Schizophrenia (Heidelberg, Germany)最新文献

{"title":"Healthy lifestyle, metabolomic signature, and risk of late-onset schizophrenia: evidence from the prospective cohort.","authors":"Xinru Guo, Ge Yu, Songyu Wu, Tingyi Jia, Zhouyang Sun, Changgui Kou, Wei Bai","doi":"10.1038/s41537-026-00752-z","DOIUrl":"https://doi.org/10.1038/s41537-026-00752-z","url":null,"abstract":"<p><p>A healthy lifestyle is associated with a reduced risk of schizophrenia, but the underlying metabolic mechanisms remain unclear. The aim of this study was to identify a metabolomic signature of a healthy lifestyle, to assess its mediation between lifestyle and schizophrenia risk, and to evaluate its potential causal link to schizophrenia. This study included 170,783 participants from the UK Biobank with comprehensive data on lifestyle, metabolomics, and relevant covariates. An elastic net regression model was employed to construct a metabolomic signature reflecting a healthy lifestyle. Associations between this signature and schizophrenia risk were examined using Cox proportional hazards models. Mediation analysis was conducted to assess the mediating role of the metabolomic signature in the association between healthy lifestyle and schizophrenia onset, while Mendelian randomization (MR) analysis was performed to explore potential causal effects. Individuals with a healthy lifestyle had a 58% lower risk of schizophrenia compared to those with an unhealthy lifestyle (HR 0.42; 95% CI, 0.29-0.61). The metabolomic signature, comprising 113 metabolites, was strongly correlated with the healthy lifestyle (r = 0.36, P < 0.001) and associated with reduced schizophrenia risk (HR 0.62 per SD increase; 95% CI, 0.49-0.79). This signature accounted for 15.59% of the association between healthy lifestyle and schizophrenia risk, and MR analysis suggested a possible causal relationship. Our study revealed a potential link between healthy lifestyle, metabolomic signature, and late-onset schizophrenia, highlighting the potential role of lifestyle-related metabolic alterations in schizophrenia development.</p>","PeriodicalId":74758,"journal":{"name":"Schizophrenia (Heidelberg, Germany)","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147694135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upregulation of DNA repair-related genes in the prefrontal cortex of patients with schizophrenia with low genetic risk.","authors":"Kazusa Miyahara, Mizuki Hino, Risa Shishido, Atsuko Nagaoka, Hideomi Hamasaki, Akiyoshi Kakita, Hiroaki Tomita, Yasuto Kunii","doi":"10.1038/s41537-026-00748-9","DOIUrl":"https://doi.org/10.1038/s41537-026-00748-9","url":null,"abstract":"<p><p>Schizophrenia is a heterogeneous disorder, with subpopulations showing a relatively higher heritable predisposition based on many common genetic variants with minimal effects, whereas other subpopulations likely have alternative pathogenic backgrounds, including rare genetic variants with large effects. These heterogeneities may hinder the identification of molecular profiles related to the disorder's pathogenesis. Therefore, this study aimed to identify transcriptional profiles specific to patients with schizophrenia with high heritable predisposition, indicated by high polygenic risk scores (PRS), and an alternative subgroup with low PRS. RNA-seq-based transcriptome data of the prefrontal cortices were compared among subgroups of patients with high PRS (PRS at or above the median; n = 12), low PRS (PRS below the median; n = 11), and controls (n = 21). Gene-category enrichment analysis of 584 differentially expressed genes (DEGs) identified 8 DEGs associated with DNA repair. Additionally, the expression levels of these DNA repair-related genes were associated with the general psychopathology scale, raising the hypothesis that oxidative stress accumulation, indicated by superoxide dismutase 2 expression may contribute to DNA repair activation. Furthermore, the expression levels of six DNA repair-related genes were significantly linked to the severity of the general psychopathology scale, suggesting that DNA repair might affect the clinical phenotypes of schizophrenia. This study used PRS to stratify patients with schizophrenia, highlighting the potential role of DNA repair-related pathways to the heterogeneity of schizophrenia. Understanding the role of DNA repair could lead to personalized treatments that target oxidative stress-related molecules.</p>","PeriodicalId":74758,"journal":{"name":"Schizophrenia (Heidelberg, Germany)","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147640800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dose reduction and discontinuation of antipsychotics in psychotic disorders: a systematic review of qualitative studies and meta-synthesis.","authors":"Sofia Francesca Aprile, Alessandro Rodolico, Antonio Munafò, Irene Bighelli, Filippo Caraci, Stefan Leucht","doi":"10.1038/s41537-026-00747-w","DOIUrl":"10.1038/s41537-026-00747-w","url":null,"abstract":"<p><p>Antipsychotic dose reduction and discontinuation are increasingly discussed in the management of psychotic disorders, yet clinical decisions remain challenging and evidence on lived experiences is fragmented. This systematic review and meta-synthesis aimed to synthesize qualitative evidence on subjective experiences of antipsychotic dose reduction and discontinuation among people with psychotic disorders, clinicians, and caregivers. A systematic search was performed on PubMed, Scopus, and PsycINFO. Peer-reviewed qualitative studies exploring subjective experiences with antipsychotic dose reduction and/or discontinuation in subjects with affective and non-affective psychotic disorders were included. Findings were integrated using thematic synthesis. A total of 13 studies were included. Eight studies focused on patients (N = 431), three on clinicians (N = 86), and two on caregivers (N = 26). From subjects' lived experiences, adverse effects were frequently reported as a driver for considering dose reduction, while concerns about relapse and the effort required to maintain stability contributed to ambivalent or cautious attitudes. Caregivers often reported unfavorable views, expressing fear of symptom recurrence, emotional distress, and risks to relational safety. Clinicians highlighted limited evidence and insufficient resources to support safe, long-term tapering and described uncertainty intensified by negative prior experiences and concerns about professional accountability in the event of relapse. Antipsychotic dose reduction and discontinuation are experienced as complex, preference-sensitive processes shaped by competing priorities and high perceived risks. The findings support the need for triadic shared decision-making that includes caregivers and for the development of structured, case-specific tapering protocols supported by adequate clinical resources and long-term monitoring.</p>","PeriodicalId":74758,"journal":{"name":"Schizophrenia (Heidelberg, Germany)","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13068915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147640781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diminished anticipatory-consummatory pleasure interplay in high schizotypal traits and subthreshold depression: potential risk for schizophrenia and depression.","authors":"Lei Shen, Chi Xie, Chang Liu, Yan-Yu Wang, Yi Wang, Chao Yan, Raymond C K Chan","doi":"10.1038/s41537-026-00746-x","DOIUrl":"https://doi.org/10.1038/s41537-026-00746-x","url":null,"abstract":"<p><p>Anhedonia is a multidimensional construct encompassing anticipatory and consummatory pleasure, and it manifests across a range of psychiatric disorders including schizophrenia (SCZ) and major depressive disorder (MDD). However, the shared and distinct mechanisms that underlie anhedonia between SCZ and MDD remain unclear. This study explored the characteristics and interplay between anticipatory and consummatory affective responses in SCZ and MDD patients as well as their subclinical counterparts. A total of 821 participants completed the Monetary Incentive Delay task. Network analysis was conducted on the full sample. For group comparisons, 59 non-clinical participants were excluded due to missing classification data or overlapping subclinical criteria, yielding 762 participants (115 SCZ, 60 MDD, 83 schizotypal traits (ST), 110 subthreshold depression (SD), and 394 healthy controls (HC)). Partial correlation networks were constructed using anticipatory and consummatory affective responses, calculated by averaging the valence subjective rating scores as nodes. Separate network comparisons were conducted to examine group differences within the subgroups. The results showed that consummatory affective responses under neutral condition was the central in the network. The global strength of network was lower in the both ST and SD participants compared to SCZ and MDD patients, respectively. Both SCZ patients and ST individuals showed stronger connections between anticipatory and consummatory pleasure compared to MDD and SD individuals. Our findings suggested that connections of multidimensional components of anhedonia played crucial role in the transdiagnostic network and the inter-relationship between anticipatory and consummatory pleasure might underlie the distinct mechanisms of anhedonia in SCZ and MDD.</p>","PeriodicalId":74758,"journal":{"name":"Schizophrenia (Heidelberg, Germany)","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147619124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning-based predictive models and subtypes patterns in peripheral blood of schizophrenia based on a machine learning computational framework.","authors":"Zhijun Li, Qing Sun, Haoyu Li, Naiyu Guan, Jing Ni, Jing Wang, Xiaolei Xu, Ye Shen, Siyu Sun, Yan Li","doi":"10.1038/s41537-026-00744-z","DOIUrl":"https://doi.org/10.1038/s41537-026-00744-z","url":null,"abstract":"<p><p>Schizophrenia (SCZ) is a complex psychiatric disorder, and its pathogenic mechanisms are not yet fully understood. The identification of reliable blood biomarkers and molecular subtypes for early diagnosis and effective therapy remains a significant challenge. To address this issue, we utilized a combination of bioinformatics and machine learning (ML) to identify potential biomarkers for SCZ. Our approach involved the integration of 12 different ML algorithms to develop a diagnostic signature based on data from several datasets, including GSE18312, GSE27383, GSE38485, GSE54913, and GSE165604. A nomogram was constructed using these datasets for potential clinical applications. In addition, clustering analysis was performed on SCZ patients using consensus clustering and non-negative matrix factorization (NMF) algorithms. We further evaluated subtype differences in biological functions and immune cells through various methods, such as gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), Proteomaps, and IOBR analyses. Our results identified a diagnostic signature composed of 16 genes (APBB2, CLCN1, SYDE1, PAX5, SNAI1, DAZL, UNC93B1, PLAGL2, HS3ST1, ITPKB, PILRA, BTLA, SWAP70, AZI2, ADM, and AVPR2), which demonstrated robust performance in diagnosing SCZ across eight different datasets. A nomogram based on these genes was created, providing clinical benefits for SCZ patients. Among the identified genes, AZI2 was found to be the most critical, influencing inflammation and immunity. We also identified potential chemical compounds that could target these 16 genes. Unsupervised clustering and NMF algorithms revealed two distinct subtypes of SCZ, each associated with unique immune cell profiles, biological functions, and protein expression levels. In conclusion, this study not only developed a diagnostic signature and a novel nomogram for SCZ but also provided new insights into the subtypes of SCZ. These findings may pave the way for personalized diagnosis and treatment strategies for SCZ patients.</p>","PeriodicalId":74758,"journal":{"name":"Schizophrenia (Heidelberg, Germany)","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147517426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rethinking language, cognition and assessment in psychosis: How bilingualism challenges psychiatry and how natural language processing can help.","authors":"Sandra Anna Just, Vincent DeLuca, Jason Rothman, Brita Elvevåg","doi":"10.1038/s41537-026-00742-1","DOIUrl":"10.1038/s41537-026-00742-1","url":null,"abstract":"<p><p>Language plays a central role in the assessment of individuals with psychosis, from taking a medical history to evaluating cognitive function. However, speaking multiple languages can significantly influence linguistic, cognitive and neural substrates. Therefore, it is essential to know whether an individual with psychosis is bilingual. Leaving modulating effects of bilingualism in psychosis unconsidered, runs high risk of confounding any clinical assessment and research. Although more than half of the world is bilingual, to date, this risk has not been addressed. This critical review challenges current basic diagnostic practices in psychiatry that conflate language and other cognitive domains. Drawing on neuropsychology, psycho-/neurolinguistics, and cognitive neuroscience, we (i) identify potential contact points between bilingualism and psychosis, (ii) present a decision tree framework for the clinical and research setting to systematically study those contact points, and (iii) provide the basis for developing and testing new treatments considering the lived realities of the majority of individuals with psychosis, namely bilingual individuals, and leveraging modern technology to do so. If the field of psychiatry embraces these conclusions, not only could bilingual individuals with psychosis experience more equity, but the larger field would benefit by reducing confounds inherent to ascribing to monolingual assumptions.</p>","PeriodicalId":74758,"journal":{"name":"Schizophrenia (Heidelberg, Germany)","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13128893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147461329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sleep and wake markers of thalamocortical functioning in early-course psychosis and first-degree relatives.","authors":"Bengi Baran, Dan Denis, Dimitrios Mylonas, Hazal Arpaci, Courtney Spitzer, Nicholas Raymund, Christine Talbot, Erin Kohnke, Olivia Larson, Robert Stickgold, Matcheri Keshavan, Dara S Manoach","doi":"10.1038/s41537-026-00735-0","DOIUrl":"10.1038/s41537-026-00735-0","url":null,"abstract":"<p><p>Thalamocortical circuits regulate information flow between sensory inputs and higher-order processing, and their disruption is increasingly implicated in psychotic disorders. However, scalable biomarkers of this circuitry remain limited. We assessed P50 sensory gating, 40 Hz auditory steady-state responses (ASSRs) and sleep spindles in relation to resting-state thalamocortical connectivity in early-course psychosis (EC, n = 19), first-degree relatives (FHR, n = 24), and demographically matched non-psychiatric comparison subjects (NC, n = 28). Compared to NC, EC, and FHR exhibited hyperconnectivity of the thalamus with the primary auditory cortex. Patients showed spindle deficits and impaired sensory gating and ASSRs, while FHR showed abnormal ASSR. In the entire sample, sleep spindles and sensory gating were associated with distinct thalamic connectivity patterns involving sensorimotor and dorsolateral prefrontal cortices, respectively. Our multimodal, circuit-informed approach points to thalamocortical pathways as potential biomarkers of risk and targets for treatment in psychosis. These findings should be interpreted in light of the modest sample sizes and the cross-sectional design, and suggest that wake EEG measures, though scalable, may not fully capture sleep-related thalamic abnormalities.</p>","PeriodicalId":74758,"journal":{"name":"Schizophrenia (Heidelberg, Germany)","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13111589/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147438328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo mapping of protein-protein interactions of schizophrenia risk factors generates an interconnected disease network.","authors":"Daniel B McClatchy, Jeff Lane, Susan B Powell, John R Yates Iii","doi":"10.1038/s41537-026-00734-1","DOIUrl":"10.1038/s41537-026-00734-1","url":null,"abstract":"<p><p>Genetic analyses of schizophrenia (SCZ) patients have identified thousands of risk factors. In silico protein-protein interaction (PPI) network analysis has provided strong evidence that disrupted PPI networks underlie SCZ pathogenesis. In this study, we performed in vivo PPI analysis of several SCZ risk factors (i.e., Grin2b, Grm5, Gsk3b, Map2k1, Ppp1ca, Stx1a, Syngap1, and Syt1) in the rodent brain. Using endogenous antibody immunoprecipitations analyzed by liquid chromatography coupled to mass spectrometry, we constructed a SCZ network comprising 1612 unique PPI with a 5% FDR. Over 90% of the PPIs have not been previously reported. AlphaFold3 was employed to identify direct PPI interactors. Our SCZ PPI network was enriched with known SCZ risk factors, which supports the hypothesis that an accumulation of disturbances in selected PPI networks underlies SCZ. We used Stable Isotope Labeling in Mammals (SILAM) to quantitate phencyclidine (PCP) perturbations in the SCZ network and found that PCP weakened most PPI but also led to some enhanced or new PPI. These findings demonstrate that quantifying PPI in perturbed biological states can reveal alterations to network biology.</p>","PeriodicalId":74758,"journal":{"name":"Schizophrenia (Heidelberg, Germany)","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13096421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An ENIGMA Consortium study of the relationship between white matter microstructure and positive and negative symptom severity in patients with schizophrenia.","authors":"Aoife Warren, Laurena Holleran, Ingrid Agartz, Ole A Andreassen, Nerisa Banaj, Dara M Cannon, Aiden Corvin, Melissa Green, Ruben Gur, Ryota Hashimoto, Elliot Hong, Cyril Hoschl, Peter Kochunov, Stephen M Lawrie, Colm McDonald, Derek Morris, David Mothersill, Emma Neilson, Christos Pantelis, Fabrizio Piras, Paul E Rasser, David Roalf, Theodore D Satterthwaite, Ulrich Schall, Kang Sim, Antonin Skoch, Gianfranco Spalletta, Filip Spaniel, Sophia Thomopoulos, David Tomecek, Andrew Zalesky, Paul M Thompson, Neda Jahanshad, Jessica A Turner, Theo G M van Erp, Gary Donohoe","doi":"10.1038/s41537-026-00728-z","DOIUrl":"10.1038/s41537-026-00728-z","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":74758,"journal":{"name":"Schizophrenia (Heidelberg, Germany)","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13087269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147370742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persistent negative symptoms in the EULAST cohort: impact on functional outcome.","authors":"Luigi Giuliani, Pasquale Pezzella, Giulia M Giordano, Andrea Perrottelli, Armida Mucci, Paola Bucci, Istvan Bitter, Celso Arango, Jurjen J Luykx, Covadonga M Díaz-Caneja, Bjørn H Ebdrup, Michael Davidson, Jari Tiihonen, Inge Winter-van Rossum, Silvana Galderisi","doi":"10.1038/s41537-026-00739-w","DOIUrl":"10.1038/s41537-026-00739-w","url":null,"abstract":"<p><p>Persistent negative symptoms (PNS), defined as negative symptoms of at least moderate severity that endure over time and are not attributable to other psychopathological dimensions such as depression or parkinsonism, have been associated with poor functional outcomes in schizophrenia, in both chronic stages and in the early phases of the disorder. This post-hoc analysis of a large cohort of schizophrenia spectrum disorder patients within their first 7 years of illness, enrolled in the European Long-acting Antipsychotics in Schizophrenia Trial (EULAST), aimed to: 1) confirm prior findings about the prevalence and clinical impact of unconfounded persistent negative symptoms (PNS) on dropout rates and psychosocial functioning after 12 and 18 months of treatment; and 2) explore the prevalence of enduring negative symptoms (E-NS), defined as persistent negative symptoms either confounded or unconfounded by depression or parkinsonism, and their influence on functional outcome. At week 0, 60.6% of patients exhibited at least one negative symptom of moderate severity. Among them, 42.8% met criteria for unconfounded negative symptoms. After 1 year, the frequency of PNS and E-NS was 7.9% and 15%, respectively, with a prospective consistency around 32%. PNS subjects had similar levels of functioning at week 0 (d = -0.179, p = 0.194), but worse functioning after 12 (d = -0.697, p = 0.028) and 18 (d = -0.676, p = 0.024) months of treatment, as compared to those with negative symptoms of similar severity at baseline that did not persist (non-persistent negative symptoms, N-PNS). No difference among groups was observed in drop-out rates. The comparison between the E-NS and N-PNS groups revealed the same functional outcome differences observed in the PNS versus N-PNS comparison. Our findings confirm that long-term persistence of negative symptoms, both primary and secondary, contributes to poor functional outcome. Future research should focus on identifying predictors of symptom persistence to guide the development of targeted interventions aimed at improving long-term functional outcomes in this patient population.</p>","PeriodicalId":74758,"journal":{"name":"Schizophrenia (Heidelberg, Germany)","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13065952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147328360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}