione, glutathione disulfide, total glutathione, glutathione peroxidase, and glutathione reductase, respectively. Patients with schizophrenia had lower levels of both glutathione and total glutathione and decreased activity of glutathione peroxidase compared to controls. Glutathione levels were lower in unmedicated patients with schizophrenia than those in controls while glutathione levels did not differ between patients with first-episode psychosis and controls.

Conclusions:

Our findings suggested that there may be glutathione deficits and abnormalities in the glutathione redox cycle in patients with schizophrenia. However, given the small number of studies examined the entire glutathione system, further studies are needed to elucidate a better understanding of disrupted glutathione function in schizophrenia, which may pave the way for the development of novel therapeutic strategies in this disorder.

Keywords

Schizophrenia glutathione redox dysregulation oxidative stress

Introduction

Schizophrenia (SZ) is a debilitating psychiatric disorder affecting approximately 1% of the population worldwide (Rajji et al., 2014). Accumulating evidence suggests that redox dysregulation, N-methyl-d-aspartate (NMDA) receptor hypofunction, and neuroinflammation contribute to the pathophysiology of SZ, and that these systems closely interact with each other (Steullet et al., 2016). Redox dysregulation might occur through an imbalance between reactive oxygen species (ROS) and antioxidant defenses. Although ROS have important roles for normal physiological functions, such as protecting cells from infections, regulating vascular cell functioning, and mediating intracellular signaling cascades, excessive ROS disrupt deoxyribonucleic acid viability and protein function, and cause peroxidative damage to the cell membrane by lipid peroxidation, which in turn results in the loss of cell function, and apoptosis or necrosis (Wu et al., 2013). To guard against cell damage by ROS, the antioxidant systems decrease ROS levels using reducing equivalents, where most of these systems require glutathione (GSH) as a cofactor (Nordberg and Arner, 2001). Notably, both increasing oxidative stress and failure of antioxidant defenses were observed in patients with SZ (Flatow et al., 2013; Yao and Keshavan, 2011). This redox dysregulation is considered to contribute to the disruption of the functions of parvalbumin-positive interneurons (PVIs) and oligodendrocytes (OLs), which may lead to the pathogenesis of SZ (Do et al., 2009). Among the markers of antioxidant defenses, GSH seems to be an important antioxidant for SZ not only because there were many studies demonstrating decreased levels of GSH, but also because there is a potential therapeutic mechanism to modulate GSH system and cope with oxidative stress including N-acetyl cysteine (NAC) in this disorder.

GSH antioxidant system

GSH is the major antioxidant in the brain, and has multiple roles in maintaining the redox balance as well as protecting cells against the oxidative stress and toxicity of xenobiotic electrophiles (Forman et al., 2009). The synthesis of GSH involves two adenosine triphosphate (ATP)-requiring enzymatic steps. First, glutamate is combined with cysteine to form γ-glutamylcysteine by glutamate-cysteine ligase (GCL). Next, GSH synthetase (GS) catalyzes and combines this dipeptide with glycine to produce GSH. The first step is often considered rate-limiting not only because GCL activity is regulated through negative feedback by GSH but also because cysteine levels are low. GCL is composed of two dissociable subunits. The GCL catalytic subunit (GCLC) produces γ-glutamylcysteine and the GCL modifier subunit (GCLM) increases enzyme activity (Seelig et al., 1984).

GSH is utilized as a cofactor in redox reactions, which reduce hydrogen peroxide and organic peroxide by GSH peroxidase (GPx) or GSH S-transferase (GST), producing the oxidized dimer GSH disulfide (GSSG) (Lu, 2009). In turn, GSH reductase (GR) reduces GSSG to GSH using nicotinamide adenine dinucleotide phosphate as an electron donor. These steps form a redox cycle. Under severe oxidative stress, reduction of GSSG to GSH cannot compensate oxidation of GSH, leading to an accumulation of GSSG. To protect the cell from a redox state shift, GSSG is actively transported out of the cell. Therefore, severe oxidative stress consumes cellular GSH (Lu, 2009). Then, the ecto-enzyme γ-glutamyltranspeptidase transfers GSH released from the cell to γ-glutamyl amino acid and cysteinyl-glycine, which is transported back into the cell (Figure 1).

GSH antioxidant system and SZ

Mounting evidence suggests that dysregulation of GSH metabolism may be implicated in the pathophysiology of SZ; this is supported by findings from previous studies examining postmortem brain, blood, cerebrospinal fluid (CSF), and genes, or employing proton magnetic resonance spectroscopy (¹H-MRS) (Altuntas et al., 2000; Ballesteros et al., 2013a, 2013b; Dadheech et al., 2006; Do et al., 2000; Gysin et al., 2007; Matsuzawa et al., 2008; Xin et al., 2016). However, findings from previous studies still remain inconsistent with respect to the differences in GSH levels or GSH-related enzyme activities between patients with SZ and healthy controls (HCs). To the best of our knowledge, there have been six meta-analyses on this metabolic pathway. Fraguas et al. reported two meta-analyses. One study found no significant differences in oxidative and inflammatory markers including GSH and GPx between patients with early-onset first-episode psychosis (FEP) and HCs (Fraguas et al., 2017). The same group showed lower antioxidant capacity and higher pro-inflammatory markers in patients with FEP although GSH levels and GPx activities did not differ between the two groups (Fraguas et al., 2018). However, the limitations of these meta-analyses are: small number of studies and small sample sizes, the sample being limited to FEP, and the sample source being limited to blood quantification (Fraguas et al., 2017). Das et al. reported decreased GSH levels measured with ¹H-MRS in the anterior cingulate cortex of patients with SZ compared with those of HCs (Das et al., 2018). Zhang et al. meta-analyzed GPx levels and four other oxidative markers in SZ and reported no difference in GPx activity between patients with SZ (n=544) and HCs (n=380) (Zhang et al., 2010), while another more recent meta-analysis by Flatow et al. showed that GPx activities were decreased in patients with chronic SZ (n=317) compared to HCs (n=151) (Flatow et al., 2013). No meta-analyses, however, examined GSH levels as well as GSH-related enzymes other than GPx in whole patients with SZ ranging from FEP to chronic SZ and combining the results of different measuring methods or sample sources.

Study aims

The present study had two objectives. The primary aim was to detect differences in GSH levels between patients with SZ and HCs. The second aim was to compare enzymatic activity in the GSH metabolic pathway between the two groups. Moreover, subgroup analyses were performed for measurement techniques and clinical status, as well as medication status. Furthermore, the influences of patients’ characteristics were explored through meta-regression analyses.

Method

Literature search

The current meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) flow diagram. Three authors (ST, YM, and RT) performed the initial search (last search: 25 February 2019) and two authors (ST and ME) assessed eligibility independently. Subsequently, one author (ST) extracted all data, which was verified independently by another author (MK). Human studies written in English were screened using Embase, Medline, PsycINFO, and PubMed. The literature search for each metabolite or enzyme was conducted using the following terms: (glutathione or GSH) for GSH, GSSG, and total GSH (tGSH), which represents the sum of the amount of GSH and two times the amount of GSSG, ((glutamate-cysteine and ligase) or (gamma-glutamylcysteine and synthetase)) for GCL, (glutathione and reductase) for GR, (glutathione and peroxidase) for GPx, (glutathione and synthetase) for GS, and (glutathione and S-transferase) for GST, in addition to (schizophreni* or psychosis).

Inclusion criteria

Full-length articles written in English were included, which met the following criteria: studies compared (a) levels of GSH metabolites or activities of GSH metabolism enzymes between (b) patients with SZ or related disorders and (c) HCs, and (d) the provided dataset enabled calculation of standardized mean differences (SMDs).

Exclusion criteria

The following articles were excluded: (a) studies reporting on a sample completely overlapping with another study, (b) studies examining protein contents of GSH metabolism enzymes, or (c) genetic studies related to GSH metabolism enzymes.

Outcome measures

The primary outcome measures were GSH, GSSG, and tGSH levels. The secondary outcome measures were activities of GSH metabolism enzymes (GCL, GS, GPx, GR, and GST).

Data extraction

The variables recorded from each included study were metabolite levels, enzyme activities, diagnoses, age, sex, antipsychotics status, and methods of measurement. If the identified articles did not report mean or standard deviation (SD) values of the outcome measures, we asked the authors for additional data. Where SD values were not reported and other statistical values were available, these values were transformed to SD through calculations according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins and Green, 2011) (http://www.handbook.cochrane.org).

Statistical analysis

Meta-analyses

The following analyses were performed using the Comprehensive Meta-Analysis software (www.meta-analysis.com). SMDs were used to calculate differences in metabolite levels or enzyme activities between patients and HCs. Effect sizes were classified as small (SMD=0.2), moderate (SMD=0.5), and large (SMD=0.8), with positive values indicating elevated metabolite levels or enzyme activities in the patient group. We calculated effect sizes and two-sided 95% confidence intervals (CIs) employing the inverse variance statistical method and random effects model to adjust for the study heterogeneity such as patient population or sample sources (Borenstein et al., 2010). The primary analyses regarding levels of GSH metabolites examined the whole samples and investigated sample sources (i.e. central or peripheral) of the metabolites separately. The central group consisted of studies examining CSF, brain tissue, and ¹H-MRS, while the peripheral group comprised studies examining whole blood, erythrocyte, plasma, serum, and fibroblast cells. Moreover, the I² statistic was applied to assess study heterogeneity as a measure of the proportion of variance in the summary effect size attributable to heterogeneity, interpreting I²⩾50% to indicate significant heterogeneity not attributable to random error (Higgins and Thompson, 2002). Potential publication bias was assessed using funnel plots and Egger’s regression test: if identified, the trim-and-fill procedure was used (Duval and Tweedie, 2000; Egger et al., 1997). Additional meta-analyses were conducted to investigate differences in secondary outcomes within the whole sample in the same manner as the primary analyses.

Moderator analyses

Moderator analyses were conducted to investigate the influence of study and patient characteristics on primary outcomes. Subgroup analyses were performed for materials (for whole blood, erythrocyte, plasma/serum, or magnetic resonance spectroscopy (MRS)), antipsychotic status (for unmedicated or medicated groups), and clinical status (only for the FEP group). For subgroup analysis of ¹H-MRS studies, we examined the group difference of GSH levels in each region of interest separately. Meta-regression analyses were conducted for age, proportion of medicated patients, proportion of males, chlorpromazine equivalent dose, duration of illness, and Positive and Negative Syndrome Scale total score. Subgroup analyses and meta-regressions were performed when at least five studies were available for moderator variables.

Risk of bias of the included studies

The Risk of Bias Assessment tool for Nonrandomized Studies (Kim et al., 2013) was employed for the following factors: participant selection, confounding variables, measurement of exposure, blinding of outcome assessment, incomplete outcome data, and selective outcome reporting.

The signiﬁcance level was set at 0.05/the number of analyses for the primary and secondary outcomes, separately, to control the risk of both type I and type II errors. The signiﬁcance levels were set at 0.05/3(=0.017), 0.05/1(=0.05), and 0.05/3(=0.017) for the whole, central, and peripheral samples, respectively, in the primary meta-analyses and at 0.05/2(=0.025) in the secondary meta-analyses. The signiﬁcance level for subgroup analyses and meta-regression analyses were set at 0.05/10(=0.005) and 0.05/6(=0.0083) adjusted by the number of analyses. Continuous variables are reported as mean±SD.

Results

Included individual studies

The PRISMA flow diagram is presented in Supplementary Material Figure 1. The characteristics of the included studies are summarized in Supplementary Material Table 1.

Primary outcome

Out of 1313 initial records, 47 articles were identified for the studies included in the primary meta-analyses comprising an overall sample of 1862 patients and 1860 HCs. The comparisons in GSH, GSSG, and tGSH between the two groups were reported in 41, 9, and 15 studies, respectively. The average number of patients and HCs in each study was 40±25 (range: 12–138) and 40±26 (range: 9–123), respectively. Average age and percentage males in the patient group and control group were 31.9±9.3 and 30.6±8.9 years and 68.4±15.6% and 63.0±17.8%, respectively. Materials used in studies and their number were as follows: for GSH studies, whole blood (k=12), erythrocyte (k=5), plasma (k=4), serum (k=2), ¹H-MRS (k=13), brain tissue (k=3), and fibroblast cell (k=2); for GSSG studies, whole blood (k=3), erythrocyte (k=1), plasma (k=2), serum (k=1) and brain tissue (k=2), and for tGSH studies, whole blood (k=4), erythrocyte (k=3), plasma (k=5), brain tissue (k=2), and CSF (k=2).

Among the 41 GSH studies, 25 studies and one study showed significantly decreased and increased GSH levels, respectively, in patients with SZ (Baxter et al., 2015; Das et al., 2018; Dietrich-Muszalska et al., 2009; Diken et al., 2001; Do et al., 2015; Duval and Tweedie, 2000; Evans et al., 2003; Forman et al., 2009; Fraguas et al., 2017; Hardingham and Do, 2016; Hoftman et al., 2015; Kartalci et al., 2011; Kumar et al., 2018; Langbein et al., 2017; Li et al., 2006; Miljevic et al., 2010a; Mills and Lang, 1996; Nordberg and Arner, 2001; Raffa et al., 2011, 2012a; Simsek et al., 2016; Steullet et al., 2010; Tharoor et al., 2018; Tseng et al., 2008; Wang et al., 2019; Zhang et al., 2010) compared to HCs, while 15 studies did not report any significant difference between the two groups (Barak et al., 1958; Baumann et al., 2016; Brandt et al., 2016; Gysin et al., 2007, 2011; Kartalci et al., 2011; Langbein et al., 2017; Matsuzawa et al., 2008; Parellada et al., 2012; Reid et al., 2019; Rowland et al., 2016a, 2016b; Taylor et al., 2017; Terpstra et al., 2005; Wijtenburg et al., 2017). With regard to GSSG, two and two studies reported decreased and increased levels of GSSG (Ballesteros et al., 2013a; Gawryluk et al., 2011; Raffa et al., 2011, 2012a), respectively, in patients with SZ in comparison with HCs, while five studies noted no difference in the GSSG levels between the two groups (Ivanova et al., 2015; Langbein et al., 2017; Raffa et al., 2009, 2016; Yao et al., 2006). Among the tGSH studies, 10 studies noted decreased tGSH levels in patients with SZ compared to HCs (Do et al., 2000; Gawryluk et al., 2011; Gonzalez-Liencres et al., 2014; Mico et al., 2011; Nucifora et al., 2017; Raffa et al., 2009, 2011, 2012a, 2016; Zhang et al., 2017), and six studies showed no difference between the two groups (Langbein et al., 2017; Looney and Childs, 1934; Martinez-Cengotitabengoa et al., 2012; Samuelsson et al., 2013; Tuncel et al., 2015).

Secondary outcome

Thirty-eight and seven articles were identified for the meta-analyses of GPx (n=1359 for HCs and n=1779 for patients) and GR (n=261 for HCs and n=297 for patients), respectively. Materials and the number of studies were as follows: for GPx studies, whole blood (k=13), erythrocyte (k=16), plasma (k=8), brain tissue (k=1); for GR studies, whole blood (k=1), erythrocyte (k=5), plasma (k=1) and brain tissue (k=1). Among the 38 GPx studies, 22 and six studies showed significantly decreased and increased GPx activity, respectively, in patients with SZ (Abdalla et al., 1986; Al-Asmari and Khan, 2014; Altuntas et al., 2000; Atmaca et al., 2005; Bai et al., 2018; Ben Othmen et al., 2008; Evans et al., 2003; Herken et al., 2001; Kuloglu et al., 2002; Li et al., 2006; Martinez-Cengotitabengoa et al., 2012; Mico et al., 2011; Miljevic et al., 2010a, 2010b, 2018; Pavlović et al., 2002; Raffa et al., 2009, 2011, 2012b; Ranjekar et al., 2003; Ravikumar et al., 2000; Reyazuddin et al., 2014; Sarandol et al., 2015; Yao et al., 2006; Yapislar, 2012; Zhang et al., 2015; Zhang et al., 2006, 2007) compared to HCs, while 10 studies did not find any significant differences between the two groups (Akyol et al., 2002; Langbein et al., 2017; Mukherjee et al., 1996; Parellada et al., 2012; Raffa et al., 2012a; Reddy et al., 1991; Sarandol et al., 2007; Simsek et al., 2016; Srivastava et al., 2001; Yao et al., 1998). With regard to GR, four studies and one study reported decreased and increased levels of GR (Al-Asmari and Khan, 2014; Langbein et al., 2017; Miljevic et al., 2010a; Ravikumar et al., 2000; Yao et al., 2006), respectively, in patients with SZ in comparison with HCs, whereas two studies noted no difference in the GR levels between the two groups (Langbein et al., 2017; Miljevic et al., 2010b, 2018). Two studies each examined GCL and GST activity (Gysin et al., 2007, 2009; Jordan et al., 2018; Langbein et al., 2017). One study reported decreased GCL activity in patients with SZ compared to HCs, while no difference between the groups were found in another study. Any studies of GST did not show significant differences between the two groups. No research reported GS activity differences between the two groups.

Risk of bias

Out of 76 studies, 57 (75%) showed a “low” risk of bias for five items, excluding “selective outcome reporting”, which we judged to be unclear since we could not obtain experimental protocols. The detailed assessment is displayed in Supplementary Material Figure 2.

Meta-analyses

Details of the results of primary and secondary meta-analyses are shown in Figure 2.

The primary meta-analyses

Whole samples

GSH and tGSH levels in the whole samples were decreased in patients with SZ in comparison to HCs (GSH: k=48, SMD=−0.67, CI=−0.88 to −0.45, p<0.001; tGSH: k=16, SMD=−0.91, CI=−1.39 to −0.44, p<0.001). GSSG levels did not differ between the two groups (k=9, SMD=−0.25, CI=−0.64 to 0.15, p=0.221).

Central samples

There was a decrease in central GSH levels in patients with SZ in comparison to HCs (k=23, SMD=−0.26, CI=−0.41 to −0.10, p=0.001). We could not perform meta-analyses for central GSSG and tGSH due to the small number of these studies.

Peripheral samples

GSH and tGSH levels in peripheral samples were decreased in patients with SZ in comparison to HCs (GSH: k=25, SMD=−1.02, CI=−1.37 to −0.67, p<0.001; tGSH: k=12, SMD=−1.01, CI=−1.59 to −0.42, p=0.001). Peripheral GSSG levels did not differ between the two groups (k=7, SMD=−0.22, CI=−0.67 to 0.23, p=0.340).

The secondary meta-analyses

GPx activity was lower in patients with SZ than in HCs (k=38, SMD=−0.69, CI=−1.07 to −0.30, p=0.002). There was no difference in GR activity between the two groups (k=8, SMD=−0.33, CI=−0.98 to 0.32, p=0.314). For other GSH metabolism enzymes (GCL, GS, and GST), we could not perform meta-analyses because there were less than five studies concerning these enzymes.

Subgroup analyses

Details of the results of subgroup analyses are shown in Supplementary Material Figure 3.

Materials

Both GSH levels in the whole blood and plasma/serum were lower in patients with SZ than in HCs (whole blood: k=12, SMD=−1.15, CI=−1.77 to −0.52, p<0.001; plasma/serum: k=6, SMD=−1.23, CI=−1.90 to −0.57, p<0.001). GSH levels in the anterior cingulate cortex (ACC) measured with ¹H-MRS were also significantly decreased in patients with SZ (k=10, SMD=−0.24, CI=−0.38 to 0.10, p=0.001). Erythrocyte GSH and plasma/serum tGSH levels showed a trend towards a decrease in patients with SZ than in HCs (erythrocyte GSH: k=5, SMD=−0.69, CI=−1.18 to −0.19, p=0.006; plasma/serum tGSH: k=5, SMD=−0.56, CI=−1.12 to −0.002, p=0.049). We could not conduct subgroup analyses for GSSG or the primary outcomes from CSF, brain tissue, fibroblast cells, and other regions of ¹H-MRS due to the small number of studies.

Antipsychotics

In unmedicated patients with SZ, GSH levels were lower (k=7, SMD=−1.45, CI=−2.40 to −0.50, p=0.003), and tGSH levels showed a trend towards being lower (k=5, SMD=−0.66, CI=−1.15 to −0.16, p=0.010) than levels in HCs. In medicated patients with SZ, GSH levels were lower (k=17, SMD=−0.69, CI=−1.00 to −0.37, p<0.001), while tGSH levels did not differ (k=5, SMD=−0.62, CI=−1.64 to 0.39, p=0.230) compared to those in HCs. We could not perform the subgroup analyses for GSSG due to the small number of studies in those patients.

Illness stage

There was no difference in GSH levels between patients with FEP and HCs (k=11, SMD=−0.20, CI=−0.41 to 0.01, p=0.068). We could not perform the subgroup analysis for GSSG and tGSH due to the small number of studies.

Meta-regression analyses

A higher patient’s age was associated with lower SMDs of GSH between patients with SZ and HCs (slope=−0.030, CI=−0.049 to −0.0123, p=0.0010), while a trend towards a positive relationship was found between the SMDs of GSH and the proportion of medicated patients (slope=0.0078, CI=0.0013 to 0.0143, p=0.019) (Supplementary Material Figure 4). No relationship was found between the SMDs of primary outcomes and other modulators.

Sensitivity analysis

Study heterogeneities were small for whole, peripheral, and central GSH, whole and peripheral GSSG, and GR (I²=17.5%, 15.5%, 20.4%, 0.0%, 4.3%, 0.0%, respectively), and there were non-significant but moderate study heterogeneities in whole and peripheral tGSH and GPx (I²=40.4%, 46.1%, and 27.8%, respectively).

Publication bias

Egger’s test showed no publication bias in both the primary and secondary meta-analyses. The funnel plots are displayed in Supplementary Material Figure 5.

Discussion

Our study is the first meta-analysis to comprehensively compare levels of GSH, GSSG, and tGSH between patients with SZ and HCs, including data from various sample sources and measurement methods combined. Our main findings are fivefold: (a) GSH and tGSH levels were decreased in patients with SZ compared to HCs with moderate and large effect sizes, respectively; (b) there was no difference in GSSG levels between the two groups; (c) decreases in GSH and tGSH levels were greater in unmedicated patients than in medicated patients; (d) no difference was found in GSH levels between patients with FEP and HCs; and (e) the age of patients and proportion of medicated patients were associated with the effect sizes of metabolite levels in patients with SZ. Furthermore, secondary analyses revealed that: (a) GPx activity was lower in patients with SZ compared to HCs with a moderate effect size and (b) no difference was found in GR activity between the two groups.

Main findings

Our results of decreased levels of both GSH and tGSH indicate that a GSH deficit seems to exist in patients with SZ, given that GSH levels may reflect 80–95% of tGSH levels (Ballesteros et al., 2013a; Gawryluk et al., 2011; Ivanova et al., 2015; Langbein et al., 2017; Raffa et al., 2011, 2012a, 2016, 2009; Yao et al., 2006). These results are consistent with animal and clinical studies, which have suggested that GSH deficits may be involved in the underlying pathophysiology of SZ. For example, GCLM knockout mice, an animal model of impaired GSH synthesis, showed reduced kainate-induced gamma oscillations and impaired sensorimotor gating in prepulse inhibition paradigms, which are also observed in patients with SZ (Kulak et al., 2012; Steullet et al., 2010; Williams, 2010). These neurophysiological findings might be caused by anomalies in PVI and myelination, which could result from GSH deficits (Do et al., 2015; Hardingham and Do, 2016; Steullet et al., 2016). Anomalies in PVIs are seen in both patients (Hoftman et al., 2015; Wang et al., 2011) and animal models of SZ, such as the neonatal ventral hippocampal lesion (NVHL) model, in which the hippocampus was damaged by a neurotoxin in the neonatal period (O’Donnell et al., 2002; Tseng et al., 2008). It has been demonstrated that PVIs are vulnerable to redox dysregulation and oxidative stress, especially early in development, since PVIs are energy-demanding in order to support high-frequency neuronal synchronization, which results in the elevation of ROS from mitochondria (Steullet et al., 2016). Moreover, it was found that GSH precursor NAC treatment (Berk et al., 2013; Conus et al., 2018) prevented the reduction of PVI activity and behavioral deficits in NVHL model rats (Cabungcal et al., 2014).

In addition, myelination that is derived from OL precursor cells (OPCs) is impaired in both patients and model animals of SZ (Maas et al., 2017). It has been observed that there are smaller OL sizes and higher levels of OL apoptosis and necrosis in the prefrontal cortex of patients with SZ, accompanied by lower levels of myelin (Flynn et al., 2003; Hof et al., 2003; Maas et al., 2017; Stark et al., 2004). Furthermore, several studies have revealed lower white matter integrity, reflected by a reduced amount of myelination (Peckham and Choi, 1988), which is correlated with more severe cognitive symptoms in this population (Calver et al., 1998; Richardson et al., 1988). As with PVIs, OLs are vulnerable to redox dysregulation and oxidative stress. OLs and OPCs contain high amounts of ROS and lower levels of GSH compared to astrocytes, probably due to the high metabolic activity entailed by myelin synthesis (Steullet et al., 2016). ROS causes downregulation of gene transcription and protein synthesis that is necessary for OPC proliferation and differentiation, which leads to OPC proliferation arrest, apoptosis, and hypomyelination (Maas et al., 2017). Furthermore, GCLM knockout mice at a peripubertal age presented with a reduction of myelin-associated proteins and impairment in OL maturation in the anterior cingulate cortex (Monin et al., 2015). Moreover, a positive correlation between GSH levels in the medial prefrontal cortex and white matter integrity in the cingulum bundle was also found in patients with early psychosis (Monin et al., 2015). Thus, given that maintaining redox balance is important for normal myelination, lower levels of GSH may contribute to disrupted myelination, which may in turn result in clinical symptoms such as cognitive impairment in patients with SZ.

On the other hand, increasing evidence suggests that NMDA receptor hypofunction, which is considered to have an important role in the pathophysiology of SZ (de la Fuente-Sandoval et al., 2015; Nakajima et al., 2015; Plitman et al., 2014, 2016a, 2016b), may induce dysfunction of PVIs and myelination in similar ways to redox imbalance (Gonzalez-Burgos and Lewis, 2012; Hardingham and Do, 2016). Moreover, Hardingham and Do suggested a reciprocal link between NMDA receptor hypofunction and GSH deficits (Hardingham and Do, 2016). Since NMDA receptors are redox-sensitive proteins, GSH deficits may induce NMDA receptor hypofunction via its redox site (Kohr et al., 1994; Steullet et al., 2006). In contrast, it was reported that synaptic NMDA receptor activity boosted GSH biosynthesis, utilization, and recycling by controlling transcription of the enzymes in GSH system, while NMDA receptor blockade caused transcriptional downregulation of GCLC and reduced GCL activity (Baxter et al., 2015). Thus, these findings are also in line with our finding of lower GSH levels in patients with SZ in comparison with HCs.

The association between oxidative stress and GSH deficit, and pathophysiology of SZ, is further corroborated by clinical studies. A previous meta-analysis revealed that levels of antioxidants, such as catalase, oxygen, and superoxide dismutase, were significantly decreased in both patients with FEP and chronic SZ compared to HCs (Flatow et al., 2013), while malondialdehyde, an important end product of lipid peroxidation induced by ROS, was significantly higher in the same groups of patients than HCs (Flatow et al., 2013). Similarly, GSH levels showed an inverse relationship with malondialdehyde levels in patients with SZ (Dadheech et al., 2012). Thus, oxidative stress is presumed to be exacerbated in SZ, in which lower concentrations of GSH seems to play an important role. However, it still remains unclear whether GSH levels may be related to the severity of clinical symptoms and cognitive function and brain function/structure. Seven studies included in the present meta-analyses suggest correlations between lower GSH levels and greater severity of clinical symptoms, including cognitive dysfunction (Ballesteros et al., 2013a; Martinez-Cengotitabengoa et al., 2012; Matsuzawa et al., 2008; Nucifora et al., 2017; Raffa et al., 2009, 2011; Wang et al., 2019) while the remaining six studies did not show any associations among them (Altuntas et al., 2000; Dadheech et al., 2012; Gonzalez-Liencres et al., 2014; Martinez-Cengotitabengoa et al., 2014; Mico et al., 2011; Wood et al., 2009). In addition, two studies reported that GSH levels were not associated with brain structure, although these studies demonstrated the relationships between GPx and GR activities and brain structures (Baumann et al., 2016; Langbein et al., 2017). On the other hand, a recent meta-analysis on effectiveness of adjunctive NAC treatment of SZ reported that it might be an effective treatment to improve the symptoms of this disorder with an effect size of 0.74, although it was limited by the small number of randomized controlled trials (Zheng et al., 2018). Moreover, recent studies demonstrated that augmentation therapy with NAC improved negative symptoms and increased white matter integrity in the fornix, which might be vulnerable to oxidative stress early in the course of illness (Klauser et al., 2018; Tharoor et al., 2018). Therefore, GSH may have a neuroprotective effect and have an influence on symptom severity in patients with SZ. Overall, previous studies support the GSH deficit hypothesis in schizophrenia, which is also in line with our results of decreased levels of GSH and tGSH in both the whole and peripheral samples, as well as central GSH in patients with SZ.

Moderator analysis

Subgroup analyses for materials demonstrated decreased levels of whole blood GSH and plasma/serum GSH and a trend-toward decrease of erythrocyte GSH and plasma/serum tGSH in patients with SZ compared to HCs, keeping in line with the results in our primary analyses. One animal study demonstrated that blood GSH can cross the blood-brain barrier (Kannan et al., 1990), thus plasma or serum GSH may reflect central GSH. Furthermore, to our best knowledge, one previous study thus fur suggested the possibility of estimating GSH levels in CSF from plasma GSH levels in HCs (Samuelsson et al., 2011). Thus, the results of the subgroups analyses suggest decreased levels of GSH in the central nervous systems in patients with SZ. However, there are several technical problems in measuring plasma or serum GSH. First, about 99% of GSH in blood is in erythrocytes so that minor hemolysis (0.1–1%) can result in erroneously high plasma GSH levels (Jones et al., 1998; Mills and Lang, 1996). Second, GSH can be lost due to oxidation or degradation which occurs with a half-time of about five minutes in plasma at room temperature although use of a preservative solution minimizes the loss during processing (Jones et al., 1998; Lash and Jones, 1985).

GSH levels in the ACC as measured with ¹H-MRS were also decreased in patients with SZ compared with HCs. This result is consistent with the previous meta-analysis by Das et al. which also found lower GSH levels in the ACC in patients with SZ compared to HCs (Das et al., 2018). We included the studies based on more stringent criteria than Das et al. As a result, this meta-analysis only included the studies which examined GSH levels in the medial prefrontal cortex or ACC, while Das et al. also included other studies that examined the prefrontal or posterior medial frontal cortexes. These abnormal GSH levels in the ACC may be related to negative symptoms and cognitive dysfunction of this illness since previous evidence suggests the relationship between abnormal ACC function and emotional and cognitive impairments. Kumar et al. noted that patients with residual SZ, whose positive symptoms diminish while negative symptoms persist, had lower GSH levels compared with non-residual patients with SZ, suggesting the former sub-population of SZ may reflect neural damage due to oxidative stress (Kumar et al., 2018). Wang et al. also demonstrated that higher GSH levels in the ACC were related to higher verbal memory (Wang et al., 2019). These studies suggest the contribution of GSH deficit in the ACC to negative and cognitive symptoms of SZ. Although both meta-analyses are consistent, there may be a regional specificity in the group differences of GSH levels because several studies on regions other than the ACC did not find significant differences in GSH levels between these two groups (Kumar et al., 2018; Taylor et al., 2017; Wang et al., 2019). Of note, Wang et al. examined GSH levels in five regions of interest, which demonstrated lower GSH levels in the ACC and thalamus in patients with SZ but no significant differences in the other three regions (Wang et al., 2019). On the other hand, studies of the thalamus and prefrontal cortex showed lower GSH levels in patients with SZ compared to HCs, respectively, while one study reported a higher GSH level in the hippocampus (Kumar et al., 2018; Wood et al., 2009). Therefore, it is unclear due to the limited number of studies whether GSH levels are also decreased in other regions as well as the medial prefrontal cortex and ACC in this illness. Moreover, there are technical difficulties in ¹H-MRS measurement of GSH levels in human subjects. In human ¹H-MRS studies, point-resolved spectroscopy (PRESS) and stimulated echo acquisition (STEAM) are standard methods and widely available. However, a recent review article suggested that measurements of GSH levels with these sequences at 1.5–3 Tesla make it difficult to identify the specific spectrum due to the overlap of resonance spectra with other neurochemicals, the high level of spin coupling, and low concentrations of GSH (Rae and Williams, 2017). Using spin-echo editing methods such as MEGA-PRESS, GSH can be measured more accurately in the human brain (Rae and Williams, 2017). Although seven out of the 10 studies on other regions acquired spectra with MEGA-PRESS or at field strength higher than 3 Tesla, further studies with more accurate methods are needed to examine regional specificity of GSH levels in patients with SZ.

We also found that decreases in GSH and tGSH levels were greater in unmedicated patients than in medicated patients and a higher proportion of medicated patients was associated with smaller group differences in GSH levels between patients with SZ and HCs. These results suggest that antipsychotic treatment may be not the cause of GSH deficit in SZ and rather improve GSH deficits in patients with SZ. Quincozes-Santos et al. showed that risperidone, an atypical antipsychotic, significantly increased GSH levels in astrocyte-like cell while haloperidol, a typical antipsychotic, did not change the GSH levels or these glial functions (Quincozes-Santos et al., 2010). Ivanova et al. demonstrated that atypical antipsychotics produced no effects on the GSH system in patients with SZ, whereas typical antipsychotics decreased GSH levels (Ivanova et al., 2015). On the other hand, An et al. showed that higher body mass index was associated with higher oxidative stress in chronic patients with SZ (An et al., 2018). Atypical antipsychotics often induce obesity, which may in turn alter redox regulation. Thus, further studies are required to assess the effects of both typical and atypical antipsychotics separately on metabolites in the GSH system within this population.

On the other hand, we did not detect any significant differences in GSH levels between patients with FEP and HCs. This result is consistent with a recent meta-analysis which showed no differences in GSH levels and GPx activities between patients with FEP and HCs, whereas total antioxidant status was significantly lower in patients with FEP than in HCs (Fraguas et al., 2018). Therefore, GSH levels may not play crucial roles for oxidative stress at the stage of FEP although patients with FEP may have insufficient antioxidants, leading to higher levels of ROS. However, a recent 7-Tesla ¹H-MRS study by Wang et al. showed decreased GSH levels in the ACC in patients with FEP compared with HCs (Wang et al., 2019), thus further studies may confirm decreased GSH levels even in the early stage of this illness. Moreover, the present null finding may, at least in part, be due to the fact that FEP includes psychotic illnesses other than SZ, which might have different pathophysiologies. In addition, we could not rule out the aforementioned potential influence of antipsychotics since five out of seven studies in the subgroup analysis of FEP included medicated patients. Further longitudinal studies are needed to evaluate oxidative stress parameters including GSH over the clinical course in patients with medication-naïve first-episode SZ.

The meta-regression analyses suggest that higher patients’ age is associated with greater group differences of GSH metabolite concentrations between patients with SZ and HCs. These results suggest that the age-related decrease of GSH levels in patients with SZ is greater than those in HCs or illness progression may be associated with decrease of GSH levels in patients with SZ.

Secondary findings

Accumulating evidence has suggested that abnormalities in GSH metabolism enzymes may also contribute to the pathophysiology of SZ. The present study found that GPx activity was lower in patients with SZ than in HCs. This result is consistent with a previous meta-analysis finding that chronic patients with SZ had decreased GPx activity (Flatow et al., 2013). However, it is uncertain whether GPx activity may be decreased in the early stage of this illness because the meta-analysis by Flatow et al. did not find any significant difference in its activity between patients with FEP and HCs. Almeda et al. demonstrated that, in the early psychosis, patients who had childhood trauma showed smaller hippocampus volume compared with patients who did not have childhood trauma, and that the smaller hippocampus volume was related to higher GPx activity in patients who had childhood trauma (Alameda et al., 2018). They also found higher GPx activity was associated with more severe psychotic symptoms, cognitive impairment, and smaller hippocampus volume in patients with early psychosis who had childhood trauma. Conus et al. noted that, among patients with early psychosis, those who had higher baseline GPx activity were likely to show improvement in positive symptoms during treatment with NAC compared with those who had lower baseline GPx activity (Conus et al., 2018). These findings suggest that higher GPx activity may reflect higher oxidative stress in the early stage of this illness, and that NAC may be beneficial especially in the subpopulation of patients who are likely to be exposed to greater oxidative stress. On the other hand, GPx activity may be downregulated in the chronic stage of SZ and thus NAC may not offset the oxidative stress effectively in this subpopulation of SZ. Indeed, chronic patients with SZ have decreased GPx activity and elevated oxidative stress (Flatow et al., 2013). Since lower GPx activity may lead to poorer ability to reduce peroxides, it may be beneficial to use the medication ‘ebselen’, which has a GPx-like effect in catalyzing the ROS reduction, in combination with NAC (Azad and Tomar, 2014; Cabungcal et al., 2014).

GR, another enzyme composing the redox cycle along with GPx, catalyzes the reduction of GSSG to GSH (Deponte, 2013). Langbein et al. noted that GR activity was positively correlated with the gray matter volume of the left orbitofrontal cortex in HCs, while GR activity was negatively correlated with the gray matter volume of the left inferior frontal cortex in patients with FEP (Langbein et al., 2017). These findings suggest that an intact antioxidant defense system may protect the grey matter in HCs while the system may be disrupted in the ill population. In the present meta-analysis, we found no difference in GR activity between patients with SZ and HCs. However, four out of the seven included studies reported significantly lower GR activity in patients with SZ compared with HCs (Langbein et al., 2017; Miljevic et al., 2010b; Ravikumar et al., 2000; Yao et al., 2006), while one study reported higher GR activity in patients with SZ (Al-Asmari and Khan, 2014). Therefore, hypoactivity of GR in patients with SZ might be confirmed if further research is conducted in a large sample size.

The downregulation of the GSH redox cycle may contribute to oxidative stress and the GSH deficit because lower GPx activity may reflect a poor ability to catalyze the reduction of peroxides utilizing GSH as the reducing reagent while lower GR activity may decrease GSH (Seelig et al., 1984). However, the relationships between GSH levels and GSH enzyme activities remain unclear, given that correlations between GSH levels and GPx activity vary throughout the course of illness (Xin et al., 2016; Yao et al., 2006).

With regard to other secondary outcomes, we could not perform meta-analyses for GCL and GST activities since only a small number of studies examined these outcomes, two and two respectively. As for GCL, several studies showed that GCLC high risk genotypes, which displayed decreased levels of fibroblast GSH, were more common in patients with SZ compared to HCs (Gysin et al., 2007, 2011; Xin et al., 2016). There were, however, no significant differences in either GCLC-like protein content or GCLC mRNA expression between patients with SZ and HCs (Gawryluk et al., 2011; Zhang et al., 2017). One of the included studies showed lower GCL activity in patients with SZ in comparison to HCs, but the sample size of each group was just three (Gysin et al., 2009). The other included GCL study found no difference in GCL activity (Gysin et al., 2007). Thus, it is possible that a specific subgroup of patients with SZ have a genotype of GCL linked to pathology. With regard to GST, a meta-analysis on GST polymorphisms revealed that GSTM1, GSTT1, or GSTP1 polymorphisms were not significantly related to the risk of onset of SZ (Kim et al., 2015). Our study supports these findings since neither of the two included studies found a significant difference in GST activity between the two groups.

Limitations

The present study has several limitations. First, the methods examining metabolites were different amongst the included studies. Postmortem studies, as well as ¹H-MRS studies, measured metabolites from different brain regions; however, all of these results were assessed as part of the central group. Second, most of the studies used blood samples; however, it remains unclear the extent to which the metabolites in the periphery correlate with those in the central nervous system. Third, the present study did not consider confounding factors such as food or smoking although several studies showed their effects on GSH levels (Barbosa et al., 2018; Diken et al., 2001; Zaki et al., 2019). Fourth, the sample sizes of the studies were relatively small. Fifth, we could not perform several subgroup analyses and meta-regression analyses because of the limited number of the studies. Sixth, we could not focus on antipsychotic-naive patients or patients with treatment-resistant SZ due to the small number of included studies. Finally, the present study included only cross-sectional studies or baseline data of longitudinal studies.

Summary and future directions

In summary, our results suggest that GSH deficits and abnormalities in the GSH redox cycle may contribute to the pathophysiology of SZ. Future longitudinal studies with a large sample size and reliable methodology are required to thoroughly examine the entire redox dysregulation, symptom severity, and alteration of brain structure in SZ utilizing multimodal magnetic resonance imaging (MRI). Furthermore, metabolites and enzymes in both peripheral and central GSH systems, and other oxidative stress factors from various sample sources should be examined simultaneously in the same patients with SZ. These future studies may reveal the origin of a GSH deficit and how oxidative stress and a GSH deficit may contribute to abnormality in brain function. Future clinical research should also employ prospective treatment designs to track antipsychotic-naive patients with SZ using various treatment modalities. It is also important to identify the subpopulation of patients with SZ who may be able to respond to antioxidative treatment. Previous studies suggested higher GPx activity of patients in the early stage of SZ may reflect higher oxidative stress and link to the efficacy of NAC (Alameda et al., 2018; Conus et al., 2018). These findings warrant further studies to investigate the possible biomarker of the antioxidant treatment response. Finally, in consideration of lower GPx activity as well as decreased GSH levels in chronic patients with SZ, it may be beneficial to use the medication ‘ebselen’, which has a GPx-like role in catalyzing the ROS reduction, in combination with NAC. These findings warrant further studies to investigate the possible biomarker of the antioxidant treatment response. Finally, in consideration of lower GPx activity as well as decreased GSH levels in chronic patients with SZ, it may be beneficial to use the medication ‘ebselen’, which has a GPx-like effect in catalyzing the ROS reduction, in combination with NAC (Azad and Tomar, 2014; Cabungcal et al., 2014), which may pave the way for the development of novel therapeutic strategies for this disorder.

Supplemental Material

GSH_meta_supplementary_figures_20190320 – Supplemental material for Glutathione levels and activities of glutathione metabolism enzymes in patients with schizophrenia: A systematic review and meta-analysis

Supplemental material, GSH_meta_supplementary_figures_20190320 for Glutathione levels and activities of glutathione metabolism enzymes in patients with schizophrenia: A systematic review and meta-analysis by Sakiko Tsugawa, Yoshihiro Noda, Ryosuke Tarumi, Yu Mimura, Kazunari Yoshida, Yusuke Iwata, Muhammad Elsalhy, Minori Kuromiya, Shin Kurose, Fumi Masuda, Shinji Morita, Kamiyu Ogyu, Eric Plitman, Masataka Wada, Takahiro Miyazaki, Ariel Graff-Guerrero, Masaru Mimura and Shinichiro Nakajima in Journal of Psychopharmacology

Supplemental Material

GSH_meta_supplementary_table_20190320 – Supplemental material for Glutathione levels and activities of glutathione metabolism enzymes in patients with schizophrenia: A systematic review and meta-analysis

Supplemental material, GSH_meta_supplementary_table_20190320 for Glutathione levels and activities of glutathione metabolism enzymes in patients with schizophrenia: A systematic review and meta-analysis by Sakiko Tsugawa, Yoshihiro Noda, Ryosuke Tarumi, Yu Mimura, Kazunari Yoshida, Yusuke Iwata, Muhammad Elsalhy, Minori Kuromiya, Shin Kurose, Fumi Masuda, Shinji Morita, Kamiyu Ogyu, Eric Plitman, Masataka Wada, Takahiro Miyazaki, Ariel Graff-Guerrero, Masaru Mimura and Shinichiro Nakajima in Journal of Psychopharmacology

Footnotes

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: ST, RT, YM, ME, MK, SK, FM, SM, KO, MW, and TM report no biomedical interests. YN has received a Grant-in-Aid for Young Scientists (KAKENHI), a research grant from the Japan Agency for Medical Research and Development (AMED), an investigator-initiated clinical study grant from Teijin Pharma Ltd. He also receives research grants from the Japan Health Foundation, Meiji Yasuda Mental Health Foundation, Mitsui Life Social Welfare Foundation, Takeda Science Foundation, SENSHIN Medical Research Foundation, Health Science Center Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, and Daiichi Sankyo Scholarship Donation Program. He receives equipment-in-kind support for an investigator-initiated study from Magventure Inc. and research supports from Otsuka Pharmaceutical, Shionogi, and Meiji Seika Pharma. KY has received fellowship grants from the Japan Research Foundation for Clinical Pharmacology and manuscript fees from Sumitomo Dainippon Pharma and consultant fees from Bracket within the past three years. YI has received fellowship grants from the Canadian Institute of Health Research (CIHR), Keio University Medical Science Foundation, Mitsukoshi Foundation. EP reports receiving funding from the Vanier Canada Graduate Scholarship, the Ontario Graduate Scholarship, and the Canada Graduate Scholarship – Master’s. YI has also received manuscript fees from Dainippon Sumitomo Pharma. AG has received support from the United States National Institute of Health, CIHR, Ontario Mental Health Foundation, Consejo Nacional de Ciencia y Tecnología, Instituto de Ciencia y Tecnología del DF, Brain & Behavior Research Foundation (formerly NARSAD), Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation Early Research Award, and Janssen. MM has received research support from the Japan Society for the Promotion of Science and grants or speaker’s honoraria from Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, Fuji Film RI Pharma, Janssen Pharmaceutical, Mochida Pharmaceutical, MSD, Nippon Chemipher, Novartis Pharma, Ono Yakuhin, Otsuka Pharmaceutical, Pfizer, Takeda Yakuhin, Tsumura, and Yoshitomi Yakuhin within the past three years. SN has received fellowship grants from CIHR, the Japan Research Foundation for Clinical Pharmacology, Naito Foundation, Takeda Science Foundation, Uehara Memorial Foundation, and Daiichi Sankyo Scholarship Donation Program within the past three years. SN has also received research support, manuscript fees or speaker’s honoraria from Dainippon Sumitomo Pharma, Meiji-Seika Pharma, Otsuka Pharmaceutical, Shionogi, and Yoshitomi Yakuhin within the past three years.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Japan Society for the Promotion of Science and AMED to SN, YN, and MM. The funding agency did not contribute to the study design; the data collection, analyses, and interpretation; the writing of the manuscript; and the decision to submit the manuscript for publication.

Supplemental material

Supplemental material for this article is available online.

ORCID iD

Yoshihiro Noda

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