INTRODUCTION
Schizophrenia is a complex, severe mental disorder which imposes substantial burden on its sufferers. Treatment outcomes in schizophrenia are often sub-optimal; a meta-analysis of more than 50 studies found that only 1 out of 7 individuals with schizophrenia met criteria for clinical, social, and functional recovery at study endpoint.[1] It is now well accepted that this relatively low proportion of treatment success and sub-optimal functioning in schizophrenia can be attributed, in a large part, to persistent neurocognitive deficits.[2] Indeed, cognitive impairment is now considered a hallmark of schizophrenia with impairments in attention, working memory, and executive functions often predating the onset of illness and following a stable course throughout the illness trajectory.[3]
High levels of oxidative stress, caused by an imbalance between endogenous antioxidant systems and production of toxic free radicals, such as reactive oxygen species (ROS), have been implicated in the etiopathogenesis of cognitive dysfunction in schizophrenia. A wide range of environmental insults, starting from maternal stress and immune activation in utero, have been identified as risk factors for oxidative stress or redox imbalance. This imbalance, caused by an accumulation of ROS in glial stem cells, adversely affects their proliferation and maturation leading to myelination deficits in key brain regions such as the prefrontal cortex, disruption in neuronal connectivity, and resultant cognitive deficits.[4] Prenatal stress may also increase the production of pro-inflammatory cytokines which contributes to redox imbalance by inducing ROS expression and peroxisomal dysfunction.[5]
In this context, we carried out the present review with the objective of examining the available evidence linking oxidative stress and cognitive impairment in schizophrenia. Special focus was given to examination of epidemiological links between oxidative stress and cognitive deficits, biomarkers of oxidative stress that may aid identification of cognitive impairment, and intervention studies evaluating the effect of antioxidant therapeutics on symptom domains in schizophrenia.
METHODOLOGY
Search strategy
A literature search of the MEDLINE, ProQuest, Scopus, and Google Scholar databases was undertaken using the search terms "schizophrenia," "oxidative stress," and variations of "cognition," "cognitive function," and "cognitive dysfunction" in September 2022. A total of 744 citations were retrieved using these terms (PubMed: 98, ProQuest: 149, Scopus: 234, and Google Scholar: 263). Additionally, hand searches of the bibliography section of generated articles were performed to identify potentially relevant articles. The search was done by a qualified psychiatrist (RPR).
Study selection and data extraction
Titles generated through the above search were screened using the following inclusion criteria: original English language articles published in a peer-reviewed journal that either compared levels of oxidative stress markers (or antioxidants) between patients with schizophrenia and healthy controls or examined the association between selected markers of oxidative stress and neurocognitive impairment in schizophrenia or evaluated the effect of treatment with antioxidant agents on cognition in this group. We excluded animal/in vitro studies, review articles, and published study protocols which did not provide original data.
After removal of duplicate citations, 249 articles were screened for possible inclusion, of which 213 were excluded after applying the inclusion/exclusion criteria. The remaining 36 papers were selected and included in the current review. The search process is depicted as a flow diagram in Figure 1.
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Figure 1: Flowchart for literature search
Study screening and selection was carried out by two authors (RPR and VM). We neither performed a quality assessment nor computed effect size estimates as this was intended to be a narrative review on the topic. Selected studies are discussed below under the following headings: description of study designs, patient population, cognitive assessments performed, measures of oxidative stress studied, epidemiological findings in oxidative stress markers in schizophrenia, association between markers of oxidative stress and cognitive functioning, and findings from intervention trials with antioxidants.
RESULTS
Description of the included studies
Of the 36 studies included in this review, 30 were observational studies examining the relationship between specific biological markers of oxidative stress and specific domains of cognition in patients with schizophrenia, while 6 were clinical trials of putative antioxidants which also assessed cognition as an outcome measure.
Patient population
Among observational studies (n = 30), half (n = 15) involved patients with chronic illness who had been stable on medication for over 6 months; seven were conducted in patients with first-episode or early psychosis; four included patients who had been hospitalized for an acute episode of chronic schizophrenia; and four involved subgroups of patients with schizophrenia. Among clinical trials (n = 6), four were conducted in stable outpatients with chronic schizophrenia, while two were conducted in patients with early psychosis.
Cognitive assessments
The most frequently used neuropsychological test batteries were the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (n = 9), the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (n = 3), and the Brief Assessment of Cognition in Schizophrenia (BACS) (n = 2); other studies largely used selected tests from these batteries, or combinations of individual tests to assess specific cognitive domains. A single study did not use any standardized assessment of cognition, instead using a "cognitive score" derived from the sum of items P2, N5, and G11 of the clinician-rated Positive and Negative Syndrome Scale (PANSS) for schizophrenia.[6]
Measures of oxidative stress
There was significant variation in the markers of oxidative stress examined across studies. Some studies measured markers of oxidative damage, while others estimated the levels of enzymes or proteins that act as antioxidants. These markers, their standard abbreviations, and their putative biological functions vis-à-vis oxidative stress are summarized in Table 1. The most frequently estimated parameters were superoxide dismutase (SOD) activity (n = 7), glutathione (GSH) (n = 6), total antioxidant status (TAS) (n = 5), malondialdehyde (MDA) (n = 5), GSH peroxidase (GPx) (n = 4), manganese SOD (MnSOD) activity (n = 4), thiobarbituric acid reactive substances (TBARS, a measure of lipid peroxidation) (n = 3), catalase (n = 3), and thioredoxin (n = 3). Blood and blood-derived products such as serum, plasma, lymphocytes, or red cell hemolysate were the most commonly assessed biological substance; two studies used estimates of regional brain GSH through magnetic resonance spectroscopy,[7,8] and a single study estimated the cerebrospinal fluid (CSF) level of SOD-1 activity.[9]
Table 1: Biological markers of oxidative stress, standard abbreviations, and their significance with respect to oxidative stress
Epidemiological findings in markers of oxidative stress in schizophrenia
A total of 28 studies[6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33] have compared levels of oxidative stress markers between patients with schizophrenia and healthy controls. The characteristics of these studies are summarized in Table 2. All of them, except one,[8] were published in the last 10 years. The sample size of these studies ranged from 36 to 1489. Study designs were mostly cross-sectional (n = 25) but also included cohort (n = 2) and case–control studies (n = 1). Biomarkers studied included total plasma antioxidant status, serum thioredoxin (TRX), serum bilirubin, antioxidant compounds such as SOD, GSH, GPx, chemokines, and oxidative stress markers such as MDA and TBARS.
Table 2: Characteristics of included studies
In general, levels of pro-oxidant compounds such as nitric oxide (NO) and MDA were increased and levels of antioxidants such as serum bilirubin, GSH, GPx, as well as SOD (and its different mammalian forms such as MnSOD and copper/zinc-containing SOD [CuZnSOD]) were found to be lower among patients with schizophrenia compared to healthy controls. Three studies[8,12,31] failed to find significant differences between patients and controls while three other studies[23,25,28] noted findings in the opposite direction. Of the latter, two studies noted that patients exhibited increased activity of SOD[28] and CuZnSOD[25] relative to controls while a third study[23] found that serum cysteine levels were significantly higher among patients.
One study that analyzed sex differences in levels of serum bilirubin found sex-specific differences in association between serum bilirubin levels and cognitive impairment: while serum bilirubin was significantly lower among male patients with schizophrenia and cognitive impairment, among female patients, serum bilirubin tended to be higher in the cognitive impairment group though this difference was not statistically significant.[15] Five studies have examined levels of oxidative stress markers between clinically defined subgroups of patients with schizophrenia.[11,17,18,25,26] Two studies[17,18] compared markers between schizophrenia patients with and without deficit syndrome; authors found that those with deficit syndrome displayed evidence of increased nitrosylation and lowered natural IgM to oxidative-specific epitopes (OSEs). Likewise, two studies that compared schizophrenia patients with and without tardive dyskinesia (TD) found that those with TD had lower levels of SOD activity and TAS but higher MDA levels than those without TD.[25,26] One study found evidence for a gradient in serum TRX levels with the highest levels being seen in acute psychotic states followed by remitted patients and, finally, healthy controls.[11]
Association between markers of oxidative stress and cognitive functioning
Of the 36 papers included in this review, thirty papers examined the association between putative markers of oxidative stress or antioxidant activity and functioning in one or more cognitive domains. These studies are summarized in Table 2 and described below.
Studies in early and first-episode psychosis
A relatively small number of studies (n = 7) have examined the association between markers of oxidative stress and cognitive functioning in this patient population.[9,19,20,22,27,28,34] These may be further subdivided into studies of early psychosis in which patients have not yet met standard criteria for a psychotic disorder (n = 2), studies of first-episode psychosis which included both affective and nonaffective psychoses (n = 2), and studies in patients with a specific diagnosis of first-episode schizophrenia as per standard criteria (n = 3). In patients with early psychosis, Alameda et al.[34] identified an association between low GPx and better cognitive performance across multiple domains, particularly in those exposed to childhood trauma. They explained this finding on the basis of earlier literature suggesting an association between high GPx and lower brain GSH, indicative of increased oxidative stress. Thus, patients who were experiencing lower redox dysregulation, as evidenced by low GPx, had better cognitive functioning as would be expected on theoretical grounds. Consistent with this hypothesis, Coughlin et al.[9] found that CSF levels of SOD-1, an antioxidant enzyme that reduces free radical levels, were associated with better overall cognitive performance in patients with early psychosis, but not in controls.
Three studies examined patients with first-episode syndromal psychosis.[19,20,22] In the first, which was a longitudinal study involving a larger sample of patients with an age of onset of <18 years (n = 80, 62.5% schizophrenia and related disorders), baseline TAS was associated with better global cognitive scores as well as scores for memory and attention, both at baseline and after 2 years of treatment. In the second, involving 28 patients (53.6% with schizophrenia spectrum disorders), levels of plasma GSH were associated with better scores on tests of executive functioning. In the third, oxidized GSH and NO were negatively correlated with global cognition. These results are consistent with those of studies in early psychosis and suggest an association between higher antioxidant status and improved cognition in the earliest phases of psychosis and, conversely, between higher oxidative stress and impaired cognition.
In studies of patients with a specific diagnosis of first-episode schizophrenia, Xie et al.[27] found a positive association between TAS and global cognitive scores, as well as scores on domains related to learning, memory, and problem-solving, which remained significant even after correction for confounders such as age, education, and duration of illness. In contrast, Xiu et al.[28] found a marginally positive association between CuZnSOD levels and scores on tests of attention, construction, and global cognition but a negative association between MnSOD levels and scores on tests of attention and global cognition. Overall, the picture that emerges from studies of early and first-episode psychosis is of a significant positive association between antioxidant activity – indicative of reduced oxidative stress – and various cognitive domains, though the discrepant finding related to the MnSOD enzyme requires further exploration.
Studies in patients with an acute episode or exacerbation of schizophrenia
Three studies examined the relationship between markers of oxidative stress and cognition in medicated patients who were hospitalized for an acute episode of schizophrenia.[6,11,29,30] One of them[30] found a negative correlation between MnSOD and both global cognition and attention, which is similar to the findings of Xiu et al.[28] in first-episode schizophrenia; they also observed that this finding was significant only in those with a specific allele (Ala) of the MnSOD gene. Zhang et al.[6] studied several oxidative markers and found a negative association between catalase (CAT) and cognition; however, this study did not use any formal cognitive tests and relied on a "cognitive score" obtained from items of the PANSS. Both these studies suggest an inverse relationship between antioxidant enzyme activity and cognition in acute exacerbations of chronic schizophrenia, which is in contrast to the findings observed in early psychosis. In contrast, Bas et al.[11] examined the relationship between levels of TRX, a protein protecting against oxidative stress, and cognitive test scores both during an acute episode and after 16 weeks of treatment with an atypical antipsychotic. While TRX was not correlated with any test score at baseline, there was a significant positive correlation between TRX and scores on the Trail Making Test-A (TMT-A) at follow-up.
In contrast, Yin et al.[29] studied the association between the putative antioxidant total bilirubin (TBIL) and cognitive performance in acutely ill patients with schizophrenia who had been off medications for at least 2 weeks, and observed a positive correlation between TBIL and the immediate memory score of the RBANS, even after correction for confounders. Taken together, these results suggest that there may not be a consistent relationship between oxidative stress markers and cognitive performance during an acute psychotic episode in patients on medication. Such a relationship may exist in acutely ill unmedicated patients, or after remission from an episode, but these findings require replication.
Studies in patients with chronic schizophrenia
A relatively larger number of studies have examined the relationship between peripheral oxidative stress markers and cognition in medicated patients with schizophrenia of 2 or more years' duration.[7,8,10,12,13,14,15,17,18,21,23,24,31,33,35] Notable positive findings in these studies include a negative correlation between protein carbonyl content and working memory scores;[10] a negative correlation between quinolinic acid and global cognition;[12] a positive correlation between GSH and global, executive function, and visuospatial memory scores;[7] a negative correlation between TBARS and digit span test scores;[13] a positive correlation between neurotrophin-4 and performance on the Wisconsin Card Sorting Test (WCST) and Trail Making Test-A (TMT-A);[14] a positive correlation between cysteine and BACS global, attention, memory, fluency, and executive function scores;[23] a negative correlation between CAT and WCST scores;[24] a negative association between TAS and RBANS total and attention scores;[33] and a negative correlation between TRX and the RBANS attention score.[31] In contrast, Nucifora et al.[21] found no association between GSH and global cognitive performance. Two of these studies[13,14] also assessed the relationship between oxidative stress markers and performance on tests of social cognition, but results were negative for this domain in both cases. These results are broadly consistent with a negative relationship between oxidative stress and cognition, and with a protective effect of endogenous antioxidants. These effects may be influenced by confounding factors such as age, sex, and duration of illness; for example, He et al.[15] observed a positive relationship between TBIL and cognitive test scores only in male patients.
Two studies[17,18] examined the relationship between IgM antibodies directed against ROS; one of these studies found an association between IgM against MDA and performance on the Word List Recall test, while the second found no association between IgM antibody levels and scores for any domain of cognition.
Fisher and Drago[35] examined the relationship between genetic polymorphisms related to oxidative stress pathways and cognition in patients with chronic schizophrenia and observed a significant relationship between genes involved in GSH synthesis, recycling, and conjugation and performance on tests of verbal and working memory. Two studies[7,8] examined the levels of brain GSH in chronic schizophrenia in relation to cognition. While Matsuzawa et al.[8] observed a negative correlation between GSH and TMT-A scores, Coughlin et al.[7] noted a positive association between GSH and both global and ideational fluency scores in patients. The reason for these discrepant findings is uncertain, and it is not clear to what extent brain GSH is correlated with oxidative stress.
Studies in special populations
Two studies[25,26] examined the relationship between oxidative stress and cognition in patients with schizophrenia with and without TD. This subgroup was studied because of the putative relationship between oxidative stress-induced damage to the basal ganglia and TD.[42] In the first of these studies, a negative association was observed between MnSOD and RBANS total and attention scores regardless of TD status, which is consistent with other studies of MnSOD in schizophrenia.[28,30] In the second, CuZnSOD was negatively correlated with attention score in the entire sample but was also specifically and negatively correlated with RBANS total and immediate memory scores in patients with TD. Although these findings require replication, they suggest that further investigation of the links between oxidative stress and cognition in TD may be of value.
In view of evidence for gender differences in oxidative stress,[43] Zhang et al.[32] examined the relationship between MnSOD and RBANS scores in male patients with chronic schizophrenia and observed a negative correlation between MnSOD and RBANS total scores. This finding suggests that the association between MnSOD and lower cognitive performance may be independent of gender.
Finally, Huo et al.[16] examined the relationship between SOD and cognitive functioning in elderly (age >60 years) patients with schizophrenia and found a negative correlation between SOD and RBANS total and language scores even after correcting for confounders. This finding raises the possibility that the relationship between peripheral oxidative stress markers and cognition in schizophrenia is influenced by age.
Intervention trials evaluating the effect of antioxidant agents on cognitive functioning
Six intervention trials have evaluated the clinical efficacy of antioxidants on neurocognition and clinical symptoms in schizophrenia. Three of them used a randomized, placebo-controlled design while three were single-group, open-label trials. Three trials evaluated the effects of NAC (N-acetyl cysteine)[36,38,39] and one each evaluated the effects of red yeast rice,[37] α-lipoic acid,[40] and sulforaphane-rich broccoli sprout extract.[41] Two trials of NAC[38,39] found significant positive effects on working memory and information processing speed while the third trial[36] found that it failed to improve cognitive scores but improved clinical symptoms. All the three open-label trials[37,40,41] found evidence for statistically significant improvement in neurocognitive parameters such as visual recognition learning, complex attention, and executive functions.
DISCUSSION
The most commonly studied patient population in both observational studies and interventional trials were chronic, clinically stable patients with schizophrenia; the next most common subgroup examined were patients with first-episode schizophrenia or early psychosis. The present review found significant methodological variability across studies in terms of patient population, cognitive parameters assessed, and markers of oxidative stress or antioxidant activity. This marked heterogeneity in biomarkers, cognitive measures, and sampling methods, as well as in patient subgroups studied, limits the comparisons that can be made between individual studies as well as the confidence with which conclusions can be drawn regarding the utility of specific biomarkers in this context.
Results from most studies that compared levels of oxidative stress markers in schizophrenia supported the notion of increased oxidative stress and disrupted redox balance in schizophrenia. The brain tissue is particularly vulnerable to this imbalance due to its high oxygen consumption, high levels of polyunsaturated fatty acids (and consequent susceptibility to lipid peroxidation), and concurrent modest endogenous antioxidant defenses.[44] Although pathways involved in oxidative stress, such as GSH metabolism, have been shown to modulate cognitive deficits in animal models,[45,46] their exact role in contributing to the onset and progression of schizophrenia remains unclear. A better understanding of the mechanisms involved in the links between oxidative stress and pathophysiology of schizophrenia would enable designing appropriate antioxidant therapies that may help treat and prevent schizophrenia.
Interestingly, few studies[23,25,28] showed discordant findings including increased levels of antioxidant enzymes such as SOD in patients with schizophrenia compared to healthy controls. No clear patterns could be made out in these studies which spanned patient age groups and clinical subtypes of schizophrenia. However, this raises the possibility that oxidative stress is not an across-the-board phenomenon in schizophrenia; instead, the patterns may differ between patients. Analogies can be drawn here with findings from studies on inflammation in schizophrenia[47] and major depression.[48] If this is indeed true, then it opens up new opportunities for research into identifying molecular signatures of oxidative stress among different patient populations with schizophrenia; this, in turn, may assist and inform the personalization of treatment with antioxidant agents. Notably, studies in the present review showed differences in nature and levels of markers between schizophrenia patients with and without tardive dyskinesia[25,26] and between patients with and without deficit schizophrenia.[17]
When considering the relationship between measures of oxidative stress and scores on tests of cognition, either global or confined to a particular domain, it is important to be aware of the methodological limitations discussed earlier. Despite this, there is significant evidence for an inverse relationship between measures of oxidative stress and both global and domain-specific cognitive performance; patients with higher peripheral antioxidant levels performed better on these tests, while those with lower levels of antioxidants or higher levels of redox dysregulation markers performed worse.[9,19,22] These consistent findings suggest that there may be a "window of opportunity" for intervention in patients with prodromal or early schizophrenia in which the links between redox dysregulation, inflammation, and cognition are clearer.[49]
While similar relationships have been observed in both the acute and stable phases of chronic schizophrenia,[7,10,23] findings in this regard are less consistent and may reflect the confounding effects of chronicity, comorbidity, and antipsychotic medications. Some studies in these populations have reported null or even paradoxical negative associations between antioxidant status and cognition.[21,33] These findings may reflect a later stage of the illness where changes in neural structure and function are less amenable to modification and may no longer correlate meaningfully with peripheral markers of oxidative stress.[50] Long-term longitudinal studies, tracing the relationship between the different markers of oxidative stress and cognition at different stages in the progression of schizophrenia, may be required to provide definitive answers to unresolved questions in this area, and to provide a clearer picture of the relative importance of oxidative stress as a determinant of cognition at each stage. It is also notable that in the few studies examining this domain, no significant relationship was observed between oxidative stress and social cognition, suggesting that this aspect of cognitive function may not be directly related to redox dysregulation.[13,14]
The present review has certain limitations, not all of which were in our control. Many of the included studies had modest sample sizes limiting the study power to detect small effects. The cross-sectional designs used in most studies preclude any causal inferences from being drawn with regard to the observed association. Strengths of the review are the well-characterized populations in the studies reviewed and reviewing association data between a range of oxidative stress biomarkers and cognitive measures.
To conclude, patients with schizophrenia demonstrate increased levels of oxidative stress compared to general population. There appears to be a significant positive association between antioxidant activity and cognitive measures in schizophrenia though this relationship is less consistent among those who are acutely ill and on medications. Limited data exist on possible confounders in this relationship such as age, sex, and duration of illness. Preliminary findings indicate that antioxidant compounds may beneficially impact cognitive functioning and clinical presentation in schizophrenia. A better understanding of the signaling pathways mediating the relationship between oxidative stress and cognitive dysfunction in schizophrenia may potentially uncover new targets for pharmacologic manipulation to limit the cognitive symptomatology of this disabling illness.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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