Schizophrenia is a major psychiatric illness which mostly begins in adolescence and leads to impairments of social functioning. Some patients with schizophrenia have been associated with ultra-high risk state for psychosis (UHR), a condition used to operationally represent the prodromal stage of the illness. In previous studies, the UHR and the progression to overt psychosis has been reported to be accompanied with alterations in the quality of sleep and the immune system, as represented by change of blood levels of cytokines. Currently, biomarkers to predict the development of psychosis in persons at UHR have not yet reached a steady consensus. Therefore, we present a study protocol to explore predictors of transitions to psychosis, in the realm of monitoring of sleep condition and cytokine measurement, in subjects with the UHR.

This is a multicenter, longitudinal cohort study participated by 7 hospitals in Japan. We will recruit 50 UHR people and 30 healthy volunteers as a control group, and measure positive symptom, depressive symptoms, cognitive function, and social function. Blood cytokines levels and sleep indices, as well as actigraphy data will be monitored. After the baseline assessment, clinical symptoms, sleep indices, and cytokine levels will be measured every 12 weeks for 52 weeks. Actigraphy devices will continue to be worn for 52 weeks, while social function will be assessed over 104 weeks. The results of this study are expected to facilitate the development of novel intervention therapies to reduce the risk of psychosis and improve functional outcomes.

Exposure to maternal immune activation (MIA) in utero is a major risk factor for neurodevelopmental disorders, including schizophrenia. However, a proportion of individuals are resilient to developing schizophrenia following exposure to MIA, which has also been reported in animal models of MIA. The molecular mechanisms leading to resilient and vulnerable behavioural phenotypes remain poorly understood, and we currently lack reliable blood biomarkers that predict resilience or vulnerability. Redox dysregulation, caused by an imbalance between oxidative stress and antioxidant defence mechanisms, has recently been predicted to be central to the pathogenesis of schizophrenia. Here, we use a poly(I:C)-induced MIA model of schizophrenia to investigate mechanisms underlying cognitive dysfunction and redox dysregulation in resilient and vulnerable individuals. We show that activity of the antioxidant enzyme superoxide dismutase (SOD) was reduced in the plasma of poly(I:C) offspring with a cognitive deficit, in contrast to individuals with typical cognition during both adolescence and adulthood. However, SOD activity in the hippocampus was not significantly different between vulnerable and resilient offspring. In addition, the lipid peroxidation marker malondialdehyde (MDA) and the pro-inflammatory cytokine IL-6 were not differentially expressed within the hippocampus or plasma of vulnerable poly(I:C) offspring. Our results suggest that reduced plasma SOD activity may be a potential blood biomarker to identify resilience or vulnerability to MIA-induced cognitive deficits. Further research is necessary to determine if reduced antioxidant capacity is present in plasma prior to symptom presentation and to understand if this predicts redox dysregulation in the brain.

Advances in proteomic assay methodologies and genomics have significantly improved our understanding of the blood proteome. Schizophrenia and psychosis risk are linked to polygenic scores for schizophrenia and other mental disorders, as well as to altered blood and saliva levels of biomarkers involved in hormonal signaling, redox balance, and chronic systemic inflammation. The Accelerating Medicines Partnership® Schizophrenia (AMP®SCZ) aims to ascertain biomarkers that both predict clinical outcomes and provide insights into the biological processes driving clinical outcomes in persons meeting CHR criteria. AMP®SCZ will follow almost 2000 CHR and 640 community study participants for two years, assessing biomarkers at baseline and two-month follow-up including the collection of blood and saliva samples. The following provides the rationale and methods for plans to utilize polygenic risk scores for schizophrenia and other disorders, salivary cortisol levels, and a discovery-based proteomic platform for plasma analyses. We also provide details about the standardized methods used to collect and store these biological samples, as well as the study participant metadata and quality control measures related to preanalytical factors that could influence the values of the biomarkers. Finally, we discuss our plans for analyzing the results of blood- and saliva-based biomarkers. Watch Dr. Perkins discuss their work and this article: https://vimeo.com/1062879582?share=copy#t=0 .

Methamphetamine-associated psychosis (MAP) can present a spectrum of clinical manifestations, ranging from transient psychotic symptoms to a full-blown primary psychotic disorder. Differentiating between acute exacerbations of MAP and primary psychotic disorders remains challenging due to the overlapping clinical symptoms. In this study, we aimed to investigate whether CBC-derived inflammatory markers, C-reactive protein/albumin ratio (CAR), and neutrophil/albumin ratio (NAR) levels can be used as inflammatory markers in the differential diagnosis of MAP and schizophrenia.

The study sample included 206 patients hospitalized with acute exacerbation of psychosis (103 diagnosed with MAP, 103 diagnosed with schizophrenia) and 103 matched healthy controls. Logistic regression models were developed to determine the predictive value of group membership: Model 1 compared schizophrenia and MAP; Model 2 compared MAP and the control group; Model 3 compared the schizophrenia and the control group.

NLR, MLR, PLR, and NAR levels were significantly higher in patients with schizophrenia and MAP when compared with healthy controls. The NLR level was found to be a significant predictor of group membership in regression analysis for schizophrenia (Model 1, Model 3; p < 0.001). As a result of the regression model created with the MAP patients and control group, NAR was found to be a predictive variable for the MAP patients (Model 2, p = 0.011).

The results showed that NLR may be a potential biomarker for distinguishing patients with schizophrenia from patients with MAP and healthy controls. NAR level may be a potential biomarker for distinguishing MAP patients from healthy controls.

Though accumulating evidence suggests an association between childhood trauma and anhedonia, further analysis is needed to consider specific traumatic dimensions, both traits and state anhedonia, and the role of circulating proteins. Therefore, this study investigated the association between different types of childhood traumas and their influence on anhedonia-related symptoms, and to evaluate the influence of anhedonia traits and plasma proteins as mediators.

This study included 170 patients with schizophrenia, bipolar disorder, major depressive disorder, and healthy controls aged 19-65 years. Multiple reaction monitoring was performed to quantify plasma proteins, and 464 proteins were analyzed. The association between childhood trauma dimensions, anhedonic traits, and related symptoms was analyzed with linear regression. A series of mediation analyses was performed to determine whether anhedonic traits and plasma proteins mediated the association between childhood trauma and anhedonia-related symptoms.

Childhood emotional neglect was significantly associated with anhedonic traits and anhedonia-related symptoms. Mediation analysis revealed that the indirect effect of anhedonic traits for childhood emotional neglect on anhedonia-related symptoms (effect = 0.037; bias-corrected CI, 0.009 to 0.070) was statistically significant. The indirect effect of plasma TNR5 for anhedonic traits on anhedonia-related symptoms was statistically significant (effect = -0.011; bias-corrected CI, -0.026 to -0.002). Serial mediation analysis revealed that the indirect effect of childhood emotional neglect on anhedonia-related symptoms via anhedonic traits and TNR5 was statistically significant (effect = 0.007; bias-corrected CI, 0.001 to 0.017).

Anhedonic traits and plasma TNR5 protein levels serially mediated the association between childhood emotional neglect and anhedonia-related symptoms. The study highlights the importance of considering both psychopathological traits and biological correlates when investigating the association between childhood trauma and psychopathological symptoms.

Studies have reported that white matter hyperintensities (WMHs) are associated with disturbances in immune function, and the relationship between WMHs and cognitive impairments have been documented in various clinical populations. The present study was to examine the relationship between WMHs, immune function, and cognitive impairments in patients with schizophrenia (SCH) remains unknown.

A sample of 127 drug-naïve first episode SCH and 72 healthy controls (HCs) were included in this study. Serum levels of cytokines and oxidative stress indices were measured using enzyme-linked immunosorbent assay and microtiter plate method. WMHs were assessed using T2-weighted magnetic resonance imaging scanning, and cognitive performance was evaluated using the MATRICS Consensus Cognitive Battery.

We found patients with SCH are more likely to present with WMHs compared with HCs (OR = 2.076, 95%CI 1.007-4.277, p = 0.048). SCH with WMHs displayed more pronounced cognitive deficits in domains including speed of processing, working memory, verbal learning, visual learning, reasoning, and problem-solving compared with patients without WMHs (p < 0.05). Correlation analysis showed that the volume of WMHs was negative correlated with the problem-solving score (r=-0.331, p = 0.042) in patients with SCH. Within the SCH group, patients with WMHs exhibited elevated levels of interleukin-2 (IL-2), reactive oxygen species (ROS), and superoxide dismutase (SOD), along with lower levels of serum interleukin-4 (IL-4) and interferon-γ (IFN-γ) compared with those without WMHs (p < 0.05). The mediation analyses demonstrated that serum levels of IFN-γ in SCH had fully indirect effects on cognitive function, mediated by the WMHs.

This study suggests that WMHs may play a vital mediating role in the relationship between inflammation, oxidative stress, and cognitive impairments in SCH. Future studies exploring the potential clinical utility of WMHs as biomarkers for early detection and intervention of SCH are warranted.

(1) Background: The lack of reliable biomarkers remains a significant barrier to improving outcomes for patients with schizophrenia. While metabolomic analyses of blood, urine, and feces have been explored, results have been inconsistent. Compared to peripheral compartments, cerebrospinal fluid (CSF) more closely reflects the chemical composition of brain extracellular fluid. Given that brain dysregulation may be more pronounced during the first episode of psychosis (FEP), we hypothesized that metabolomic analysis of CSF from FEP patients could reveal disease-associated biomarkers. (2) Methods: We recruited 15 patients within 24 months of psychosis onset (DSM-4 criteria) and 14 control participants through the Johns Hopkins Schizophrenia Center. CSF samples were analyzed using both non-targeted and targeted liquid chromatography-mass spectrometry. (3) Results: The non-targeted analysis identified lower levels of N-acetylneuraminic acid and N-acetyl-L-aspartic acid in the FEP group, while levels of uric acid were elevated. The targeted analysis focused on indolic and phenolic molecules previously linked to neuropsychiatric disorders. Notably, L-phenylalanine and 4-hydroxycinnamic acid levels were lower in the FEP group, and this difference remained significant after adjusting for age and sex. However, none of the significant differences in analyte levels between the groups survived an adjustment for multiple comparisons. (4) Conclusions: Our intriguing but preliminary associations align with results from other investigational approaches and highlight potential CSF analytes that warrant further study in larger samples.

Given the available findings confirming accelerated brain aging in schizophrenia (SZ), we conducted a study aimed at verifying whether quantitative retinal morphological data enable age prediction and whether schizophrenia patients present with a positive retinal age gap (RAG).

Two samples of patients and controls were enrolled: one included 59 SZ patients and 60 controls, all of whom underwent optical coherence tomography (OCT) enabling the measurement of 72 variables. A second sample of 65 SZ patients and 70 controls was then combined with the first sample, to generate a database where each subject was represented by 28 morphological variables. Four different machine learning (ML) algorithms were used for age prediction based on z-standardized OCT data. The associations between RAG, demographic, and clinical data were also analyzed.

Patients from both samples had significantly higher retinal age and positive RAG ranging between 5.88 and 7.44 years depending on the specific sample. Predictions based on the larger group but with fewer OCT variables exhibited higher prediction relative error. All ML algorithms generated similar outcomes regarding retinal age. RAG correlated with the dose of antipsychotic medication and the severity of symptoms. Correlations with chronological age showed that RAG was the highest in younger patients, and from the age of about 45 years, it decreased.

ML-based results corroborated accelerated retinal aging in schizophrenia and showed its associations with pharmacological treatment and syndrome severity. The finding of a larger RAG in younger patients is novel and requires replication.

First episode psychosis (FEP) individuals show biological abnormalities preceding antipsychotic treatment. However, it remains unclear whether such alterations are also present before the onset of psychosis. We aim to provide estimates of standardized mean differences for immune, cardiometabolic, prolactin, and HPA axis parameters in individuals at clinical high-risk for psychosis (CHR-P) compared to healthy controls (HC) and FEP individuals, and between CHR-P transitioning to psychosis (CHR-T) compared non-transitioning (CHR-NT). A multistep literature search was performed from database inception until September 25, 2023. PRISMA/MOOSE-compliant and pre-registered (PROSPERO: CRD42024507670) systematic review identified studies reporting on immune, cardiovascular or endocrine parameters in CHR-P samples compared with HC or FEP samples or comparing CHR-T vs CHR-NT. Inter-group differences in magnitude of effect were estimated using Hedges g and estimates were pooled using random-effects meta-analysis. Heterogeneity was high for most outcomes. 37 studies were included, total sample 2509 CHR-P, 710 FEP, and 1444 HC individuals. A statistically significant elevation of pro-inflammatory proteins was found among CHR-P compared with HC (k = 12; N = 1710; g = 0.16; p < 0.01) and FEP (k = 7; g = 0.15; p = 0.04) subjects. Interleukin-6 (IL-6) was increased in CHR-P compared to HC (k = 9; N = 1243; g = 0.54; p < 0.01), and interleukin-4 (IL-4) was increased in CHR-T compared with CHR-NT (k = 2; N = 318; g = 0.36; p < 0.01). CHR-P exhibited stronger cortisol awakening response than FEP subjects (k = 3; N = 173; g = 0.51; p = 0.01). CHR-P and FEP individuals did not show statistically significant differences in terms of prolactin levels. An inflammatory state (particularly marked by elevated IL-6 and IL-4 levels) and HPA axis alterations are present in CHR-P individuals.

The pathological mechanisms of negative symptoms and cognitive impairment in schizophrenia may involve oxidative stress and neuroinflammation. Sulforaphane is an organosulfur compound with antioxidant and anti-inflammatory properties. This study aimed to evaluate its efficacy in ameliorating negative symptoms and cognitive impairments in chronic schizophrenia patients.

This 24-week double-blind randomised trial (NCT04521868) recruited schizophrenia patients with significant negative symptoms. Participants were randomly assigned to receive either sulforaphane or placebo and were required to complete at least one post-intervention assessment to evaluate changes in negative symptoms and cognitive functioning. Existing antipsychotic medication treatment regimens remained unchanged throughout the study.

A total of 42 patients were included in the statistical analysis, with 28 receiving sulforaphane and 14 assigned to placebo. Sulforaphane significantly reduced the Negative Symptom Score from the PANSS 5-Factor model between groups (p = 0.007) and exhibited a significant time-by-group interaction (p = 0.023), with more pronounced group differences observed after 12 weeks compared to 24 weeks of treatment. Sulforaphane also demonstrated a significant reduction in the original PANSS Negative Symptom Score between groups (p = 0.029). However, sulforaphane showed no significant effects on the MATRICS Consensus Cognitive Battery composite score or its subscores.

The significant improvements in the Negative Symptom Score from the PANSS 5-Factor model and the original PANSS Negative Symptom Score in the sulforaphane group suggest the potential of sulforaphane as an adjunctive treatment for ameliorating negative symptoms in chronic schizophrenia. Further research is warranted to explore the effects of sulforaphane on cognitive function.

Depressive and negative symptoms are related to poor functional outcomes in schizophrenia. Cognitive deficits, reduced brain cortical thickness and volumes, and inflammation may contribute to depressive and negative symptoms, but pharmacological treatment and disease progression may confound the associations.

We evaluated whether higher plasma interleukin 6 (IL-6) levels would be associated with more severe negative or depressive symptoms in schizophrenia and explored illness stage utilizing early (BeneMin [Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism], n = 201, 72.8% male) and established (iRELATE [Immune Response & Social Cognition in Schizophrenia], n = 94, 67.3% male) schizophrenia cohorts. Using structural equation modeling in a subsample (iRELATE: n = 42, 69.0% male; BeneMin: n = 102, 76.5% male) with data on structural brain metrics (cortical thickness and volume), general cognitive performance, and plasma IL-6 levels, we assessed the interrelationships between these variables on depressive and negative symptom severity in early and established schizophrenia samples combined and in early schizophrenia only. All analyses were adjusted for sex, age, and chlorpromazine equivalent dose.

Higher plasma IL-6 levels were related to more severe depressive symptoms in early schizophrenia (p < .05) and negative symptoms in established schizophrenia (p < .05). Structural equation modeling findings in early and established schizophrenia samples combined and early schizophrenia only showed that the interrelationship between higher plasma IL-6 levels, structural brain metrics, and general cognitive performance did not predict the severity of depressive and negative symptoms (p > .05). Higher plasma IL-6 levels and lower general cognitive performance were associated with reduced brain metrics (p < .05).

Our results indicate that higher plasma IL-6 levels may be differently associated with the severity of depressive and negative symptoms dependent on the illness stage. Future work identifying elevated levels of inflammation in larger samples may allow stratification and personalized intervention by subgroups who are at risk of poor outcomes.

About one in three persons with a schizophrenia related disorder (SRD) have elevated anti-gliadin IgG antibodies (AGA). This AGA positive (AGA+) subgroup of SRD clinically has a higher burden of negative symptoms and are symptoms associated with high functional impairments with a lack of effective therapeutics. Alterations in T cells have been demonstrated in SRD, and we have previously shown regulatory T cells (Tregs) are increased and correlate with fewer negative symptoms in persons with SRD compared with healthy controls.

To further elucidate the role of the immune system in AGA+ SRD pathology, we investigated the relationship of T cells and negative symptoms in 26 medicated and clinically stable persons with SRD. Participants had blood drawn; AGA-IgG measured by ELISA (AGA positive defined as ≥20 U); had flow cytometry performed to quantify proportions of pan T cells (CD3+), helper T cells (CD3+CD4+), Tregs (CD3+CD4+CD25+Foxp3+), and activated Tregs (aTregs) (CD3+CD4+CD25+Foxp3+RA-); had serum cytokines measured; and completed the Scale for the Assessment of Negative Symptoms (SANS) to measure negative symptoms.

46% of persons with SRD in this study were AGA+ and, in this group specifically, pan-T cells were correlated with worse SANS total, anhedonia, alogia, and avolition (p<0.05), while helper T cells and Tregs were correlated with less negative symptoms (respectively, SANS total and alogia; SANS total, anhedonia, alogia; P<0.05). AGA+ persons with SRD also had several elevated serum cytokines, corresponding with a broadly pro-inflammatory phenotype.

These hypothesis-generating findings highlight T cell dysfunction in AGA+ positive SRD, suggesting Tregs protecting against negative symptom severity but also an unidentified other T cell population to possibly be driving negative symptom severity.

Schizophrenia is one of the most severe and chronic psychiatric disorders. Over the years, numerous treatment options have been introduced for schizophrenia. Although they are relatively successful in managing the positive symptoms of schizophrenia, most of the current treatments have a negligible effect on the negative and cognitive symptoms. Thus, none of them could prevent the relapse of psychotic episodes. Among the numerous hypotheses explaining the development and progression of schizophrenia, the cytokine hypothesis explains the role of inflammatory markers as a significant culprit in the development of schizophrenia. Elevated cytokines are reported in animal models and schizophrenic patients. The cytokine hypothesis is based on how increased inflammatory markers can cause changes in the dopaminergic, glutamate, and tryptophan metabolism pathways, like that observed in schizophrenic patients. Reasons, such as autoimmune disease, maternal immune activation, infection, etc., can pave the way for the development of schizophrenia and are associated with the negative, positive and cognitive symptoms of schizophrenia. Thus, there is a need to focus on the significance of anti-inflammatory drugs against these symptoms. The development of new treatment strategies in the management of schizophrenia can provide better therapeutic outcomes in terms of the severity of symptoms and treatment of drug-resistant schizophrenia. This review attempts to explain the association between elevated inflammatory markers and various neurotransmitters, and the possible use of medications like nonsteroidal anti-inflammatory drugs, monoclonal antibodies, statins, and estrogens as adjuvant therapy. Over the years, these hypotheses have been the basis for drug discovery for the treatment of schizophrenia.

Schizophrenia is a serious mental illness that is a leading cause of disability worldwide. While antipsychotic agents are the most effective medications, up to one-third of patients experience treatment resistance, and approximately one-sixth of patients experience ultra-resistant illness. There is a growing body of evidence that inflammation, oxidative stress, and neurodegeneration may be contributing to pathophysiology and treatment response. Several agents with potential to improve inflammation and oxidative stress have been investigated, with some showing statistically significant benefits, though robust improvement in symptomatology has not been consistently demonstrated. Hericium erinaceus (HE) is an edible mushroom that has been used as a medicinal food for centuries. In pre-clinical studies, it has demonstrated anti-inflammatory, antioxidant, neuroprotective, and neurogenesis-promoting effects. The specific inflammatory markers that are impacted by HE align well with biomarkers shown to be altered in chronic and treatment resistant schizophrenia. Most clinical studies to date have assessed HE for the treatment of mild cognitive impairment, depression, and anxiety. In clinical studies, HE has been well tolerated, with the most common adverse effect of gastrointestinal disturbance. Given potential for HE to improve inflammation, reduce oxidative stress, and promote adult neurogenesis in the hippocampus, it is theorized that HE may have beneficial effects on symptomatology when used as an add-on to antipsychotic therapy in those with residual symptoms or treatment resistance. The goal of this review is to describe theoretical benefits and potential dosing strategies based on pre-clinical and clinical data.

Interest in preventative dietary interventions for human health has increasingly focused on the endocannabinoid (eCB)-like compound palmitoylethanolamide (PEA), a bioactive lipid mediator with anti-inflammatory, analgesic, and neuroprotective properties. This Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020-compliant systematic review aimed at collecting and comprehensively discussing all available data from Randomized Controlled Trials (RCTs) evaluating the efficacy and tolerability of PEA supplementation across human illnesses in patient populations. Overall, 48 eligible outputs from 47 RCTs were extracted, covering neuropsychiatric (n = 15), neurological (n = 17), somatic (n = 13), and visceral (n = 11) disturbances, as well as PEA effects on blood/plasma or other tissue biomarkers (n = 10). The strongest evidence emerged from RCTs exploring PEA impact on pain management and measures of general wellbeing, especially in its ultramicronized/micronized or cold-water dispersible formulations, showing good tolerability compared to controls. Also, alongside symptom improvement, PEA demonstrated to modulate biomarkers early altered in the initial phases of an illness or contributing to its progression, suggesting a disease-modifying potential. This systematic review provided a comprehensive overview of the therapeutic potential of PEA across RCTs, highlighting its versatility either as monotherapy or add-on treatment for various clinical conditions.

Alzheimer's disease is caused by modifiable and non-modifiable risk factors. Randomised controlled trials have investigated whether the strongest genetic risk factor for Alzheimer's disease, APOE4, impacts the effectiveness of exercise on health. Systematic reviews are yet to evaluate the effect of exercise on physical and cognitive outcomes in APOE genotyped participants. A quality assessment of these randomised controlled trials is needed to understand the impact genotype has on the potential success of intervention. This systematic review aimed to determine if the APOE4 genotype influences the effectiveness of exercise-based randomised controlled trials.

Searches on MEDLINE, EMBASE, and PsycINFO identified eligible exercise based randomised controlled trials incorporating participants with varied cognitive abilities. Quality assessments were conducted.

Nineteen studies met the inclusion criteria for systematic review, and 3 for the meta-analysis. Very low to moderate quality evidence showed that APOE4 carriers benefitted more than APOE4 non-carriers on cognitive (e.g. executive function, learning) and physical (e.g. relative telomere length) outcomes after exercise; and that APOE4 non-carriers benefited over carriers for physical (serum BDNF, gait speed) and cognitive (global cognition, verbal memory) markers. Very low quality evidence indicated that there was no evidence of difference between APOE4 carriers and non-carriers on physical function outcomes in meta-analysis. Several areas of study design and reporting, including maintenance of relative exercise intensity and complete statistical reporting, were identified as needing improvement.

This systematic review found very limited evidence to suggest that exercise interventions can benefit APOE4 carriers and non-carriers equally, though conclusions were limited by evidence quality. Further randomised controlled trials, stratifying participants by APOE status are required to better understand the relationship between APOE genotype and the effect of exercise on health-related outcomes.

This review was registered with PROSPERO (CRD42023436842). Registered on June 16, 2023.

To explore the intricate interplay among cytokines, cognitive functioning, and conversion to psychosis in individuals at clinical high-risk (CHR) for psychosis.

We initially enrolled 385 individuals at CHR and 95 healthy controls (HCs). Subsequently, 102 participants at CHR completed the 1-year follow-up assessments, and 47 participants transitioned to psychosis. We assessed the levels of interleukins (IL-1β, IL-2, IL-6, IL-8, IL-10), tumor necrosis factor-α (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF). We comprehensively evaluated cognitive performance across six domains, including speed of processing (SP), attention/vigilance (AV), working memory (WM), verbal learning (VeL), visual learning (ViL), and reasoning and problem-solving (RPS).

Higher baseline cognitive domain scores were associated with elevated GM-CSF and reduced VEGF levels. In the follow-up analysis, significant time effects were observed for IL-1β and IL-2. We also observed significant interaction effects between specific cognitive domains (AV, WM, VeL, and OCS) and levels of cytokine (GM-CSF, IL-1β, IL-6, and TNF-α). Changes in WM were negatively correlated with changes in TNF-α levels and positively correlated with changes in VEGF levels. Variations in VeL were inversely correlated with changes in GM-CSF and IL-10 levels, whereas changes in RPS were positively associated with changes in GM-CSF and IL-8 levels.

Our results revealed intricate associations among cytokine levels, cognitive performance, and psychosis progression.

Epilepsy is a prevalent chronic neurological disorder that can significantly impact patients' lives. The incidence and risk of psychosis in individuals with epilepsy are notably higher than in the general population, adversely affecting both the management and rehabilitation of epilepsy and further diminishing patients' quality of life. This review provides an overview of the classification and clinical features of psychosis of epilepsy, with the aim of offering insights and references for the clinical diagnosis and treatment of various types of psychosis of epilepsy. Additionally, we examine the potential pathophysiological mechanisms underlying the psychosis of epilepsy from three perspectives: neuroimaging, neurobiology, and genetics. The alterations in brain structure and function, neurotransmitters, neuroinflammatory mediators, and genetic factors discussed in this review may offer insights into the onset and progression of psychotic symptoms in epilepsy patients and are anticipated to inform the identification of novel therapeutic targets in the future.

Objective: Identifying individuals at ultra-high risk for psychosis (UHRP) is crucial for early intervention and prevention strategies. Neurocognitive deficits have been increasingly recognized as potential predictors of psychosis onset. This overview aims to consolidate current evidence and elucidate the role of neurocognitive predictors in identifying UHRP individuals. Method : we systematically searched three scientific databases, i.e., PubMed, Scopus, and Google Scholar using predefined keywords related to predictive neurocognitive markers and ultra-high risk psychosis. By following the PRISMA procedure, we included all relevant systematic-reviews and meta-analyses in our data-synthesis. Results: Neurocognitive deficits, including impairments in working memory, attentional control, verbal learning, and executive functions, have been consistently identified as predictors of psychosis conversion in individuals at UHRP. Structural and functional neuroimaging studies have further revealed aberrant brain connectivity, reduced gray matter volume, and altered neural activation patterns in key brain regions to be involved in psychosis. Moreover, the combination of neurocognitive and clinical risk factors has been shown to enhance the accuracy of predicting psychosis onset and inform personalized intervention strategies. Conclusion: Neurocognitive deficits serve as valuable predictors of the risk of psychosis in individuals with UHRP, offering insights into the underlying neurobiological mechanisms and potential targets for early intervention. Future research should focus on refining predictive models, elucidating the neurodevelopmental trajectories, and evaluating the efficacy of targeted interventions in mitigating the psychosis risk.

Elevated inflammation and impaired white matter (WM) microstructure have been observed in bipolar disorder (BD). The link between inflammation, WM integrity, and psychiatric symptoms in BD-II depression (BDII-D) remains unknown. We aimed to define BDII-D subgroups through the interplay of inflammation and WM microstructure, and to explore differences in psychiatric symptoms between subgroups, thus offering insight into elucidating the explanatory measures linked to BDII-D.

WM differences were compared between 146 BDII-D individuals and 151 health controls (HCs) by Tract-Based Spatial Statistics. Partial correlation with multiple comparison corrections was used to explore associations between WM, inflammation, and psychiatric symptoms. The canonical correlation analysis metrics of WM and inflammation followed by k-means clustering were used to define WM microstructural-inflammation subgroups of BDII-D. The differences in clinical profiles were compared between the subgroups.

Compared with HCs, BDII-D showed significant WM alterations in the anterior thalamic radiation (ATR), cingulum, forceps, and inferior fronto-occipital fasciculus. In BDII-D, lower fraction anisotropy (FA) within the right ATR and cingulum were significantly associated with higher interleukin-6, while lower FA in the cingulum and lower axial diffusivity in the forceps major exhibited significant links with higher C-reactive protein. Among the subgroups identified, subgroup II characterized by elevated inflammation and impaired WM integrity displayed greater psychiatric symptoms.

WM alterations are concentrated in emotional neurocircuits and are linked to inflammation in BDII-D. WM-inflammation subgroups exhibit distinct variations in psychiatric symptoms. Thus, WM alterations and inflammation might be an explanatory process in the pathophysiology of BDII-D.

Psychotic disorder is associated with altered levels of various inflammatory markers in blood, but existing studies have typically focused on a few selected biomarkers, have not examined specific symptom domains notably negative symptoms, and are based on individuals with established/chronic illness. Based on data from young people aged 24 years from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK birth cohort, we have examined the associations of 67 plasma immune/inflammatory proteins assayed using the Olink Target 96 Inflammation panel with psychotic disorder, positive (any psychotic experiences and definite psychotic experiences) and negative symptoms, using linear models with empirical Bayes estimation. The analyses included between 2317 and 2854 individuals. After adjustment for age, sex, body mass index and smoking and correction for multiple testing, positive symptoms and psychotic disorder were consistently associated with upregulation of CDCP1 and IL-6, and psychotic disorder was additionally associated with upregulation of MMP-10. Negative symptoms were associated with upregulation of CDCP1 and TRAIL. CDCP1 and MMP-10 are novel markers of psychosis identified in this study, and are involved in immune regulation, immune cell activation/migration, blood-brain barrier disruption, and extracellular matrix abnormalities. Our findings highlight psychosis symptom domains have overlapping and distinct immune associations, and support a role of inflammation and immune dysfunction in the pathogenesis of psychosis.

Schizophrenia is a complex and heterogenous psychiatric disorder characterized by positive, negative, and cognitive symptoms. Our previous study identified three subgroups of schizophrenia patients based on plasma microRNA (miRNA) profiles. The present study aims to (1) verify the reproducibility of the miRNA-based patient stratification and (2) explore the pathophysiological pathways linked to the symptoms using plasma miRNAs. We measured levels of 376 miRNAs in plasma samples of schizophrenia patients and obtained their Positive and Negative Syndrome Scale (PANSS) scores and the Brief Assessment of Cognition in Schizophrenia (BACS) scores. The plasma miRNA profiles identified similar subgroups of patients as in the previous study, suggesting miRNA-based patient stratification is potentially reproducible. Our multivariate analysis identified optimal combinations of miRNAs to estimate the PANSS positive and negative subscales and BACS composite scores. Those miRNAs consistently enriched 'inflammation' and 'NFκB1' according to miRNA set enrichment analysis. Our literature-based text mining and survey confirmed that those miRNAs were associated with IL-1β, IL-6, and TNFα, suggesting that exacerbated positive, negative, and cognitive symptoms are associated with high inflammation. In conclusion, miRNAs are a potential biomarker to identify patient subgroups reflecting pathophysiological conditions and to investigate symptom-related molecular mechanisms in schizophrenia.

Schizophrenia (SCZ) is a complex psychotic syndrome whose pathogenesis involves countless protagonists, none of which, to date, can fully explain how this disorder develops. In this narrative review, an overview of the biochemical impairment is offered according to several perspectives. Indeed, the metabolic framework behind SCZ dopaminergic hypotheses, glutamate - gamma-amynobutyric acid dysregulation, norepinephrine and serotonin, calcium channel dysfunction is addressed together with the energetic impairment, involving glucose and lipids in SCZ etiopathogenesis, in order to highlight the multilevel pathways affected in this neuropsychiatric disorder. Furthermore, neuroinflammation is analyzed, by virtue of its important role, widely investigated in recent years, in neurodegeneration. Tracing the neurotransmitter activity at the brain level by assessing the metabolic network behind the abovementioned molecules puts into light as unavoidable the need for future studies to adopt an integrate approach to address SCZ pathological and clinical picture. The combination of all these factors, essential in acquiring an overview on the complexity of SCZ pathophysiology represents a crucial step in the development of a more targeted management of SCZ patients.

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.

Immune dysregulation has been identified as a contributing factor in the pathophysiology of schizophrenia. This study aimed to investigate variations in specific immune regulators and their correlation with psychopathology and cognitive functions in male patients with chronic schizophrenia.

Employing a cross-sectional design, this study included 72 male patients with chronic schizophrenia. The Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status were utilized to assess psychopathology and cognitive functions, respectively.

Serum levels of interleukin (IL)-4, IL-10, IL-12p40, IL-13, and monocyte chemoattractant protein-1 (MCP-1) were measured. There were significantly increased levels of IL-4, IL-13, and MCP-1, alongside decreased levels of IL-10 in patients compared to controls (all P < 0.05). IL-4 levels showed a significant negative association with PANSS positive symptoms (beta=-0.222, P = 0.042). After controlling for antipsychotic medication, BMI, and smoking, this correlation was no longer significant (r=-0.232, P = 0.055). Additionally, positive correlations of IL-4 (beta = 0.297, P = 0.008), IL-13 (beta = 0.371, P = 0.001), and MCP-1 (beta = 0.280, P = 0.013) with language scores were observed. Increased levels of IL-4 (P = 0.044, OR = 1.994), IL-13 (P = 0.019, OR = 2.245), as well as IL-4 and MCP-1 interactions (P = 0.043, OR = 2.000) were positively associated with the risk of chronic schizophrenia, while lower levels of IL-10 (P = 0.003, OR = 0.2.867) were also linked to an increased risk.

The identified associations between specific immune markers and the clinical and cognitive features of chronic schizophrenia in males underscored the potential immune-mediated mechanisms underlying schizophrenia.

Genetic copy number variants (CNVs; i.e., a deletion or duplication) at the 22q11.2 locus confer increased risk of neuropsychiatric disorders and immune dysfunction. Inflammatory profiles of 22q11.2 CNV carriers can shed light on gene-immune relationships that may be related to neuropsychiatric symptoms. However, little is known about inflammation and its relationship to clinical phenotypes in 22q11.2 CNV carriers. Here, we investigate differences in peripheral inflammatory markers in 22q11.2 CNV carriers and explore their relationship with psychosis risk symptoms and sleep disturbance.

Blood samples and clinical assessments were collected from 22q11.2 deletion (22qDel) carriers (n=45), 22q11.2 duplication (22qDup) carriers (n=29), and typically developing (TD) control participants (n=92). Blood plasma levels of pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), and anti-inflammatory cytokine interleukin-10 (IL-10) were measured using a MesoScale Discovery multiplex immunoassay. Plasma levels of C-reactive protein (CRP) were measured using Enzyme-linked Immunosorbent Assay (ELISA). Linear mixed effects models controlling for age, sex, and body mass index were used to: a) examine group differences in inflammatory markers between 22qDel, 22qDup, and TD controls, b) test differences in inflammatory markers between 22qDel carriers with psychosis risk symptoms (22qDelPS+) and those without (22qDelPS-), and c) conduct an exploratory analysis testing the effect of sleep disturbance on inflammation in 22qDel and 22qDup carriers. A false discovery rate correction was used to correct for multiple comparisons.

22qDup carriers exhibited significantly elevated levels of IL-8 relative to TD controls (q<0.001) and marginally elevated IL-8 levels relative to 22qDel carriers (q=0.08). There were no other significant differences in inflammatory markers between the three groups (q>0.13). 22qDelPS+ exhibited increased levels of IL-8 relative to both 22qDelPS- (q=0.02) and TD controls (p=0.002). There were no relationships between sleep and inflammatory markers that survived FDR correction (q>0.14).

Our results suggest that CNVs at the 22q11.2 locus may have differential effects on inflammatory processes related to IL-8, a key mediator of inflammation produced by macrophages and microglia. Further, these IL-8-mediated inflammatory processes may be related to psychosis risk symptoms in 22qDel carriers. Additional research is required to understand the mechanisms contributing to these differential levels of IL-8 between 22q11.2 CNV carriers and IL-8's association with psychosis risk.

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.

While inflammation is associated with cognitive impairment in severe mental illnesses (SMI), there is substantial heterogeneity and evidence of transdiagnostic subgroups across schizophrenia (SZ) and bipolar (BD) spectrum disorders. There is however, limited knowledge about the longitudinal course of this relationship.

Systemic inflammation (C-Reactive Protein, CRP) and cognition (nine cognitive domains) was measured from baseline to 1 year follow-up in first treatment SZ and BD (n = 221), and healthy controls (HC, n = 220). Linear mixed models were used to evaluate longitudinal changes separately in CRP and cognitive domains specific to diagnostic status (SZ, BD, HC). Hierarchical clustering was applied on the entire sample to investigate the longitudinal course of transdiagnostic inflammatory-cognitive subgroups.

There were no case-control differences or change in CRP from baseline to follow-up. We confirm previous observations of case-control differences in cognition at both time-points and domain specific stability/improvement over time regardless of diagnostic status. We identified transdiagnostic inflammatory-cognitive subgroups at baseline with differing demographics and clinical severity. Despite improvement in cognition, symptoms and functioning, the higher inflammation - lower cognition subgroup (75% SZ; 48% BD; 38% HC) had sustained inflammation and lower cognition, more symptoms, and lower functioning (SMI only) at follow-up. This was in comparison to a lower inflammation - higher cognition subgroup (25% SZ, 52% BD, 62% HC), where SMI participants showed cognitive functioning at HC level with a positive clinical course.

Our findings support heterogenous and transdiagnostic inflammatory-cognitive subgroups that are stable over time, and may benefit from targeted interventions.

Chronic low-grade inflammation is observed across mental disorders and is associated with difficult-to-treat-symptoms of anhedonia and functional brain changes, reflecting a potential transdiagnostic dimension. Previous investigations have focused on distinct illness categories in people with enduring illness, but few have explored inflammatory changes. We sought to identify an inflammatory signal and the associated brain function underlying anhedonia among young people with recent-onset psychosis and recent-onset depression.

Resting-state functional magnetic resonance imaging, inflammatory markers, and anhedonia symptoms were collected from 108 (mean [SD] age = 26.2 [6.2] years; female = 50) participants with recent-onset psychosis (n = 53) and recent-onset depression (n = 55) from the European Union/Seventh Framework Programme-funded PRONIA (Personalised Prognostic Tools for Early Psychosis Management) study. Time series were extracted using the Schaefer atlas, defining 100 cortical regions of interest. Using advanced multimodal machine learning, an inflammatory marker model and a functional connectivity model were developed to classify participants into an anhedonic group or a normal hedonic group.

A repeated nested cross-validation model using inflammatory markers classified normal hedonic and anhedonic recent-onset psychosis/recent-onset depression groups with a balanced accuracy of 63.9% and an area under the curve of 0.61. The functional connectivity model produced a balanced accuracy of 55.2% and an area under the curve of 0.57. Anhedonic group assignment was driven by higher levels of interleukin 6, S100B, and interleukin 1 receptor antagonist and lower levels of interferon gamma, in addition to connectivity within the precuneus and posterior cingulate.

We identified a potential transdiagnostic anhedonic subtype that was accounted for by an inflammatory profile and functional connectivity. Results have implications for anhedonia as an emerging transdiagnostic target across emerging mental disorders.

Inflammation is associated with the pathophysiology of schizophrenia. The blood markers for systemic inflammation include neutrophil-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), lymphocyte-monocyte ratio (LMR), system inflammation response index (SIRI), and platelet-lymphocyte ratio (PLR). However, these inflammation markers and their relationships with clinical phenotypes among Han Chinese patients with first-episode adolescent-onset schizophrenia (AOS) is unclear. This investigation aimed to elucidate the impact of inflammation on Han Chinese AOS patients as well as the association of blood-based inflammation markers with clinical symptoms.

Altogether, 203 Han Chinese individuals participated in this study, 102 first-episode AOS patients and 101 healthy controls. The assessment of inflammatory indices was based on complete blood cell count. Furthermore, schizophrenia-related clinical symptoms were evaluated using the five-factor model of the Positive and Negative Syndrome Scale (PANSS).

In Han Chinese first-episode AOS patients, levels of SIRI, PLR, SII, and NLR were significantly increased (p < 0.001), while LMR decreased (p < 0.001) compared to healthy controls. Furthermore, multivariate logistic regression showed that LMR, NLR, SII, and SIRI (all p < 0.05) were independently associated with AOS. Moreover, Receiver operating characteristics assessment indicated that NLR, SIRI, LMR, and SII could effectively distinguish AOS patients from healthy controls. Their areas under the curves were 0.734, 0.701, 0.715, and 0.730 (all p < 0.001). In addition, Correlation analysis revealed that LMR was negatively correlated with the PANSS total, negative, and cognitive factor scores (all p < 0.05); NLR was positively correlated with the cognitive factor score (p < 0.01); SII was negatively correlated with the positive factor score and positively with the negative and cognitive factor scores (all p < 0.05); SIRI was positively correlated with the PANSS total and cognitive factor scores (all p < 0.01).

This research established the involvement of peripheral blood inflammatory markers (LMR, NLR, SII, and SIRI) with the clinical manifestations and pathophysiology of schizophrenia, and these can serve as screening tools or potential indices of the inflammatory state and AOS symptoms severity.

Due to its reliance on heterogeneous symptomatology, the accurate diagnosis of psychotic disorders remains a challenging task in clinical practice. Precise and early diagnosis of psychotic disorders facilitates early intervention, which has been shown to have substantial benefits for long-term outcomes. Still, the lack of specific biomarkers is an important limitation in early diagnosis and intervention. Exosomes, which act as messengers between cells, including brain cells, contain a vast array of molecules that hold promise for unveiling disorder-specific abnormalities. In this review, we discuss recent evidence highlighting the potential of circulating exosomes and brain-derived exosomes as valuable tools for the identification of accessible, non-invasive, and blood-based biomarkers of psychotic symptomatology and risk. We discuss current limitations in biomarker discovery studies focusing on exosomes. To enhance diagnosis specificity and treatment response, we also provide guidance for future investigations that need to target biomarkers of risk and relapse, as well as consider duration of untreated psychosis, biological sex, and other factors in the multifactorial biosignature of psychosis.

Increasing evidence implicates that inflammatory factors do play a crucial role in the pathophysiology of schizophrenia. However, the association between inflammatory markers and different symptom dimensions and cognitive function of schizophrenia remains unclear. A total of 140 drug-naïve patients with schizophrenia and 69 healthy controls matched for age and gender were enrolled. Peripheral blood plasma concentrations of S-100 calcium-binding protein B (S100B), neutrophil gelatinase-associated lipocalin (NGAL), and interferon-γ (IFN-γ) were detected by enzyme-linked immunosorbent assay (ELISA). Psychotic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS), and cognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB). Compared with healthy controls, patients with schizophrenia had significantly worse cognitive function and lower levels of NGAL and IFN-γ (P < 0.001). In schizophrenia, plasma NGAL and IFN-γ levels negatively correlated with positive symptom scores (all P < 0.05). There was a positive correlation between plasma levels of NGAL and IFN-γ with visual learning, neurocognition, and MCCB total score (all P < 0.05). We found that NGAL levels (β = 0.352, t = 5.553, 95% CI 0.228-0.477, P < 0.001) and negative symptoms subscale scores (β = - 0.321, OR = 0.725, 95% CI 648-0.811, P < 0.001) were independently associated with the MCCB total score. Further, binary logistic regression analysis indicated that the concentrations of NGAL (β = - 0.246, OR = 0.782, 95% CI 0.651-0.939, P = 0.008) were independently associated with the diagnosis of schizophrenia. There was a positive correlation between NGAL and IFN-γ levels and MCCB total score in schizophrenia. NGAL level was an independent protective factor for cognitive function and an independent risk factor for the diagnosis of schizophrenia.

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.

Brain development/aging is not uniform across individuals, spawning efforts to characterize brain age from a biological perspective to model the effects of disease and maladaptive life processes on the brain. The brain age gap represents the discrepancy between estimated brain biological age and chronological age (in this case, based on structural magnetic resonance imaging, MRI). Structural MRI studies report an increased brain age gap (biological age > chronological age) in schizophrenia, with a greater brain age gap related to greater negative symptom severity. Less is known regarding the nature of this gap early in schizophrenia (ESZ), if this gap represents a psychosis conversion biomarker in clinical high-risk (CHR-P) individuals, and how altered brain development and/or aging map onto specific symptom facets.

Using structural MRI, we compared the brain age gap among CHR-P (n = 51), ESZ (n = 78), and unaffected comparison participants (UCP; n = 90), and examined associations with CHR-P psychosis conversion (CHR-P converters n = 10; CHR-P non-converters; n = 23) and positive and negative symptoms.

ESZ showed a greater brain age gap relative to UCP and CHR-P (Ps < .010). CHR-P individuals who converted to psychosis showed a greater brain age gap (P = .043) relative to CHR-P non-converters. A larger brain age gap in ESZ was associated with increased experiential (P = .008), but not expressive negative symptom severity.

Consistent with schizophrenia pathophysiological models positing abnormal brain maturation, results suggest abnormal brain development is present early in psychosis. An increased brain age gap may be especially relevant to motivational and functional deficits in schizophrenia.