An ENIGMA Consortium study of the relationship between white matter microstructure and positive and negative symptom severity in patients with schizophrenia Aoife Warren, Laurena Holleran, Ingrid Agartz, Ole A. Andreassen, Nerisa Banaj, et al. Schizophrenia, 2026 Symptom severity in schizophrenia has been repeatedly associated with thinner cortical gray matter. While global and regional white matter microstructure alterations in schizophrenia are well-documented, their association with clinical symptom severity remains unclear. As this is likely due to methodological heterogeneity across studies, we tested whether symptom severity in schizophrenia was associated with regional and global white matter alterations using standardized methods. We hypothesized that positive symptom severity would be associated with temporal white matter changes and that negative symptom severity would be associated with alterations in frontal white matter. Using a standardized fractional anisotropy (FA) analysis pipeline developed by the ENIGMA consortium, we conducted a meta-analysis of the association between white matter microstructure and symptom severity in n = 1025 (ages 16–68 years; 369 women/656 men) across 19 ENIGMA sites. Where significant heterogeneity was detected across sites, we examined whether variation in association strength between white matter microstructure and symptom severity was explained by duration of illness and/or current antipsychotic use. Positive symptom severity was significantly associated with white matter microstructure as measured using temporal lobe FA and global FA. Negative symptom severity showed no significant association with white matter microstructure as measured using frontal lobe FA or global FA. Significant heterogeneity across sites was observed for the negative symptom analysis, explained partly by duration of illness. Post-hoc exploratory analyses identified one site as disproportionately contributing to this heterogeneity, and when removed, negative symptom severity was significantly associated with both global and frontal FA. These findings support the view of schizophrenia as a disorder of brain connectivity, in a manner relevant to understanding variation in clinical symptom severity.
Is Temporal Variability a Standalone Predictor in Medical Data? An Actigraphy Study in Bipolar Disorder Carmen-Anna Konicarová, Jakub Schneider, Marian Kolenič, Filip Španiel, Eduard Bakštein Studies in Health Technology and Informatics, 2026 In medical data, measures of central tendency (e.g., mean) and temporal variability (e.g., standard deviation, SD) are widely used as biomarkers to quantify physiological states and disease dynamics. However, both metrics are sensitive to skewed distributions, which can obscure their true predictive value and thereby reduce interpretability. This study investigates whether temporal variability in actigraphy data carries outcome-relevant information about clinical states in bipolar disorder (BD), or whether its apparent predictive capacity is confounded by mean activity levels. Actigraphy recordings from 326 individuals with BD were analyzed, and a subset of 34 participants who experienced both manic and remission periods was used for statistical modeling. Daily features were power-transformed (Box–Cox, Yeo–Johnson) and aggregated weekly by mean (μ7) and SD (σ7). Mixed-effects logistic regression models were fitted to distinguish manic weeks from remission. Power transformations reduced μ7–σ7 correlations, and variability remained a retained outcome-relevant predictive information for most features; however, for some features (27%), the effects were partially explained by mean-variance coupling.
The ILIA study: protocol for a randomized-controlled multicenter clinical trial on smartphone- and web-based relapse monitoring for patients with schizophrenia or schizoaffective disorder Selina Hiller, Laura Emde, Denise Jais, Soňa Nevická Sikorová, Eduard Bakstein, et al. European Archives of Psychiatry and Clinical Neuroscience, 2026 Background Despite the proven efficacy of antipsychotics in relapse prevention in schizophrenia and schizoaffective disorder, every third patient experiences a relapse within less than one year. Relapses can worsen psychosocial and treatment related outcomes and lead to substantial economic costs, primarily due to frequent and prolonged hospitalizations. The aim of this project is to evaluate a smartphone- and web-based digital solution for detecting early warning signs of schizophrenia and schizoaffective disorder to reduce relapses and subsequent hospitalizations. Methods This randomized controlled trial compares the add-on use of a smartphone-based app for monitoring relapse warning signs in patients with schizophrenia and schizoaffective disorders (ICD-10 F20/F25) used within the routine psychiatric outpatient treatment against treatment as usual (TAU) without any further study-related intervention. Patients in the intervention group use the app for one year, fill in the weekly ten-item Early Warning Signs Questionnaire (EWSQ-10P) and obtain in-app feedback. Clinicians can access the symptom trajectory via a browser-accessible dashboard. If a threshold is exceeded in the inbuilt automatic algorithm, an alert is sent to both, the clinician and patient, enabling timely contact and, as part of a shared decision-making process, an optional adjustment of treatment decision. A total of 110 outpatients are recruited across eight study sites. Discussion Continuous monitoring of early warning signs is expected to lead to behavioral changes and to decrease the necessity and duration of psychiatric hospital stays, thereby lowering healthcare costs. Additionally, the intervention could reduce symptom severity, alleviate medication adherence, shared decision-making, patient activation or quality of life. Qualitative data is collected to better understand patient needs and preferences regarding app usage and relapses. Insights gained from this study can be integrated into routine psychiatric care, improving the long-term treatment of patients with schizophrenia or schizoaffective disorder. Trial registration German Clinical Trials Register (ID: DRKS00034991; registration date: 30.08.2024).
Antipsychotics lower peripheral markers of inflammation in drug-naïve early psychosis: a pilot study Nicole Šafářová, Marián Kolenič, Ivana Tašková, Václav Čapek, Petra Fürstová, et al. Frontiers in Psychiatry, 2026 Introduction Neuroinflammation is increasingly recognized as a core pathophysiological mechanism in schizophrenia and can be indirectly assessed through peripheral inflammatory markers. Therefore, this pilot study investigated the impact of antipsychotic treatment on inflammation in patients with first-episode psychosis (FEP) who were antipsychotic-naive at study entry. Methods Thirty-three drug-naïve FEP patients provided blood samples upon admission (V0) and follow-up (V1), from which peripheral inflammatory markers—i.e., neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)—were calculated. Antipsychotic doses during continuous hospitalization between V0 and V1 (34 days, IQR: 21–49 days) were converted into cumulative chlorpromazine equivalents (cCPZ). Results In multiple regression models adjusting for sex, age, BMI, DUP, and clozapine use, cumulative antipsychotic exposure significantly predicted reductions in ΔNLR (p = 0.048), ΔMLR (p = 0.041), ΔPLR (p = 0.028), and ΔSII (p = 0.028). All associations remained significant following false discovery rate adjustment (pFDR = 0.048 for all outcomes). Conclusion These findings suggest a consistent dose-dependent anti-inflammatory effect during early antipsychotic treatment in FEP. Given the exploratory nature of this study, larger studies are needed to confirm these findings.
The Relationship between 25-Hydroxy Vitamin D Serum Level and Memory in Patients with a First Episode of Schizophrenia Spectrum Disorder Martin Ihln, Denis Poltoradnev, Mabel Rodriguez, Filip Španiel, Miloslav Kopeček Neuropsychobiology, 2025 Introduction: The relationship between vitamin D levels and cognition in young patients with schizophrenia remains incompletely understood. We explored the association between serum 25-hydroxy vitamin D concentration and long-term memory (i.e., 30-min delayed recall in the Rey Auditory Verbal Learning Test) in patients with first-episode schizophrenia. The body mass index was measured due to the accumulation of vitamin D in fat. Methods: Forty-six male participants aged 20.9 ± 2.3 years old with first-episode schizophrenia spectrum disorder were recruited. The median body mass index was 24.1, and 25-hydroxy vitamin D was 39.3 nmol/L. The mean delayed recall was 7.6 ± 3.4 words. Serum 25-hydroxy vitamin D concentration and memory performance were below the normative values for healthy adults. 25-hydroxy vitamin D concentrations and ten clinical variables were included as independent variables, and delayed recall values were included as dependent variables in the multiple regression analysis. Results: Regression analysis revealed a statistically significant link between 25-hydroxy vitamin D concentration, benzodiazepine use, and delayed recall, but not for other clinical variables. Conclusion: We found a positive association between 25-hydroxy vitamin D serum concentration and delayed recall in patients with first-episode schizophrenia, supporting a need for interventional study investigating vitamin D supplementation for the cognition of patients with schizophrenia. A negative association between benzodiazepine intake and memory performance calls for attention to minimalize benzodiazepine use.
Extracellular vesicles as precision therapeutics for psychiatric conditions: targeting interactions among neuronal, glial, and immune networks Ivana Kawiková, Václav Špička, James C. K. Lai, Philip W. Askenase, Li Wen, et al. Frontiers in Immunology, 2025 The critical role of the immune system in brain function and dysfunction is well recognized, yet development of immune therapies for psychiatric diseases has been slow due to concerns about iatrogenic immune deficiencies. These concerns are emphasized by the lack of objective diagnostic tools in psychiatry. A promise to resolve this conundrum lies in the exploitation of extracellular vesicles (EVs) that are physiologically produced or can be synthetized. EVs regulate recipient cell functions and offer potential for EVs-based therapies. Intranasal EVs administration enables the targeting of specific brain regions and functions, thereby facilitating the design of precise treatments for psychiatric diseases. The development of such therapies requires navigating four dynamically interacting networks: neuronal, glial, immune, and EVs. These networks are profoundly influenced by brain fluid distribution. They are crucial for homeostasis, cellular functions, and intercellular communication. Fluid abnormalities, like edema or altered cerebrospinal fluid (CSF) dynamics, disrupt these networks, thereby negatively impacting brain health. A deeper understanding of the above-mentioned four dynamically interacting networks is vital for creating diagnostic biomarker panels to identify distinct patient subsets with similar neuro-behavioral symptoms. Testing the functional pathways of these biomarkers could lead to new therapeutic tools. Regulatory approval will depend on robust preclinical data reflecting progress in these interdisciplinary areas, which could pave the way for the design of innovative and precise treatments. Highly collaborative interdisciplinary teams will be needed to achieve these ambitious goals.
Longitudinal assessment of ventricular volume trajectories in early-stage schizophrenia: evidence of both enlargement and shrinkage Patrik Svancer, Vaclav Capek, Antonin Skoch, Miloslav Kopecek, Kristyna Vochoskova, et al. BMC Psychiatry, 2024 Background Lateral ventricular enlargement represents a canonical morphometric finding in chronic patients with schizophrenia; however, longitudinal studies elucidating complex dynamic trajectories of ventricular volume change during critical early disease stages are sparse. Methods We measured lateral ventricular volumes in 113 first-episode schizophrenia patients (FES) at baseline visit (11.7 months after illness onset, SD = 12.3) and 128 age- and sex-matched healthy controls (HC) using 3T MRI. MRI was then repeated in both FES and HC one year later. Results Compared to controls, ventricular enlargement was identified in 18.6% of patients with FES (14.1% annual ventricular volume (VV) increase; 95%CI: 5.4; 33.1). The ventricular expansion correlated with the severity of PANSS-negative symptoms at one-year follow-up (p = 0.0078). Nevertheless, 16.8% of FES showed an opposite pattern of statistically significant ventricular shrinkage during ≈ one-year follow-up (-9.5% annual VV decrease; 95%CI: -23.7; -2.4). There were no differences in sex, illness duration, age of onset, duration of untreated psychosis, body mass index, the incidence of Schneiderian symptoms, or cumulative antipsychotic dose among the patient groups exhibiting ventricular enlargement, shrinkage, or no change in VV. Conclusion Both enlargement and ventricular shrinkage are equally present in the early stages of schizophrenia. The newly discovered early reduction of VV in a subgroup of patients emphasizes the need for further research to understand its mechanisms.
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