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Abstract: Schizophrenia is a debilitating mental health disorder that imposes profound economic, societal, and personal burdens. The negative symptoms of schizophrenia ( i.e. , blunted affect, alogia, anhedonia, asociality, and avolition) are highly prevalent and pervasive in the psychotic disorder and pose significant resistance to available treatment options. Traumatic childhood experiences are strongly linked with the risk of developing schizophrenia. Most prior studies have primarily focused on positive symptoms of schizophrenia ( e.g. , hallucinations and delusions), whereas less attention has been given to negative symptoms. The current study investigated the relationship between childhood trauma ( i.e. , physical abuse, sexual abuse, and emotional abuse and neglect) and negative symptoms in a sample of schizophrenia outpatients and healthy controls ( n = 159 participants, including 99 patients with schizophrenia). The observations from the current study revealed that schizophrenia patients experienced a significantly greater degree of childhood trauma and negative symptoms than the control individuals. The results of the current study also indicated that more severe experiences of total childhood trauma ( i.e. , summation of all trauma types), physical abuse, and emotional neglect may increase the risk of schizophrenia patients reporting negative symptoms. However, childhood sexual and emotional abuse was found to have no impact on the degree of negative symptoms experienced by schizophrenia patients. Implications and limitations of the current study are discussed. In conclusion, we found that the severity of overall childhood trauma, physical abuse, and emotional neglect may play an important role in increasing the likelihood of schizophrenia patients reporting negative symptoms., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Adverse childhood experiences (ACEs) are a well-known risk factor of schizophrenia. Moreover, individuals with schizophrenia are likely to use maladaptive stress coping strategies. Although it has been reported that a history of ACEs might be associated with a pro-inflammatory phenotype in patients with schizophrenia, the interacting effect of coping styles on this association has not been tested so far. In the present study, we aimed to investigate the levels of immune-inflammatory markers in patients with schizophrenia and healthy controls (HCs), taking into consideration a history of ACEs and coping strategies. Participants included 119 patients with schizophrenia and 120 HCs. Serum levels of 26 immune-inflammatory markers were determined. A history of any categories of ACEs was significantly more frequent in patients with schizophrenia. Moreover, patients with schizophrenia were significantly more likely to use emotion-focused coping and less likely to use active coping strategies compared to HCs. The levels of interleukin(IL)-6, RANTES, and tumor necrosis factor-α (TNF-α), appeared to be elevated in patients with schizophrenia after adjustment for potential confounding factors in all tested models. Participants reporting a history of any ACEs had significantly higher levels of TNF-α and IL-6. No significant main and interactive effects of active strategies as the predominant coping on immune-inflammatory markers with altered levels in patients with schizophrenia were found. Findings from the present study indicate that ACEs are associated with elevated TNF-α and IL-6 levels regardless of schizophrenia diagnosis and predominant coping styles., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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 CpG mean and MD of CCR1 in SCH. Weaker positive correlations were found for CpG mean 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., Competing Interests: Declaration of competing interest The authors of submitted manuscript entitled: Higher methylation of IL-6 promoter region is associated with decreased integrity of corpus callosum in schizophrenia declare that they do not have any competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., (© 2024. The Author(s).)

The present study had the following aims: 1) to compare gut microbiota composition in patients with schizophrenia and controls and 2) to investigate the association of differentially abundant bacterial taxa with markers of inflammation, intestinal permeability, lipid metabolism, and glucose homeostasis as well as clinical manifestation. A total of 115 patients with schizophrenia during remission of positive and disorganization symptoms, and 119 controls were enrolled. Altogether, 32 peripheral blood markers were assessed. A higher abundance of Eisenbergiella, Family XIII AD3011 group, Eggerthella, Hungatella, Lactobacillus, Olsenella, Coprobacillus, Methanobrevibacter, Ligilactobacillus, Eubacterium fissicatena group, and Clostridium innocuum group in patients with schizophrenia was found. The abundance of Paraprevotella and Bacteroides was decreased in patients with schizophrenia. Differentially abundant genera were associated with altered levels of immune-inflammatory markers, zonulin, lipid profile components, and insulin resistance. Moreover, several correlations of differentially abundant genera with cognitive impairment, higher severity of negative symptoms, and worse social functioning were observed. The association of Methanobrevibacter abundance with the level of negative symptoms, cognition, and social functioning appeared to be mediated by the levels of interleukin-6 and RANTES. In turn, the association of Hungatella with the performance of attention was mediated by the levels of zonulin. The findings indicate that compositional alterations of gut microbiota observed in patients with schizophrenia correspond with clinical manifestation, intestinal permeability, subclinical inflammation, lipid profile alterations, and impaired glucose homeostasis. Subclinical inflammation and impaired gut permeability might mediate the association of gut microbiota alterations with psychopathological symptoms and cognitive impairment., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Previous studies have reported a variety of gut microbiota alterations in patients with schizophrenia. However, none of these studies has investigated gut microbiota in patients with the deficit subtype of schizophrenia (D-SCZ) that can be characterized by primary and enduring negative symptoms. Therefore, in this study we aimed to profile gut microbiota of individuals with D-SCZ, compared to those with non-deficit schizophrenia (ND-SCZ) and healthy controls (HCs)., Methods: A total of 115 outpatients (44 individuals with D-SCZ and 71 individuals with ND-SCZ) during remission of positive and disorganization symptoms as well as 120 HCs were enrolled. Gut microbiota was analyzed using the 16 rRNA amplicon sequencing. Additionally, the levels of C-reactive protein (CRP), glucose and lipid metabolism markers were determined in the peripheral blood samples., Results: Altogether 14 genera showed differential abundance in patients with D-SCZ compared to ND-SCZ and HCs, including Candidatus Soleaferrea, Eubacterium, Fusobacterium, Lachnospiraceae UCG-002, Lachnospiraceae UCG-004, Lachnospiraceae UCG-010, Libanicoccus, Limosilactobacillus, Mogibacterium, Peptococcus, Prevotella, Prevotellaceae NK3B31 group, Rikenellaceae RC9 gut group, and Slackia after adjustment for potential confounding factors. Observed alterations were significantly associated with cognitive performance in both groups of patients. Moreover, several significant correlations of differentially abundant genera with the levels of CRP, lipid profile parameters, glucose and insulin were found across all subgroups of participants., Conclusion: Findings from the present study indicate that individuals with D-SCZ show a distinct profile of gut microbiota alterations that is associated with cognitive performance, metabolic parameters and subclinical inflammation., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest related to the subject of this study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: It has been shown that various aspects of clinical manifestation of schizophrenia are strongly related to social functioning. However, it remains unknown as to whether similar factors predict social functioning at various stages of psychosis. Therefore, the present study aimed to compare the effects of interconnections between various domains of psychopathology and neurocognition on social functioning in people during acute phase of psychosis and those during remission of positive and disorganization symptoms using a network analysis., Methods: Two independent samples of individuals with schizophrenia spectrum disorders were enrolled (89 inpatients during acute phase and 90 outpatients during remission of positive and disorganization symptoms). Clinical assessment covered the levels of functioning, positive, negative and depressive symptoms. Cognition was recorded using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Data were analyzed by means of the network analysis. Two separate networks of clinical symptoms, social functioning, and cognition (i.e., in patients during acute phase of psychosis and remitted outpatients with schizophrenia) were analyzed and compared with respect to the measures of centrality (betweenness, closeness, strength, and expected influence) and edge weights., Results: In both networks, the majority of centrality metrics (expected influence, strength, and closeness) had the highest values for the RBANS scores of attention (the sum of scores from two tasks, i.e., digit span and coding) and immediate memory. In both networks, social functioning was directly connected to positive, negative and depressive symptoms as well as the RBANS scores of attention and language. Additionally, in remitted patients, social functioning was directly connected to the RBANS score of immediate memory., Conclusions: Findings from the present study indicate the central role of cognitive deficits, especially those related to attention, processing speed, working and immediate memory in shaping functional impairments regardless of schizophrenia phase. Therapeutic interventions that aim to improve functional capacity need to target these domains of neurocognitive performance., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Schizophrenia is a multi-systemic disorder that is associated with lipid profile disturbances, altered glucose homeostasis and subclinical inflammation. It has been proposed that dysfunction of the gut-brain axis might underlie these alterations. Short-chain fatty acids (SCFAs) are considered to play a pivotal role in the gut-brain axis. In this study, we aimed to compare fecal levels of SCFAs in patients with schizophrenia and healthy controls (HCs), taking into consideration their relationship with common peripheral blood alterations observed in schizophrenia. The study included 100 stable outpatients with schizophrenia and 55 HCs. The levels of SCFAs (acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and lactic acid) in fecal samples were measured. Also, lipid profile together with the levels of C-reactive protein, glucose and insulin were determined. The levels of isovaleric acid were significantly higher in patients with schizophrenia after co-varying for age, sex, and the adherence to the Mediterranean diet. Moreover, there were significant positive correlations of the levels of valeric acid, isovaleric acid and CRP in patients with schizophrenia. In this group of participants, higher levels of isovaleric acid were associated with significantly lower scores of delayed memory after adjustment for potential covariates and interactions with CRP levels. Our results indicate that individuals with schizophrenia show altered levels of isovaleric acid that might be associated with impairments of delayed memory. The association with cognitive impairments might be independent of interactions with immune-inflammatory processes. Longitudinal and experimental studies are needed to test causal mechanisms of observed correlations., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Specific mechanisms underlying gut microbiota alterations in schizophrenia remain unknown. We aimed to compare gut microbiota between patients with schizophrenia and controls, taking into consideration exposure stress across lifespan, dietary habits, metabolic parameters and clinical manifestation. A total of 142 participants, including 89 patients with schizophrenia and 52 controls, were recruited. Gut microbiota were analyzed using the 16 S rRNA sequencing. Additionally, biochemical parameters related to glucose homeostasis, lipid profile and inflammation were assessed. Increased abundance of Lactobacillus and Limosilactobacillus as well as decreased abundance of Faecalibacterium and Paraprevotella were found in patients with schizophrenia. The machine learning analysis demonstrated that between-group differences in gut microbiota were associated with psychosocial stress (a history of childhood trauma, greater cumulative exposure to stress across lifespan and higher level of perceived stress), poor nutrition (lower consumption of vegetables and fish products), lipid profile alterations (lower levels of high-density lipoproteins) and cognitive impairment (worse performance of attention). Our findings indicate that gut microbiota alterations in patients with schizophrenia, including increased abundance of lactic acid bacteria (Lactobacillus and Limosilactobacillus) and decreased abundance of bacteria producing short-chain fatty acids (Faecalibacterium and Paraprevotella) might be associated with exposure to stress, poor dietary habits, lipid profile alterations and cognitive impairment., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The ongoing developments of psychiatric classification systems have largely improved reliability of diagnosis, including that of schizophrenia. However, with an unknown pathophysiology and lacking biomarkers, its validity still remains low, requiring further advancements. Research has helped establish multiple sclerosis (MS) as the central nervous system (CNS) disorder with an established pathophysiology, defined biomarkers and therefore good validity and significantly improved treatment options. Before proposing next steps in research that aim to improve the diagnostic process of schizophrenia, it is imperative to recognize its clinical heterogeneity. Indeed, individuals with schizophrenia show high interindividual variability in terms of symptomatic manifestation, response to treatment, course of illness and functional outcomes. There is also a multiplicity of risk factors that contribute to the development of schizophrenia. Moreover, accumulating evidence indicates that several dimensions of psychopathology and risk factors cross current diagnostic categorizations. Schizophrenia shares a number of similarities with MS, which is a demyelinating disease of the CNS. These similarities appear in the context of age of onset, geographical distribution, involvement of immune-inflammatory processes, neurocognitive impairment and various trajectories of illness course. This article provides a critical appraisal of diagnostic process in schizophrenia, taking into consideration advancements that have been made in the diagnosis and management of MS. Based on the comparison between the two disorders, key directions for studies that aim to improve diagnostic process in schizophrenia are formulated. All of them converge on the necessity to deconstruct the psychosis spectrum and adopt dimensional approaches with deep phenotyping to refine current diagnostic boundaries.

There is evidence that subclinical inflammation and increased gut permeability might be involved in the pathophysiology of schizophrenia. Less is known about these phenomena in patients with the deficit subtype of schizophrenia (D-SCZ) characterized by primary and enduring negative symptoms. Therefore, in the present study we aimed to compare the levels of zonulin (the marker of gut permeability) and immune-inflammatory markers in patients with D-SCZ, those with non-deficit schizophrenia (ND-SCZ) and healthy controls (HCs). A total of 119 outpatients with schizophrenia and 120 HCs were enrolled. The levels of 26 immune-inflammatory markers and zonulin were determined in serum samples. The following between-group differences were significant after adjustment for multiple testing and the effects of potential confounding factors: 1) higher levels of interleukin(IL)- 1β and C-reactive protein (CRP) in patients with D-SCZ compared to those with ND-SCZ and HCs; 2) higher levels of tumor necrosis factor-α and RANTES in both groups of patients with schizophrenia compared to HCs and 3) higher levels of IL-17 in patients with D-SCZ compared to HCs. No significant between-group differences in zonulin levels were found. Higher levels of IL-1β and CRP were associated with worse performance of attention after adjustment for age, education and chlorpromazine equivalents. Also, higher levels of IL-1β were correlated with greater severity of negative symptoms after adjustment for potential confounding factors. In conclusion, individuals with D-SCZ are more likely to show subclinical inflammation. However, findings from the present study do not support the hypothesis that this phenomenon is secondary to increased gut permeability., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The pathogenesis of schizophrenia is multidimensional and intensively studied. The gut-brain axis disturbances might play a significant role in the development of schizophrenia., Methods: We compared the gut microbiota of 53 individuals with schizophrenia and 58 healthy controls, using the 16S rRNA sequencing method. Individuals with schizophrenia were assessed using the following scales: the Positive and Negative Syndrome Scale, the Calgary Depression Scale for Schizophrenia, the Social and Occupational Functioning Assessment Scale and the Repeatable Battery for the Assessment of Neuropsychological Status., Results: No significant between-group differences in α-diversity measures were observed. Increased abundance of Lactobacillales (order level), Bacilli (class level) and Actinobacteriota (phylum level) were found in individuals with schizophrenia regardless of potential confounding factors, and using two independent analytical approaches (the distance-based redundancy analysis and the generalised linear model analysis). Additionally, significant correlations between various bacterial taxa (the Bacteroidia class, the Actinobacteriota phylum, the Bacteroidota phylum, the Coriobacteriales order and the Coriobacteria class) and clinical manifestation (the severity of negative symptoms, performance of language abilities, social and occupational functioning) were observed., Conclusions: The present study indicates that gut microbiota alterations are present in European patients with schizophrenia. The abundance of certain bacterial taxa might be associated with the severity of negative symptoms, cognitive performance and general functioning. Nonetheless, additional studies are needed before the translation of our results into clinical practice.

Schizophrenia is a neurodevelopmental disorder with genetic and environmental factors involved in its aetiology. Genetic liability contributing to the development of schizophrenia is a subject of extensive research activity, as reliable data regarding its aetiology would enable the improvement of its therapy and the development of new methods of treatment. A multitude of studies in this field focus on genetic variants, such as copy number variations (CNVs) or single-nucleotide variants (SNVs). Certain genetic disorders caused by CNVs including 22q11.2 microdeletion syndrome, Burnside-Butler syndrome (15q11.2 BP1-BP2 microdeletion) or 1q21.1 microduplication/microdeletion syndrome are associated with a higher risk of developing schizophrenia. In this article, we provide a unifying framework linking these CNVs and their associated genetic disorders with schizophrenia and its various neural and behavioural abnormalities., (© 2022. The Author(s).)

Introduction: Psychometric properties of the Self-evaluation of Negative Symptoms (SNS) in subjects with the deficit subtype of schizophrenia (SCZ-D) have not been investigated so far. This study had the following aims: (1) to assess psychometric properties of SNS in subjects with SCZ-D and (2) to explore the usefulness of SNS, in comparison with other clinical characteristics, in screening for SCZ-D., Methods: Participants were 82 stable outpatients with schizophrenia, including 40 individuals with SCZ-D and 42 individuals with the non-deficit subtype (SCZ-ND)., Results: Internal consistency was acceptable-to-good in both groups. Factor analysis revealed two dimensions (apathy and emotional). There were significant positive correlations of the SNS total score with the subscore of negative symptoms from the Positive and Negative Syndrome Scale (PANSS) and significant negative correlations with scores of the Social and Occupational Functioning Assessment Scale (SOFAS) in both groups, indicating good convergent validity. The following measures were found to be appropriate screening tools for differentiating SCZ-D and SCZ-ND (p < 0.001): the SNS total score (area under the curve [AUC]: 0.849, cut-off ≥16, sensitivity: 80.0%, specificity: 78.6%), the PANSS subscore of negative symptoms (AUC: 0.868, cut-off ≥11, sensitivity: 90.0%, specificity: 78.6%), and the SOFAS (AUC: 0.779, cut-off ≤59, sensitivity: 69.2%, specificity: 82.5%). Also, adding the SOFAS (cut-off ≤59) to the SNS (cut-off: ≥16) further improved sensitivity and specificity (AUC: 0.898, p < 0.001, sensitivity = 87.5%, specificity = 82.2%). Cognitive performance and age of psychosis onset were not found to be suitable measures for differentiating SCZ-D and SCZ-ND., Conclusion: The present findings indicate that the SNS has good psychometric properties in subjects with SCZ-D and those with SCZ-ND. Moreover, the SNS, the PANSS, and the SOFAS might be used as screening tools for SCZ-D., (© 2023 S. Karger AG, Basel.)

Aim: It has been observed that deficit and non-deficit schizophrenia (SCZ-D and SCZ-ND) might be characterized by different risk factors. Therefore, the present study aimed to assess as to whether previously reported risk factors of schizophrenia are specifically associated with SCZ-D and SCZ-ND., Method: This study was based on a cohort of 118 stable outpatients with schizophrenia. A diagnosis of SCZ-D was established using the Schedule for the Deficit Syndrome (SDS). Risk factors were recorded using structured interview, the Operational Criteria for Psychotic Illness (OPCRIT) checklist and the Traumatic Experience Checklist (TEC). The following risk factors were explored: male sex, a history of schizophrenia in first-degree relatives, seasonality of birth, birth weight <3000g, delivery by cesarean section, a history of childhood trauma (emotional abuse, emotional neglect, physical abuse and sexual abuse) as well as substance abuse (other than nicotine) and cigarette smoking at psychosis onset., Results: Individuals with SCZ-D were more likely to be males as well as reported higher rates of birth weight <3000g and any categories of childhood trauma. In turn, substance abuse (other than nicotine) at psychosis onset was significantly more frequent in patients with SCZ-ND. Binary logistic regression, controlling for multiple comparisons, revealed similar findings, except for the association with any categories of childhood trauma that appeared to be not significant., Conclusion: Our findings partially replicate differential patterns of risk factors for SCZ-D (male sex and birth weight <3000g) and SCZ-ND (substance abuse at psychosis onset), likely attributable to the effects of timing of exposure., (Copyright © 2022 SEP y SEPB. Published by Elsevier España, S.L.U. All rights reserved.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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.

There is accumulating evidence that individuals with schizophrenia show altered levels of thyroid hormones. However, a qualitative and quantitative synthesis of findings in this field has not been performed so far. Therefore, we aimed to perform a systematic review and meta-analysis of studies investigating the levels of thyroid-stimulating hormone (TSH), free thyroxine (fT4), total thyroxine (tT4), free triiodothyronine (fT3) and total triiodothyronine (tT3) in multiple-episode schizophrenia (MES) and first-episode psychosis (FEP). Electronic databases were searched from their inception until 30th May 2020 by two independent reviewers. Random-effects meta-analyses and meta-regression analyses were performed. Altogether, 19 studies were included. Persons with FEP had significantly lower TSH levels (5 studies, g = -0.26, 95%CI: -0.47 to -0.06, p = 0.013, I 2  = 21.3%), higher fT4 levels (3 studies, g = 0.58, 95%CI: 0.15-1.01, p = 0.008, I 2  = 64.6%) and lower tT3 levels (2 studies, g = -0.60, 95%CI: -0.82 to -0.37, p < 0.001, I 2  = 0%) compared to controls. Elevated TSH levels were found in persons with MES (13 studies, g = 0.20, 95%CI: 0.02-0.39, p = 0.031, I 2  = 50.0%). Our findings imply that the levels of TSH might be decreased in persons with FEP and increased in those with MES. Other alterations need to be confirmed by additional studies. These findings imply the need to monitor the levels of TSH and thyroid hormones from the onset of psychosis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Accumulating evidence indicates that there are bidirectional interactions between the gut microbiota and functioning of the central nervous system. Consequently, it has been proposed that gut microbiota alterations might play an important role in the pathophysiology of schizophrenia. Therefore, in this article, we aimed to perform a narrative review of studies addressing gut microbiota alterations in patients with schizophrenia that were published in the years 2019-2020., Recent Findings: Several studies have shown a number of gut microbiota alterations at various stages of schizophrenia. Some of them can be associated with neurostructural abnormalities, psychopathological symptoms, subclinical inflammation and cardiovascular risk. Experimental studies clearly show that transplantation of gut microbiota from unmedicated patients with schizophrenia to germ-free mice results in a number of behavioural impairments accompanied by altered neurotransmission. However, findings from clinical trials do not support the use of probiotics as add-on treatments in schizophrenia., Summary: Gut microbiota alterations are widely observed in patients with schizophrenia and might account for various biological alterations involved in the cause of psychosis. However, longitudinal studies are still needed to conclude regarding causal associations. Well designed clinical trials are needed to investigate safety and efficacy of probiotics and prebiotics in schizophrenia., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Dysregulation of epigenetic processes might account for alterations of the hypothalamic-pituitary-adrenal axis observed in patients with schizophrenia. Therefore, in this study, we aimed to investigate methylation of the glucocorticoid receptor (NR3C1) gene in patients with schizophrenia-spectrum disorders, individuals at familial high risk of schizophrenia (FHR-P), and healthy controls with respect to clinical manifestation and a history of psychosocial stressors., Methods: We recruited 40 first-episode psychosis patients, 45 acutely relapsed schizophrenia (SCZ-AR) patients, 39 FHR-P individuals, and 56 healthy controls. The level of methylation at 9 CpG sites of the NR3C1 gene was determined using pyrosequencing., Results: The level of NR3C1 methylation was significantly lower in first-episode psychosis patients and significantly higher in SCZ-AR patients compared with other subgroups of participants. Individuals with FHR-P and healthy controls had similar levels of NR3C1 methylation. A history of adverse childhood experiences was associated with significantly lower NR3C1 methylation in all subgroups of participants. Higher methylation of the NR3C1 gene was related to worse performance of attention and immediate memory as well as lower level of general functioning in patients with psychosis., Conclusions: Patients with schizophrenia-spectrum disorders show altered levels of NR3C1 methylation that are significantly lower in first-episode psychosis patients and significantly higher in SCZ-AR patients. Higher methylation of the NR3C1 gene might be related to cognitive impairment observed in this clinical population. The association between a history of adverse childhood experiences and lower NR3C1 methylation is not specific to patients with psychosis. Longitudinal studies are needed to establish causal mechanisms underlying these observations., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

Previous transcriptome analyses of brain samples provided several insights into the pathophysiology of schizophrenia. In this study, we aimed to re-investigate gene expression datasets from seven brain regions of patients with schizophrenia and healthy controls by adopting a unified approach. After adjustment for confounding factors, we detected gene expression changes in 2 out of 7 brain regions - the dorsolateral prefrontal cortex (DLPFC) and parietal cortex (PC). We found relatively small effect sizes, not exceeding absolute log fold changes of 1. Gene-set enrichment analysis revealed the following alterations: 1) down-regulation of GABAergic signaling (in DLPFC and PC); 2) up-regulation of interleukin-23 signaling together with up-regulation of transcription mediated by RUNX1 and RUNX3 as well as down-regulation of RUNX2 signaling (in DLPFC) and 3) up-regulation of genes associated with responses to metal ions and RUNX1 signaling (PC). The number of neurons was significantly lower and the number of astrocytes was significantly higher at both brain regions. In turn, the index of microglia was increased in DLPFC and decreased in PC. Finally, our unsupervised analysis demonstrated that cellular composition of the samples was a major confounding factor in the analysis of gene expression across all datasets. In conclusion, our analysis provides further evidence that small but significant changes in the expression of genes related to GABAergic signaling, brain development, neuroinflammation and responses to metal ions might be involved in the pathophysiology of schizophrenia. Cell sorting techniques need to be used by future studies to dissect the effect of cellular content., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

It has been proposed that type 2 diabetes and schizophrenia-spectrum disorders share overlapping genetic backgrounds. Therefore, we aimed to perform a systematic review and meta-analysis of studies comparing fasting levels of glucose and insulin, the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), glucose levels during the oral glucose tolerance test (OGTT) and the levels of glycated hemoglobin (HbA1c) in unaffected first-degree relatives of patients with schizophrenia and controls. Online searches covered the publication period from database inception until May 8th 2020. Meta-analyses were performed using random-effects models with Hedges' g as the effect size estimate. Out of 2556 records identified, 12 studies representing 672 relatives of schizophrenia patients and 6446 controls were found to be eligible. There were no significant differences in fasting levels of glucose (g = 0.54, 95%CI = -0.26 to 1.35, p = 0.188) and insulin (g = 0.07, 95%CI = -0.14 to 0.29, p = 0.491), HOMA-IR (g = 0.12, 95%CI = -0.19 to 0.43, p = 0.433), and the levels of HbA1c (g = 0.38, 95%CI = -0.02 to 0.77, p = 0.061) between relatives of schizophrenia patients and controls. Two studies demonstrated significantly higher 2-hour glucose levels during OGTT in relatives of patients with schizophrenia (g = 0.90, 95%CI = 0.49 to 1.31, p < 0.001). Our findings do not support the hypothesis that familial liability to psychosis is related to altered fasting parameters of glucose homeostasis. However, this population might show impaired glucose tolerance. More studies are needed to confirm these observations., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cardiometabolic diseases are the main contributor of reduced life expectancy in patients with schizophrenia. It is now widely accepted that antipsychotic treatment plays an important role in the development of obesity and its consequences. However, some intrinsic mechanisms need to be taken into consideration. One of these mechanisms might be related to impaired hormonal regulation of appetite in this group of patients. In this narrative review, we aimed to dissect impairments of appetite-regulating hormones attributable to intrinsic mechanisms and those related to medication effects. Early hormonal alterations that might be associated with intrinsic mechanisms include low levels of leptin and glucagon-like peptide-1 (GLP-1) together with elevated insulin levels in first-episode psychosis (FEP) patients. However, evidence regarding low GLP-1 levels in FEP patients is based on one large study. In turn, multiple-episode schizophrenia patients show elevated levels of insulin, leptin and orexin A together with decreased levels of adiponectin. In addition, patients receiving olanzapine may present with low ghrelin levels. Post mortem studies have also demonstrated reduced number of neuropeptide Y neurons in the prefrontal cortex of patients with schizophrenia. Treatment with certain second-generation antipsychotics may also point to these alterations. Although our understanding of hormonal regulation of appetite in schizophrenia has largely been improved, several limitations and directions for future studies need to be addressed. This is of particular importance since several novel pharmacological interventions for obesity and diabetes have already been developed and translation of these developments to the treatment of cardiometabolic comorbidities in schizophrenia patients is needed., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of competing interest Authors declare no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Elevated allostatic load (AL) index, which is a cumulative measure of biological dysregulations associated with stress exposure, has been demonstrated in patients with psychosis. However, it remains unknown whether a history of childhood trauma (CT) might contribute to elevated AL index in psychosis. Therefore, we aimed to investigate the association between AL index, a history of CT and coping styles in patients with psychotic disorders. Participants were 65 patients with schizophrenia-spectrum disorders and 56 healthy controls (HCs). The AL index was computed based on percentile distributions of 15 biomarkers in HCs. The AL index was significantly higher in patients with psychosis. A history of parental antipathy was associated with elevated AL index in both groups of participants. A history of any categories of CT and sexual abuse were associated with higher AL index only in patients with psychosis. Social diversion (seeking social interactions in case of stressful experiences) mediated the association between sexual abuse and the AL index in the group of patients. There was a significant direct effect of sexual abuse on the AL index (this specific CT was associated with higher AL index). However, indirect effect of sexual trauma on AL through social diversion was opposite to direct effect. Childhood adversities, especially sexual abuse and parental antipathy, might contribute to elevated AL index in patients with psychosis. The effect of sexual abuse on the AL index might be specific to psychosis. Engagement in social interactions in case of stressful situations might alleviate biological dysregulations associated with CT., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

There is evidence that hyperhomocysteinemia may be associated with the development of schizophrenia and cognitive impairment. Therefore, the aim of this study was to analyze the relationship between cognitive functions and normal homocysteine concentrations vs. hyperhomocysteinemia in schizophrenia patients before and after supplementation with vitamins B6, B12 and folate. An 8-week prospective, non-randomized study enrolled 122 adult patients with schizophrenia (67F/55M, mean age 43.54 ± 11.94 years). Homocysteine concentrations were measured in all individuals and afterwards hyperhomocysteinemia patients (n = 42) were divided into two subgroups: treated with oral vitamins supplementation (B6 - 25 mg/d, B12 - 20 μg/d, folate - 2,5 mg/d) (n = 22) and without supplementation (n = 20). The assessment of schizophrenia symptoms severity in study group was performed using the Positive and Negative Syndrome Scale (PANSS). Cognitive functions were evaluated using the Stroop test and the Trail Making Test (TMT). We observed a higher prevalence of hyperhomocysteinemia in schizophrenia patients (34.4%) in comparison to the general population. Individuals with schizophrenia and coexisting hyperhomocysteinemia had worse performance on the Stroop and the TMT tests as well as higher PANSS scores. In these patients, supplementation with vitamins effectively decreased the homocysteine concentrations to the normal values, however there was no statistically significant improvement in the PANSS and cognitive test scores, except a significant decrease in the number of the Stroop test errors. We conclude that significant results obtained in this study show that there is a relationship between homocysteine blood concentration and schizophrenia severity. Moreover, homocysteine concentration lowering might be beneficial in schizophrenia patients with hyperhomocysteinemia in terms of cognitive functions improvement., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Accumulating evidence indicates systemic biological dysregulations in patients with psychosis that have been conceptualized as the "allostatic load" (AL) index. We aimed to investigate the AL index in 37 subjects at familial high risk of psychosis (FHRP), 42 first-episode psychosis (FEP) patients, 25 acutely relapsed schizophrenia (SCZ-AR) patients and 42 healthy controls (HCs), taking into account psychopathology and cognitive impairment. The AL index was calculated based on 15 biomarkers (cardiovascular markers, anthropometric measures, inflammatory markers, glucose homeostasis parameters, lipids and steroids). Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The AL index was significantly higher in patients with psychosis and FHR-P individuals compared to HCs. Patients with FEP and FHR-P individuals had similar AL index. Moreover, the AL index was significantly higher in SCZ-AR patients compared to other groups of participants. Higher AL index was associated with more severe general psychopathology and depressive symptoms, lower scores of attention (total score, digit span and digit coding tasks) and semantic fluency, as well as worse general functioning in patients with psychosis. There was a significant negative correlation between the AL index and the scores of attention (total score and digit coding task) in FHR-P individuals. No significant correlations between the AL index and cognition were found in HCs. Our results indicate that biological dysregulations, captured by the AL index, appear already in FHR-P individuals and progress with psychotic exacerbations. Elevated AL index might contribute to cognitive impairments in FHR-P individuals and patients with psychosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We aimed to perform a systematic review and meta-analysis of appetite regulating hormones in patients with first-episode psychosis (FEP). Meta-analyses were conducted using random-effects models with Hedges' g as the effect size estimate. We identified 31 eligible studies, investigating the levels of 7 appetite regulating hormones (adiponectin, insulin, leptin, ghrelin, orexin, resistin and visfatin) in 1792 FEP patients and 1364 controls. The insulin levels in FEP patients were higher than in controls (g = 0.34, 95%CI: 0.19 - 0.49, p < 0.001), even considering only antipsychotic-naïve patients (g = 0.39, 95%CI: 0.12 - 0.66, p = 0.005). The severity of negative symptoms was positively associated with the effect size estimates (β = 0.08, 95%CI: 0.01 - 0.16, p = 0.030). Moreover, we found lower levels of leptin in antipsychotic-naïve FEP patients (g = -0.62, 95%CI: -1.11 - 0.12, p = 0.015). Impaired appetite regulation, in terms of elevated insulin levels and decreased leptin levels, occurs in early psychosis, before antipsychotic treatment. Hyperinsulinemia might be related to negative symptoms., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Human endogenous retroviruses (HERV) have been widely associated with schizophrenia etiology. Aberrant epigenetic processes may play a role in the etiology of schizophrenia. In this study, we tested whether schizophrenia patients at different stages of illness might present alterations in the levels of HERV-K methylation. We recruited 49 first-episode schizophrenia (FES) patients with 47 age- and sex-matched healthy controls (HCs), and 100 multi-episode schizophrenia (MES) patients with 50 age- and sex-matched HCs. Based on the Schedule for Deficit Schizophrenia, patients with MES were also divided into two subgroups: deficit (D-SCZ) and non-deficit schizophrenia (ND-SCZ). DNA methylation levels of HERV-K sequences were examined in peripheral blood leukocytes. We found significantly lower levels of HERV-K methylation in FES patients compared to HCs. Patients with MES and matched HCs had similar levels of HERV-K methylation. There was a significant positive correlation between chlorpromazine equivalent dosage and HERV-K methylation levels in MES patients, but not in FES individuals. No significant differences in HERV-K methylation levels between D-SCZ and ND-SCZ as well as HCs were found. Our results indicate lower HERV-K methylation levels at early stages of schizophrenia. This difference might normalize with subsequent exacerbations of schizophrenia, likely due to the effects of antipsychotics., (Copyright © 2018. Published by Elsevier B.V.)

Although the development of second-generation antipsychotics was a cornerstone in the treatment of schizophrenia, several unmet treatment needs in the field still exist. It is particularly important to note that available antipsychotics have limited efficacy in the treatment of negative symptoms and cognitive impairment. At this point, it should be noted that primary negative symptoms, i.e., those that are not due to depression, extrapyramidal symptoms or psychotic withdrawal, might affect even one-fourth of patients with schizophrenia and are associated with poor clinical and functional outcomes. Cariprazine, is an emerging antipsychotic drug, D3/D2 receptor partial agonist, with affinity to several serotonin receptors. In this article, we provide an overview of pharmacokinetic and pharmacodynamic properties of cariprazine, showing its unique receptor profile. Next, we discuss results of double-blind, placebo-controlled, randomized clinical trials and post hoc analyses of cariprazine that have been published to date. These studies have provided evidence for efficacy of cariprazine in the treatment of schizophrenia exacerbations compared to placebo, with safety and good tolerability. In addition, one clinical trial published to date revealed superior efficacy of cariprazine compared to risperidone in the treatment of predominant negative symptoms that had been also associated with concomitant improvement of functional performance. Overall, current evidence in the field supports the use of cariprazine in exacerbation of schizophrenia and suggests promising efficacy in the treatment of predominant negative symptoms.

Dysregulation of innate and adaptive immunity is increasingly being recognized as one of core characteristics of schizophrenia pathophysiology. Several studies have revealed that patients with schizophrenia present various alterations in the levels of distinct leukocyte subpopulations. However, studies addressing this point have provided mixed results. Therefore, in this study we translated a computational deconvolution algorithm in order to estimate counts of distinct leukocyte subpopulations in peripheral blood of patients with schizophrenia. Our analysis was based on publicly available data from peripheral blood DNA methylation profiling in 711 schizophrenia patients and 713 healthy controls (2 independent samples). In both datasets, there were significantly lower levels of CD8 and NK cells together with significantly higher levels of granulocytes. However, the levels of CD8 cells were insignificant after controlling for age and sex differences in one dataset. Our results indicate that patients with schizophrenia present innate immunity dysregulation in terms of NK cells depletion and increased levels of granulocytes. Longitudinal studies of various clinical subgroups of schizophrenia patients are required in order to disentangle whether our findings reflect trait- or state-dependent alterations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Accumulating evidence indicates that schizophrenia might be accompanied by abnormal vascularization. Vascular endothelial growth factor (VEGF) is one of key molecules involved in the development of vessels with vasodilatory activities., Objectives: We aimed to perform a systematic review and meta-analysis of studies investigating serum or plasma levels of VEGF in patients with schizophrenia and first-episode psychosis (FEP)., Methods: Electronic databases were searched from their inception until 18th Apr 2018. Meta-analysis was performed using random-effects models with Hedges' g as the effect size estimate. Quality assessment was performed using the Newcastle-Ottawa Scale., Results: We included 15 eligible studies, representing 982 patients and 791 healthy controls. Main analysis revealed no significant differences in VEGF levels between patients and controls (g = 0.10, 95%CI = -0.24-0.45, p = .553). Subgroup analysis demonstrated unaltered levels of VEGF in FEP patients (g = 0.03, 95%CI = -0.53-0.59, p = .911), including antipsychotic-naïve individuals (g = 0.34, 95%CI = -0.07-0.74, p = .103). However, the levels of VEGF were significantly higher in medicated multiple-episode schizophrenia (MES) patients (g = 0.45, 95%CI = 0.03-0.87, p = .036) compared to controls. Heterogeneity across studies was significant in the majority of analyses, except for the analysis of antipsychotic-naïve FEP patients. Tests of asymmetry were insignificant, indicating a lack of publication bias., Limitations: Main limitations of our meta-analysis include inability to address medication effects exhaustively and relatively low number of studies in subgroup analyses., Conclusions: Our results indicate elevated levels of VEGF in MES patients that are unaltered in FEP individuals. Longitudinal studies are required to disentangle whether elevated levels of VEGF in MES patients reflect illness progression, comorbid physical health impairments or appear due to medication effects., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We aimed to profile a broad panel of inflammatory markers in patients with schizophrenia and healthy controls. Additionally, we performed a meta-analysis of chemokine alterations that have not been subjected to quantitative synthesis so far. We recruited 78 patients with schizophrenia and 78 healthy controls, and measured inflammatory markers using the Luminex technology. After adjustment for multiple testing, we found elevated levels of interleukin (IL)-1 receptor antagonist (IL-1RA), IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, interferon-γ, eotaxin-1, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), platelet-derived growth factor with two B subunits (PDGF-BB), macrophage inflammatory protein (MIP)-1α, MIP-1β, vascular endothelial growth factor A (VEGF-A) and RANTES in multiple-episode schizophrenia (MES) patients. These differences, except for the difference in eotaxin-1 levels, appeared to be significant after co-varying for the dosage of antipsychotics. There were no significant differences in the levels of immune markers between first-episode schizophrenia (FES) patients and controls. Our meta-analysis revealed elevated levels of MCP-1 in first-episode psychosis (FEP) patients and MES individuals. Other chemokine alterations (elevated levels of IL-8, eotaxin-1 and MIP-1β) were present only in MES patients. Our results indicate that dysregulation of immune response in schizophrenia develops with illness progression or appears as a long-term medication effect. Chemokine alterations are another example of aberrant immune response in schizophrenia patients. Elevated levels of MCP-1 might represent trait markers since these alterations were found in FEP and MES patients. Other chemokine alterations might be the markers of disease progression or might represent medication effects., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Schizophrenia and bipolar disorder (BD) are complex and multidimensional disorders with high heritability rates. The contribution of genetic factors to the etiology of these disorders is increasingly being recognized as the action of multiple risk variants with small effect sizes, which might explain only a minor part of susceptibility. On the other site, numerous environmental factors have been found to play an important role in their causality. Therefore, in recent years, several studies focused on gene × environment interactions that are believed to bridge the gap between genetic underpinnings and environmental insults. In this article, we performed a systematic review of studies investigating gene × environment interactions in BD and schizophrenia spectrum phenotypes. In the majority of studies from this field, interacting effects of variation in genes encoding catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), and FK506-binding protein 5 (FKBP5) have been explored. Almost consistently, these studies revealed that polymorphisms in COMT, BDNF, and FKBP5 genes might interact with early life stress and cannabis abuse or dependence, influencing various outcomes of schizophrenia spectrum disorders and BD. Other interactions still require further replication in larger clinical and non-clinical samples. In addition, future studies should address the direction of causality and potential mechanisms of the relationship between gene × environment interactions and various categories of outcomes in schizophrenia and BD.

Neuroactive steroids, including testosterone, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) might play an important role in the pathophysiology of schizophrenia. Therefore, we performed a systematic review and meta-analysis of studies comparing the levels of testosterone, DHEA and DHEA-S in patients with schizophrenia and healthy controls. We searched electronic databases from their inception until Oct 29, 2017. Effect size (ES) estimates were calculated as Hedges' g. Data analysis was performed using random-effects models. Our analysis included 34 eligible studies, representing 1742 patients and 1604 controls. Main analysis revealed elevated DHEA-S levels in the whole group of patients (ES = 0.75, 95%CI: 0.23-1.28, p = 0.005). In subgroup analyses, patients with first-episode psychosis (FEP) had significantly higher levels of free testosterone (ES = 1.21, 95%CI: 0.30-2.12, p = 0.009) and DHEA-S (ES = 1.19, 95%CI: 0.66-1.71, p < 0.001). Acutely relapsed schizophrenia patients presented significantly higher levels of total testosterone (ES = 0.50, 95%CI: 0.21-0.70, p < 0.001). Total testosterone levels were also elevated in stable multi-episode schizophrenia (sMES) females (ES = 0.56, 95%CI: 0.33-0.80, p < 0.001) and reduced in sMES males (ES = -0.62, 95%CI: -1.07 to 0.18, p = 0.006). Increased levels of biologically active, free testosterone and DHEA-S in FEP suggest that these alterations might appear as a response to stress that becomes blunted during subsequent exacerbations of schizophrenia. Differential changes in total testosterone levels in male and female sMES patients might represent medication effects related to prolactin-releasing effects of antipsychotics., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Polymorphisms in immune-inflammatory response genes are believed to impact schizophrenia susceptibility. However, it remains unknown whether immunogenetic factors play a role in the etiology of deficit schizophrenia (D-SCZ). Therefore, we genotyped four polymorphisms in genes encoding two immune system regulatory proteins (CTLA-4 rs231775 and CD28 rs3116496), interleukin-6 (IL6 rs1800795) and transforming growth factor-β (TGFB1 rs1800470) in 513 schizophrenia patients and 374 controls. The CD28 rs3116496-CC genotype and C-allele were significantly more frequent in the whole group of patients and D-SCZ patients compared to controls. Our results indicate that the CD28 rs3116496 polymorphism might impact the risk of schizophrenia, especially D-SCZ., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The aim of this article was to perform a systematic review of studies investigating the association between peripheral levels of cytokines and C-reactive protein (CRP), cytokine gene polymorphisms and cognition in patients with schizophrenia and bipolar disorder (BD)., Methods: The following databases: PubMed, CINAHL Complete, Academic Search Complete, ERIC and Health Source: Nursing/Academic Edition databases were searched according to the PRISMA guidelines. We included studies that investigated the association between peripheral levels of CRP and cytokines, cytokine gene polymorphisms and cognitive performance in schizophrenia and/or BD patients. Subsequently, quality assessment of eligible publications was performed. Results were synthesized by discussing main findings around correlations between inflammatory markers and cognition., Results: Most consistent results indicate worse cognitive performance in schizophrenia patients with higher CRP levels. Less consistent evidence suggests better cognitive functioning of schizophrenia patients with higher levels of tumour necrosis factor-α (TNF-α). Evidence for the involvement of other cytokines in cognitive impairment in patients with schizophrenia is less convincing due to discordant results or scarcity of studies. Due to low number of studies, it is difficult to draw conclusions on the involvement of CRP and cytokine alterations in the development of cognitive deficits in BD. Single studies suggest the role of CRP, interleukin(IL)-1 receptor antagonist, IL-6 and TNF-α with its receptors in the development of cognitive impairment in BD., Conclusions: Peripheral inflammation might be related to cognitive deficits in schizophrenia and BD. Unequivocal conclusions cannot be made due to methodological heterogeneity and low number of studies investigating particular cytokines., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests: None declared.

The new area of research in psychiatric disorders is concerned with abnormal regeneration processes. The role of brain neurogenesis has been studied for decades. New discoveries, concerned with the pluripotency of VSEL cells and the role of factors involved in stem cell trafficking in peripheral blood create hope that it will be possible to develop a better understanding of the processes of neuroregeneration/neurodegeneration. There is an ongoing research investigating concentrations of: sphingosine -1-phosphate, SDF-1, elements of complement cascade, and stem cells in peripheral blood, including their possible connection to psychiatric disorders. Collected data, suggesting an abnormal course of regeneration processes in psychiatric disorders, raises hope of finding new potential markers of psychosis and anxiety disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Dyslipidaemia is one of the most prevalent metabolic disturbances observed in schizophrenia patients and has been largely attributed to the effects of poor lifestyle habits and adverse effects of antipsychotic treatment. However, less is known whether patients with first-episode non-affective psychosis (FENP) present subthreshold indices of dyslipidaemia. Therefore, we tested the hypothesis whether subclinical lipid profile alterations occur already in antipsychotic-naïve FENP patients., Methods: In this systematic review and meta-analysis we adhered to the PRISMA guidelines and searched PubMed, CINAHL Complete, Academic Search Complete, ERIC and Health Source: Nursing/Academic Edition from database inception to Dec 12, 2016, for case-control studies measuring the levels of total cholesterol, low- and high-density lipoproteins (LDL and HDL) and triglycerides in patients with FENP and controls. W calculated effect size (ES) estimates as Hedges' g and pooled data using random- or fixed-effects models depending on heterogeneity. Our study was registered in the PROSPERO database (CRD42016051732)., Results: Out of 2466 records identified, 19 studies representing 1803 participants were finally included in our systematic review and meta-analysis. Pooled analysis revealed that FENP patients had significantly lower levels of total cholesterol [ES=-0.16 (95% CI: -0.27, -0.06), p=0.003], LDL [ES=-0.13 (95% CI: -0.24, -0.01), p=0.034] and HDL [ES=-0.27 (95% CI: -0.49, -0.05), p=0.018] as well as significantly higher levels of triglycerides [ES=0.22 (95% CI: 0.11, 0.32), p<0.001] compared to controls. After removing single studies in sensitivity analysis, ES estimate for LDL levels was insignificant., Conclusions: Antipsychotic-naïve patients with FENP present subclinical dyslipidaemia. Future studies should disentangle whether our findings reflect disease-specific mechanisms., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this review, we provide an overview of the relationship between cannabis use and the development of schizophrenia, using both animal and human studies. We further discuss the potential neural mechanism that may mediate the relationship between cannabis use and schizophrenia symptoms. We finally provide clinical implications and future studies that can further elucidate the relationship between cannabis and schizophrenia.

Background: The excess mortality in schizophrenia is still a phenomenon insufficiently studied on the cross-national level. It is important to analyse current studies on morality in schizophrenia since significant changes have recently taken place in psychiatric health care systems and guidelines of pharmacological treatment have been developed in European countries., Subjects and Methods: This article reviews studies addressing mortality in schizophrenia in Europe that were published in English in the Pubmed database in 2009-2014. It aimed at determining countries where studies were conducted, methodologies and tools used, and current main mortality rates, as well as direction of causality in this group of patients., Results: The recently published studies were conducted only in few European countries. The majority of data was obtained from general medical records and death records. The studies indicate that schizophrenia patients are characterized by higher mortality rate than the general population, with natural causes (cardiovascular diseases and cancers) and suicides predominating. The increasing mortality gap with significantly shorter life expectancy of patients with schizophrenia in comparison with the general population is considerable., Conclusions: Death records are a crucial tool in studies on mortality in schizophrenia patients; however they are insufficiently employed. Recent European reports do not show positive tendencies, indicating that standardized mortality rates in schizophrenia remain on the same level or even increase, particularly for deaths resulting from natural causes. Due to various methodologies used in studies, their direct comparison is difficult. This limitation warrants further discussion on methods used in future studies on schizophrenia mortality in Europe.

Background: In this study, we aimed to investigate the effects of polymorphisms in genes encoding 1-carbon metabolism enzymes on differential development of metabolic parameters during 12 weeks of treatment with second-generation antipsychotics in first-episode schizophrenia patients., Methods: The following polymorphisms in 1-carbon metabolism genes were genotyped: MTHFR (C677T and A1298C), MTHFD1 (G1958A), MTRR (A66G), and BHMT (G742A). A broad panel of metabolic parameters including body mass index, waist circumference, total cholesterol low and high density lipoproteins, triglycerides, homocysteine, folate, and vitamin B12 was determined., Results: There was a significant effect of the interaction between the MTHFR C677T polymorphism and time on body mass index and waist circumference in the allelic and genotype analyses. Indeed, patients with the MTHFR 677CC genotype had higher increase in body mass index and waist circumference compared with other corresponding genotypes or the MTHFR 677T allele carriers (CT and TT genotypes). In addition, patients with the MTHFR 677TT genotype had higher waist circumference in all time points. Similarly, patients with the MTHFR 677TT genotype had higher body mass index in all time points, but this effect was not significant after correction for multiple testing., Conclusions: Our results indicate that the MTHFR C677T polymorphism may predict antipsychotic-induced weight gain. Effects of the MTHFR C677T polymorphism might be different in initial exposure to antipsychotics compared with long-term perspective., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)

In this study, we aimed to investigate whether a history of childhood trauma (CT) can help predict early response to antipsychotic treatment in patients with first-episode schizophrenia (FES). We recruited 64 FES patients who were followed up after 12 weeks of treatment with second-generation antipsychotics. Symptomatic manifestation was examined using the Positive and Negative Syndrome Scale (PANSS). Childhood adversities were assessed using the Early Trauma Inventory Self-Report-Short Form. Nonresponders had significantly higher general trauma score, emotional abuse score, total trauma score, and baseline PANSS negative factor score. A history of CT was significantly more frequent among nonresponders. Logistic regression analysis revealed that positive history of CT, higher emotional abuse score, and higher baseline PANSS negative factor score are significant predictors of poor response to treatment. Our results indicate that a history of CT, especially emotional abuse, and higher severity of negative symptoms are independent predictors of poor response to treatment with antipsychotics.

We aimed to investigate whether antipsychotics differentially impact insight and whether these effects appear because of improvement in psychopathological manifestation in 132 first-episode schizophrenia patients and 201 acutely relapsed schizophrenic patients, who were followed up for 12 weeks. Olanzapine and risperidone were administered to first-episode schizophrenia patients, whereas acutely relapsed schizophrenic patients were treated with olanzapine, perazine and ziprasidone. The Positive And Negative Syndrome Scale (PANSS) was used to assess psychopathology. Insight was assessed using the G12 item of PANSS. Unadjusted mixed-model regression analysis indicated a significant improvement in the PANSS G12 item score in both groups. There were no significant differences between distinct treatment subgroups of patients in terms of improvement in the PANSS G12 item score. After adjustment for the trajectories of changes in symptom dimensions, a decrease in the PANSS G12 item score was because of an improvement in positive, negative and excitement symptoms. A decrease in the PANSS G12 item score was also related to an increase in the severity of depressive symptomatology. Our results indicate that antipsychotics exert similar effects on insight in acute psychosis. These effects are likely because of an improvement in psychopathological manifestation. The improvement in insight might be related to the development of depressive symptoms.