The importance of oxidative biomarkers in diagnosis, treatment, and monitoring schizophrenia patients.

INTRODUCTION: The etiology of schizophrenia (SCZ), an incredibly complex disorder, remains multifaceted. Literature suggests the involvement of oxidative stress (OS) in the pathophysiology of SCZ. OBJECTIVES: Determination of selected OS markers and brain-derived neurotrophic factor (BDNF) in patients with chronic SCZ and those in states predisposing to SCZ-first episode psychosis (FP) and ultra-high risk (UHR). MATERIALS AND METHODS: Determination of OS markers and BDNF levels by spectrophotometric methods and ELISA in 150 individuals (116 patients diagnosed with SCZ or in a predisposed state, divided into four subgroups according to the type of disorder: deficit schizophrenia, non-deficit schizophrenia, FP, UHR). The control group included 34 healthy volunteers. RESULTS: Lower activities of analyzed antioxidant enzymes and GSH and TAC concentrations were found in all individuals in the study group compared to controls (p < 0.001). BDNF concentration was also lower in all groups compared to controls except in the UHR subgroup (p = 0.01). Correlations were observed between BDNF, R-GSSG, GST, GPx activity, and disease duration (p < 0.02). A small effect of smoking on selected OS markers was also noted (rho<0.06, p < 0.03). CONCLUSIONS: OS may play an important role in the pathophysiology of SCZ before developing the complete clinical pattern of the disorder. The redox imbalance manifests itself with such severity in individuals with SCZ and in a state predisposing to the development of this psychiatric disease that natural antioxidant systems become insufficient to compensate against it completely. The discussed OS biomarkers may support the SCZ diagnosis and predict its progression.

Impulsivity and inhibitory control in deficit and non-deficit schizophrenia.

BACKGROUND: There is conflicting evidence on impulsivity and its potential relationship with inhibitory control in schizophrenia. This study therefore aimed to identify differences in impulsivity and cognitive and motor inhibition between patients with deficit (DS) and non-deficit (NDS) schizophrenia and healthy controls (HC). We also explored the relationships between impulsivity and different dimensions of inhibitory control in all studied groups. METHODS: The sample comprised 28 DS patients, 45 NDS patients, and 39 age-matched HC. A neuropsychological battery was used. RESULTS: DS patients scored lower in venturesomeness, while those with NDS scored higher in impulsiveness compared to HC. In addition, both groups of patients scored higher on measures of cognitive and motor inhibition, including those relatively independent of information processing speed (although the results were slightly different after adjusting for IQ and/or years of education). Correlations between impulsivity and cognitive inhibition emerged in DS patients, while links between impulsivity and motor inhibition were observed in HC. CONCLUSIONS: Our results suggest the presence of deficits in experimentally assessed inhibitory control in schizophrenia patients, with predominant impulsivity in the NDS population. In addition, impulsivity may affect the cognitive control of inhibition in deficit schizophrenia. Nevertheless, due to the preliminary nature of these findings, they require further empirical verification in future research.

Greater methylation of the IL-6 promoter region is associated with decreased integrity of the corpus callosum in schizophrenia.

BACKGROUND: Schizophrenia is associated with chronic subclinical inflammation and decreased integrity of the corpus callosum (CC). Our previous study showed associations between peripheral IL-6 levels and the integrity of the CC. Epigenetic studies show associations between methylation of the genes related to immunological processes and integrity of the CC. AIM: To investigate correlations between methylation status of IL-6 promotor and peripheral IL-6 levels and the integrity of the CC in schizophrenia. MATERIAL AND METHODS: The participants were 29 chronic schizophrenia patients (SCH) and 29 controls. Decreased integrity of the CC was understood as increased mean diffusivity (MD) and/or decreased fractional anisotropy (FA) in diffusion tensor imaging. Peripheral IL-6 concentrations were measured in serum samples and IL-6 promoter methylation status of 6 CpG sites was analyzed in peripheral leukocytes by pyrosequencing. RESULTS: Moderate positive correlations were found between CpG1 methylation and the MD of proximal regions of the CC (CCR1-CCR3) and between CpGmean and MD of CCR1 in SCH. Weaker positive correlations were found for CpGmean with CCR2 and CCR3 and negative correlations were found for CpG1 and FA of CCR3 in SCH. Multivariate regression showed that methylation of CpG1, type of antipsychotic treatment, and their interaction were significant independent predictors of MD of CCR1 in SCH. Methylation of CpG2 was negatively correlated with serum IL-6 in SCH. CONCLUSIONS: The methylation level of the IL-6 promotor region in peripheral leukocytes is associated with the integrity of the CC in schizophrenia and this association may depend on the type of antipsychotic treatment. Further studies are necessary to explain the mechanisms of the observed associations.

Cognitive Dysfunctions Measured with the MCCB in Deficit and Non-Deficit Schizophrenia.

This study compared cognitive domains between deficit schizophrenia (DS) and non-deficit schizophrenia (NDS) patients and healthy controls (HC), analyzing relationships between psychopathological dimensions and cognitive domains. A total of 29 DS patients, 45 NDS patients, and 39 HC subjects participated. Cognitive domains were measured using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Battery. Psychopathological symptoms were evaluated with the Positive and Negative Syndrome Scale. Clinical groups performed poorer than HC groups in regards to speed of processing, attention/vigilance, working memory, verbal and visual learning and memory, reasoning and problem solving, and social cognition. DS patients scored poorer than NDS patients in terms of all cognitive domains and the overall score, except for reasoning and problem solving. Positive, negative, disorganization, and resistance symptoms were related to cognitive functions only in NDS patients. Our findings suggest that the MCCB battery is sensitive to detecting cognitive dysfunctions in both deficit and non-deficit schizophrenia.

Executive Functions and Psychopathology Dimensions in Deficit and Non-Deficit Schizophrenia.

This study: (a) compared executive functions between deficit (DS) and non-deficit schizophrenia (NDS) patients and healthy controls (HC), controlling premorbid IQ and level of education; (b) compared executive functions in DS and NDS patients, controlling premorbid IQ and psychopathological symptoms; and (c) estimated relationships between clinical factors, psychopathological symptoms, and executive functions using structural equation modelling. Participants were 29 DS patients, 44 NDS patients, and 39 HC. Executive functions were measured with the Mazes Subtest, Spatial Span Subtest, Letter Number Span Test, Color Trail Test, and Berg Card Sorting Test. Psychopathological symptoms were evaluated with the Positive and Negative Syndrome Scale, Brief Negative Symptom Scale, and Self-evaluation of Negative Symptoms. Compared to HC, both clinical groups performed poorer on cognitive flexibility, DS patients on verbal working memory, and NDS patients on planning. DS and NDS patients did not differ in executive functions, except planning, after controlling premorbid IQ and negative psychopathological symptoms. In DS patients, exacerbation had an effect on verbal working memory and cognitive planning; in NDS patients, positive symptoms had an effect on cognitive flexibility. Both DS and NDS patients presented deficits, affecting the former to a greater extent. Nonetheless, clinical variables appeared to significantly affect these deficits.

Complement Activation Products in Patients with Chronic Schizophrenia.

Evidence suggests a role of the immune system in the pathogenesis of a number of mental conditions, including schizophrenia (SCH). In terms of physiology, aside from its crucial protective function, the complement cascade (CC) is a critical element of the regeneration processes, including neurogenesis. Few studies have attempted to define the function of the CC components in SCH. To shed more light on this topic, we compared the levels of complement activation products (CAP) (C3a, C5a and C5b-9) in the peripheral blood of 62 patients with chronic SCH and disease duration of ≥ 10 years with 25 healthy controls matched for age, sex, BMI and smoking status. Concentrations of all the investigated CAP were elevated in SCH patients. However, after controlling for potential confounding factors, significant correlations were observed between SCH and C3a (M = 724.98 ng/mL) and C5a (M = 6.06 ng/mL) levels. In addition, multivariate logistic regression showed that C3a and C5b-9 were significant predictors of SCH. There were no significant correlations between any CAP and SCH symptom severity or general psychopathology in SCH patients. However, two significant links emerged between C3a and C5b-9 and global functioning. Increased levels of both complement activation products in the patient group as compared to healthy controls raise questions concerning the role of the CC in the etiology of SCH and further demonstrate dysregulation of the immune system in SCH patients.

Serum Inflammatory Markers and Integrity of the Superior Longitudinal Fasciculus and the Inferior Longitudinal Fasciculus in Schizophrenia, from Prodromal Stages to Chronic Psychosis-A Cross-Sectional Study.

Chronic subclinical inflammation is believed to be an important factor in the pathogenesis of schizophrenia. Meta-analyses confirm the presence of increased levels of peripheral inflammatory markers (IM) in schizophrenia and its prodromal stages. Peripheral cytokines may affect the brain microstructure through chronic activation of microglia. Disruptions in the integrity of the superior longitudinal fasciculus (SLF) and inferior longitudinal fasciculus (ILF) are commonly seen in patients with schizophrenia spectrum disorders. We therefore attempted to verify in a cross-sectional study whether there is a correlation between levels of peripheral IM and the integrity of these brain regions in healthy controls, from prodromal states and first episode psychosis to long-term schizophrenia. The integrity of white matter was measured using diffusion tensor imaging. Despite a broad analysis of six IM (CRP, IL-6, IL-8, IL-10, TNF-α, and IFN-γ), we did not find any correlations with the integrity of the SLF or ILF in any of the analyzed groups (after correction for multiple comparisons). In conclusion, our study does not support the existence of a link between disrupted levels of peripheral IM and reduced integrity of ILF and SLF in schizophrenia spectrum disorders. However, prospective studies are needed to verify this over a long period of time.

Serum Inflammatory Markers and Their Associations with the Integrity of the Cingulum Bundle in Schizophrenia, from Prodromal Stages to Chronic Psychosis.

Peripheral cytokines may affect the brain through chronic activation of microglia and, as a result, can potentially lead to decreased integrity of white matter of cingulum bundle (CB). Therefore, the aim of the study was to analyze the relationships between peripheral inflammatory markers and the integrity of the CB in various states: from healthy controls, through prodromal states and first-episode psychosis, to long-term schizophrenia. The integrity of the CB was measured using diffusion tensor imaging. We analyzed six parameters: CRP, IL-6, IL-8, IL-10, TNF-α, and IFN-γ. We found that levels of IL-6 and IFN-γ differed significantly between groups. Initial analysis showed some correlations between the inflammatory markers and CB integrity, in particular a correlation with IL-6 that was present in several groups. However, none of the analyzed parameters were associated with the integrity of the CB after correction for multiple comparisons. Conclusions: Our results supported our hypothesis that there are increased levels of inflammatory markers in psychotic disorders, but did not allow to confirm our hypothesis that there is a link between increased peripheral inflammatory markers and decreased integrity of the CB. However, we found some interesting trend levels that need to be verified in larger studies.

Psychopathology and Stem Cell Mobilization in Ultra-High Risk of Psychosis and First-Episode Psychosis Patients.

Although regenerative and inflammatory processes are involved in the etiopathogenesis of many psychiatric disorders, their roles are poorly understood. We investigate the potential role of stem cells (SC) and factors influencing the trafficking thereof, such as complement cascade (CC) components, phospholipid substrates, and chemokines, in the etiology of schizophrenia. We measured sphingosine-1-phosphate (S1P), stromal-derived factor 1 (SDF-1), and CC cleavage fragments (C3a, C5a, and C5b-C9; also known as the membrane attack complex) in the peripheral blood of 49 unrelated patients: 9 patients with ultra-high risk of psychosis (UHR), 22 patients with first-episode psychosis (FEP), and 18 healthy controls (HC). When compared with the HC group, the UHR and FEP groups had higher levels of C3a. We found no significant differences in hematopoietic SC, very small embryonic-like stem cell (VSEL), C5a, S1P, or SDF-1 levels in the UHR and FEP groups. However, among FEP patients, there was a significant positive correlation between VSELs (CD133+) and negative symptoms. These preliminary findings support the role of the immune system and regenerative processes in the etiology of schizophrenia. To establish the relevance of SC and other factors affecting the trafficking thereof as potential biomarkers of schizophrenia, more studies on larger groups of individuals from across the disease spectrum are needed.

The Relationship between Cognitive Functions and Psychopathological Symptoms in First Episode Psychosis and Chronic Schizophrenia.

Impairments in cognitive functions are one of the main features of schizophrenia. A variety of factors can influence the extent of cognitive deficits. In our study, we examined the severity of cognitive deficits at different stages of the disease and the relationship between psychopathological symptoms and cognitive functions. We recruited 32 patients with first-episode psychosis (FEP), 70 with chronic schizophrenia (CS), and 39 healthy controls (HC). Psychopathological symptoms were evaluated with the Positive and Negative Syndrome Scale (PANSS) and cognitive functions were measured with the MATRICS Cognitive Consensus Battery (MCCB). Cognitive deficits were present in both FEP and CS participants. CS individuals had lower overall scores and poorer working memory; however, clinical variables appeared to play a significant role in these scores. In FEP, disorganization correlated negatively with verbal and visual learning and memory, social cognition, and overall score; negative symptoms negatively correlated with social cognition. In CS participants, disorganization correlated negatively with speed of processing, reasoning, problem solving, and overall score; negative symptoms were negatively correlated with speed of processing, visual learning, memory, and overall score; positive symptoms were negatively correlated with reasoning and problem solving. Our findings indicate that psychopathological symptoms have a significant impact on cognitive functions in FEP and CS patients.

Relationship between White Matter Alterations and Pathophysiological Symptoms in Patients with Ultra-High Risk of Psychosis, First-Episode, and Chronic Schizophrenia.

Some symptoms of schizophrenia might be present before full-blown psychosis, so white matter changes must be studied both in individuals with emerging psychosis and chronic schizophrenia. A total of 86 patients­12 ultra-high risk of psychosis (UHR), 20 first episode psychosis (FEP), 54 chronic schizophrenia (CS), and 33 healthy controls (HC)­underwent psychiatric examination and diffusion tensor imaging (DTI) in a 3-Tesla MRI scanner. We assessed fractional anisotropy (FA) and mean diffusivity (MD) of the superior longitudinal fasciculus (SLF) and inferior longitudinal fasciculus (ILS). We found that CS patients had lower FA than FEP patients (p = 0.025) and HC (p = 0.088), and higher MD than HC (p = 0.037) in the right SLF. In the CS group, we found positive correlations of MD in both right ILF (rho = 0.39, p < 0.05) and SLF (rho = 0.43, p < 0.01) with disorganization symptoms, as well as negative correlation of FA in the right ILF with disorganization symptoms (rho = −0.43, p < 0.05). Among UHR individuals, we found significant negative correlations between MD in the left ILF and negative (r = −0.74, p < 0.05) and general symptoms (r = −0.77, p < 0.05). However promising, these findings should be treated as preliminary, and further research must verify whether they can be treated as potential biomarkers of psychosis.

Psychopathology and Integrity of the Superior Longitudinal Fasciculus in Deficit and Nondeficit Schizophrenia.

The superior longitudinal fasciculus (SLF) is a white matter bundle that connects the frontal areas with the parietal areas. As part of the visuospatial attentional network, it may be involved in the development of schizophrenia. Deficit syndrome (DS) is characterized by primary and enduring negative symptoms. The present study assessed SLF integrity in DS and nondeficit schizophrenia (NDS) patients and examined possible relationships between it and psychopathology. Twenty-six DS patients, 42 NDS patients, and 36 healthy controls (HC) underwent psychiatric evaluation and diffusion tensor imaging (DTI). After post-processing, fractional anisotropy (FA) values within the SLF were analyzed. Psychopathology was assessed with the Positive and Negative Syndrome Scale, Brief Negative Symptom Scale, and Self-evaluation of Negative Symptoms. The PANSS proxy for the deficit syndrome was used to diagnose DS. NDS patients had lower FA values than HC. DS patients had greater negative symptoms than NDS patients. After differentiating clinical groups and HC, we found no significant correlations between DTI measures and psychopathological dimensions. These results suggest that changes in SLF integrity are related to schizophrenia, and frontoparietal dysconnection plays a role in its etiopathogenesis. We confirmed that DS patients have greater negative psychopathology than NDS patients. These results are preliminary; further studies are needed.

Serum inflammatory markers and their associations with white matter integrity of the corpus callosum in schizophrenia patients and healthy controls.

Schizophrenia is associated with disrupted integrity of white matter microstructure of a variety of brain regions, especially the corpus callosum (CC). Chronic subclinical inflammation is considered to be one of the factors involved in the pathogenesis of this disease, and increased levels of peripheral inflammatory markers are often observed in schizophrenia patients. Therefore, we decided to investigate whether the integrity of the corpus callosum is correlated with levels of these markers. A total of 50 patients with stable chronic schizophrenia (SCH) and 30 controls (CON) were enrolled in the study. All participants underwent psychiatric evaluation, neuroimaging, and blood sampling including the measurement of serum concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL - 10), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and C-reactive protein (CRP). Additional potentially related factors, such as age, gender, BMI, smoking, disease duration, and treatment were included in the analysis. Significantly higher IL-6 and IFN-γ levels were observed in SCH compared to CON. In SCH, IFN-γ was positively correlated with mean diffusivity of region 2 of the CC. In CON, IL-6 was inversely correlated with fractional anisotropy of region 1 of the CC. These results support the potential influence of peripheral inflammatory markers on the integrity of the CC in schizophrenia, but require verification in longitudinal studies.

Neurocognition and Social Cognition- Possibilities for Diagnosis and Treatment in Ultra-High Risk for Psychosis State.

In recent decades, clinicians have developed the construct of ultra-high risk (UHR) for psychosis to characterize the prodromal phase of psychosis or classify people with weakly expressed psychotic symptoms. In this conceptual analysis, we have gathered up-to-date data about the clinical picture of neurocognition and social cognition in people at UHR for psychosis. We also discuss treatment options. A well-chosen therapeutic approach can help to deal with difficulties and delay or even prevent the development of full-blown psychotic disorders in the UHR group. Despite much evidence supporting the benefits of therapy, early interventions are still not as widely used as they should be. Thus, a better understanding of the UHR state is very important for all healthcare workers.

The Impact of Adverse Childhood Experiences on Coping Strategies in Schizophrenia Spectrum Disorders: A Case-Control Study.

PURPOSE: Several studies have shown that individuals with schizophrenia-spectrum disorders (SSD) employ ineffective coping styles. However, it remains unknown whether a history of adverse childhood experiences (AC Es), associated with a risk of SSD, contributes to these observations. Therefore, in this study, we aimed to investigate whether exposure to ACEs is associated with coping styles in subjects with SSD. PATIENTS AND METHODS: We recruited 127 inpatients with SSD and 56 healthy controls. Coping styles and ACEs were recorded using self-reports. RESULTS: Individuals with SSD had significantly higher use of using avoidance coping. A history of parental antipathy, physical and sexual abuse was significantly more frequent in subjects with SSD compared to controls. Subjects with SSD had significantly higher multiplicity and severity of ACEs. Individuals with SSD and a history of parental loss had significantly higher use of avoidance coping compared to controls with and without a history of parental loss. Other characteristics of ACEs (age at first exposure, severity and multiplicity) were not associated with using specific coping strategies. CONCLUSION: These findings imply that higher use of using avoidance coping by individuals with SSD might be related to a history of parental loss.

Disturbances in White Matter Integrity in the Ultra-High-Risk Psychosis State-A Systematic Review.

Schizophrenia is a severe and disabling mental illness whose etiology still remains unclear. The available literature indicates that there exist white matter (WM) abnormalities in people with schizophrenia spectrum disorders. Recent developments in modern neuroimaging methods have enabled the identification of the structure, morphology, and function of the underlying WM fibers in vivo. The purpose of this paper is to review the existing evidence about WM abnormalities in individuals at ultra-high risk of psychosis (UHR) with the use of diffusion tensor imaging (DTI) available from the National Center for Biotechnology Information PubMed (Medline) and Health Source: Nursing/Academic Edition databases. Of 358 relevant articles identified, 25 papers published in the years 2008-2020 were ultimately included in the review. Most of them supported the presence of subtle aberrations in WM in UHR individuals, especially in the superior longitudinal fasciculus (SLF), the inferior longitudinal fasciculus (ILF), and the inferior fronto-occipital fasciculus (IFOF). These alterations may therefore be considered a promising neurobiological marker for the risk of psychosis. However, due to methodological discrepancies and the relative scarcity of evidence, further investigation is called for, especially into connectome analysis in UHR patients.

Relationship of Corpus Callosum Integrity with Working Memory, Planning, and Speed of Processing in Patients with First-Episode and Chronic Schizophrenia.

There is a paucity of reports examining the relationship between the integrity of the corpus callosum (CC) and different aspects of cognitive functioning in patients with first-episode (FES) and chronic schizophrenia (CS) simultaneously; furthermore, what results exist are inconclusive. We used diffusion tensor imaging tractography to investigate differences in integrity in five regions of the CC between FES, CS, and healthy controls (HC). Additionally, we analyzed correlations between these regions' integrity and working memory, planning, and speed of processing. Eighteen patients with FES, 55 patients with CS, and 30 HC took part in the study. We assessed cognitive functions with four tasks from Measurement and Treatment Research to Improve Cognition in Schizophrenia. Patients with CS showed lower fractional anisotropy (FA) in Region 5 (statistical trend) and higher mean diffusivity (MD) in Regions 4 and 5 than HC, and patients with FES had higher MD in Region 3 (statistical trend) than HC. Both clinical groups performed worse on working memory and speed of processing tasks than HC, and patients with CS scored worse than HC on independent planning, and worse than FES and HC on dependent planning. Moreover, in patients with CS, MD in Region 3 was correlated with verbal working memory. Our results suggest that patients with FES and CS are characterized by impaired integrity of the middle and posterior CC, respectively. We confirmed that both clinical groups have cognitive impairments. Moreover, the integrity of the middle CC may influence planning in patients with CS.

White Matter Integrity of the Corpus Callosum and Psychopathological Dimensions in Deficit and Non-Deficit Schizophrenia Patients.

Deficit syndrome (DS) is a subtype of schizophrenia characterized by primary persistent negative symptoms. The corpus callosum (CC) appears to be related to psychopathology in schizophrenia. This study assessed white matter integrity in the CC using diffusion tensor imaging (DTI) in deficit and non-deficit schizophrenia (NDS) patients. We also investigated the psychopathological dimensions of schizophrenia and their relationship to CC integrity. Fifteen DS patients, 40 NDS patients, and 30 healthy controls (HC) underwent psychiatric evaluation and neuroimaging. We divided the CC into five regions and assessed their fractional anisotropy (FA) and mean diffusivity (MD). Psychopathology was assessed with the Positive and Negative Syndrome Scale. DS patients had lower FA than NDS patients and HC, and higher MD in Region 5 of the CC than did HC. NDS patients had higher MD in Region 4 of the CC. The patient groups differed in terms of negative symptoms. After differentiating clinical groups and HC, no significant correlations were observed between DTI measures and psychopathological symptoms. Our results suggest that DS and NDS are characterized by minor impairments of the posterior CC. We confirmed that DS patients have greater negative psychopathology than NDS patients. Our results are preliminary, and further studies are needed.

The relationship between cingulum bundle integrity and different aspects of executive functions in chronic schizophrenia.

BACKGROUND: Evidence suggests that disruption in the cingulum bundle (CB) may influence executive dysfunctions in schizophrenia, but findings are still inconsistent. Using diffusion tensor imaging tractography, we investigated the differences in fiber integrity between schizophrenia patients and healthy controls together with the association between fiber integrity and executive functions. METHODS: Thirty-two patients with chronic schizophrenia and 24 healthy controls took part in the study. Both groups were matched for age, sex, and years of education. Assessment of cognitive functions was performed using the Berg Card Sorting Test (BCST), the Color Trail Test (CTT), and the Stroop Color-Word Test (SCWT). RESULTS: Results showed group differences, bilaterally (left and right) in fractional anisotropy (FA) of the CB, where patients showed less anisotropy than controls. Moreover, normal asymmetry (left FA > right FA) in the CB in schizophrenia was found. There were no group differences in mean diffusivity (MD). Patients had a similar but reduced profile of executive functions compared to healthy controls. However, when premorbid IQ was controlled for, the differences were no longer statistically significant. In schizophrenia patients, a negative correlation was found between FA of the left CB and perseverative errors in the BCST. CONCLUSIONS: These findings provide evidence that CB disruption appears in schizophrenia patients and might account for impairments of executive processes, including concept formation.