This study aims to provide robust evidence to support or challenge the immune hypothesis of schizophrenia.

To conduct a meta-analysis of reports on blood leukocyte subpopulations in schizophrenia vs healthy controls, examining disease- and treatment-related differences as well as potential confounders.

Systematic database search for English and non-English peer-reviewed articles in PubMed, Web of Science, Scopus, and Cochrane Library databases, with the last search in January 2024.

Cross-sectional, case-control, and longitudinal studies comparing leukocyte numbers in patients with schizophrenia and healthy controls. After duplicates were removed, 3691 studies were identified for screening.

Data extraction and quality assessment were conducted following PRISMA and MOOSE guidelines. Data were independently extracted by 2 authors and pooled using random-effects models.

The planned primary outcomes were differences in leukocyte subpopulation counts between individuals with schizophrenia and healthy controls to increase our understanding of the immune system dysfunction in schizophrenia.

Sixty-four relevant articles were identified (60 cross-sectional/case-control studies and 4 longitudinal studies) with data on leukocyte numbers from 26 349 individuals with schizophrenia and 16 379 healthy controls. Neutrophils (g = 0.69; 95% CI, 0.49 to 0.89; Bonferroni-adjusted P < .001; n = 40 951 [47 between-group comparisons]) and monocytes (g = 0.49; 95% CI, 0.24 to 0.75; Bonferroni-adjusted P < .001; n = 40 513 [44 between-group comparisons]) were higher in schizophrenia compared with control participants. Differences were greater in first-episode vs chronic schizophrenia and in patients who were not treated vs treated with antipsychotic medication. There were no significant differences in eosinophils (g = 0.02; 95% CI, -0.16 to 0.20; Bonferroni-adjusted P > .99; n = 3277 [18 between-group comparisons]), basophils (g = 0.14; 95% CI, -0.06 to 0.34; Bonferroni-adjusted P = .85; n = 2614 [13 between-group comparisons]), or lymphocytes (g = -0.08; 95% CI, -0.21 to 0.06; Bonferroni-adjusted P > .99; n = 41 693 [59 between-group comparisons]). Neutrophils decreased longitudinally (g = -0.30; 95% CI, -0.45 to -0.15; Bonferroni-adjusted P < .001; n = 896 [4 within-group comparisons]) and eosinophils increased longitudinally (g = 0.61; 95% CI, 0.52 to 0.71; Bonferroni-adjusted P < .001; n = 876 [3 within-group comparisons]) after successful treatment of acute psychosis.

Our findings of increased blood neutrophils and monocytes support the immune hypothesis of schizophrenia, particularly highlighting the role of innate immune activation. As these effects were more pronounced in early disease stages and also reflected clinical improvement, they may pave the way for innovative treatment strategies based on immunological and inflammatory pathways and help revolutionize the treatment landscape for schizophrenia.

It has been well-established that the allostatic load (AL) index, a cumulative score of multi-system dysregulation in response to chronic stress, is significantly increased at the time of a psychiatric diagnosis. However, no studies have investigated if there is an association between the AL index in childhood and the later development of mental health symptoms in young adults.

Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population cohort from Bristol, United Kingdom, we investigated the AL index at age 9 years and the risks for mental health symptoms at age 24 years. We used multinomial logistic regression analysis to investigate the association between AL threshold (categorised into bottom third: AL index ≤ 7, middle third: AL index = 7.1-9.9, and top third: AL index ≥ 10) and mental health symptoms while adjusting for sex, the age of mother at delivery, and social class. We used a relative risk ratio (RRR) and 95 % confidence interval(CI) for each variable. We further investigated the association between adverse childhood experiences (ACEs) and mental health symptoms.

We identified a significant association between sex and mental health symptoms, with more females (59 % vs 41 %) showing mental health symptoms than males. We found no direct association between the AL index at age 9 and the later development of mental health symptoms. However, an RRR analysis showed that individuals in the middle and the top third of the AL index had an RRR of 1.99 and 2.20, respectively, to develop mental health symptoms if they were females. We found that individuals who experienced ACE had a much higher risk of developing mental health symptoms as young adults, with the adjusted RRR of 5.39 (95 % CI: 3.00;9.67), 6.79 (95 % CI: 2.55; 18.1), and 2.10 (95 % CI: 0.37;11.8) for neglect, physical and sexual abuse, respectively, in individuals with mood disorder symptoms. The adjusted RRR for neglect and physical and sexual abuse in individuals with psychotic symptoms was 0.99 (95 % CI: 0.37; 2.59), 2.92 (95 % CI: 0.35; 24.4), and 10.5 (95 % CI: 0.99; 112), respectively.

Although the AL index in childhood was not directly associated with the later development of psychotic and mood disorder symptoms in this cohort, females in the higher tertiles of the AL index measured at 9 years of age had an elevated risk of mental health symptoms as young adults. In line with previous work, a strong association was identified between childhood adversity and mental health symptoms in young adulthood. These results highlight the importance of considering the impact of early stress on biological embedding and the later emergence of mental health problems, especially in females.

Rising studies have consistently reported gut bacteriome alterations in schizophrenia (SCZ). However, little is known about the role of the gut virome on shaping the gut bacteriome in SCZ. Here in, we sequenced the fecal virome, bacteriome, and host peripheral metabolome in 49 SCZ patients and 49 health controls (HCs). We compared the gut bacterial community composition and specific abundant bacteria in SCZ patients and HCs. Specific gut viruses and host peripheral metabolites co-occurring with differential bacteria were identified using Multiple Co-inertia Analysis (MCIA). Additionally, we construct a latent serial mediation model (SMM) to investigate the effect of the gut virome on SCZ through the bacteriome and host metabolic profile. SCZ patients exhibited a decreased gut bacterial β-diversity compared to HCs, with seven differentially abundant bacteria, including Coprobacillaceae, Enterococcaceae etc. Gut viruses including Suoliviridae and Rountreeviridae, co-occur with these SCZ-related bacteria. We found that the viral-bacterial transkingdom correlations observed in HCs were dramatically lost in SCZ. The altered correlations profile observed in SCZ may impact microbiota-derived peripheral metabolites enriched in the bile acids pathway, eicosanoids pathway, and others, contributing to host immune dysfunction and inflammation. The SMM model suggested potential causal chains between gut viruses and SCZ, indicating that the effect of gut virome on SCZ is significantly mediated by bacteriome and metabolites. In conclusion, these findings provide a comprehensive perspective on the role of gut microbiota in the pathogenesis of SCZ. They reveal that patients with schizophrenia harbor an abnormal virome-bacteriome ecology, shedding light on the potential development of microbial therapeutics.

Ketamine, a psychoactive substance strictly regulated by international drug conventions, is classified as a "new type drug" due to its excitatory, hallucinogenic, or inhibitory effects. The etiology of ketamine-induced psychiatric symptoms is multifaceted, with the immune regulatory mechanism being the most prominent among several explanatory theories. In recent years, the interaction between the immune system and nervous system have garnered significant attention in neuropsychiatric disorder research. Notably, the infiltration of peripheral lymphocytes into the central nervous system has emerged as an early hallmark of certain neuropsychiatric disorders. However, a notable gap exists in the current literature, regarding the immune regulatory mechanisms, specifically the peripheral immune alterations, associated with ketamine-induced psychiatric symptoms. To address this void, this article endeavors to provide a comprehensive overview of the pathophysiological processes implicated in psychiatric disorders or symptoms, encompassing those elicited by ketamine. This analysis delves into aspects such as nerve damage, alterations within the central immune system, and the regulation of the peripheral immune system. By emphasizing the intricate crosstalk between the peripheral immune system and the central nervous system, this study sheds light on their collaborative role in the onset and progression of psychiatric diseases or symptoms. This insight offers fresh perspectives on the underlying mechanisms, diagnosis and therapeutic strategies for mental disorders stemming from drug abuse.

Mental health represents a major challenge to our societies. One key difficulty associated with neuropsychiatric drug development is the lack of connection between the underlying biology and the disease. Nevertheless, there is growing optimism in this field with recent drug approvals (the first in decades) and renewed interest from pharmaceutical companies and investors. Here we review some of the most promising drug discovery and development endeavors currently deployed by industry. We also present elements illustrating the renewed interest from key stakeholders in neuropsychiatric drug development and provide potential future directions in this field.

Abnormal immune and inflammatory responses are considered to contribute to schizophrenia (SZ). The neutrophil/lymphocyte ratio (NLR) is an inexpensive and reproducible marker of systemic inflammatory responses. Accumulating studies have demonstrated that NLR values are increased in SZ compared to healthy controls and closely related to clinical symptoms in antipsychotic-naïve first-episode SZ (ANFES) patients. However, to our knowledge, only one study has examined NLR in relation to neurocognition in 27 first-episode psychosis patients and 27 controls. This study aimed to examine the relationship of NLR values with cognitive performances in ANFES patients with a larger sample size. Whole blood cell counts were measured in ninety-seven ANFES patients and fifty-six control subjects. The neurocognitive functions of all subjects were measured by the repeatable battery for the assessment of neuropsychological status (RBANS). ANFES patients performed worse on cognition and had increased NLR values relative to healthy controls. In addition, increased NLR was negatively associated with cognitive functions in ANFES patients. Lymphocyte count was positively correlated with cognitive functions in patients. These findings suggest that the abnormal immune and inflammation system indicated by NLR may be involved in the cognitive functions in ANFES patients.

In the last decade, the kynurenine pathway (KP) has gained attention in the pathogenesis of cognitive impairment in schizophrenia being at the croassroad between neuroinflammation and glutamatergic and cholinergic neurotransmission. However, clinical findings are scarse and conflicting, and the specific contributions of these two systems to the neurobiology of cognitive symptoms are far from being elucidated. Furthermore, little is known about the molecular underpinnings of non-pharmacological interventions for cognitive improvement, including rehabilitation strategies.

The current study examined 72 patients with schizophrenia, divided in two clusters depending on the severity of the cognitive impairment, with the aim to evaluate the impact of inflammatory biomarkers and KP metabolites depending on cognitive functioning. Moreover, we studied their possible link to the cognitive outcome in relation to sessions of cognitive remediation therapy (CRT) and aerobic exercise (AE) in a longitudinal arm of 42 patients.

Neuroinflammation appeared to exert a more pronounced influence on cognition in patients exhibiting a higher cognitive functioning, contrasting with the activation of the KP, which had a greater impact on individuals with a lower cognitive profile. Cognitive improvements after the treatments were negatively predicted by levels of TNF-α and positively predicted by the 3-hydroxykynurenine (3-HK)/kynurenine (KYN) ratio, an index of the kynurenine-3-monooxygenase (KMO) enzyme activity.

Overall, these findings add novel evidence on the biological underpinnings of cognitive impairment in schizophrenia pointing at a differential role of neuroinflammation and KP metabolites in inducing cognitive deficits depending on the cognitive reserve and predicting outcomes after rehabilitation.

Patients with schizophrenia with early onset age have been shown to exhibit more severe negative symptoms. Genetic, biomarker, postmortem brain, and imaging studies indicate the involvement of immune abnormalities in the pathophysiology of schizophrenia. In this study, we examined the moderating role of early onset on the associations between clinical symptoms and neutrophil-to-lymphocyte ratio (NLR) in medication-naïve first-episode schizophrenia (MNFES). A total of 97 MNFES patients were recruited. Neutrophil (NEU), LYM, and NLR values were compared between early-onset (EO) and non-early-onset (non-EO) patients with schizophrenia to explore the potential influence of EO on the correlations between NLR and symptoms. The results showed no differences in NEU and NLR values between the EO and non-EO groups. In the EO group, NEU and NLR values significantly correlated with general psychopathology and total score (all p < 0.05), whereas lymphocyte counts were not correlated with symptoms of schizophrenia. NEU and NLR were not associated with symptoms in the non-EO group. Linear regression analysis in the EO group revealed that NEU or NLR values were a predictive biomarker for the clinical symptoms. Our study indicates that EO patients had greater severe negative symptoms compared with non-EO patients. In addition, onset age mediates the relationships of NEU and NLR values with clinical symptoms, suggesting that an immune disturbance, particularly increased innate immune response in EO patients, may be involved in the psychophysiology of schizophrenia.

Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism. The genetic defect in WD affects the ATP7B gene, which encodes the ATP7B transmembrane protein, which is essential for maintaining normal copper homeostasis in the body. It is primarily expressed in the liver and acts by incorporating copper into ceruloplasmin (Cp), the major copper transport protein in the blood. In conditions of excess copper, ATP7B transports it to bile for excretion. Mutations in ATP7B lead to impaired ATP7B function, resulting in copper accumulation in hepatocytes leading to their damage. The toxic "free"-unbound to Cp-copper released from hepatocytes then accumulates in various organs, contributing to their damage and clinical manifestations of WD, including hepatic, neurological, hematological, renal, musculoskeletal, ophthalmological, psychiatric, and other effects. While most clinical manifestations of WD correspond to identifiable organic or cellular damage, the pathophysiology underlying its psychiatric manifestations remains less clearly understood. A search for relevant articles was conducted in PubMed/Medline, Science Direct, Scopus, Willy Online Library, and Google Scholar, combining free text and MeSH terms using a wide range of synonyms and related terms, including "Wilson's disease", "hepatolenticular degeneration", "psychiatric manifestations", "molecular mechanisms", "pathomechanism", and others, as well as their combinations. Psychiatric symptoms of WD include cognitive disorders, personality and behavioral disorders, mood disorders, psychosis, and other mental disorders. They are not strictly related to the location of brain damage, therefore, the question arises whether these symptoms are caused by WD or are simply a coincidence or a reaction to the diagnosis of a genetic disease. Hypotheses regarding the etiology of psychiatric symptoms of WD suggest a variety of molecular mechanisms, including copper-induced CNS toxicity, oxidative stress, mitochondrial dysfunction, mitophagy, cuproptosis, ferroptosis, dysregulation of neurotransmission, deficiencies of neurotrophic factors, or immune dysregulation. New studies on the expression of noncoding RNA in WD are beginning to shed light on potential molecular pathways involved in psychiatric symptomatology. However, current evidence is still insufficient to definitively establish the cause of psychiatric symptoms in WD. It is possible that the etiology of psychiatric symptoms varies among individuals, with multiple biological and psychological mechanisms contributing to them simultaneously. Future studies with larger samples and comprehensive analyses are necessary to elucidate the mechanisms underlying the psychiatric manifestations of WD and to optimize diagnostics and therapeutic approaches.

Observational studies have shown a link between autoimmune diseases and schizophrenia, with conflicting conclusions. Due to the existence of confounding factors, the causal link between autoimmune diseases and schizophrenia is still unknown.

We conducted a comprehensive Mendelian randomization (MR) analysis of schizophrenia and ten common autoimmune diseases in individuals of European descent using genome-wide association studies (GWASs). To evaluate the relationships between autoimmune diseases and schizophrenia, inverse variance weighted, MR-RAPS, Bayesian weighted MR, constrained maximum likelihood, debiased IVW, MR-Egger, and weighted median were utilized. Several sensitivity analyses were performed to ensure the reliability of the study's results.

Our findings reveal that genetically predicted ankylosing spondylitis is related to an increased risk of schizophrenia, whereas celiac disease, type 1 diabetes, and systemic lupus erythematosus are associated with a lower risk of schizophrenia. In the reverse MR analysis, our study indicated that genetically predicted schizophrenia is linked to higher risks of ankylosing spondylitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and psoriasis. Neither multiple sclerosis nor rheumatoid arthritis have been linked to schizophrenia, and vice versa.

Despite contradicting some other observational reports, this study showed support for a causal link between autoimmune diseases and schizophrenia. To gain a better understanding of the mechanisms underlying the development of immune-mediated schizophrenia, additional research is required to identify potential mechanisms identified in observational studies.

Schizophrenia and bipolar disorder frequently face significant delay in diagnosis, leading to being missed or misdiagnosed in early stages. Both disorders have also been associated with trait and state immune abnormalities. Recent machine learning-based studies have shown encouraging results using diagnostic biomarkers in predictive models, but few have focused on immune-based markers. Our main objective was to develop supervised machine learning models to predict diagnosis and illness state in schizophrenia and bipolar disorder using only a panel of peripheral kynurenine metabolites and cytokines.

The cross-sectional I-GIVE cohort included hospitalized acute bipolar patients (n = 205), stable bipolar outpatients (n = 116), hospitalized acute schizophrenia patients (n = 111), stable schizophrenia outpatients (n = 75) and healthy controls (n = 185). Serum kynurenine metabolites, namely tryptophan (TRP), kynurenine (KYN), kynurenic acid (KA), quinaldic acid (QUINA), xanthurenic acid (XA), quinolinic acid (QUINO) and picolinic acid (PICO) were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS), while V-plex Human Cytokine Assays were used to measure cytokines (interleukin-6 (IL-6), IL-8, IL-17, IL-12/IL23-P40, tumor necrosis factor-alpha (TNF-ɑ), interferon-gamma (IFN-γ)). Supervised machine learning models were performed using JMP Pro 17.0.0. We compared a primary analysis using nested cross-validation to a split set as sensitivity analysis. Post-hoc, we re-ran the models using only the significant features to obtain the key markers.

The models yielded a good Area Under the Curve (AUC) (0.804, Positive Prediction Value (PPV) = 86.95; Negative Prediction Value (NPV) = 54.61) for distinguishing all patients from controls. This implies that a positive test is highly accurate in identifying the patients, but a negative test is inconclusive. Both schizophrenia patients and bipolar patients could each be separated from controls with a good accuracy (SCZ AUC 0.824; BD AUC 0.802). Overall, increased levels of IL-6, TNF-ɑ and PICO and decreased levels of IFN-γ and QUINO were predictive for an individual being classified as a patient. Classification of acute versus stable patients reached a fair AUC of 0.713. The differentiation between schizophrenia and bipolar disorder yielded a poor AUC of 0.627.

This study highlights the potential of using immune-based measures to build predictive classification models in schizophrenia and bipolar disorder, with IL-6, TNF-ɑ, IFN-γ, QUINO and PICO as key candidates. While machine learning models successfully distinguished schizophrenia and bipolar disorder from controls, the challenges in differentiating schizophrenic from bipolar patients likely reflect shared immunological pathways by the both disorders and confounding by a larger state-specific effect. Larger multi-centric studies and multi-domain models are needed to enhance reliability and translation into clinic.

Diagnosing patients suffering from psychotic disorders is far from being achieved with molecular support, despite all the efforts to study these disorders from different perspectives. Characterizing the proteome of easily obtainable blood specimens, such as the peripheral blood mononuclear cells (PBMCs), has particular interest in biomarker discovery and generating pathophysiological knowledge. This approach has been explored in psychiatry, and while generating valuable information, it has not translated into meaningful biomarker discovery. In this project, we report the proof-of-concept of a methodology that aims to explore further information obtained with classical proteomics approaches that is easily overlooked. PBMC samples from first-episode psychosis and control subjects were subjected to a SWATH-MS approach, and the classical protein relative quantification was performed, where 389 proteins were found to be important to distinguish the two groups. Individual analysis of the quantified peptides was also performed, highlighting peptides of unchanged proteins that were significantly altered. With the combination of protein- and peptide-centered proteomics approaches, it is possible to highlight that information about proteoforms, namely regulation at the peptide level possibly due to post-translational modifications, is routinely overlooked and that its diagnostic potential should be further explored. SIGNIFICANCE: Our exploratory findings highlight the potential of MS-based proteomics strategies, combining protein- and peptide-centered approaches, to aid clinical decision-making in first-episode psychosis, helping to establish early biomarkers for schizophrenia and other psychotic disorders. Particularly, the less popular peptide-centered approach allows the identification/measurement of overlooked modulated peptides that may have potential biomarker characteristics. The application in parallel of protein- and peptide-centered strategies is transversal to research of other diseases, potentially allowing a more comprehensive characterization of the metabolic/pathophysiological alterations related to a specific disease.

Schizophrenia (SCZ) shares high clinical relevance with the immune system, and the potential interactions of psychopharmacological drugs with the immune system are still an overlooked area. Here, we aimed to identify whether the second-generation antipsychotics (SGA) monotherapy or combined therapy of SGA with other psychiatric medications influence the routine blood immunity biomarkers of patients with SCZ.

Medical records of inpatients with SCZ from January 2019 to June 2023 were retrospectively screened from June 2023 to August 2023. The demographic data and peripheral levels of cytokines (IL-2, IL-4, IL-6, TNF-α, INF-γ, and IL-17 A), lymphocyte subtype proportions (CD3+, CD4+, CD8 + T-cell, and natural killer (NK) cells), and thyroid autoimmune antibodies (thyroid peroxidase antibody (TPOAb), and antithyroglobulin antibody (TGAb)) were collected and analyzed.

30 drug-naïve patients, 64 SGA monotherapy (20 for first-episode SCZ, 44 for recurrent SCZ) for at least one week, 39 combined therapies for recurrent SCZ (18 with antidepressant, 10 with benzodiazepine, and 11 with mood stabilizer) for at least two weeks, and 23 used to receive SGA monotherapy (had withdrawn for at least two weeks) were included despite specific medication. No difference in cytokines was found between the SGA monotherapy sub-groups (p > 0.05). Of note, SGA monotherapy appeared to induce a down-regulation of IFN-γ in both first (mean [95% confidence interval]: 1.08 [0.14-2.01] vs. 4.60 [2.11-7.08], p = 0.020) and recurrent (1.88 [0.71-3.05] vs. 4.60 [2.11-7.08], p = 0.027) episodes compared to drug-naïve patients. However, the lymphocyte proportions and thyroid autoimmune antibodies remained unchanged after at least two weeks of SGA monotherapy (p > 0.05). In combined therapy groups, results mainly resembled the SGA monotherapy for recurrent SCZ (p > 0.05).

The study demonstrated that SGA monotherapy possibly achieved its comfort role via modulating IFN-γ, and SGA combined therapy showed an overall resemblance to monotherapy.

Our previous studies have found that functional changes in the hippocampal circuit from dentate gyrus (DG) to cornu ammonis 3 and 1 (CA3, CA1) are highly associated with schizophrenia (SZ). However, no studies have explored the genetic expression across the three and two human hippocampal subfields (DG-CA3-CA1 and CA3-CA1) between subjects with SZ and healthy controls (CT).

We matched cohorts between CT (n = 13) and SZ (n = 13). Among SZ, 6 subjects were on antipsychotics (AP) while 7 were off AP. We combined RNA-seq data from all three and two hippocampal subfields and performed differentially expressed gene analyses across DG-CA3-CA1 and CA3-CA1 affected by either SZ or AP.

We found that differentially expressed genes (DEGs) from effects of SZ and AP across DG-CA3-CA1 and CA3-CA1 were highly associated with gene ontology terms related to hormonal and immune signaling, cellular mitosis and apoptosis, ion and amino acid transports, and protein modification and degradation. Additionally, we found that multiple genes related to solute-carrier family and immune signaling were significantly upregulated across DG-CA3-CA1 and CA3-CA1 in patients with SZ relative to CT, and AP consistently and robustly repressed the expression of these upregulated genes in the DG-CA3-CA1 and CA3-CA1 from subjects with SZ.

Together, these data suggest that the upregulated solute-carrier family genes in the hippocampus might have important roles in the pathophysiology of SZ, and that AP may reduce the symptoms of psychosis in SZ via rescuing the solute-carrier gene expression.

The complex and unresolved pathogenesis of schizophrenia has posed significant challenges to its diagnosis and treatment. While recent research has established a clear association between immune function and schizophrenia, the causal relationship between the two remains elusive.

We employed a bidirectional two-sample Mendelian randomization approach to investigate the causal relationship between schizophrenia and 731 immune cell traits by utilizing public GWAS data. We further validated the causal relationship between schizophrenia and six types of white cell measures.

We found the overall causal effects of schizophrenia on immune cell traits were significantly higher than the reverse ones (0.011 ± 0.049 vs 0.001 ± 0.016, p < 0.001), implying that disease may lead to an increase in immune cells by itself. We also identified four immune cell traits that may increase the risk of schizophrenia: CD11c+ monocyte %monocyte (odds ratio (OR): 1.06, 95% confidence interval (CI): 1.03~1.09, FDR = 0.027), CD11c+ CD62L- monocyte %monocyte (OR:1.06, 95% CI: 1.03~1.09, FDR = 0.027), CD25 on IgD+ CD38- naive B cell (OR:1.03, 95% CI:1.01~1.06, FDR = 0.042), and CD86 on monocyte (OR = 1.04, 95% CI:1.01~1.06, FDR = 0.042). However, we did not detect any significant causal effects of schizophrenia on immune cell traits. Using the white blood cell traits data, we identified that schizophrenia increases the lymphocyte counts (OR:1.03, 95%CI: 1.01-1.04, FDR = 0.007), total white blood cell counts (OR:1.02, 95%CI: 1.01-1.04, FDR = 0.021) and monocyte counts (OR:1.02, 95%CI: 1.00-1.03, FDR = 0.034). The lymphocyte counts were nominally associated with the risk of schizophrenia (OR:1.08,95%CI:1.01-1.16, P=0.019).

Our study found that the causal relationship between schizophrenia and the immune system is complex, enhancing our understanding of the role of immune regulation in the development of this disorder. These findings offer new insights for exploring diagnostic and therapeutic options for schizophrenia.

A comprehensive meta-analysis on the composition of circulating immune cells from both the myeloid and the lymphoid lines including specialized subsets in blood and cerebrospinal fluid (CSF) of patients with psychotic disorders compared with healthy control participants has been lacking.

Multiple databases (PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, and PsycINFO) were searched for eligible studies up until October 18, 2022. All studies investigating circulating immune cells in the blood and CSF from patients with psychotic disorders (ICD-10: F20 and F22-29) compared with healthy control participants were included.

A total of 86 studies were included in the meta-analysis. In the blood, the following categories of immune cells were elevated: leukocyte count (31 studies, standardized mean difference [SMD] = 0.35; 95% CI, 0.24 to 0.46), granulocyte count (4 studies, SMD = 0.57; 95% CI, 0.12 to 1.01), neutrophil granulocyte count (21 studies, SMD = 0.32; 95% CI, 0.11 to 0.54), monocyte count (23 studies, SMD = 0.40; 95% CI, 0.23 to 0.56), and B lymphocyte count (10 studies, SMD = 0.26; 95% CI, 0.04 to 0.48). Additionally, the neutrophil/lymphocyte ratio (23 studies, SMD = 0.40; 95% CI, 0.19 to 0.60), the monocyte/lymphocyte ratio (9 studies, SMD = 0.31; 95% CI, 0.04 to 0.57), and the platelet/lymphocyte ratio (10 studies, SMD = 0.23; 95% CI, 0.03 to 0.43) were elevated. The CSF cell count showed a similar tendency but was not significantly elevated (3 studies, SMD = 0.14; 95% CI, -0.04 to 0.32).

The results indicate a broad activation of the immune system in psychotic disorders, with cells from both the myeloid and the lymphoid line being elevated. However, CSF analyses were lacking in most of the studies, and many studies were hampered by insufficient adjustment for confounding factors such as body mass index and smoking.

Immunopsychiatric field has rapidly accumulated evidence demonstrating the involvement of both innate and adaptive immune components in psychotic disorders such as schizophrenia. Nevertheless, researchers are facing dilemmas of discrepant findings of immunophenotypes both outside and inside the brains of psychotic patients, as discovered by recent meta-analyses. These discrepancies make interpretations and interrogations on their roles in psychosis remain vague and even controversial, regarding whether certain immune cells are more activated or less so, and whether they are causal or consequential, or beneficial or harmful for psychosis. Addressing these issues for psychosis is not at all trivial, as immune cells either outside or inside the brain are an enormously heterogeneous and plastic cell population, falling into a vast range of lineages and subgroups, and functioning differently and malleably in context-dependent manners. This review aims to overview the currently known immunophenotypes of patients with psychosis, and provocatively suggest the premature immune "burnout" or inflamm-aging initiated since organ development as a potential primary mechanism behind these immunophenotypes and the pathogenesis of psychotic disorders.

Systemic inflammatory biomarkers recently studied in schizophrenia include neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PLR), systemic immune inflammation index (SII), and systemic inflammation response index (SIRI). SIRI, a novel inflammatory marker, has not been studied in different stages of schizophrenia. We aimed to compare NLR, MLR, PLR, SII, and SIRI values between psychotic exacerbation and remission values of the same patients with schizophrenia and a healthy control group.

In this study, 86 patients with schizophrenia who were hospitalized due to psychotic relapse, the same patient group who were in remission after treatment, and 86 age-sex-matched healthy control subjects were analyzed. Inflammatory marker values of the patient group in both the psychotic exacerbation (PE) and the remission (R) period were analyzed and compared with healthy controls (HC).

NLR, MLR, PLR, SII, and SIRI values were significantly higher in the schizophrenia-PE group than in the HC group. NLR, MLR, SII, and SIRI values were significantly higher in the schizophrenia-PE group than in the schizophrenia-R group. MLR values were significantly higher in the schizophrenia-R group than in the HC group.

These findings may be interpreted as NLR, SII, and SIRI, which may be considered as state biomarkers, and MLR may be a trait marker for schizophrenia.

First-Episode Psychosis (FEP) is a devastating mental health condition that commonly emerges during early adulthood, and is characterised by a disconnect in perceptions of reality. Current evidence suggests that inflammation and perturbed immune responses are involved in the pathology of FEP and may be associated specifically with negative symptoms. Exercise training is a potent anti-inflammatory stimulus that can reduce persistent inflammation, and can improve mood profiles in general populations. Therefore, exercise may represent a novel adjunct therapy for FEP. The aim of this study was to assess the effect of exercise on biomarkers of inflammation, negative symptoms of psychosis, and physiological health markers in FEP.

Seventeen young males (26.67 ± 6.64 years) were recruited from Birmingham Early Intervention in Psychosis Services and randomised to a 6-week exercise programme consisting of two-to-three sessions per week that targeted 60-70 % heart-rate max (HRMax), or a treatment as usual (TAU) condition. Immune T-helper (Th-) cell phenotypes and cytokines, symptom severity, functional wellbeing, and cognition were assessed before and after 6-weeks of regular exercise.

Participants in the exercise group (n = 10) achieved 81.11 % attendance to the intervention, with an average exercise intensity of 67.54 % ± 7.75 % HRMax. This led to favourable changes in immune cell phenotypes, and a significant reduction in the Th1:Th2 ratio (-3.86 %) compared to the TAU group (p = 0.014). After the exercise intervention, there was also a significant reduction in plasma IL-6 concentration (-22.17 %) when compared to the TAU group (p = 0.006). IL-8, and IL-10 did not show statistically significant differences between the groups after exercise. Symptomatically, there was a significant reduction in negative symptoms after exercise (-13.54 %, Positive and Negative Syndrome Scale, (PANSS) Negative) when compared to the TAU group (p = 0.008). There were no significant change in positive or general symptoms, functional outcomes, or cognition (all p > 0.05).

Regular moderate-to-vigorous physical activity is feasible and attainable in clinical populations. Exercise represents a physiological tool that is capable of causing significant inflammatory biomarker change and concomitant symptom improvements in FEP cohorts, and may be useful for treatment of symptom profiles that are not targeted by currently prescribed antipsychotic medication.

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.

The purpose of this study was to investigate the relationship between peripheral immune cell markers and cognitive functions in patients with schizophrenia and healthy controls.

Thirty-five patients diagnosed with schizophrenia with a stable course and a control group of 35 individuals matched in terms of sex, education, and age were included in this cross-sectional study. The Wisconsin Card Sorting Test (WCST), the Rey Auditory Verbal Learning Test (RAVLT), and the Stroop Test were used for neuropsychological evaluation. Blood neutrophil and lymphocyte percentages, neutrophil-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII) values were calculated.

The female patients exhibited significantly higher NLR and neutrophil percentages than the female controls and higher NLR, neutrophil percentage, and SII than the male patients. The increased neutrophil percentages and NLR and decreased lymphocyte percentages in the female patients were significantly correlated with worsening Stroop interference and RAVLT 1 scores. Additionally, a longer duration of illness was significantly correlated with elevated NLR, SII, and neutrophil percentage and a decreased lymphocyte percentage. A higher number of previous hospitalizations was correlated with elevated SII and decreased lymphocyte percentages. Regression analysis showed a significant association between neutrophil percentages and Stroop interference scores used to evaluate attentional functions in patients with schizophrenia.

These study results suggest that gender and the course of the illness may affect NLR and SII values. An elevated neutrophil percentage may be one of the factors affecting attentional dysfunction in patients with schizophrenia. Prospective studies are now needed to verify these findings.

Schizophrenia is a mental disorder affecting approximately 0.32% of the global population, according to the World Health Organization. Antipsychotic medications are used to treat this condition by inhibiting D2 dopamine and 5HT2 serotonin receptors. The selection of the appropriate mode of delivery for these drugs is based on factors such as patient adherence, clinical presentation, and patient preferences. However, additional drivers of treatment selection are required in clinical practice. Mounting evidence suggests that neuroinflammation plays a crucial role in the pathogenesis of schizophrenia. NLR, a cost-effective biomarker of inflammation, has increased in several psychiatric conditions and may represent a valid method for studying the inflammatory stage in schizophrenia, relapse, and the first episode of psychosis. The aim of this study is to evaluate whether there are any variations in NLR values between patients given oral antipsychotics and those given long-acting antipsychotics.

The study included 50 individuals with schizophrenia, either acute or in the follow-up phase. NLR was obtained by calculating the ratio of absolute neutrophil count (cells/μL) and absolute lymphocyte count (cells/μL).

Patients on long-acting antipsychotics exhibited significantly lower mean NLR scores (1.5 ± 0.7) compared to those on oral antipsychotics (2.2 ± 1.3) (p < 0.05).

NLR appears promising as a neuroinflammatory biomarker. This study reveals significantly lower NLR values in patients on long-acting antipsychotics, which may signify reduced systemic inflammation and improved adherence.

Schizophrenia and white blood cell counts (WBC) are both complex and polygenic traits. Previous evidence suggests that increased WBC are associated with higher all-cause mortality, and other studies have found elevated WBC in first-episode psychosis and chronic schizophrenia. However, these observational findings may be confounded by antipsychotic exposures and their effects on WBC. Mendelian randomization (MR) is a useful method for examining the directions of genetically-predicted relationships between schizophrenia and WBC.

We performed a two-sample MR using summary statistics from genome-wide association studies (GWAS) conducted by the Psychiatric Genomics Consortium Schizophrenia Workgroup (N = 130,644) and the Blood Cell Consortium (N = 563,946). The MR methods included inverse variance weighted (IVW), MR Egger, weighted median, MR-PRESSO, contamination mixture, and a novel approach called mixture model reciprocal causal inference (MRCI). False discovery rate was employed to correct for multiple testing.

Multiple MR methods supported bidirectional genetically-predicted relationships between lymphocyte count and schizophrenia: IVW (b = 0.026; FDR p-value = 0.008), MR Egger (b = 0.026; FDR p-value = 0.008), weighted median (b = 0.013; FDR p-value = 0.049), and MR-PRESSO (b = 0.014; FDR p-value = 0.010) in the forward direction, and IVW (OR = 1.100; FDR p-value = 0.021), MR Egger (OR = 1.231; FDR p-value < 0.001), weighted median (OR = 1.136; FDR p-value = 0.006) and MRCI (OR = 1.260; FDR p-value = 0.026) in the reverse direction. MR Egger (OR = 1.171; FDR p-value < 0.001) and MRCI (OR = 1.154; FDR p-value = 0.026) both suggested genetically-predicted eosinophil count is associated with schizophrenia, but MR Egger (b = 0.060; FDR p-value = 0.010) and contamination mixture (b = -0.013; FDR p-value = 0.045) gave ambiguous results on whether genetically predicted liability to schizophrenia would be associated with eosinophil count. MR Egger (b = 0.044; FDR p-value = 0.010) and MR-PRESSO (b = 0.009; FDR p-value = 0.045) supported genetically predicted liability to schizophrenia is associated with elevated monocyte count, and the opposite direction was also indicated by MR Egger (OR = 1.231; FDR p-value = 0.045). Lastly, unidirectional genetic liability from schizophrenia to neutrophil count were proposed by MR-PRESSO (b = 0.011; FDR p-value = 0.028) and contamination mixture (b = 0.011; FDR p-value = 0.045) method.

This MR study utilised multiple MR methods to obtain results suggesting bidirectional genetic genetically-predicted relationships for elevated lymphocyte counts and schizophrenia risk. In addition, moderate evidence also showed bidirectional genetically-predicted relationships between schizophrenia and monocyte counts, and unidirectional effect from genetic liability for eosinophil count to schizophrenia and from genetic liability for schizophrenia to neutrophil count. The influence of schizophrenia to eosinophil count is less certain. Our findings support the role of WBC in schizophrenia and concur with the hypothesis of neuroinflammation in schizophrenia.

This study aimed to investigate the role of immune dysfunction in the pathogenesis of schizophrenia through single-cell transcriptome and bulk RNA data analyses.

The single-cell RNA sequencing (scRNA-seq) was selected to assess the cellular composition and gene expression profiles of the brain tissue. Further, bulk RNA sequencing data was utilized to corroborate findings from the single-cell analyses and provide additional insights into the molecular changes associated with the disease. Gene-drug interaction data was also included to identify potential therapeutic drugs targeting these dysregulated immune-related genes in schizophrenia.

We discovered significant differences in cellular composition within schizophrenia tissue, including increased infiltration of fibroblasts, horizontal basal cells, monocytes, mesenchymal cells, and smooth muscle cells. The investigation of immune-related genes revealed significantly different expression of genes such as S100A2, CCL14, IGHA1, BPIFA1, GDF15, IL32, BPIFB2, HLA-DRA, S100A8, PTX3, TPM2, TNFRSF12A, GREM1 and others. These genes possibly contribute to the progression of schizophrenia through various pathways such as humoral immune response, IL-17 signaling pathway, adaptive immune response, antigen processing and presentation, and gut IgA production. Our findings also suggest possible transcriptional regulation in schizophrenia's immune dysfunction by transcription factors in monocytes, neutrophils, endothelial cells, and epithelial cells. Lastly, potential therapeutic drugs were identified through gene-drug interaction data, such as those targeting HLA-A and HLAB.

The cellular heterogeneity and immune-related gene dysregulation play important roles in schizophrenia, which provides a foundation for understanding the pathogenesis and developing new treatment methods.

Inflammation has been related to schizophrenia (SZ). The neutrophil-to-lymphocyte ratio (NLR) is an inexpensive inflammatory marker, however, its potential predictive value in patients with SZ has not been extensively investigated. This study aimed to examine whether NLR could predict the clinical response to antipsychotics in this population. One hundred and ninety-five medication-naïve first-episode schizophrenia (MNFES) patients were recruited and received treatment with risperidone for 12 weeks in the present study. Clinical symptoms were evaluated at week 0 and the end of 12 weeks of treatment using the PANSS scales. Complete blood counts were determined at baseline. We found that baseline NEU counts and NLR were positively associated with improvements in clinical symptoms in patients. In addition, MNFES patients with higher baseline NLR values showed a better treatment response to antipsychotics. Linear regression analysis revealed a predictive role of baseline NLR for the improvements of clinical symptoms in SZ patients. Our findings demonstrate that higher NLR was related to better improvements in symptoms after 12 weeks of treatment with antipsychotics, which renders it a promising biomarker of the response to antipsychotics in clinical practice.

Innate immunity has been shown to be associated with schizophrenia (Sch). This study explored the relationship between symptoms and neutrophil-to-lymphocyte ratio (NLR) (a marker of innate immunity) in patients with Sch. Ninety-seven first-episode medication-naïve (FEMN) patients with Sch and 65 healthy controls were recruited in this study. We measured the complete blood count and assessed the clinical symptoms using the PANSS scales. We found higher NEU counts and NLR in patients with Sch compared with control subjects. Male patients showed a higher NEU count than female patients. In addition, FEMN patients with higher NLR and NEU values showed higher PANSS-p, PANSS-g, and PANSS-total scores (all p < 0.05). Regression analysis revealed that NLR was a predictor for PANSS total scores in patients with Sch. Higher NLR value was observed in patients with Sch and the significant associations between NLR and psychotic symptoms indicate that an imbalance in inflammation and innate immune system may be involved in the pathophysiology of Sch.

There is a growing amount of evidence suggesting that immunity and inflammation play an important role in the pathophysiology of schizophrenia. In this study, we aimed to examine the relationship between hematological and inflammatory markers with symptom severity in Han Chinese patients with drug-free schizophrenia.

This retrospective study was conducted at Chaohu Hospital of Anhui Medical University and data were extracted from the electronic medical record system over a 5-year period (May 2017 to April 2022), including participants' general and clinical information as well as Brief Psychiatric Rating Scale (BPRS) scores and hematological parameters.

A total of 2,899 patients with schizophrenia were identified through the initial search. After screening, 91 patients and 141 healthy controls (HCs) were included. The patients had a higher value of neutrophils/lymphocytes ratio (NLR), monocyte/lymphocyte ratio (MLR), and platelet/lymphocyte ratio (PLR) than HCs (all P < 0.001). MLR was positively correlated with BPRS total score (r = 0.337, P = 0.001) and resistance subscale score (r = 0.350, P = 0.001). Binary logistic regression analyses revealed that severely ill was significantly associated with being male and a higher value of MLR (Natural Logaruthm, Ln) (all P < 0.05), and the receiver operating characteristic (ROC) analysis showed good performance of a regression model with an area under the curve (AUC) value of 0.787.

Patients with drug-free schizophrenia have an unbalanced distribution of peripheral blood granulocytes, and elevated NLR, MLR and PLR. Patients with higher value of MLR tend to have more psychotic symptoms, especially those symptoms of hostility, uncooperativeness, and suspiciousness. Our study gives a preliminary indication that MLR is a potential predictor of disease severity in patients with drug-free schizophrenia.

Immune inflammation has long been implicated in the pathogenesis of schizophrenia. Despite as a rapid and effective physical therapy, the role of immune inflammation in electroconvulsive therapy (ECT) for schizophrenia remains elusive. The neutrophils to lymphocytes (NLR), platelets to monocytes (PLR) and monocytes to lymphocytes (MLR) are inexpensive and accessible biomarkers of systemic inflammation. In this study, 70 schizophrenia patients and 70 age- and sex-matched healthy controls were recruited. The systemic inflammatory biomarkers were measured before and after ECT. Our results indicated schizophrenia had significantly higher peripheral NLR, PLR and MLR compared to health controls at baseline, while lymphocytes did not differ. After 6 ECT, the psychiatric symptoms were significantly improved, as demonstrated by the Positive and Negative Syndrome Scale (PANSS). However, there was a decline in cognitive function scores, as indicated by the Mini-Mental State Examination (MMSE). Notably, the neutrophils and NLR were significantly reduced following ECT. Although lymphocytes remained unchanged following ECT, responders had significantly higher lymphocytes compared to non-responders. Moreover, the linear regression analyses revealed that higher lymphocytes served as a predictor of larger improvement in positive symptom following ECT. Overall, our findings further highlighted the presence of systemic inflammation in schizophrenia patients, and that ECT may exert a therapeutic effect in part by attenuating systemic inflammation. Further research may therefore lead to new treatment strategies for schizophrenia targeting the immune system.

An analysis of placental chorionic villous and decidual basalis tissue immunoreactivity in patients after cesarean section due to a placenta accreta spectrum disorder and elective cesarean section followed by a depressed mood.

Over the past few years, interest in investigating immune dysfunction in patients with psychiatric disorders has increased. B7-H4 is a molecule with immunosuppressive properties that seems to play a key role in establishing maternal tolerance against fetal antigens. The aim of this study was to compare the B7-H4 immunoreactivity levels in patients after cesarean section.

Placental and decidual tissue samples were obtained from 49 women who delivered at Bielański Hospital in Warsaw between 2009 and 2015. Fifteen of the patients developed postpartum depression and 14 had a diagnosis of placenta accreta spectrum. The control group consisted of 20 healthy patients on whom cesarean section was performed due to breech presentation at term.

The highest levels of B7-H4 immunoreactivity were found in the placental chorionic villous and decidual basalis tissue samples of the patients who later developed postpartum depression, while the lowest levels were found in the samples of those patients with a placenta accreta spectrum disorder. The difference between the B7-H4 immunoreactivity levels of these two groups was statistically significant. The B7-H4 expression levels were statistically significantly higher in the women in the postpartum depression group than in the control group.

Postpartum depression follows a disturbance of the suppressive milieu responsible for rebalancing the maternal immune system after the initial cytotoxic activation during labor.

Psychosocial stress is a well-established risk factor for psychosis, yet the neurobiological mechanisms underlying this relationship have yet to be fully elucidated. Much of the research in this field has investigated hypothalamic-pituitary-adrenal (HPA) axis function and immuno-inflammatory processes among individuals with established psychotic disorders. However, as such studies are limited in their ability to provide knowledge that can be used to develop preventative interventions, it is important to shift the focus to individuals with increased vulnerability for psychosis (i.e., high-risk groups). In the present article, we provide an overview of the current methods for identifying individuals at high-risk for psychosis and review the psychosocial stressors that have been most consistently associated with psychosis risk. We then describe a network of interacting physiological systems that are hypothesised to mediate the relationship between psychosocial stress and the manifestation of psychotic illness and critically review evidence that abnormalities within these systems characterise highrisk populations. We found that studies of high-risk groups have yielded highly variable findings, likely due to (i) the heterogeneity both within and across high-risk samples, (ii) the diversity of psychosocial stressors implicated in psychosis, and (iii) that most studies examine single markers of isolated neurobiological systems. We propose that to move the field forward, we require well-designed, largescale translational studies that integrate multi-domain, putative stress-related biomarkers to determine their prognostic value in high-risk samples. We advocate that such investigations are highly warranted, given that psychosocial stress is undoubtedly a relevant risk factor for psychotic disorders.

Many studies have investigated the changes of immune cells and proinflammatory cytokines in patients with acute schizophrenia, but few studies have investigated the functional phenotypes of immune cells and the expression rate of programmed cell death protein 1 (PD-1)/ programmed cell death-Ligand 1 (PD-L1). The aim of this study was to investigate the extent of immune cells activation, PD-1/PD-L1 expressions, and altered cytokine levels in drug-naïve schizophrenia patients with acute-phase. 23 drug-naïve schizophrenia patients in acute-phase and 23 healthy individuals were enrolled in this study as experimental and control groups, separately. Socio-demographic information including gender, age, duration of illness, and smoking status was collected for each subject. Beckman DXFLEX triple laser thirteen-color flow cytometer and self-contained software CytoFLEX flow cytometric analysis software were used to detect the expressions of PD-1/PD-L1 on CD4+/CD8+ T lymphocytes, B lymphocytes, monocytes and NK cells. BD Bioscience was used to examine the levels of cytokines including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, Interleukin (IL)-2, IL-4, IL-6, and IL-10. Drug-naïve schizophrenia patients in acute-phase had higher levels of peripheral blood CD4+ T lymphocytes and B lymphocytes, higher PD-1 expression in B lymphocytes, and lower levels of CD8+ T lymphocytes. In addition, IL-6 levels of peripheral blood were higher in schizophrenia patients (all P < 0.05). Significant immune stress was present in schizophrenia patients with acute-phase.

Little is known about genetic predisposition to relapse. Previous studies have linked cognitive and psychopathological (mainly schizophrenia and bipolar disorder) polygenic risk scores (PRS) with clinical manifestations of the disease. This study aims to explore the potential role of PRS from major mental disorders and cognition on schizophrenia relapse. 114 patients recruited in the 2EPs Project were included (56 patients who had not experienced relapse after 3 years of enrollment and 58 patients who relapsed during the 3-year follow-up). PRS for schizophrenia (PRS-SZ), bipolar disorder (PRS-BD), education attainment (PRS-EA) and cognitive performance (PRS-CP) were used to assess the genetic risk of schizophrenia relapse.Patients with higher PRS-EA, showed both a lower risk (OR=0.29, 95% CI [0.11-0.73]) and a later onset of relapse (30.96± 1.74 vs. 23.12± 1.14 months, p=0.007. Our study provides evidence that the genetic burden of neurocognitive function is a potentially predictors of relapse that could be incorporated into future risk prediction models. Moreover, appropriate treatments for cognitive symptoms appear to be important for improving the long-term clinical outcome of relapse.

Psychotic disorders, notably schizophrenia, impose a detrimental burden on both an individual and a societal level. The mechanisms leading to psychotic disorders are multifaceted, with genetics and environmental factors playing major roles. Increasing evidence additionally implicates neuro-inflammatory processes within at least a subgroup of patients with psychosis. While numerous studies have investigated anti-inflammatory add-on treatments to current antipsychotics, the exploration of immunological biomarkers as a predictor of treatment response remains limited. This review outlines the current evidence from trials exploring the potential of baseline inflammatory biomarkers as predictors of the treatment effect of anti-inflammatory drugs as add-ons to antipsychotics and of antipsychotics alone. Several of the studies have found correlations between baseline immunological biomarkers and treatment response; however, only a few studies incorporated baseline biomarkers as a primary endpoint, and the findings thus need to be interpreted with caution. Our review emphasizes the need for additional research on the potential of repurposing anti-inflammatory drugs while utilizing baseline inflammatory biomarkers as a predictor of treatment response and to identify subgroups of individuals with psychotic disorders where add-on treatment with immunomodulating agents would be warranted. Future studies investigating the correlation between baseline inflammatory markers and treatment responses can pave the way for personalized medicine approaches in psychiatry centred around biomarkers such as specific baseline inflammatory biomarkers in psychotic disorders.

C-reactive protein (CRP) and inflammatory ratios have been proposed to study immune dysregulation in schizophrenia. Nevertheless, links between CRP and inflammatory ratios in acute SCZ inpatients have been understudied. This study investigated the relationship between CRP and inflammatory ratios (Neutrophil-Lymphocyte Ratio [NRL], Platelet-Lymphocyte Ratio [PLR], Monocyte-Lymphocyte ratio [MLR] and Basophil-Lymphocyte Ratio [BLR]) in a total of 698 acute SCZ inpatients; and analysed how this relationship is affected by sex and type of episode. CRP correlated with NLR (rs = 0.338, p < 0.001), PLR (rs = 0.271, p < 0.001) and MLR (rs = 0.148, p < 0.001) but not with BLR (rs = 0.059, p = 0.121). Multiple lineal regression analysis showed that high levels of NLR, MLR and PLR but not BLR were independently associated with high CRP levels. No sex-related variations were found. Significant associations were maintained for NLR and MLR in first-episode and multiepisode SCZ, although the strength of the association was stronger in multiepisode SCZ. Again, no sex-related differences were found in these associations. In conclusion, inflammatory ratios were low to moderately associated with CRP in acute SCZ inpatients. NLR and multiepisode SCZ showed the highest associations with CRP. Future studies should consider inflammatory ratios not as a substitute for CRP but as a complementary biomarker.

Signatures of immune dysregulation as clinical biomarker for psychosis have remained unclear. We aimed to compare the Neutrophil-to-lymphocyte ratio (NLR) of patients with acute non-affective first-episode psychosis (FEP) with healthy controls after accounting for emotional states. We also explored the associations of NLR with symptom severity, onset profile and cognitive functions. The NLR was enumerated from complete blood count taken within a week of assessment. All FEP patients were rated on the Positive and Negative Syndrome Scale (PANSS) and the Clinician Global Impression-Severity (CGI-S) with verbal memory and executive functions assessed with the Cambridge Neuropsychological Test Automated Battery. Prevailing emotional state was measured with Beck Depression Inventory-II and Beck Anxiety Inventory. Out of seventy-nine consecutive FEP patients presenting to the study site, twenty-seven subjects were eligible and recruited. Twenty-seven age-/sex-matched controls were recruited. FEP patients had an NLR of 1.886 over the controls after accounting for scores on emotional states. The NLR of FEP patients was positively associated with CGI-S scores, PANSS positive symptom, disorganization and excitation scores. There was no significant correlation between NLR with the duration of untreated psychosis and cognitive performances. These findings support using NLR as a clinical biomarker in FEP, purporting further prospective study to measure NLR changes in the course of treatment.

Insomnia occurs frequently in schizophrenia patients and is often accompanied with severe psychotic symptoms and cognition impairment. Moreover, chronic insomnia is associated with immune alterations. This study explored the correlations between insomnia and clinical manifestations of schizophrenia and analyzed mediation effects of regulatory T cells (Tregs) on these correlations. In a total of 655 chronic schizophrenia patients, 70 persons (10.69%) had an ISI (Insomnia Severity Index) score >7 and were referred to as Insomnia group. Compared to non-Insomnia group, Insomnia group presented more severe psychotic symptoms (assessed by PANSS) and cognitive impairment (assessed by RBANS). The total effect of ISI on PANSS/RBANS total score was not significant due to the mediation effects by Tregs, in which Tregs strongly mediated the effect of ISI on PANSS total score in negative direction but mediated the effect of ISI on RBANS total score in positive direction. Pearson Correlation Coefficient revealed negative correlations between Tregs and PANSS total score or disorganization subscale of PANSS. Positive correlations existed between Tregs and RBANS total score, between Tregs and the subscales of attention, delayed memory, or language of RBANS. These mediation effects of Tregs on insomnia-related psychotic symptoms and cognitive impairment in chronic schizophrenia patients point to a potential therapeutic strategy of modulating Tregs for the patients.

Immune-related mechanisms have been suggested to be involved in schizophrenia. Various studies have shown changes in monocytes isolated from the blood of schizophrenia patients, including changes in monocyte numbers, as well as altered protein and transcript levels of important markers. However, validation of these findings and understanding how these results are related to immune-related changes in the brain and schizophrenia genetic risk factors, is limited. The goal of this study was to better understand changes observed in monocytes of patients with early-onset schizophrenia. Using RNA sequencing, we analyzed gene expression profiles of monocytes isolated from twenty patients with early-onset schizophrenia and seventeen healthy controls. We validated expression changes of 7 out of 29 genes that were differentially expressed in previous studies including TNFAIP3, DUSP2, and IL6. At a transcriptome-wide level, we found 99 differentially expressed genes. Effect sizes of differentially expressed genes were moderately correlated with differential expression in brain tissue (Pearson's r = 0.49). Upregulated genes were enriched for genes in NF-κB and LPS signaling pathways. Downregulated genes were enriched for glucocorticoid response pathways. These pathways have been implicated in schizophrenia before and play a role in regulating the activation of myeloid cells. Interestingly, they are also involved in several non-inflammatory processes in the central nervous system, such as neurogenesis and neurotransmission. Future studies are needed to better understand how dysregulation of the NF-κB and glucocorticoid pathways affects inflammatory and non-inflammatory processes in schizophrenia. The fact that dysregulation of these pathways is also seen in brain tissue, provides potential possibilities for biomarker development.

Redox biology and immune signaling play major roles in the body, including in brain function. A rapidly growing literature also suggests that redox and immune abnormalities are implicated in neuropsychiatric conditions such as schizophrenia (SZ), bipolar disorder, autism, and epilepsy. In this article we review this literature, its implications for the pathophysiology of SZ, and the potential for development of novel treatment interventions targeting redox and immune signaling. Redox biology and immune signaling in the brain are complex and not fully understood; in addition, there are discrepancies in the literature, especially in patient-oriented studies. Nevertheless, it is clear that abnormalities arise in SZ from an interaction between genetic and environmental factors during sensitive periods of brain development, and these abnormalities disrupt local circuits and long-range connectivity. Interventions that correct these abnormalities may be effective in normalizing brain function in psychotic disorders, especially in early phases of illness.