Viral infections may disrupt the structural and functional integrity of the nervous system, leading to acute conditions such as encephalitis, and neuropsychiatric conditions as mood disorders, schizophrenia, and neurodegenerative diseases. Investigating viral interactions of human proteins may reveal mechanisms underlying these effects and offer insights for therapeutic interventions. This study explores molecular interactions of virus and human proteins that may be related to neuropsychiatric disorders.

Herpes Simplex Virus-1 (HSV-1), Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Influenza A virus (IAV) (H1N1, H5N1), and Human Immunodeficiency Virus (HIV1&2) were selected as key viruses. Protein structures for each virus were accessed from the Protein Data Bank and analyzed using the HMI-Pred web server to detect interface mimicry between viral and human proteins. The PANTHER classification system was used to categorize viral-human protein interactions based on function and cellular localization.

Energetically favorable viral-human protein interactions were identified for HSV-1 (467), CMV (514), EBV (495), H1N1 (3331), H5N1 (3533), and HIV 1&2 (62425). Besides immune and apoptosis-related pathways, key neurodegenerative pathways, including those associated with Parkinson's and Huntington's diseases, were frequently interacted. A total of 38 human proteins, including calmodulin 2, Ras-related botulinum toxin substrate 1 (Rac1), PDGF-β, and vimentin, were found to interact with all six viruses.

The study indicates a substantial number of energetically favorable interactions between human proteins and selected viral proteins, underscoring the complexity and breadth of viral strategies to hijack host cellular mechanisms. Further in vivo and in vitro validation is required to understand the implications of these interactions.

Attempts to delineate an immune subtype of schizophrenia have not yet led to the clear identification of potential treatment targets. An unbiased informatic approach at the level of individual immune cytokines and symptoms may reveal organisational structures underlying heterogeneity in schizophrenia, and potential for future therapies. The aim was to determine the network and relative influence of pro- and anti-inflammatory cytokines on depressive, positive, and negative symptoms. We further aimed to determine the effect of exposure to minocycline or placebo for 6 months on cytokine-symptom network connectivity and structure. Network analysis was applied to baseline and 6-month data from the large multi-center BeneMin trial of minocycline (N = 207) in schizophrenia. Pro-inflammatory cytokines IL-6, TNF-α, and IFN-γ had the greatest influence in the inflammatory network and were associated with depressive symptoms and suspiciousness at baseline. At 6 months, the placebo group network connectivity was 57% stronger than the minocycline group, due to significantly greater influence of TNF-α, early wakening, and pathological guilt. IL-6 and its downstream impact on TNF-α, and IFN-γ, could offer novel targets for treatment if offered at the relevant phenotypic profile including those with depression. Future targeted experimental studies of immune-based therapies are now needed.

Both cortisol and interleukins appear at abnormal levels in schizophrenia. Our previous study has shown that cortisol and interleukins are associated with psychopathology and response to antipsychotic medications in a relatively small sample size of patients with schizophrenia. The current study was designed to investigate how cortisol, interleukins (ILs) and their interactions would correlate with clinical presentation in a relatively large sample size of patients with schizophrenia.

We compared serum cortisol, IL-2, IL-6, and IL-8 levels in 162 medicated schizophrenia patients (including 27 patients in remission) and 62 healthy controls. Serum levels of cortisol and interleukins were measured by radioimmunoassay and quantitative ELISA, respectively. Clinical symptoms were assessed according to the Positive and Negative Syndrome Scale (PANSS).

Patients with schizophrenia had significantly higher levels of cortisol and IL-2 compared to controls. Patients in remission had higher levels of IL-6 than non-remitting patients. PANSS positive symptoms, general psychopathology, cortisol and IL-2 were the most central nodes in the cortisol-IL-symptom network. The interaction between cortisol and IL-2 was associated with PANSS positive symptoms, general psychopathology and depressive factor. For patients with cortisol level above the median, IL-2 was negatively associated with PANSS positive symptoms and general psychopathology.

Our results indicated that the interaction between cytokines and cortisol may be associated with the pathophysiology of some symptoms in chronic schizophrenia. In particular, the interaction between cortisol and IL-2 is associated with the clinical phenotypes of schizophrenia.

Immune gene variants are known to be associated with the risk of psychiatric disorders, their clinical manifestations, and their response to therapy. This narrative review summarizes the current literature over the past decade on the association of polymorphic variants of cytokine genes with risk, severity, and response to treatment for severe mental disorders such as bipolar disorder, depression, and schizophrenia. A search of literature in databases was carried out using keywords related to depressive disorder, bipolar disorder, schizophrenia, inflammation, and cytokines. Gene lists were extracted from publications to identify common genes and pathways for these mental disorders. Associations between polymorphic variants of the IL1B, IL6, and TNFA genes were the most replicated and relevant in depression. Polymorphic variants of the IL1B, IL6, IL6R, IL10, IL17A, and TNFA genes have been associated with schizophrenia. Bipolar disorder has mainly been associated with polymorphic variants of the IL1B gene. Interestingly, the IL6R gene polymorphism (rs2228145) was associated with all three diseases. Some cytokine genes have also been associated with clinical presentation and response to pharmacotherapy. There is also evidence that some specific polymorphic variants may affect the expression of cytokine genes. Thus, the data from this review indicate a link between neuroinflammation and severe mental disorders.

Catalytic antibodies, or abzymes, are capable of not only binding but also hydrolyzing various proteins. Previously, an increase in the level of myelin basic protein (MBP)-hydrolyzing activity of antibodies was shown in patients with a number of neurological and mental disorders, including schizophrenia. Furthermore, antipsychotic therapy is known to induce a change in cytokine levels in patients with schizophrenia, which affects regulation of the immune response and inflammatory status. This study investigated the influence of typical and atypical antipsychotics on catalytic antibody activity and the 10 major pro- and anti-inflammatory serum cytokine levels. The study included 40 patients with schizophrenia: 15 treated with first-generation antipsychotics and 25 treated with atypical antipsychotics for 6 weeks. It was found that treatment with atypical antipsychotics changed the levels of some pro-inflammatory cytokines. Antipsychotic therapy also caused a significant decrease in MBP-hydrolyzing activity in patients with schizophrenia (p = 0.0002), and associations of catalytic activity with interleukins were observed.

In psychotic and mood disorders, immune alterations are hypothesized to underlie cognitive symptoms, as they have been associated with elevated blood levels of inflammatory cytokines, kynurenine metabolites, and markers of microglial activation. The current meta-analysis synthesizes all available clinical evidence on the associations between immunomarkers (IMs) and cognition in these psychiatric illnesses.

Pubmed, Web of Science, and Psycinfo were searched for peer-reviewed studies on schizophrenia spectrum disorder (SZ), bipolar disorder (BD), or major depressive disorder (MDD) including an association analysis between at least one baseline neuropsychological outcome measure (NP) and one IM (PROSPERO ID:CRD42021278371). Quality assessment was performed using BIOCROSS. Correlation meta-analyses, and random effect models, were conducted in Comprehensive Meta-Analysis version 3 investigating the association between eight cognitive domains and pro-inflammatory and anti-inflammatory indices (PII and AII) as well as individual IM.

Seventy-five studies (n = 29,104) revealed global cognitive performance (GCP) to be very weakly associated to PII (r = -0.076; p = 0.003; I² = 77.4) or AII (r = 0.067; p = 0.334; I² = 38.0) in the combined patient sample. Very weak associations between blood-based immune markers and global or domain-specific GCP were found, either combined or stratified by diagnostic subgroup (GCP x PII: SZ: r = -0.036, p = 0.370, I² = 70.4; BD: r = -0.095, p = 0.013, I² = 44.0; MDD: r = -0.133, p = 0.040, I² = 83.5). We found evidence of publication bias.

There is evidence of only a weak association between blood-based immune markers and cognition in mood and psychotic disorders. Significant publication and reporting biases were observed and most likely underlie the inflation of such associations in individual studies.

Neurocognitive difficulties are highly prevalent among people with schizophrenia and have been linked to increased inflammation, as well as dysfunction and disability. Poor neurocognitive functioning has also been documented in individuals at clinical high risk for psychosis (CHR) and a burgeoning literature point to alterations in inflammation markers in this population. However, there is limited information regarding the putative link between inflammation and neurocognition in CHR individuals, and the potential role of inflammation in the development of cognitive difficulties and psychosis. As previous reports indicate that early treatment in schizophrenia is associated with better outcomes, there is an urgent need to identify neurobiological mechanisms underlying cognitive deterioration and psychosis in CHR individuals to provide them with care prior to significant cognitive and functional declines. To address this gap in the literature, we review and summarize the relevant literatures on inflammation and neurocognitive dysfunction in schizophrenia and CHR individuals, point to remaining gaps, and suggest directions for future research.

While abnormal neurodevelopment contributes to schizophrenia (SCZ) risk, there is also evidence to support a role for immune dysfunction in SCZ. BCL11B, associated with SCZ in genome-wide association study (GWAS), is a transcription factor that regulates the differentiation and development of cells in the central nervous and immune systems. Here, we use functional genomics data from studies of BCL11B to investigate the contribution of neuronal and immune processes to SCZ pathophysiology. We identified the gene targets of BCL11B in brain striatal cells (n = 223 genes), double negative 4 (DN4) developing T cells (n = 114 genes) and double positive (DP) developing T cells (n = 518 genes) using an integrated analysis of RNA-seq and ChIP-seq data. No gene-set was enriched for genes containing common variants associated with SCZ but the DP gene-set was enriched for genes containing missense de novo mutations (DNMs; p = .001) using data from 3,447 SCZ trios. Post hoc analysis revealed the enrichment to be stronger for DP genes negatively regulated by BCL11B. Biological processes enriched for genes negatively regulated by BCL11B in DP gene-set included immune system development and cytokine signaling. These analyses, leveraging a GWAS-identified SCZ risk gene and data on gene expression and transcription factor binding, indicate that DNMs in immune pathways contribute to SCZ risk.

Negative symptoms of schizophrenia are debilitating and chronic in nature, are difficult to treat, and contribute to poor functional outcomes. Motivational deficits are a core negative symptom and may involve alterations in reward processing, which involve subcortical regions such as the basal ganglia. More specifically, dopamine-rich regions like the ventral striatum, have been implicated in these reward-processing deficits. Inflammation is one mechanism that may underlie negative symptoms, and specifically motivational deficits, via the effects of inflammatory cytokines on the basal ganglia. Previous work has demonstrated that inflammatory stimuli decrease neural activity in the ventral striatum and decrease connectivity in reward-relevant neural circuitry. The immune system has been shown to be involved in the pathophysiology of schizophrenia, and inflammatory cytokines have been shown to be altered in patients with the disorder. This paper reviews the literature on associations between inflammatory markers and negative symptoms of schizophrenia as well as the role of anti-inflammatory drugs to target negative symptoms. We also review the literature on the role of inflammation and reward processing deficits in both healthy controls and individuals with depression. We use the literature on inflammation and depression as a basis for a model that explores potential mechanisms responsible for inflammation modulating certain aspects of negative symptoms in patients with schizophrenia. This approach may offer novel targets to treat these symptoms of the disorder that are significant barriers to functional recovery and do not respond well to available antipsychotic medications.

Schizophrenia, a multisystem disorder with an unknown etiology, is associated with several immune dysfunctions, including abnormal levels of circulating cytokines. In this review, we investigated the changes of cytokines in schizophrenic patients, their connection with behavioral symptoms severity and their potential clinical implications. We also assessed the possible causative role of abnormal cytokine levels in schizophrenia pathogenesis. Based on meta-analyses, we categorized cytokines according to their changes in schizophrenic patients into four groups: (1) increased cytokines, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, IL-12, and transforming growth factor (TGF)-β, (2) non-altered cytokines, including IL-2, IL-4, and IL-17, (3) increased or non-altered cytokines, including IL-8 and interferon (IFN)-γ, and (4) IL-10 with increased, decreased, and non-altered levels. Notably, alterations in cytokines may be variable in four different categories of SP, including first-episode and drug-naïve, first-episode and non-drug-naïve, stable chronic, and chronic in acute relapse. Furthermore, disease duration, symptoms severity, incidence of aggression, and cognitive abilities are correlated with levels of certain cytokines. Clinical implications of investigating the levels of cytokine in schizophrenic patients include early diagnosis, novel therapeutic targets development, patient stratification for choosing the best therapeutic protocol, and predicting the prognosis and treatment response. The levels of IL-6, IL-8, IFN-γ, IL-2 are related to the treatment response. The available evidence shows a potential causative role for cytokines in schizophrenia development. There is a substantial need for studies investigating the levels of cytokines before disease development and delineating the therapeutic implications of the disrupted cytokine levels in schizophrenia.

Multiple lines of evidence indicate that patients with chronic schizophrenia (SCZ) display executive dysfunction across the illness course. However, the potential molecular pathophysiologic mechanisms remain poorly elucidated. Neurodevelopmental changes caused by alterations of inflammatory mediators and neurotrophins have been shown to occur in the earliest stages of SCZ, and be associated with executive dysfunction (ED) in SCZ. Therefore, the current study was to investigate whether the interplay between BDNF and inflammatory mediators was involved in the disruption of executive function of long-term hospitalized patients with chronic SCZ. Serum cytokines and BDNF levels were measured in 112 long-term hospitalized patients with chronic SCZ and 44 healthy normal controls. Executive functions were assessed by verbal fluency tests (VFT), the Stroop word-color test (Stroop), and the Wisconsin card sorting tests (WCST).The results showed that the patients had higher IL-2, IL-6, IL-8, but lower TNF-α and BDNF compared to control subjects. In the patient group, BDNF was positively associated with IL-2 and IL-8 levels, while lower BDNF levels were correlated with ED measured by VFT and WCST tests. Multiple stepwise regression analyses confirmed that BDNF × IL-8 and BDNF × TNF-α were factors influencing the total score of VFT, while BDNF × IL-8 and BDNF × TNF-α were recognized as influencing factors for WCST scores. Our results suggest complex interactions between BDNF and cytokines were involved in the pathophysiology of executive function impairments in patients with SCZ.

Several lines of evidence indicate that aberrations in immune-inflammatory pathways may contribute to the pathophysiology of schizophrenia spectrum disorders. Here, we propose a novel theoretical framework that was previously developed for major depression and bipolar disorder, namely, the compensatory immune-regulatory reflex system (CIRS), as applied to the neuro-immune pathophysiology of schizophrenia and its phenotypes, including first-episode psychosis (FEP), acute relapses, chronic and treatment-resistant schizophrenia (TRS), comorbid depression, and deficit schizophrenia. These schizophrenia phenotypes and manifestations are accompanied by increased production of positive acute-phase proteins, including haptoglobin and α2-macroglobulin, complement factors, and macrophagic M1 (IL-1β, IL-6, and TNF-α), T helper (Th)-1 (interferon-γ and IL-2R), Th-2 (IL-4, IL-5), Th-17 (IL-17), and T regulatory (Treg; IL-10 and transforming growth factor (TGF)-β1) cytokines, cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway, and chemokines, including CCL-11 (eotaxin), CCL-2, CCL-3, and CXCL-8. While the immune profiles in the different schizophrenia phenotypes indicate the activation of the immune-inflammatory response system (IRS), there are simultaneous signs of CIRS activation, including increased levels of the IL-1 receptor antagonist (sIL-1RA), sIL-2R and tumor necrosis factor-α receptors, Th-2 and Treg phenotypes with increased IL-4 and IL-10 production, and increased levels of TRYCATs and haptoglobin, α2-macroglobulin, and other acute-phase reactants, which have immune-regulatory and anti-inflammatory effects. Signs of activated IRS and CIRS pathways are also detected in TRS, chronic, and deficit schizophrenia, indicating that these conditions are accompanied by a new homeostatic setpoint between upregulated IRS and CIRS components. In FEP, increased baseline CIRS activity is a protective factor that may predict favorable clinical outcomes. Moreover, impairments in the CIRS are associated with deficit schizophrenia and greater impairments in semantic and episodic memory. It is concluded that CIRS plays a key role in the pathophysiology of schizophrenia by negatively regulating the primary IRS and contributing to recovery from the acute phase of illness. Therefore, components of the CIRS may offer promising therapeutic targets for schizophrenia.

Psychiatric illnesses are cognitive and behavioral disorders of the brain. At present, psychiatric diagnosis is based on DSM-5 criteria. Even if endophenotype specificity for psychiatric disorders is discussed, it is difficult to study and identify psychiatric biomarkers to support diagnosis, prognosis, or clinical response to treatment. This chapter investigates the innovative biomarkers of psychiatric diseases for diagnosis and personalized treatment, in particular post-genomic data and proteomic analyses.

Negative symptoms are common in individuals at clinical high-risk (CHR) for psychosis and are associated with worse functional outcomes. Inflammation may be one mechanism underlying negative symptoms. Inflammatory markers are altered in individuals at CHR and are associated with negative symptoms in patients with schizophrenia. We thus hypothesized that baseline inflammatory markers would predict the development of negative symptoms in individuals at CHR for psychosis. Thirty seven individuals from the North American Prodromal Longitudinal Study who met CHR criteria were included in the study. Inflammatory cytokines, including interferon (IFN)-λ, Interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), IL-4, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF) were measured at baseline. Negative symptoms as measured by the Scale of Prodromal Symptoms, were measured at baseline and six and twelve months. Associations between inflammatory markers and the trajectory of negative symptoms (slope) over the first year of follow-up, were assessed using linear regression models controlling for age, sex, race and depressive symptom severity (as assessed by the Calgary Depression Scale for Schizophrenia). Baseline TNF (beta = 0.361, p = 0.007) and IL-6 (beta = -0.306, p = 0.026) predicted negative symptoms slopes, along with depressive symptom severity at baseline (beta = -0.596, p = 0.000). These findings demonstrate that inflammatory cytokines may underlie the development of negative symptoms in some individuals at CHR for psychosis. TNF predicted the development of negative symptoms independent of baseline depression. Given the heterogeneity of the CHR population, the comorbidity of negative symptoms and depression in this population, and the particular challenges in treating negative symptoms, immune markers could represent potential biomarkers that underlie the development of negative symptoms, representing a potential treatment target.

Increased inflammatory markers have been found in patients with chronic schizophrenia, and have been associated with negative symptoms. The deficit syndrome is a distinct subtype of schizophrenia, characterized by primary and enduring negative symptoms.

We measured inflammatory markers in patients with and without deficit schizophrenia and controls.

Using multivariate analyses, tumor necrosis factor (TNF)-α and interleukin-6 were associated with the deficit syndrome, and TNF-α predicted blunted affect, alogia, and total negative symptoms.

Findings suggest that deficit schizophrenia subtype is associated with increased inflammation and immunotherapies may be a novel target for negative symptoms.

When considering neurodevelopmental disorders (NDDs), Schizophrenia (SZ) and Autism Spectrum Disorder (ASD) are considered to be among the most severe in term of prevalence, morbidity and impact on the society. Similar features and overlapping symptoms have been observed at multiple levels, suggesting common pathophysiological bases. Indeed, recent genome-wide association studies (GWAS) and epidemiological data report shared vulnerability genes and environmental triggers across the two disorders. In this review, we will discuss the possible biological mechanisms, including glutamatergic and GABAergic neurotransmissions, inflammatory signals and oxidative stress related systems, which are targeted by adverse environmental exposures and that have been associated with the development of SZ and ASD. We will also discuss the emerging role of the gut microbiome as possible interplay between environment, immune system and brain development. Finally, we will describe the involvement of epigenetic mechanisms in the maintenance of long-lasting effects of adverse environments early in life. This will allow us to better understand the pathophysiology of these NDDs, and also to identify novel targets for future treatment strategies.

Over the last decade, finding a reliable biomarker for the early detection of schizophrenia (Scz) has been a topic of interest. The main goal of the current review is to provide a comprehensive view of the brain, blood, cerebrospinal fluid (CSF), and serum biomarkers of Scz disease. Imaging studies have demonstrated that the volumes of the corpus callosum, thalamus, hippocampal formation, subiculum, parahippocampal gyrus, superior temporal gyrus, prefrontal and orbitofrontal cortices, and amygdala-hippocampal complex were reduced in patients diagnosed with Scz. It has been revealed that the levels of interleukin 1β (IL-1β), IL-6, IL-8, and TNF-α were increased in patients with Scz. Decreased mRNA levels of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), neurotrophin-3 (NT-3), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) genes have also been reported in Scz patients. Genes with known strong relationships with this disease include BDNF, catechol-O-methyltransferase (COMT), regulator of G-protein signaling 4 (RGS4), dystrobrevin-binding protein 1 (DTNBP1), neuregulin 1 (NRG1), Reelin (RELN), Selenium-binding protein 1 (SELENBP1), glutamic acid decarboxylase 67 (GAD 67), and disrupted in schizophrenia 1 (DISC1). The levels of dopamine, tyrosine hydroxylase (TH), serotonin or 5-hydroxytryptamine (5-HT) receptor 1A and B (5-HTR1A and 5-HTR1B), and 5-HT1B were significantly increased in Scz patients, while the levels of gamma-aminobutyric acid (GABA), 5-HT transporter (5-HTT), and 5-HT receptor 2A (5-HTR2A) were decreased. The increased levels of SELENBP1 and Glycogen synthase kinase 3 subunit α (GSK3α) genes in contrast with reduced levels of B-cell translocation gene 1 (BTG1), human leukocyte antigen DRB1 (HLA-DRB1), heterogeneous nuclear ribonucleoprotein A3 (HNRPA3), and serine/arginine-rich splicing factor 1 (SFRS1) genes have also been reported. This review covers various dysregulation of neurotransmitters and also highlights the strengths and weaknesses of studies attempting to identify candidate biomarkers.

Evidence suggests the existence of cytokine disturbances in patients with schizophrenia but their association with psychopathology is still unclear. The aim of the current study was to determine if pro-inflammatory cytokine levels (tumor necrosis factor-α, interleukin (IL)-6, IL-2, IL-1β, IL-1RA) are increased in stable outpatients compared with healthy subjects, and to analyze if they could be specific biomarkers of clinical dimensions in schizophrenia.

We studied 73 stable outpatients with schizophrenia in their first 10 years of illness and 73 age- and sex-matched healthy controls. An accurate assessment of clinical dimensions (positive, negative, depressive, cognitive) was performed in patients.

Only IL-6 levels were significantly increased in patients after controlling for body mass index, waist circumference, smoking, and psychopharmacological treatment, compared with healthy subjects. After adjusting for several confounders, multiple linear regression models identified that Positive and Negative Syndrome Scale negative symptoms, general psychopathology, and global severity are predicted by IL-1β concentrations, while motivation and pleasure domain of Clinical Assessment Interview for Negative Symptoms and Personal and Social Performance global functioning scores are predicted by IL-2 levels. Cognitive performance, positive, and depressive symptom severity did not correlate with any cytokine.

Our findings suggested that IL-6 concentrations are elevated in stable patients with schizophrenia. Whereas IL-2 specifically marks severity of the motivation and pleasure domain of negative symptoms, IL-1β is not specific to this dimension as it also predicts severity of general and global symptomatology.

Previous studies consistently showed that IL-3 signaling may be involved in the pathophysiology of schizophrenia. However, investigations of associations between IL-3 and the neurocognitive impairments are lacking, including the study of how this may vary with stage of illness. We recruited 45 first-episode drug-naïve (FE-Sz), 35 chronic medicated schizophrenia (Ch-Sz) and 40 healthy controls (HC) and examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum IL-3. Altered serum IL-3 levels were found in both patient groups compared with HC group (both p < 0.001). There were significantly lower neurocognitive scores on the RBANS and nearly all of its five subscales, except for Visuospatial/Constructional index in both FE-Sz and Ch-Sz patients vs healthy controls. Moreover, a significant reduction in Immediate memory index (p = 0.021) and a trend-level reduction in RBANS total score (p = 0.094) in Ch-Sz than FE-Sz patients. Interestingly, there was a significant negative correlation between IL-3 and the Immediate memory index only in Ch-Sz patients (p = 0.03). Our findings showed that neurocognitive impairments present in schizophrenia emerge during the first episode with further diminished functioning with disease progression, and IL-3 may be involved in the immediate memory deficits in the chronic phase of schizophrenia.

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).

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.

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.

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.

Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome. Recent studies have considered HERVs as potential pathogenic factors. The majority of HERV genes are mutated and not capable of encoding functional proteins; regardless, some HERV genes, such as HERV-W envelope (env) glycoprotein, are known to have intact open reading frames. The HERV-W element on 7q21.2, which encodes a protein referred to as Syncytin-1, participates in human placental morphogenesis and can activate a pro-inflammatory and autoimmune cascade. Neuropsychological disorders are typically linked to inflammatory abnormalities. In this study, we review that Syncytin-1 has been increasingly involved in the development of neuropsychological disorders, such as schizophrenia and multiple sclerosis (MS). This study also presents inflammation imbalances in schizophrenia and MS. More importantly, we discuss the potential role and molecular mechanisms by which Syncytin-1 regulates inflammatory abnormalities in neuropsychological diseases. In summary, Syncytin-1 activity may represent a novel molecular pathogenic mechanism in neuropyschological diseases, such as schizophrenia and MS.

Schizophrenia is a complex illness in which genetic, environmental, and epigenetic components have been implicated. However, recently, psychiatric disorders appear to be related to a chronic inflammatory state, at the level of specific cerebral areas which have been found as well impaired and responsible for schizophrenia symptomatology. Hence, a role of inflammatory mediators and cytokines has been as well defined. Accordingly, the role of an acute inflammatory phase protein, the C-reactive protein (CRP) has been recently investigated.

The objective of the present study is to evaluate how PCR may represent a biomarker in schizophrenia, i.e. correlated with illness phases and/or clinical manifestation and/or psychopathological severity.

A systematic review was here carried out by searching the following keywords ((C-reactive protein AND ((schizophrenia) OR (psychotic disorder))) for the topics 'PCR' and 'Schizophrenia', by using MESH terms.

An immune dysfunction and inflammation have been described amongst schizophrenic patients. Findings reported elevated CRP levels in schizophrenia, mainly correlated with the severity of illness and during the recrudescent phase. CRP levels are higher when catatonic features, negative symptomatology and aggressiveness are associated. CRP levels appeared not to be related to suicidal behaviour and ideation.

CRP and its blood levels have been reported higher amongst schizophrenic patients, by suggesting a role of inflammation in the pathogenesis of schizophrenia. Further studies are needed to better understand if CRP may be considered a biomarker in schizophrenia.

Despite progress in identifying molecular pathophysiological processes in schizophrenia, valid biomarkers are lacking for both the disease and treatment response.

This comprehensive review summarises recent efforts to identify molecular mechanisms on the level of protein and gene expression and epigenetics, including DNA methylation, histone modifications and micro RNA expression. Furthermore, it summarises recent findings of alterations in lipid mediators and highlights inflammatory processes. The potential that this research will identify biomarkers of schizophrenia is discussed.

Recent studies have not identified clear biomarkers for schizophrenia. Although several molecular pathways have emerged as potential candidates for future research, a complete understanding of these metabolic pathways is required to reveal better treatment modalities for this disabling condition.

Large longitudinal cohort studies are essential that pair a thorough phenotypic and clinical evaluation for example with gene expression and proteome analysis in blood at multiple time points. This approach might identify biomarkers that allow patients to be stratified according to treatment response and ideally also allow treatment response to be predicted. Improved knowledge of molecular pathways and epigenetic mechanisms, including their potential association with environmental influences, will facilitate the discovery of biomarkers that could ultimately be effective tools in clinical practice.

Many studies have indicated that immune dysfunction might be involved in the physiopathology of schizophrenia and aggression. This study aimed to investigate the correlation between high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-10 and clinical characteristics, especially aggression, and to explore the potential role of hsCRP and IL-10 as plasma biomarkers of schizophrenia.

Forty-one patients with schizophrenia and forty healthy individuals were enrolled. Psychopathological severity and aggression were assessed using the Positive and Negative Syndrome Scale (PANSS) and Modified Overt Aggression Scale (MOAS). Plasma concentrations of hsCRP and IL-10 were assessed by enzyme-linked immunosorbent assay (ELISA).

(1) Higher levels of hsCRP (p<0.001), lower levels of logIL-10 (p<0.001) and higher ratio of hsCRP to IL-10 (p<0.001) were observed in the plasma of patients with schizophrenia, compared to healthy controls; (2) ROC (receiver operating characteristic) curve analysis revealed that ratio of hsCRP/IL-10 (predictive value: 0.783, p<0.01; sensitivity: 85.4%; specificity: 67.5%) was more applicable as a biomarker to distinguish patients with schizophrenia from the control group than hsCRP and IL-10 alone (predictive value: 0.718, p<0.01; 0.275, p<0.001, respectively); (3) we found positive correlations between hsCRP and the total score and verbal aggression score of MOAS (r=0.654, p<0.01; r=0.678, p<0.05), and between hsCRP/IL-10 and the total score of MOAS (r=0.636, p<0.01).

Our results suggest the possible function of hsCRP and IL-10 in the pathogenesis of schizophrenia and the possible value of hsCRP/IL-10 as a potential peripheral biomarker of schizophrenia. This finding also suggests a relationship between hsCRP, IL-10 and their ratio with aggression in patients with schizophrenia.

Schizophrenia, bipolar disorder and major depressive disorder (MDD) have all been associated with aberrant blood cytokine levels; however, neither the pattern of cytokine alterations nor the impact of clinical status have been compared across disorders. We performed a meta-analysis of blood cytokines in acutely and chronically ill patients with these major psychiatric disorders. Articles were identified by searching the PubMed, PsycInfo and Web of Science, and the reference lists of these studies. Sixty-eight studies met the inclusion criteria (40 schizophrenia, 10 bipolar disorder and 18 MDD) for acutely ill patients. Forty-six studies met the inclusion criteria (18 schizophrenia, 16 bipolar disorder and 12 MDD) for chronically ill patients. Levels of two cytokines (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)), one soluble cytokine receptor (sIL-2R), and one cytokine receptor antagonist (IL-1RA) were significantly increased in acutely ill patients with schizophrenia, bipolar mania and MDD compared with controls (P<0.01). Following treatment of the acute illness, IL-6 levels significantly decreased in both schizophrenia and MDD (P<0.01); sIL-2R levels increased in schizophrenia; and IL-1RA levels in bipolar mania decreased. In chronically ill patients, the levels of IL-6 were significantly increased in schizophrenia, euthymic (but not depressed) bipolar disorder and MDD compared with controls (P<0.01). The levels of IL-1β and sIL-2R were significantly increased in both chronic schizophrenia and euthymic bipolar disorder. Overall, there were similarities in the pattern of cytokine alterations in schizophrenia, bipolar disorder and MDD during acute and chronic phases of illness, raising the possibility of common underlying pathways for immune dysfunction. Effects of treatment on cytokines were more robust for schizophrenia and MDD, but were more frequently studied than for acute mania. These findings have important implications for our understanding of the pathophysiology and treatment of major psychiatric disorders.

Gastro-intestinal (GI) microbiota and the 'gut-brain axis' are proving to be increasingly relevant to early brain development and the emergence of psychiatric disorders. This review focuses on the influence of the GI tract on Brain-Derived Neurotrophic Factor (BDNF) and its relationship with receptors for N-methyl-D-aspartate (NMDAR), as these are believed to be involved in synaptic plasticity and cognitive function. NMDAR may be associated with the development of schizophrenia and a range of other psychopathologies including neurodegenerative disorders, depression and dementias. An analysis of the routes and mechanisms by which the GI microbiota contribute to the pathophysiology of BDNF-induced NMDAR dysfunction could yield new insights relevant to developing novel therapeutics for schizophrenia and related disorders. In the absence of GI microbes, central BDNF levels are reduced and this inhibits the maintenance of NMDAR production. A reduction of NMDAR input onto GABA inhibitory interneurons causes disinhibition of glutamatergic output which disrupts the central signal-to-noise ratio and leads to aberrant synaptic behaviour and cognitive deficits. Gut microbiota can modulate BDNF function in the CNS, via changes in neurotransmitter function by affecting modulatory mechanisms such as the kynurenine pathway, or by changes in the availability and actions of short chain fatty acids (SCFAs) in the brain. Interrupting these cycles by inducing changes in the gut microbiota using probiotics, prebiotics or antimicrobial drugs has been found promising as a preventative or therapeutic measure to counteract behavioural deficits and these may be useful to supplement the actions of drugs in the treatment of CNS disorders.

Identifying biomarkers that can be used as diagnostics or predictors of treatment response (theranostics) in people with schizophrenia (Sz) will be an important step towards being able to provide personalized treatment. Findings from the studies in brain tissue have not yet been translated into biomarkers that are practical in clinical use because brain biopsies are not acceptable and neuroimaging techniques are expensive and the results are inconclusive. Thus, in recent years, there has been search for blood-based biomarkers for Sz as a valid alternative. Although there are some encouraging preliminary data to support the notion of peripheral biomarkers for Sz, it must be acknowledged that Sz is a complex and heterogeneous disorder which needs to be further dissected into subtype using biological based and clinical markers. The scope of this review is to critically examine published blood-based biomarker of Sz, focusing on possible uses for diagnosis, treatment response, or their relationship with schizophrenia-associated phenotype. We sorted the studies into six categories which include: (1) brain-derived neurotrophic factor; (2) inflammation and immune function; (3) neurochemistry; (4) oxidative stress response and metabolism; (5) epigenetics and microRNA; and (6) transcriptome and proteome studies. This review also summarized the molecules which have been conclusively reported as potential blood-based biomarkers for Sz in different blood cell types. Finally, we further discusses the pitfall of current blood-based studies and suggest that a prediction model-based, Sz specific, blood oriented study design as well as standardize blood collection conditions would be useful for Sz biomarker development.

Accumulating evidence showed that interleukin-2 (IL-2) may be involved in the pathophysiology of schizophrenia. Increased IL-2 levels have been found in the serum of schizophrenia patients with mixed results. In the present study, we assessed serum IL-2 levels in a large group of 160 schizophrenia patients compared to 60 healthy control subjects matched for age and gender. The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS), and serum IL-2 levels were measured by sandwich ELISA. The results showed that IL-2 levels were significantly higher in chronic patients with schizophrenia than in healthy control subjects (p<0.001). Correlation analysis revealed a significantly negative association between IL-2 levels and the PANSS cognitive and positive subscales (both p<0.01). Stepwise multiple regression analyses confirmed IL-2 as the influencing factor for the cognitive and positive subscales of the PANSS. Our findings suggested that increased IL-2 may be involved in the cognitive impairments and psychopathology of chronic schizophrenia.

Recent schizophrenia (SCZ) research aims to establish biomarkers with high predictive value for the diagnosis, severity of illness or treatment resistance. SCZ is accompanied by activated immune-inflammatory pathways, including increased levels of cytokines and chemokines, but few studies tried to identify predictive properties of such measures.

We included 54 medicated SCZ patients and 118 healthy controls and examined 15 cytokines and chemokines. Possible associations between these immune-inflammatory biomarkers and the diagnosis of SCZ, severity of illness and treatment resistance were investigated.

SCZ is associated with a specific cytokine - chemokine profile, i.e., increased CCL11, MIP-1α, sTNF-R1 and sTNF-R2 levels, and decreased levels of IP-10, TNF-α, IL-2 and IL-4. The combination of five biomarkers (sTNF-R1, sTNF-R2, CCL11, IP-10, IL-4) may predict the diagnosis of SCZ with a sensitivity of 70.0% and a specificity of 89.4%. There was a weak association between the negative symptoms and biomarkers, i.e., IL-2 (inversely) and CCL11 (positively). Patients with treatment resistance showed increased levels of sTNF-R1, sTNF-R2 and MCP-1.

The findings of this study reinforce that SCZ is associated with a pro-inflammatory profile and suggest that some immune mediators may be used as reliable biomarkers for the diagnosis of SCZ and treatment resistance.

The mechanisms underlying cognitive impairment in schizophrenia and bipolar disorders are largely unknown. Immune abnormalities have been found in both disorders, and inflammatory mediators may play roles in cognitive function. We investigated if inflammatory markers are associated with general cognitive abilities.

Participants with schizophrenia spectrum (N=121) and bipolar spectrum (N=111) disorders and healthy controls (N=241) were included. General intellectual abilities were assessed using the Wechsler Abbreviated Scale of Intelligence (WASI). Serum concentrations of the following immune markers were measured: Soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin 1 receptor antagonist (IL-1Ra), osteoprotegerin, von Willebrand factor, C-reactive protein, interleukin-6 and CD40 ligand.

After adjusting for age, sex and diagnostic group, significant negative associations with general cognitive function were found for sTNF-R1 (p=2×10(-5)), IL-1Ra (p=0.002) and sCD40 ligand (p=0.003). Among patients, the associations remained significant (p=0.006, p=0.005 and p=0.02) after adjusting for possible confounders including education, smoking, psychotic and affective symptoms, body mass index, cortisol, medication and time of blood sampling. Subgroup analysis, showed that general cognitive abilities were significantly associated with IL-1Ra and sTNF-R1 in schizophrenia patients, with sCD40L and IL-1Ra in bipolar disorder patients and with sTNF-R1 in healthy controls.

The study shows significant negative associations between inflammatory markers and general cognitive abilities after adjusting for possible confounders. The findings strongly support a role for inflammation in the neurophysiology of cognitive impairment.

Schizophrenia is a neuropsychiatric disorder affecting 1% of the world's population. Due to both a broad range of symptoms and disease heterogeneity, current therapeutic approaches to treat schizophrenia fail to address all symptomatic manifestations of the disease. Therefore, disease models that reproduce core pathological features of schizophrenia are needed for the elucidation of pathological disease mechanisms. Here, we employ a comprehensive global label-free liquid chromatography-mass spectrometry proteomic (LC-MS(E)) and metabonomic (LC-MS) profiling analysis combined with the targeted proteomics (selected reaction monitoring and multiplex immunoassay) of serum and brain tissues to investigate a chronic phencyclidine (PCP) rat model in which glutamatergic hypofunction is induced through noncompetitive NMDAR-receptor antagonism. Using a multiplex immunoassay, we identified alterations in the levels of several cytokines (IL-5, IL-2, and IL-1β) and fibroblast growth factor-2. Extensive proteomic and metabonomic brain tissue profiling revealed a more prominent effect of chronic PCP treatment on both the hippocampal proteome and metabonome compared to the effect on the frontal cortex. Bioinformatic pathway analysis confirmed prominent abnormalities in NMDA-receptor-associated pathways in both brain regions, as well as alterations in other neurotransmitter systems such as kainate, AMPA, and GABAergic signaling in the hippocampus and in proteins associated with neurodegeneration. We further identified abundance changes in the level of the superoxide dismutase enzyme (SODC) in both the frontal cortex and hippocampus, which indicates alterations in oxidative stress and substantiates the apoptotic pathway alterations. The present study could lead to an increased understanding of how perturbed glutamate receptor signaling affects other relevant biological pathways in schizophrenia and, therefore, support drug discovery efforts for the improved treatment of patients suffering from this debilitating psychiatric disorder.

Since decades immunological aberrancies have been reported in schizophrenia patients. As schizophrenia represents a heterogenous disorder with a variety of clinical manifestations, complex interactions between the immune system in the brain might have important etiological implications.

Recent findings of altered expression of immune-related genes, changes of peripheral and central cytokines, antibodies and immune cells point toward dysbalanced immune response processes in schizophrenia.

Based on immunogenetic factors, immune dysfunctions caused by infections, increased autoimmune reactivity and low-grade inflammatory processes in the periphery as well as in central nervous system may affect neurobiological circuits including changed neurotransmitter metabolisms contributing to pathophysiological alterations in schizophrenia. These immunological abnormalities might provide tools for better diagnostic characterization of this heterogenous disease and on the other side, they may also support the development of immune-related therapeutic strategies.

The relationship between the pathophysiology of dementia and neuroinflammation is well-known. The number of reports stating that depression is a risk factor for dementia has recently been increasing. These epidemiological findings suggest the possibility that both depression and dementia have common pathophysiological backgrounds of neuroinflammation.

The sample consists of 64 non-demented community-dwelling older participants aged 65 years or over. Participants were assessed at baseline (2004-2006) and 3 years later (2007-2009). Plasma concentration of markers of inflammation (interleukins (IL)-1β, IL-2, IL-6, soluble interleukin-2 receptor (sIL-2R), soluble interleukin-6 receptor (sIL-6R), high sensitivity C-reactive protein (hsCRP) and tumor necrosis factor (TNF)-α) were measured at baseline. Depression symptoms were assessed with the Beck Depression Inventory (BDI) and cognitive decline was assessed with the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB) and Clock Drawing Test (CDT) at baseline and follow-up. All analyses were adjusted for age, gender and years of education.

In the cross-sectional analysis, the present study found soluble IL-2 receptor (sIL-2R) to be associated only with the MMSE score at baseline in men. In the longitudinal analysis, none of our inflammatory biomarkers were associated with either depressive symptoms or cognitive decline.

The present study consists of small number of participants and body mass index (BMI) scores were not obtained.

Our findings suggest that sIL-2R is associated with current cognitive function in men. None of our inflammatory markers predicted future depressive state or cognitive decline in our community-dwelling healthy older sample.

Abnormal behavior and disturbed cognition, often assumed to represent psychiatric illness, may actually result from some form of occult organic brain disease that can be detected by means of one or more biomarkers. This truth was discovered more than a century ago by Aloysius Alzheimer, a German psychiatrist and neuropathologist. As a psychiatrist, he described the behavioral manifestations of "senile dementia" in a 51-year-old female; as a neuropathologist, he was the first to recognize the significance of the senile plaques and neurofibrillary tangles found in her brain after her death at age 55 years. It was Alzheimer who made the connection between these "biomarkers" and the symptoms of the increasingly prevalent disease that now bears his name. In recent years, the search for psychiatry-relevant biomarkers of major depression, schizophrenia, bipolar disease, and other important psychiatric/neuropsychiatric disorders has intensified. Biomarkers in psychiatry and neuropsychiatry have the potential of clarifying the etiology of an ambiguous clinical presentation-making it possible, for example, to detect underlying differences between psychological maladies that have confusingly similar symptoms. In addition, attempts are now being made to classify mental disorders on the basis of biomarkers. Biomarkers may also disclose the presence of a previously unsuspected physical explanation for behavior(s) originally presumed to be "psychiatric" in origin. Although clinically usable biomarkers in the diagnosis and treatment of mental illness await validation, candidate genomic biomarkers and protein profiling of candidate biomarkers in psychiatry are rapidly gaining ground as areas of interest, with considerable future potential. This review considers biomarker-related issues germane to psychiatry and neuropsychiatry in the context of new data that can be used to tailor therapies to the individual psychiatric patient.

There are studies showing that gene polymorphisms within the transforming growth factor-β (TGF-β) signaling constitute schizophrenia risk variants. However, the association between TGFB1 gene polymorphisms (+869T/C and +915G/C), TGF-β level with schizophrenia course, and its symptomatology together with cognitive functioning has not been investigated so far. We included 151 patients with schizophrenia and 279 healthy controls. Cognitive functioning was assessed using Rey Auditory Verbal Learning Test, Trail Making Test (TMT)-A and TMT-B, Verbal Fluency task, Stroop test, as well as selected subtests from the Wechsler Adults Intelligence Scale - Revised, Polish adaptation (WAIS-R-Pl): Digit Symbol Coding, Digit Span Forward and Backward, and Similarities. Additionally, serum TGF-β levels were measured in 88 schizophrenia patients and 88 healthy controls. Serum TGF-β level was significantly higher among patients with schizophrenia in comparison with healthy controls; however, the studied polymorphisms were not associated with TGF-β level in schizophrenia patients. Subjects carrying the +869T allele performed significantly worse in comparison with +869CC homozygotes on Stroop task, Verbal Fluency task and Digit Symbol Coding task. There was a significant difference in age of psychosis onset in female schizophrenia patients with respect to the TGFB1 +869T/C polymorphism. Additionally, adjustment for possible confounders revealed that there was a significant difference in cognitive performance on Digit Symbol Coding task with respect to the TGFB1 +869T/C polymorphism among female schizophrenia patients. Our results suggest that TGF-β signaling might be a valid link contributing to observed differences in age of onset and the level of cognitive decline between male and female schizophrenia patients.

With the advent of DSM 5 criticism has generally centered on a lack of biological validity of the diagnostic criteria. Part of the problem in describing a nosology of psychosis is the tacit assumption of multiple genetic causes each with an incremental loading on the clinical picture that fails to differentiate a clear underlying pathophysiology of high impact. The aim of this paper is to consolidate a primary theory of deficient muscarinic signaling underlying key clinical features of schizophrenia and its regulation by several important genetic associations including neuregulin, DISC and dysbindin. Secondary reductions in markers for GABAergic function and changes in the levels of interneuron calcium binding proteins parvalbumin and calbindin can be attributed to dysfunctional muscarinic transduction. A parallel association exists for cytokine production. The convergent pathway hypothesis is likewise used to model dopaminergic and glutamatergic theories of schizophrenia. The negative symptom dimension is correlated with dysfunction of Akt and ERK transduction, a major point of convergence. The present paradigm predicts the importance of a recent finding of a deletion in a copy number variant of PLCB1 and its potential use if replicated, as one of the first testable biological markers differentiating schizophrenia from bipolar disorder and further subtyping of schizophrenia into deficit and non-deficit. Potential limitations of PLCB1 as a prospective marker are also discussed.

Many lines of findings support the hypothesis of the inflammation-related pathways in the multifactorial pathogenesis of schizophrenia (SZ). Interleukin-10 (IL-10), a potential anti-inflammatory cytokine, was found to be altered in chronic patients with SZ. The aim of this study was to assess the serum levels of IL-10 in first-episode and drug-naïve (FEDN) patients with SZ and its relationships with the psychopathological parameters. Serum IL-10 levels were analyzed using established procedures in 128 FEDN patients with SZ and 62 healthy controls. Schizophrenia symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS) with cognitive factor derived from the five factor model of the PANSS. Compared to the healthy controls, the patients exhibited a significant decrease in IL-10 levels. Serum IL-10 was inversely correlated with the PANSS negative symptom, as well as with the PANSS cognitive factor subscores in patients. Our results suggested that decreased IL-10 may be implicated in the negative symptom and cognitive impairment at the acute stage of schizophrenia episode.