Altered serum MMP-9, TIMP-1, and IGFBP-1 concentrations in chronic male schizophrenia patients: associations with illness duration and cognitive impairments

Altered serum MMP-9, TIMP-1, and IGFBP-1 concentrations in chronic male schizophrenia patients: associations with illness duration and cognitive impairments | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Altered serum MMP-9, TIMP-1, and IGFBP-1 concentrations in chronic male schizophrenia patients: associations with illness duration and cognitive impairments Minggang Jiang, Xiaoyu Sun, Yubing Han, Man Yang, Jing Zhang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8288124/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Background Dysregulation of neuroplasticity contributes to the pathogenesis of schizophrenia. Matrix metalloproteinases (MMPs) and endogenous tissue MMP inhibitors (TIMPs) are key regulators of extracellular matrix (ECM) remodeling essential for neuroplasticity, while insulin-like growth factor binding protein-1 (IGFBP-1) modulates ECM dynamics through integrin receptor signaling and MMP-mediated proteolysis. The current study investigated potential abnormalities in serum MMP-9, TIMP-1, and IGFBP-1 concentrations as biomarkers of ECM dysfunction among long-term hospitalized male schizophrenia patients and assessed associations with clinical characteristics. Methods Serum MMP-2, MMP-9, TIMP-1, and IGFBP-1 concentrations were compared between 80 male schizophrenia patients hospitalized for ≥5 years and 59 age-matched healthy male controls. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and cognitive functions using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Correlations between serum measurements and scores on the PANSS and RBANS were assessed while controlling for multiple covariates. Results Serum TIMP-1 concentration was significantly lower in the patient group ( Z =-2.547, P = 0.012). Conversely, patients exhibited significantly elevated serum MMP-9 ( Z =-2.067, P = 0.039), MMP-9/TIMP-1 ratio ( Z =-2.195, P = 0.028), and IGFBP-1 ( Z =-5.994, P < 0.001). Serum IGFBP-1 concentration negatively correlated with RBANS immediate memory subscore ( r =-0.240, P = 0.024), and elevated IGFBP-1 was identified as an independent risk factor for long-term hospitalization ( RR = 2.257, P < 0.001, 95%CI:1.571–3.243). Serum TIMP-1 concentration also positively correlated with illness duration ( r = 0.376, P = 0.001). Conclusions Long-term hospitalized male schizophrenia patients exhibit an ECM remodeling imbalance associated with memory impairment and predictive of chronic disease status. Therefore, molecules regulating ECM dynamics may be effective therapeutic targets for schizophrenia. Schizophrenia extracellular matrix matrix metalloproteinase-9 insulin-like growth factor binding protein-1 cognitive impairment illness duration Figures Figure 1 Figure 2 Figure 3 Figure 14 Figure 15 Introduction Schizophrenia is a common, chronic, and debilitating psychiatric disorder characterized by positive symptoms such as delusional and disordered thinking, negative symptoms such as blunted affect, and cognitive impairments [ 1 ]. While symptom profile may vary among individuals and across disease stages, the core cognitive deficits tend to persist throughout the disease course, and are particularly robust predictors of poor functional outcome and reduced quality of life, often exerting a more profound impact on long-term disability than positive or negative symptoms [ 2 , 3 ]. In patients with chronic schizophrenia requiring long-term hospitalization, cognitive deterioration is especially pronounced, severely limiting the potential for rehabilitation and community reintegration [ 4 ]. Although antipsychotic medications effectively control psychotic symptoms such as delusions and hallucinations, therapeutic effects on cognitive impairments remain limited [ 5 ]. Accumulating evidence indicates that aberrant neuroplasticity, manifesting as reduced synaptic density, abnormal dendritic spine morphology, and impaired neural circuit remodeling, is a core neuropathological feature of schizophrenia [ 6 , 7 ]. The extracellular matrix (ECM) serves as a critical regulator of neuroplasticity in the central nervous system [ 8 ]. Beyond providing structural support for neurons, the ECM actively modulates synaptic formation, axonal growth, and neuronal migration through interactions with cell surface receptors [ 9 , 10 ]. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are principal mediators of ECM remodeling, with MMP-9 and MMP-2 being the most abundantly expressed in neural tissues [ 11 , 12 ]. Recent evidence suggests that astrocytes control closure of the ‘critical period’ for neuroplasticity in primary sensory cortex through regulation of MMP-9 expression, resulting in suppression of experience-dependent neuronal circuit remodeling [ 13 ]. The activities of MMPs are also regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), with TIMP-1 forming a specific regulatory pair with MMP-9 [ 14 ]. The dynamic equilibrium between MMPs and TIMPs determines the directionality and magnitude of ECM remodeling, thereby creating the microenvironmental milieu essential for neuroplasticity [ 15 ]. Several recent studies have investigated alterations in the MMP/TIMP system among patients with schizophrenia but yielded inconsistent findings [ 16 ], with some reporting elevated serum MMP-9 concentrations [ 17 ] and others reduced levels or no significant differences compared to healthy controls [ 18 ]. Similarly, specific alterations in serum TIMP-1 are inconsistent across studies [ 19 , 20 ], and it is uncertain if serum concentrations are associated with illness duration or cognitive deficits. These discrepancies suggest that alterations in MMP and TIMP expression vary across different disease stages, warranting further investigation in specific patient populations, such as the long-term hospitalized population with chronic intractable disease. Given the accessibility of peripheral blood for MMP and TIMP measurements, clinical diagnosis, prognosis, and treatment could be greatly aided by establishing consistent associations between serum concentration changes and symptom expression. Insulin-like growth factor binding protein-1 (IGFBP-1) was initially identified as a carrier protein regulating the bioavailability of insulin-like growth factors (IGFs) [ 21 ], but more recent studies have reported IGF-independent biological functions, including interactions with the ECM and modulation of cell adhesion, migration, and survival through integrin receptor signaling [ 22 , 23 ]. Notably, several IGFBPs serve as substrates for MMPs, and MMP-mediated proteolysis can liberate IGF from its binding proteins, thereby potentiating neurotrophic signaling cascades inducing neuroplasticity [ 24 , 25 ]. These findings position IGFBPs as potential bridging molecules linking ECM remodeling with growth factor bioavailability and neuroplasticity in the central nervous system. The present study examined ECM marker abnormalities in a distinct population of male patients with particularly intractable symptom expression, those with chronic schizophrenia requiring long-term hospitalization (illness duration ≥ 5 years). Serum concentrations of MMP-2, MMP-9, TIMP-1, and IGFBP-1 were compared between these patients and healthy matched controls to identify potential associations with disease characteristics. We hypothesized that patients with long-term schizophrenia would exhibit an ECM remodeling imbalance characterized by elevated MMP-9/TIMP-1 and aberrant IGFBP-1 expression, and that these abnormalities would correlate with disease chronicity and cognitive impairments. Subjects and methods Subjects and assessments Long-term hospitalized male patients with schizophrenia from Lianyungang Psychiatric Hospital and its affiliated medical institutions were recruited as the clinical group, while male volunteers matched for age were recruited from the local community as the healthy control (HC) group. The inclusion criteria for patients were as follows: (1) meeting the diagnostic criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV); (2) hospitalization duration ≥ 5 years; (3) male; (4) age 18–65 years; (5) able to cooperate with blood collection and relevant assessments. The exclusion criteria for patients were as follows: (1) severe somatic diseases (e.g., severe cardiac, hepatic, or renal insufficiency, malignant tumors); (2) comorbid substance or alcohol dependence; (3) acute infectious or inflammatory diseases within the past three months; (4) other comorbid mental disorders (e.g., mood disorders, dementia); (5) changes in antipsychotic medication or significant dose adjustments within the past three months; (6) currently receiving immunosuppressants or hormone therapy for any somatic disease; (7) incomplete clinical data or inability to cooperate with the study. Inclusion criteria (3)–(5) also applied to HCs, while exclusion criteria were as follows: (1) current or past history of mental disorders; (2) history of mental disorders in first-degree relatives; (3) severe somatic diseases; (4) history of substance or alcohol dependence; (5) acute infectious or inflammatory diseases within the past three months; (6) use of medications affecting the central nervous system (e.g., antidepressants, anxiolytics) within the past three months; (7) currently receiving immunosuppressants or hormone therapy. All HCs provided written informed consent, while written informed consent was obtained from patients or their legal guardians. This study was approved by the Ethics Committee of Lianyungang Fourth People’s Hospital (Ethics approval number: 2019LSYYXLL-P06) and was conducted according to the tenets of the Helsinki Declaration. Clinical and cognitive assessment Psychiatric symptoms in the patient group were assessed using the Positive and Negative Syndrome Scale (PANSS) [ 26 , 27 ]. The PANSS consists of 30 items yielding three subscales, positive symptoms, negative symptoms, and general psychopathology. Each item is rated on a 7-point scale ranging from 1 to 7, with higher scores indicating more severe symptoms. All assessments were conducted independently by two trained psychiatrists with attending physician or higher qualifications, and inter-rater reliability was ≥ 0.85. Cognitive functions were assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [ 28 , 29 ]. The RBANS comprises 12 subtests assessing five cognitive domains: immediate memory, visuospatial/constructional ability, language, attention, and delayed memory. Each domain score is converted to an index score based on raw scores, and the total scale score is derived from the sum of the five domain index scores. The RBANS assessment was administered by professionally trained raters with psychological testing qualifications in a quiet, private room. Each assessment session lasted approximately 30–40 minutes. All assessments were completed on the same day as blood sample collection. Measurement of serum MMP-2, MMP-9, TIMP-1, and IGFBP-1 concentration Fasting venous blood samples (5 mL) were collected from all participants between 7:00 and 9:00 AM. Samples were left standing at room temperature for 30 minutes, and the serum fractions separated by centrifugation at 3000 rpm for 15 minutes. Serum samples were then aliquoted and stored at -80°C until analysis, with repeated freeze-thaw cycles avoided. Serum concentrations of MMP-2, MMP-9, TIMP-1, and IGFBP-1 were quantified using assay kits (R&D Systems; Minneapolis, MN, USA) based on Luminex liquid suspension chip detection according to the manufacturer’s instructions. All samples were analyzed in duplicate by laboratory personnel unaware of the group assignment, and mean values recorded for analyses. The intra-assay coefficient of variation (CV) was < 10%, and the inter-assay CV was < 15% for all measurements. Statistical analyses All statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). The Shapiro–Wilk test was used to assess the normality of continuous variables. Normally distributed continuous variables are presented as mean ± standard deviation (SD) and non-normally distributed continuous variables as median (interquartile range), while categorical variables are presented as frequency (percentage of total cases). For univariable analysis, normally distributed continuous variables were compared by Student’s t-tests, non-normally distributed continuous variables by Mann–Whitney U-test, and categorical variables using the chi-square test. Analysis of covariance (ANCOVA) was also performed to assess the influence of body mass index (BMI) on normally distributed serum concentrations, while rank ANCOVA was used to assess the influence of BMI on non-normally distributed serum concentrations. Associations between variables were assessed using Pearson’s or Spearman’s method depending on data distribution. Stepwise linear regression analysis was performed to identify independent predictors of RBANS immediate memory score, with age, years of education, smoking status, BMI, duration of illness, age of onset, chlorpromazine equivalent dose, and serum IGFBP-1 concentration as independent variables. Based on tertiles of illness duration, patients were divided into three groups: short duration (< 10 years), medium duration (10–15 years), and long duration (≥15 years). One-way analysis of variance (ANOVA) was used to compare TIMP-1 levels among the three groups, followed by Bonferroni post hoc tests for pairwise comparisons. Effect sizes are expressed as eta-squared (η 2 ). Modified Poisson regression analysis was performed to identify independent risk factors for long-term hospitalization, and relative risk (RR) with 95% confidence intervals (CI) were calculated. All tests were two-tailed, and P < 0.05 was considered statistically significant. Results Comparison of demographic and clinical characteristics The demographic and clinical characteristics of the patient and HC groups are summarized in Table 1 . A total of 80 patients with schizophrenia and 59 healthy controls (HCs) were included in this study. The two groups were well-matched for age ( P = 0.617), education level ( P = 0.198), and smoking status ( P = 0.326). However, BMI was significantly lower in the patient group ( P = 0.040). As expected, patients demonstrated significantly poorer performance across all RBANS domains (all P < 0.001). Table 1. Demographic and clinical characteristics of schizophrenia patients and healthy controls (HCs) Patients (n=80) HCs (n=59) t / c 2 / Z P Age (years) 40.61 ± 9.78 39.78 ± 9.57 0.501 a 0.617 Education (years) 9.0 (6.0, 9.0) 9.0 (6.0, 12.0) -1.286 b 0.198 BMI (kg/m 2 ) 24.51 ± 3.66 25.67 ± 2.70 -2.075 a 0.040 Smoking (n, %) 42 (52.5) 26 (44.1) 0.966 c 0.326 Age of onset (years) 26.86 ± 8.68 - - - Duration of illness (years) 11.0 (7.0, 19.88) - - - Equivalent dose of chlorpromazine (mg/d) 687.14 ± 312.24 - - - PANSS total score 58.09 ± 14.90 - - - P subscores 11.10 ± 4.43 - - - N subscores 17.78 ± 7.18 - - - G subscores 29.09 ± 6.16 - - - RBANS total score 58.39 ± 10.86 87.54 ± 12.89 - 14.446 a <0.001 Immediate memory 50.36 ± 16.79 82.49 ± 18.63 - 10.641 a <0.001 Visuospatial/constructional 69.84 ± 15.13 90.68 ± 15.63 - 7.915 a <0.001 Language 72.0 ± 13.87 95.90 ± 11.29 - 10.844 a <0.001 Attention 82.23 ± 13.64 104.85 ± 13.98 - 9.561 a <0.001 Delayed memory 54.20 ± 16.23 83.27 ± 17.67 - 10.053 a <0.001 BMI, body mass index; PANSS, positive and negative syndrome scale. RBANS, repeatable battery for the assessment of neuropsychological status; a Independent samples t-test; b Mann–Whitney U test; c χ 2 test. Differences in serum MMP-2, MMP-9, TIMP-1, and IGFBP-1 concentrations between schizophrenia patients and healthy controls Serum concentrations of ECM biomarkers were compared between patients with schizophrenia and HCs ( Table 2 ). Neither serum MMP-2 concentration ( Z = -1.183, P = 0.237) nor MMP-2/TIMP-1 ratio ( Z = -1.585, P = 0.113) differed significantly between groups. However, patients with schizophrenia exhibited significantly higher serum MMP-9 levels than HCs ( Z = -2.067, P = 0.039). In contrast, serum TIMP-1 concentration was significantly lower in patients than HCs ( t = -2.547, P = 0.012). Consequently, the MMP-9/TIMP-1 ratio was significantly elevated in the patient group ( Z = -2.195, P = 0.028). Serum IGFBP-1 concentration was also markedly higher in patients with schizophrenia compared to HCs ( Z = -5.994, P < 0.001) ( Figure 1 ). Table 2. Comparison of serum MMP-2, MMP-9, TIMP-1, and IGFBP-1 concentrations between schizophrenia patients and healthy controls (HCs) Patients (n = 80) HC (n = 59) t / Z P MMP-2 (ng/mL) 30.24 (28.22, 33.47) 31.57 (28.77, 34.06) -1.183 0.237 MMP-9 (ng/mL) 23.93 (11.14, 34.96) 17.70 (8.66, 26.44) -2.067 0.039 TIMP-1 (ng/mL) 32.23 ± 7.65 35.54 ± 7.46 - 2.547 0.012 MMP-2/TIMP-1 0.94 (0.78, 1.20) 0.90 (0.72, 1.10) -1.585 0.113 MMP-9/TIMP-1 0.74 (0.29, 1.43) 0.55 (0.22, 0.87) -2.195 0.028 IGFBP-1 (ng/mL) 25.05 (12.64, 47.99) 6.95 (3.20, 14.51) -5.994 <0.001 Abbreviations: MMP-2, matrix metalloproteinase-2; MMP-9, matrix metalloproteinase-9; TIMP-1, tissue inhibitor of metalloproteinase-1; IGFBP-1, insulin-like growth factor binding protein-1. Fig 1 . Comparison of serum extracellular matrix biomarker concentrations between patients and healthy controls (HCs). (A) Matrix metalloproteinase-9 (MMP-9). (B) Tissue inhibitor of metalloproteinase-1 (TIMP-1). (C) MMP-9/TIMP-1 ratio. (D) Insulin-like growth factor binding protein-1 (IGFBP-1). Given the significant difference in BMI between patients and HCs, we evaluated the influence of BMI on group differences in ECM biomarkers by ANCOVA and rank ANCOVA. The group difference in serum TIMP-1 concentration detected by univariate analysis remained significant according to ANCOVA with group as the fixed factor and BMI as the covariate ( F = 6.383, P = 0.013). Similarly, rank ANCOVA with BMI as the covariate revealed significant group differences in MMP-9 ( F = 4.033, P = 0.047), MMP-9/TIMP-1 ( F = 4.755, P = 0.031), and IGFBP-1 ( F = 42.297, P < 0.001). Correlations of serum ECM marker concentrations with clinical variables There were no significant correlations between clinical symptom scores as measured by the PANSS and serum MMP-9 concentration, TIMP-1 concentration, MMP-9/TIMP-1 ratio, and IGFBP-1 concentration (all P > 0.05), nor between clinical symptom scores and clinicodemographic factors smoking status, age of onset, years of education, and chlorpromazine equivalent dose (all P > 0.05). However, serum TIMP-1 concentration was positively correlated with age ( r = 0.257, P = 0.022) and duration of illness ( r = 0.376, P = 0.001, Figure 2 ), while serum IGFBP-1 concentration was negatively correlated with BMI ( r = -0.294, P = 0.008). Fig 2 . Correlation between serum TIMP-1 concentration and duration of illness. Correlations of serum ECM marker concentrations with cognitive functions Serum IGFBP-1 concentration was negatively correlated with RBANS immediate memory score ( r = - 0.240, P = 0.024, Figure 3 ), while MMP-9, TIMP-1, and MMP-9/TIMP-1 were not significantly correlated with RBANS total score or any subscale score (all P > 0.05). Fig 3. Correlation between serum IGFBP-1 concentration and RBANS immediate memory score. Stepwise linear regression analysis revealed that years of education ( B = 1.637, β = 0.308, t = 2.906, P = 0.005) and serum IGFBP-1 concentration ( B = -0.112, β = -0.213, t = -2.009, P = 0.048) were independent predictors of immediate memory performance after controlling for age, years of education, smoking status, BMI, duration of illness, age of onset, and chlorpromazine equivalent dose. Variations in serum TIMP-1 concentration with illness duration Patients were divided into three illness durations groups, short (<10 years, n = 25), medium (10–15 years, n = 28), and long (³ 15 years, n = 27), and compared for serum ECM marker concentrations ( Table 3) . One-way ANOVA revealed significant differences in serum TIMP-1 concentration among the three groups ( F = 5.592, P = 0.005, h 2 = 0.127), and Bonferroni post hoc tests indicated significantly higher serum TIMP-1 concentration in the long duration group compared to both the medium duration group ( P = 0.037) and the short duration group ( P = 0.007), while there was no significant difference between medium and short duration groups ( P > 0.99). Table 3. Changes in serum TIMP-1 concentration with illness duration Group Duration (years) n TIMP-1 (ng/mL) F P h 2 Short duration < 10 25 29.65 ± 5.85 5.592 0.005 0.127 Medium duration 10–15 28 30.94 ± 8.59 - - - Long duration ³ 15 27 35.95 ± 6.88 - - - Independent risk factors for long-term hospitalization To examine the strengths of these ECM biomarkers as risk factors for chronic schizophrenia, we stratified the entire participant cohort into high and low serum TIMP-1, MMP-9, MMP-9/TIMP-1, and IGFBP-1 subgroups using the median values as cut-offs and conducted modified Poisson regression analysis. Group membership (patient vs. HC) was set as the dependent variable, age, BMI, smoking status, and education level as covariates, and binary ECM biomarker groupings as independent variables. After adjusting for confounding factors, IGFBP-1 above the median was identified as an independent risk factor for long-term hospitalization among male patients with schizophrenia ( B = 0.814, P < 0.001, RR = 2.257, 95% CI: 1.571–3.243, Table 4 ). Table 4. Modified Poisson regression analysis of independent risk factors for long-term hospitalization among male patients with schizophrenia Variables B SE P RR 95%CI Age -0.002 0.007 0.800 0.998 0.984–1.012 BMI -0.014 0.022 0.516 0.986 0.944–1.029 Smoking -0.083 0.131 0.526 0.920 0.712–1.190 Education 0.004 0.022 0.848 1.004 0.962–1.049 IGFBP-1 0.814 0.185 < 0.001 2.257 1.571–3.243 Discussion This study investigated serum concentrations of MMP-2, MMP-9, TIMP-1, and IGFBP-1 as biomarkers of ECM dysregulation in long-term hospitalized male patients with schizophrenia, as well as the associations of these biomarkers with clinical symptoms and cognitive function. The main findings of this study are as follows: 1) Compared to healthy controls, the patient group exhibited lower serum TIMP-1 concentrations, while serum MMP-9 concentration, MMP-9/TIMP-1 ratio, and IGFBP-1 concentration were elevated; 2) Serum IGFBP-1 concentration was negatively correlated with RBANS immediate memory subscore; 3) Serum TIMP-1 concentration was positively correlated with illness duration, with highest levels in the longest duration group (>15 years); 4) Elevated serum IGFBP-1 concentration was identified as an independent risk factor for long-term hospitalization. These findings support ECM dysregulation as a potential pathogenic mechanism underlying schizophrenia progression, and further suggest that serum TIMP-1 and IGFBP-1 may serve as useful prognostic biomarkers, while corresponding brain activities may be effective treatment targets. Our finding that serum MMP-9 concentration was significantly elevated in male chronic schizophrenia patients hospitalized for more than 5 years is consistent with a recent report by Liang et al. [17], and also aligns with our previous findings [30]. However, a systematic review and meta-analysis by Schoretsanitis et al. revealed inconsistent serum MMP-9 alterations across studies of schizophrenia patients [18], hinting that serum MMP-9 may be influenced by disease stage, illness duration, and medication status among other clinical and demographic factors [31]. The elevated serum MMP-9 levels in the current patient population suggests that an ECM remodeling imbalance may persist throughout the course of the disease and contribute to the pathological processes necessitating long-term institutionalization [32, 33]. Alternatively, the lower serum TIMP-1 levels among these schizophrenia patients is inconsistent with previous findings by Rahimi et al., who reported no significant difference compared to healthy controls [19], and with Dai et al., who reported that TIMP-1 expression was significantly upregulated in the anterior cingulate cortex of schizophrenia patients and associated with ferroptosis [34]. However, the elevated MMP-9/TIMP-1 ratio in the present patient cohort is consistent with the findings of Rahimi et al[19]. Furthermore, network analysis by Jeffries et al. revealed a strong correlation between TIMP-1 and anti-remodeling protein SERPINE1 expression in patients transitioning to psychosis, whereas this correlation was nearly absent in nonconverters [35], suggesting that dysregulation of ECM remodeling networks may drive psychosis. Compared to individual biomarkers, the MMP-9/TIMP-1 ratio may better reflect a dynamic imbalance of the ECM protease system, with an elevated ratio indicating a shift toward ECM protein degradation [36] and aberrant neuroplastic changes in brain circuits contributing to chronic disease status. Serum IGFBP-1 concentration was also elevated among long-term hospitalized male patients with schizophrenia, while previous studies have reported inconsistent findings, including a series of studies by Melkersson et al. reporting no significant differences in serum IGFBP-1 between schizophrenia patients treated with typical antipsychotics or chlorpromazine and healthy controls, whereas patients treated with olanzapine exhibited significantly lower serum IGFBP-1 [37, 38]. Howes et al. found that serum IGFBP-1 was lower among patients than controls prior to clozapine treatment, and that clozapine treatment did not significantly alter serum IGFBP-1 levels [39]. These inconsistencies may be attributable to differences in antipsychotic medication or other patient characteristics such as metabolic status and disease stage. Elevated IGFBP-1 levels in the current cohort may reflect metabolic disturbances occurring during the chronic course of the illness as IGFBPs not only regulate IGF bioavailability but also possess IGF-independent biological functions [40]. Furthermore, IGFBP-1 has been identified as a substrate for MMP-9 and can be proteolytically cleaved by other MMPs [41]. In the present study, patients exhibited concurrent elevations in serum MMP-9 and IGFBP-1 levels, suggesting complex interactions between the ECM remodeling network and IGF signaling, although the specific mechanistic roles in the chronic progression of schizophrenia require further investigation. Serum IGFBP-1 concentration was negatively correlated with immediate memory performance, consistent with our previous findings in treatment-resistant schizophrenia patients [42] and suggesting that IGFBP-1-dependent processes may disrupt working memory in schizophrenia. Previous studies have reported alterations in the IGF pathway across multiple psychiatric and neurological conditions. Fernández-Pereira et al. found correlations of IGFBP-3 and IGFBP-5, but not IGFBP-1, with cognitive function [43]. In contrast, significant changes in IGFBP-1 have been observed in elderly male schizophrenia patients [44] and Alzheimer’s disease patients [45, 46]. Furthermore, schizophrenia patients with lower IGF-1 levels before treatment showed more pronounced improvement in cognitive deficits following antipsychotic medication [47], in accord with the current findings. These clinical observations, together with findings from animal models [48], indicate that IGF signaling plays an important role in neurodevelopment and cognitive function. Serum TIMP-1 concentration was positively correlated with disease duration and demonstrated relative stability within the first 15 years, followed by a significant increase. This finding is consistent with the neurodevelopmental-progressive hypothesis of schizophrenia [49] and suggests that serum TIMP-1 may reflect cumulative pathological processes involving ECM remodeling, ultimately leading to intractable clinical symptoms. As an acute-phase reactant, TIMP-1 may participate in the persistent low-grade inflammatory state observed in schizophrenia [50, 51]. Longitudinal neuroimaging studies have shown progressive gray matter volume loss and ventricular enlargement in the chronic phase [52-54]. We speculate that chronically elevated peripheral TIMP-1 may reflect neurostructural damage, although the exact mechanisms remain unclear. For instance, imbalances between MMPs and TIMPs may lead to ECM dysregulation and altered neural network architecture [55]. Indeed, the 15-year time point for TIMP-1 elevation observed in our study aligns with the period of accelerated functional decline reported in clinical studies. Alternatively, the relative stability of TIMP-1 in the first 15 years suggests a potential therapeutic window for intervention beyond which neurological changes underlying symptoms are irreversible. Therefore, monitoring of serum TIMP-1 may help identify patients in a state of active disease progression. Elevated serum IGFBP-1 levels were identified as an independent risk factor for long-term hospitalization, suggesting that IGFBP-1 may contribute to these pathogenic processes resulting in intractable symptoms. Metabolic disturbances are highly prevalent in schizophrenia patients [56], and elevated IGFBP-1 may reflect this metabolic dysregulation [57]. Further, Cheng et al. identified a negative genetic correlation between plasma IGFBP-6 protein levels and schizophrenia through linkage disequilibrium score regression analysis, suggesting that members of the IGFBP family influence disease susceptibility [58]. Notably, elevated serum IGFBP-1 concentration was associated with alterations in MMP-9 and TIMP-1, suggesting that metabolic dysregulation may contribute to aberrant ECM remodeling and neuroplasticity in long-term schizophrenia patients, leading to a chronic disease condition. This study has several limitations. First, the cross-sectional design precludes causal inferences and tracking of dynamic changes in ECM biomarkers. Second, these findings may only apply to long-term hospitalized male patients with chronic schizophrenia. Larger-scale studies comparing these biomarker changes between clinical groups (e.g., first-episode, patients in remission, etc.) may provide additional support for the contributions of ECM abnormalities to the neurological changes underlying schizophrenia progression. Third, the influences of different antipsychotic medications were not considered in the analysis. Again, future studies should employ longitudinal designs and include more diverse patient populations. This study revealed that extracellular matrix (ECM) remodeling is dysregulated in male patients with chronic schizophrenia as evidenced by elevated serum MMP-9 levels and MMP-9/TIMP-1 ratio, along with reduced serum TIMP-1. Serum IGFBP-1 was also significantly elevated in patients, correlated with immediate memory impairment, and independently associated with long-term hospitalization. In addition, elevated serum TIMP-1 was associated with longer illness duration due to marked upregulation after 15 years of illness, suggesting that ECM remodeling dysregulation directly contributes to neurological changes underlying chronic pathological progression. These findings identify ECM remodeling as a promising therapeutic target for preventing schizophrenia progression to the chronic state. Declarations Acknowledgments We would like to thank all of the study participants. Author contributions Minggang Jiang and Haidong Yang wrote the manuscript; Xiaobin Zhang and Xiaoyu Sun were responsible for the study design; Haidong Yang and Yubing Han performed the statistical analysis; Yubing Han, Man Yang, and Jing Zhang performed the clinical ratings, recruited the patients, and collected the samples. All authors have contributed to and approved the final manuscript. Funding The study was financially supported by the Suzhou Clinical Medical Center for Mood Disorders (grant no. Szlcyxzx202109), Suzhou Key Laboratory (grant no. SZS2024016), Suzhou Multicenter Clinical Research Project on Major Diseases (grant no. DZXYJ202413), Guidance Project of Jiangsu Provincial Health Commission (grant no. Z2023074), and Lianyungang National Natural Science Foundation Reserved Project (General Program) (grant no. K82504). The funding sources of this study had no role in the study design, data collection and analysis, decision to publish, or preparation of the article. Data availability The data supporting the results of this study are available from the corresponding author upon reasonable request. Ethical approval and consent to participate We declare that all human experimentation was conducted in accordance with the Declaration of Helsinki and that all procedures were carried out with the adequate understanding and written consent of the subjects. All experimental protocols were approved by the Ethics Committee of Lianyungang Fourth People’s Hospital. Informed consent was obtained from all participants and/or their legal guardians. All methods were carried out in accordance with relevant guidelines and regulations. Declaration of Generative AI and AI-assisted Techniques Artificial intelligence (AI) tools were used only for minor language editing (e.g., grammar and style checks). All scientific content, interpretations, and conclusions were generated by the authors. Consent for publication Not applicable. Competing interests The authors have no competing or potential conflicts of interest to declare. Clinical trial Not applicable. References Jauhar S, Johnstone M, McKenna PJ. Schizophrenia. Lancet. 2022;399(10323):473–86. McCutcheon RA, Keefe RSE, McGuire PK. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Mol Psychiatry. 2023;28(5):1902–18. Gebreegziabhere Y, Habatmu K, Mihretu A, Cella M, Alem A. Cognitive impairment in people with schizophrenia: an umbrella review. Eur Arch Psychiatry Clin Neurosci. 2022;272(7):1139–55. Barlati S, Nibbio G, Vita A. Evidence-based psychosocial interventions in schizophrenia: a critical review. Curr Opin Psychiatry. 2024;37(3):131–9. Feber L, Peter NL, Chiocchia V, Schneider-Thoma J, Siafis S, Bighelli I, Hansen WP, Lin X, Prates-Baldez D, Salanti G, et al. Antipsychotic Drugs and Cognitive Function: A Systematic Review and Network Meta-Analysis. JAMA psychiatry. 2025;82(1):47–56. Howes OD, Bukala BR, Beck K. Schizophrenia: from neurochemistry to circuits, symptoms and treatments. Nat reviews Neurol. 2024;20(1):22–35. Speranza L, di Porzio U, Viggiano D, de Donato A, Volpicelli F. Dopamine: The Neuromodulator of Long-Term Synaptic Plasticity, Reward and Movement Control. Cells 2021, 10(4). Dzyubenko E, Hermann DM. Role of glia and extracellular matrix in controlling neuroplasticity in the central nervous system. Semin Immunopathol. 2023;45(3):377–87. Cangalaya C, Sun W, Stoyanov S, Dunay IR, Dityatev A. Integrity of neural extracellular matrix is required for microglia-mediated synaptic remodeling. Glia. 2024;72(10):1874–92. Bauch J, Faissner A. The Extracellular Matrix Proteins Tenascin-C and Tenascin-R Retard Oligodendrocyte Precursor Maturation and Myelin Regeneration in a Cuprizone-Induced Long-Term Demyelination Animal Model. Cells 2022, 11(11). Qi S, Wang S, Tan Y, Pan C, Bi X. Extracellular Matrix (ECM)-Regulated Molecular Switches: Tissue Inhibitors of Metalloproteinases in Synaptic Formation and Neuropathic Diseases. Cell Mol Neurobiol. 2025;45(1):100. Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, Ramirez-Acuña JM, Perez-Romero BA, Guerrero-Rodriguez JF, Martinez-Avila N, Martinez-Fierro ML. The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. Int J Mol Sci 2020, 21(24). Ribot J, Breton R, Calvo CF, Moulard J, Ezan P, Zapata J, Samama K, Moreau M, Bemelmans AP, Sabatet V, et al. Astrocytes close the mouse critical period for visual plasticity. Science. 2021;373(6550):77–81. Coates-Park S, Lazaroff C, Gurung S, Rich J, Colladay A, O'Neill M, Butler GS, Overall CM, Stetler-Stevenson WG, Peeney D. Tissue inhibitors of metalloproteinases are proteolytic targets of matrix metalloproteinase 9. Matrix biology: J Int Soc Matrix Biology. 2023;123:59–70. Ferreira AC, Hemmer BM, Philippi SM, Grau-Perales AB, Rosenstadt JL, Liu H, Zhu JD, Kareva T, Ahfeldt T, Varghese M, et al. Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix complexity. Mol Psychiatry. 2023;28(9):3943–54. Ganguly K, Adhikary K, Acharjee A, Acharjee P, Trigun SK, Mutlaq AS, Ashique S, Yasmin S, Alshahrani AM, Ansari MY. Biological significance and pathophysiological role of Matrix Metalloproteinases in the Central Nervous System. Int J Biol Macromol. 2024;280(Pt 3):135967. Liang Y, Pan H, Yang Z, Yu C, Jiang T, Li Y, Yu H, Qiu M, Zhang S. Alterations in the plasma concentrations of BDNF, proBDNF, and MMP-9 in patients with schizophrenia. Eur J Med Res. 2025;30(1):867. Schoretsanitis G, de Filippis R, Ntogka M, Leucht S, Correll CU, Kane JM. Matrix Metalloproteinase 9 Blood Alterations in Patients With Schizophrenia Spectrum Disorders: A Systematic Review and Meta-Analysis. Schizophr Bull. 2021;47(4):986–96. Rahimi S, Sayad A, Moslemi E, Ghafouri-Fard S, Taheri M. Blood assessment of the expression levels of matrix metalloproteinase 9 (MMP9) and its natural inhibitor, TIMP1 genes in Iranian schizophrenic patients. Metab Brain Dis. 2017;32(5):1537–42. Tylec A, Skałecki M, Kocot J, Kurzepa J. Activity of selected metalloproteinases in neurodegenerative diseases of the central nervous system as exemplified by dementia and schizophrenia. Psychiatr Pol. 2021;55(6):1221–33. Zhang WB, Aleksic S, Gao T, Weiss EF, Demetriou E, Verghese J, Holtzer R, Barzilai N, Milman S. Insulin-like Growth Factor-1 and IGF Binding Proteins Predict All-Cause Mortality and Morbidity in Older Adults. Cells 2020, 9(6). Baxter RC. Signaling Pathways of the Insulin-like Growth Factor Binding Proteins. Endocr Rev. 2023;44(5):753–78. Sechrist ZR, Cortés JS, Patel NR, Pittman ZJ, Guru Murthy G, Zhu G, Cole CL, Korman BD. Pathologic Signaling and Disease Implications of Insulin-like Growth Factor Binding Proteins in Cancer, Cardiovascular Disease, and Fibrosis. Int J Mol Sci 2025, 26(21). Coppock HA, White A, Aplin JD, Westwood M. Matrix metalloprotease-3 and – 9 proteolyze insulin-like growth factor-binding protein-1. Biol Reprod. 2004;71(2):438–43. Mañes S, Llorente M, Lacalle RA, Gómez-Moutón C, Kremer L, Mira E, Martínez AC. The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells. J Biol Chem. 1999;274(11):6935–45. Lim K, Peh OH, Yang Z, Rekhi G, Rapisarda A, See YM, Rashid NAA, Ang MS, Lee SA, Sim K, et al. Large-scale evaluation of the Positive and Negative Syndrome Scale (PANSS) symptom architecture in schizophrenia. Asian J Psychiatr. 2021;62:102732. Ismail Z, Meehan SR, Farovik A, Miguelez M, Kapadia S, Regnier SA, Zhang Z, Brown TM, Milien M, McIntyre RS. Assessment of patient life engagement in schizophrenia using items from the Positive and Negative Syndrome Scale. Schizophr Res. 2024;274:337–44. Raudeberg R, Karr JE, Iverson GL, Hammar Å. Examining the repeatable battery for the assessment of neuropsychological status validity indices in people with schizophrenia spectrum disorders. Clin Neuropsychol. 2023;37(1):101–18. Misiak B, Piotrowski P, Samochowiec J. Assessment of interrelationships between cognitive performance, symptomatic manifestation and social functioning in the acute and clinical stability phase of schizophrenia: insights from a network analysis. BMC Psychiatry. 2023;23(1):774. Yang H, Zhang C, Yang M, Liu J, Zhang Y, Liu D, Zhang X. Variations of plasma oxidative stress levels in male patients with chronic schizophrenia. Correlations with psychopathology and matrix metalloproteinase-9: a case-control study. BMC Psychiatry 2024, 24(1). Li X, Wang X, Yang Y, Zhou J, Wu X, Zhao J, Zhang J, Guo X, Shao M, Song M, et al. Elevated plasma matrix metalloproteinase 9 in schizophrenia patients associated with poor antipsychotic treatment response and white matter density deficits. Schizophrenia (Heidelb). 2024;10(1):71. Bitanihirwe BKY, Woo TW. A conceptualized model linking matrix metalloproteinase-9 to schizophrenia pathogenesis. Schizophr Res. 2020;218:28–35. Pantazopoulos H, Katsel P, Haroutunian V, Chelini G, Klengel T, Berretta S. Molecular signature of extracellular matrix pathology in schizophrenia. Eur J Neurosci. 2020;53(12):3960–87. Dai S, Xu Y, Yang T, Wang F, Jiang Y. Identification and Correlation Analysis of Ferroptosis-Related Genes in Three Brain Regions of Patients with Schizophrenia. Actas Esp Psiquiatr. 2024;52(6):800–9. Jeffries CD, Perkins DO, Fournier M, Do KQ, Cuenod M, Khadimallah I, Domenici E, Addington J, Bearden CE, Cadenhead KS et al. Networks of blood proteins in the neuroimmunology of schizophrenia. Translational Psychiatry 2018, 8(1). Włodarczyk L, Cichon N, Karbownik MS, Saluk J, Miller E. Exploring the Role of MMP-9 and MMP-9/TIMP-1 Ratio in Subacute Stroke Recovery: A Prospective Observational Study. Int J Mol Sci 2024, 25(11). Melkersson KI, Hulting AL, Brismar KE. Different influences of classical antipsychotics and clozapine on glucose-insulin homeostasis in patients with schizophrenia or related psychoses. J Clin Psychiatry. 1999;60(11):783–91. Melkersson KI, Hulting AL, Brismar KE. Elevated levels of insulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses. J Clin Psychiatry. 2000;61(10):742–9. Howes OD, Gaughran FP, Amiel SA, Murray RM, Pilowsky LS. The effect of clozapine on factors controlling glucose homeostasis. J Clin Psychiatry. 2004;65(10):1352–5. Fernández-Pereira C, Agís-Balboa RC. The Insulin-like Growth Factor Family as a Potential Peripheral Biomarker in Psychiatric Disorders: A Systematic Review. Int J Mol Sci 2025, 26(6). Kollet O, Das A, Karamanos N, auf dem Keller U, Sagi I. Redefining metalloproteases specificity through network proteolysis. Trends Mol Med. 2024;30(2):147–63. Yang H, Yang M, Zhang Y, Shi Z, Zhang X, Zhang C. Elevated serum IGFBP-1 levels correlate with cognitive deficits in treatment-resistant and chronic medicated schizophrenia patients. Cytokine 2024, 182. Fernández-Pereira C, Penedo MA, Rivera-Baltanás T, Pérez-Márquez T, Alves-Villar M, Fernández-Martínez R, Veiga C, Salgado-Barreira Á, Prieto-González JM, Ortolano S et al. Protein Plasma Levels of the IGF Signalling System Are Altered in Major Depressive Disorder. Int J Mol Sci 2023, 24(20). Al-Delaimy WK, Von Muhlen D, Barrett-Connor E. Insulinlike Growth Factor-1, Insulinlike Growth Factor Binding Protein-1, and Cognitive Function in Older Men and Women. J Am Geriatr Soc. 2009;57(8):1441–6. Murialdo G, Barreca A, Nobili F, Rollero A, Timossi G, Gianelli MV, Copello F, Rodriguez G, Polleri A. Relationships between cortisol, dehydroepiandrosterone sulphate and insulin-like growth factor-I system in dementia. J Endocrinol Invest. 2001;24(3):139–46. Miao J, Zhang Y, Su C, Zheng Q, Guo J. Insulin-Like Growth Factor Signaling in Alzheimer’s Disease: Pathophysiology and Therapeutic Strategies. Mol Neurobiol. 2024;62(3):3195–225. Xiong J, Ding Y, Wu X, Zhan J, Wan Q, Wan H, Wei B, Chen H, Yang Y. Association between serum insulin-like growth factor 1 levels and the improvements of cognitive impairments in a subgroup of schizophrenia: Preliminary findings. Schizophr Res. 2024;264:282–9. Lewitt MS, Boyd GW. Role of the Insulin-like Growth Factor System in Neurodegenerative Disease. Int J Mol Sci 2024, 25(8). Davis J, Eyre H, Jacka FN, Dodd S, Dean O, McEwen S, Debnath M, McGrath J, Maes M, Amminger P, et al. A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis. Neurosci Biobehavioral Reviews. 2016;65:185–94. Speers LJ, Bilkey DK. Inflammation in Schizophrenia: The Role of Disordered Oscillatory Mechanisms. Cells 2025, 14(9). Chaves C, Dursun SM, Tusconi M, Hallak JEC. Neuroinflammation and schizophrenia – is there a link? Front Psychiatry 2024, 15. Belliveau C, Rahimian R, Fakhfouri G, Hosdey C, Simard S, Davoli MA, Mirault D, Giros B, Turecki G, Mechawar N. Evidence of microglial involvement in the childhood abuse-associated increase in perineuronal nets in the ventromedial prefrontal cortex. Brain Behav Immun. 2025;124:321–34. Aas M, Dieset I, Hope S, Hoseth E, Mørch R, Reponen E, Steen NE, Laskemoen JF, Ueland T, Aukrust P, et al. Childhood maltreatment severity is associated with elevated C-reactive protein and body mass index in adults with schizophrenia and bipolar diagnoses. Brain Behav Immun. 2017;65:342–9. Zhang Y, Catts VS, Sheedy D, McCrossin T, Kril JJ, Shannon Weickert C. Cortical grey matter volume reduction in people with schizophrenia is associated with neuro-inflammation. Translational Psychiatry. 2016;6(12):e982–982. Vujić T, Schvartz D, Furlani IL, Meister I, González-Ruiz V, Rudaz S, Sanchez J-C. Oxidative Stress and Extracellular Matrix Remodeling Are Signature Pathways of Extracellular Vesicles Released upon Morphine Exposure on Human Brain Microvascular Endothelial Cells. Cells 2022, 11(23). Feng L, Yan G, Wang M, Lei T, Sun L, Zhou T. Prevalence of metabolic syndrome in Chinese patients with schizophrenia: a systematic review and meta-analysis. BMC Psychiatry 2025, 25(1). Li J, Mao B, Tang X, Zhang Q, Zhao J, Zhang H, Chen W, Cui S. Endocrine and metabolic drivers of sebum dysregulation: Mechanisms and therapeutic strategies. Life Sci. 2025;383:124044. Cheng S, Guan F, Ma M, Zhang L, Cheng B, Qi X, Liang C, Li P, Kafle OP, Wen Y et al. An atlas of genetic correlations between psychiatric disorders and human blood plasma proteome. Eur Psychiatry 2020, 63(1). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 23 Feb, 2026 Reviews received at journal 16 Feb, 2026 Reviewers agreed at journal 11 Feb, 2026 Reviews received at journal 07 Feb, 2026 Reviewers agreed at journal 06 Feb, 2026 Reviewers agreed at journal 07 Jan, 2026 Reviewers agreed at journal 06 Jan, 2026 Reviewers agreed at journal 05 Jan, 2026 Reviewers invited by journal 16 Dec, 2025 Editor invited by journal 10 Dec, 2025 Editor assigned by journal 08 Dec, 2025 Submission checks completed at journal 08 Dec, 2025 First submitted to journal 05 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8288124","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":561344302,"identity":"7b11439f-91e0-4e95-ad66-1164fb05d9a5","order_by":0,"name":"Minggang Jiang","email":"","orcid":"","institution":"The Fourth People’s Hospital of Jiande","correspondingAuthor":false,"prefix":"","firstName":"Minggang","middleName":"","lastName":"Jiang","suffix":""},{"id":561344303,"identity":"5f846064-3494-4f2d-8afe-1a0d62f60290","order_by":1,"name":"Xiaoyu Sun","email":"","orcid":"","institution":"The Affiliated Guangji Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoyu","middleName":"","lastName":"Sun","suffix":""},{"id":561344304,"identity":"63fd1970-40ef-4823-ad95-b336a64d1989","order_by":2,"name":"Yubing Han","email":"","orcid":"","institution":"The First Clinical Medical College of Xuzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yubing","middleName":"","lastName":"Han","suffix":""},{"id":561344305,"identity":"461ee727-8196-44d2-b883-d01e66829d79","order_by":3,"name":"Man Yang","email":"","orcid":"","institution":"Lianyungang Psychiatric Hospital","correspondingAuthor":false,"prefix":"","firstName":"Man","middleName":"","lastName":"Yang","suffix":""},{"id":561344306,"identity":"8e1938d6-ea47-4222-b366-1b4c8fb4f54d","order_by":4,"name":"Jing Zhang","email":"","orcid":"","institution":"Lianyungang Psychiatric Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Zhang","suffix":""},{"id":561344307,"identity":"28436c90-8a02-4ac1-a746-8164840f5ae5","order_by":5,"name":"Xiaobin Zhang","email":"","orcid":"","institution":"The Affiliated Guangji Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Xiaobin","middleName":"","lastName":"Zhang","suffix":""},{"id":561344308,"identity":"1b094d06-d883-4b49-8af2-72b9279f1613","order_by":6,"name":"Haidong Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABB0lEQVRIiWNgGAWjYJACZgYGCcYGBgbGAwwMNjz8/A3Ea2EAakmTkZxxgCgtDDAth20MGhLwKzc4fvbw64IaC9l+6fYLh3l+necxYDjA+OFjDh4tZ/LSrGcckzCeOedMwWHevts85swNzJIzt+HRciDHzJiHTSJxw42chMO8Pbd5LBsOsDHz4tNy/g1Qyz+4lnM8BgcSCGi5kWP8mLcNpCX9wGGeHwcIa5G88caMmbcP6JcZOQwH5zYk80jOONiM1y9853OMP/N8q5Ptl0h/+ODNHzt7fv7mgx8+4tGicICBTQLC5DFg4m0DMcBxhBvINzAwf4Aw2R8w/viDV/EoGAWjYBSMUAAAc1Bc4u2cffEAAAAASUVORK5CYII=","orcid":"","institution":"Lianyungang Psychiatric Hospital","correspondingAuthor":true,"prefix":"","firstName":"Haidong","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2025-12-05 13:08:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8288124/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8288124/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":98758868,"identity":"9c148ecc-2046-4ccc-bad1-b01a0f72b05a","added_by":"auto","created_at":"2025-12-22 09:47:17","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":135663,"visible":true,"origin":"","legend":"","description":"","filename":"Figure1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/d17739920d8d17f102d7f11c.docx"},{"id":98779823,"identity":"4bd3d933-bdf0-4ab1-ac13-1c4b217affca","added_by":"auto","created_at":"2025-12-22 12:30:47","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":274848,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/939043ddf6d7525c8199076a.docx"},{"id":98758875,"identity":"efce4841-c4f4-4278-8b38-44eb5576d1d6","added_by":"auto","created_at":"2025-12-22 09:47:17","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":77774,"visible":true,"origin":"","legend":"","description":"","filename":"Figure2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/f07f1ad2e76a6f64350a14e3.docx"},{"id":98758869,"identity":"f3bae244-d0fc-4f2b-897b-a244e001a90e","added_by":"auto","created_at":"2025-12-22 09:47:17","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":19144,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/78db2e94ed41a38810418797.docx"},{"id":98758871,"identity":"5a491332-9734-4677-a047-6347667a97ce","added_by":"auto","created_at":"2025-12-22 09:47:17","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":73590,"visible":true,"origin":"","legend":"","description":"","filename":"Figure3.docx","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/ee0f27df6db32c0ac3bce424.docx"},{"id":98758866,"identity":"c1f288d7-e0c2-44c3-ba81-3cc177fc6c4a","added_by":"auto","created_at":"2025-12-22 09:47:17","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":17710,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/8163fc58605b73b814cc45e3.docx"},{"id":98777758,"identity":"74e78cef-61eb-4c57-91c8-bcb143159f37","added_by":"auto","created_at":"2025-12-22 12:28:25","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":17208,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/8fccb4a6dcd3441c2d103bfc.docx"},{"id":98778927,"identity":"dafc3334-1826-4379-a931-00cd353d40fd","added_by":"auto","created_at":"2025-12-22 12:29:49","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":17132,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/06dc5bf879b253969931410e.docx"},{"id":98778899,"identity":"f0376032-5175-4e87-8934-d21723c8e945","added_by":"auto","created_at":"2025-12-22 12:29:47","extension":"json","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":8768,"visible":true,"origin":"","legend":"","description":"","filename":"d248d29ee8324f77a4fa09e5d5883c6a.json","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/aba93741bfdeae6361e0b96b.json"},{"id":98778907,"identity":"0e756a06-3595-40f5-b954-190aa29d8bd8","added_by":"auto","created_at":"2025-12-22 12:29:47","extension":"xml","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":187490,"visible":true,"origin":"","legend":"","description":"","filename":"d248d29ee8324f77a4fa09e5d5883c6a1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/c451e31b90dab431378081d2.xml"},{"id":98780428,"identity":"1f580457-22d1-4a5c-9e93-f17d046a67d6","added_by":"auto","created_at":"2025-12-22 12:31:20","extension":"jpeg","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":119046,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/4f456dc335e03060eaa46632.jpeg"},{"id":98758881,"identity":"c809fede-2a64-49dc-b616-ed8777a29c52","added_by":"auto","created_at":"2025-12-22 09:47:17","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12977,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/a1cbe57d958f67dba8c795fc.png"},{"id":98758886,"identity":"99afe1af-ded2-4e03-a423-56cf3cd68301","added_by":"auto","created_at":"2025-12-22 09:47:17","extension":"png","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":34023,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/44d2de5a38fdf84ebc45487b.png"},{"id":98758884,"identity":"9b5cc943-7c58-4232-891c-768e34f1e4d3","added_by":"auto","created_at":"2025-12-22 09:47:17","extension":"png","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":32313,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/e293c7f47f390fa9bc24582e.png"},{"id":98758885,"identity":"77a32c12-d313-4b2e-a4cd-9500af51f495","added_by":"auto","created_at":"2025-12-22 09:47:17","extension":"png","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":18759,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/51aae72a7a2087471907847a.png"},{"id":98758887,"identity":"66e37273-6fe1-49ee-b152-5166c64f74a0","added_by":"auto","created_at":"2025-12-22 09:47:17","extension":"png","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":34023,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/de4c0d7877fac7dfc3765647.png"},{"id":98758882,"identity":"18cad46f-0ba8-4d6d-8a1e-eec15aeda67a","added_by":"auto","created_at":"2025-12-22 09:47:17","extension":"png","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":32313,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/e419c3fc990586ac40b63ae8.png"},{"id":98758890,"identity":"3087ccf9-9596-4ff7-b3ee-da10917232f9","added_by":"auto","created_at":"2025-12-22 09:47:17","extension":"xml","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":182501,"visible":true,"origin":"","legend":"","description":"","filename":"d248d29ee8324f77a4fa09e5d5883c6a1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/d062f8b70e7f5e09711fa7bb.xml"},{"id":98758888,"identity":"a6c95fc8-8a05-434e-8362-0f2905862a78","added_by":"auto","created_at":"2025-12-22 09:47:17","extension":"html","order_by":23,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":201114,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/c333df5c4aace6b84301d625.html"},{"id":98780396,"identity":"16032acf-626d-4d2e-ab93-720cce02c859","added_by":"auto","created_at":"2025-12-22 12:31:17","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":86071,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of serum extracellular matrix biomarker concentrations between patients and healthy controls (HCs). (A) Matrix metalloproteinase-9 (MMP-9). (B) Tissue inhibitor of metalloproteinase-1 (TIMP-1). (C) MMP-9/TIMP-1 ratio. (D) Insulin-like growth factor binding protein-1 (IGFBP-1).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/7069756074ad2438d5b2195b.jpeg"},{"id":98779700,"identity":"1bd56621-cff7-4902-a753-2576dc90e37c","added_by":"auto","created_at":"2025-12-22 12:30:36","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":61241,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between serum TIMP-1 concentration and duration of illness.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/915a89660bb3fea85b2a5718.jpeg"},{"id":98780367,"identity":"31678e0c-8e9f-4ee2-8276-7043ca51beb7","added_by":"auto","created_at":"2025-12-22 12:31:16","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":57083,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between serum IGFBP-1 concentration and RBANS immediate memory score.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/0328d1e9e0ff26936ca27709.jpeg"},{"id":98780550,"identity":"43463a3f-1a67-4e67-84c9-b4c632f6ece8","added_by":"auto","created_at":"2025-12-22 12:31:28","extension":"jpeg","order_by":14,"title":"Figure 14","display":"","copyAsset":false,"role":"figure","size":61241,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between serum TIMP-1 concentration and duration of illness.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/d41328d231d4e4d83b512494.jpeg"},{"id":98758878,"identity":"f405054d-114f-4595-b30e-04eca88001d4","added_by":"auto","created_at":"2025-12-22 09:47:17","extension":"jpeg","order_by":15,"title":"Figure 15","display":"","copyAsset":false,"role":"figure","size":57083,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between serum IGFBP-1 concentration and RBANS immediate memory score.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/488e4f11f672db3aa9665f22.jpeg"},{"id":99306842,"identity":"e4bd1416-d9b6-4d9b-a205-940bc4ac9fc8","added_by":"auto","created_at":"2025-12-31 16:00:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1268444,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8288124/v1/84fd9d8c-32cc-41b6-b3eb-5878175b389a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Altered serum MMP-9, TIMP-1, and IGFBP-1 concentrations in chronic male schizophrenia patients: associations with illness duration and cognitive impairments","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSchizophrenia is a common, chronic, and debilitating psychiatric disorder characterized by positive symptoms such as delusional and disordered thinking, negative symptoms such as blunted affect, and cognitive impairments [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. While symptom profile may vary among individuals and across disease stages, the core cognitive deficits tend to persist throughout the disease course, and are particularly robust predictors of poor functional outcome and reduced quality of life, often exerting a more profound impact on long-term disability than positive or negative symptoms [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In patients with chronic schizophrenia requiring long-term hospitalization, cognitive deterioration is especially pronounced, severely limiting the potential for rehabilitation and community reintegration [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Although antipsychotic medications effectively control psychotic symptoms such as delusions and hallucinations, therapeutic effects on cognitive impairments remain limited [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Accumulating evidence indicates that aberrant neuroplasticity, manifesting as reduced synaptic density, abnormal dendritic spine morphology, and impaired neural circuit remodeling, is a core neuropathological feature of schizophrenia [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe extracellular matrix (ECM) serves as a critical regulator of neuroplasticity in the central nervous system [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Beyond providing structural support for neurons, the ECM actively modulates synaptic formation, axonal growth, and neuronal migration through interactions with cell surface receptors [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are principal mediators of ECM remodeling, with MMP-9 and MMP-2 being the most abundantly expressed in neural tissues [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Recent evidence suggests that astrocytes control closure of the \u0026lsquo;critical period\u0026rsquo; for neuroplasticity in primary sensory cortex through regulation of MMP-9 expression, resulting in suppression of experience-dependent neuronal circuit remodeling [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The activities of MMPs are also regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), with TIMP-1 forming a specific regulatory pair with MMP-9 [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The dynamic equilibrium between MMPs and TIMPs determines the directionality and magnitude of ECM remodeling, thereby creating the microenvironmental milieu essential for neuroplasticity [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral recent studies have investigated alterations in the MMP/TIMP system among patients with schizophrenia but yielded inconsistent findings [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], with some reporting elevated serum MMP-9 concentrations [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and others reduced levels or no significant differences compared to healthy controls [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Similarly, specific alterations in serum TIMP-1 are inconsistent across studies [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], and it is uncertain if serum concentrations are associated with illness duration or cognitive deficits. These discrepancies suggest that alterations in MMP and TIMP expression vary across different disease stages, warranting further investigation in specific patient populations, such as the long-term hospitalized population with chronic intractable disease. Given the accessibility of peripheral blood for MMP and TIMP measurements, clinical diagnosis, prognosis, and treatment could be greatly aided by establishing consistent associations between serum concentration changes and symptom expression.\u003c/p\u003e \u003cp\u003eInsulin-like growth factor binding protein-1 (IGFBP-1) was initially identified as a carrier protein regulating the bioavailability of insulin-like growth factors (IGFs) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], but more recent studies have reported IGF-independent biological functions, including interactions with the ECM and modulation of cell adhesion, migration, and survival through integrin receptor signaling [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Notably, several IGFBPs serve as substrates for MMPs, and MMP-mediated proteolysis can liberate IGF from its binding proteins, thereby potentiating neurotrophic signaling cascades inducing neuroplasticity [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. These findings position IGFBPs as potential bridging molecules linking ECM remodeling with growth factor bioavailability and neuroplasticity in the central nervous system.\u003c/p\u003e \u003cp\u003eThe present study examined ECM marker abnormalities in a distinct population of male patients with particularly intractable symptom expression, those with chronic schizophrenia requiring long-term hospitalization (illness duration \u0026ge; 5 years). Serum concentrations of MMP-2, MMP-9, TIMP-1, and IGFBP-1 were compared between these patients and healthy matched controls to identify potential associations with disease characteristics. We hypothesized that patients with long-term schizophrenia would exhibit an ECM remodeling imbalance characterized by elevated MMP-9/TIMP-1 and aberrant IGFBP-1 expression, and that these abnormalities would correlate with disease chronicity and cognitive impairments.\u003c/p\u003e"},{"header":"Subjects and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects and assessments\u003c/h2\u003e \u003cp\u003eLong-term hospitalized male patients with schizophrenia from Lianyungang Psychiatric Hospital and its affiliated medical institutions were recruited as the clinical group, while male volunteers matched for age were recruited from the local community as the healthy control (HC) group. The inclusion criteria for patients were as follows: (1) meeting the diagnostic criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV); (2) hospitalization duration \u0026ge; 5 years; (3) male; (4) age 18\u0026ndash;65 years; (5) able to cooperate with blood collection and relevant assessments. The exclusion criteria for patients were as follows: (1) severe somatic diseases (e.g., severe cardiac, hepatic, or renal insufficiency, malignant tumors); (2) comorbid substance or alcohol dependence; (3) acute infectious or inflammatory diseases within the past three months; (4) other comorbid mental disorders (e.g., mood disorders, dementia); (5) changes in antipsychotic medication or significant dose adjustments within the past three months; (6) currently receiving immunosuppressants or hormone therapy for any somatic disease; (7) incomplete clinical data or inability to cooperate with the study. Inclusion criteria (3)\u0026ndash;(5) also applied to HCs, while exclusion criteria were as follows: (1) current or past history of mental disorders; (2) history of mental disorders in first-degree relatives; (3) severe somatic diseases; (4) history of substance or alcohol dependence; (5) acute infectious or inflammatory diseases within the past three months; (6) use of medications affecting the central nervous system (e.g., antidepressants, anxiolytics) within the past three months; (7) currently receiving immunosuppressants or hormone therapy.\u003c/p\u003e \u003cp\u003eAll HCs provided written informed consent, while written informed consent was obtained from patients or their legal guardians. This study was approved by the Ethics Committee of Lianyungang Fourth People\u0026rsquo;s Hospital (Ethics approval number: 2019LSYYXLL-P06) and was conducted according to the tenets of the Helsinki Declaration.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eClinical and cognitive assessment\u003c/h3\u003e\n\u003cp\u003ePsychiatric symptoms in the patient group were assessed using the Positive and Negative Syndrome Scale (PANSS) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The PANSS consists of 30 items yielding three subscales, positive symptoms, negative symptoms, and general psychopathology. Each item is rated on a 7-point scale ranging from 1 to 7, with higher scores indicating more severe symptoms. All assessments were conducted independently by two trained psychiatrists with attending physician or higher qualifications, and inter-rater reliability was \u0026ge; 0.85.\u003c/p\u003e \u003cp\u003eCognitive functions were assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The RBANS comprises 12 subtests assessing five cognitive domains: immediate memory, visuospatial/constructional ability, language, attention, and delayed memory. Each domain score is converted to an index score based on raw scores, and the total scale score is derived from the sum of the five domain index scores. The RBANS assessment was administered by professionally trained raters with psychological testing qualifications in a quiet, private room. Each assessment session lasted approximately 30\u0026ndash;40 minutes. All assessments were completed on the same day as blood sample collection.\u003c/p\u003e\n\u003ch3\u003eMeasurement of serum MMP-2, MMP-9, TIMP-1, and IGFBP-1 concentration\u003c/h3\u003e\n\u003cp\u003eFasting venous blood samples (5 mL) were collected from all participants between 7:00 and 9:00 AM. Samples were left standing at room temperature for 30 minutes, and the serum fractions separated by centrifugation at 3000 rpm for 15 minutes. Serum samples were then aliquoted and stored at -80\u0026deg;C until analysis, with repeated freeze-thaw cycles avoided. Serum concentrations of MMP-2, MMP-9, TIMP-1, and IGFBP-1 were quantified using assay kits (R\u0026amp;D Systems; Minneapolis, MN, USA) based on Luminex liquid suspension chip detection according to the manufacturer\u0026rsquo;s instructions. All samples were analyzed in duplicate by laboratory personnel unaware of the group assignment, and mean values recorded for analyses. The intra-assay coefficient of variation (CV) was \u0026lt;\u0026thinsp;10%, and the inter-assay CV was \u0026lt;\u0026thinsp;15% for all measurements.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eAll statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). The Shapiro\u0026ndash;Wilk test was used to assess the normality of continuous variables. Normally distributed continuous variables are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) and non-normally distributed continuous variables as median (interquartile range), while categorical variables are presented as frequency (percentage of total cases). For univariable analysis, normally distributed continuous variables were compared by Student\u0026rsquo;s t-tests, non-normally distributed continuous variables by Mann\u0026ndash;Whitney U-test, and categorical variables using the chi-square test. Analysis of covariance (ANCOVA) was also performed to assess the influence of body mass index (BMI) on normally distributed serum concentrations, while rank ANCOVA was used to assess the influence of BMI on non-normally distributed serum concentrations. Associations between variables were assessed using Pearson\u0026rsquo;s or Spearman\u0026rsquo;s method depending on data distribution. Stepwise linear regression analysis was performed to identify independent predictors of RBANS immediate memory score, with age, years of education, smoking status, BMI, duration of illness, age of onset, chlorpromazine equivalent dose, and serum IGFBP-1 concentration as independent variables. Based on tertiles of illness duration, patients were divided into three groups: short duration (\u0026lt;\u0026thinsp;10 years), medium duration (10\u0026ndash;15 years), and long duration (\u0026ge;15 years). One-way analysis of variance (ANOVA) was used to compare TIMP-1 levels among the three groups, followed by Bonferroni post hoc tests for pairwise comparisons. Effect sizes are expressed as eta-squared (η\u003csup\u003e2\u003c/sup\u003e). Modified Poisson regression analysis was performed to identify independent risk factors for long-term hospitalization, and relative risk (RR) with 95% confidence intervals (CI) were calculated. All tests were two-tailed, and P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eComparison of demographic and clinical characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe demographic and clinical characteristics of the patient and HC groups are summarized in \u003cstrong\u003eTable 1\u003c/strong\u003e. A total of 80 patients with schizophrenia and 59 healthy controls (HCs) were included in this study. The two groups were well-matched for age (\u003cem\u003eP\u003c/em\u003e = 0.617), education level (\u003cem\u003eP\u003c/em\u003e = 0.198), and smoking status (\u003cem\u003eP\u003c/em\u003e = 0.326). However, BMI was significantly lower in the patient group (\u003cem\u003eP\u003c/em\u003e = 0.040). As expected, patients demonstrated significantly poorer performance across all RBANS domains (all \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003eTable 1. Demographic and clinical characteristics of schizophrenia patients and healthy controls (HCs)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003ePatients (n=80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eHCs (n=59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cem\u003et\u003c/em\u003e/\u003cem\u003ec\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e/\u003cem\u003eZ\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e40.61\u0026nbsp;\u0026plusmn;\u0026nbsp;9.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e39.78\u0026nbsp;\u0026plusmn;\u0026nbsp;9.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.501\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e0.617\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eEducation (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e9.0 (6.0, 9.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e9.0 (6.0, 12.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-1.286\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e0.198\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e24.51\u0026nbsp;\u0026plusmn;\u0026nbsp;3.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e25.67\u0026nbsp;\u0026plusmn;\u0026nbsp;2.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-2.075\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eSmoking (n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e42 (52.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e26 (44.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.966\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e0.326\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge of onset (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e26.86\u0026nbsp;\u0026plusmn;\u0026nbsp;8.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eDuration of illness (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e11.0 (7.0, 19.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eEquivalent dose of chlorpromazine (mg/d)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e687.14\u0026nbsp;\u0026plusmn;\u0026nbsp;312.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003ePANSS total score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e58.09\u0026nbsp;\u0026plusmn;\u0026nbsp;14.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eP subscores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e11.10\u0026nbsp;\u0026plusmn;\u0026nbsp;4.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eN subscores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e17.78\u0026nbsp;\u0026plusmn;\u0026nbsp;7.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eG subscores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e29.09\u0026nbsp;\u0026plusmn;\u0026nbsp;6.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eRBANS total score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e58.39\u0026nbsp;\u0026plusmn;\u0026nbsp;10.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e87.54\u0026nbsp;\u0026plusmn;\u0026nbsp;12.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e- 14.446\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eImmediate memory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e50.36\u0026nbsp;\u0026plusmn;\u0026nbsp;16.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e82.49\u0026nbsp;\u0026plusmn;\u0026nbsp;18.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e- 10.641\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eVisuospatial/constructional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e69.84\u0026nbsp;\u0026plusmn;\u0026nbsp;15.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e90.68\u0026nbsp;\u0026plusmn;\u0026nbsp;15.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e- 7.915\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eLanguage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e72.0\u0026nbsp;\u0026plusmn;\u0026nbsp;13.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e95.90\u0026nbsp;\u0026plusmn;\u0026nbsp;11.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e- 10.844\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAttention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e82.23\u0026nbsp;\u0026plusmn;\u0026nbsp;13.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e104.85\u0026nbsp;\u0026plusmn;\u0026nbsp;13.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e- 9.561\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eDelayed memory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e54.20\u0026nbsp;\u0026plusmn;\u0026nbsp;16.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e83.27\u0026nbsp;\u0026plusmn;\u0026nbsp;17.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e- 10.053\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBMI, body mass index; PANSS, positive and negative syndrome scale. RBANS, repeatable battery for the assessment of neuropsychological status; a Independent samples t-test; b Mann\u0026ndash;Whitney U test; c \u003cem\u003e\u0026chi;\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e test.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDifferences in serum MMP-2, MMP-9, TIMP-1, and IGFBP-1 concentrations between schizophrenia patients and healthy controls\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerum concentrations of ECM biomarkers were compared between patients with schizophrenia and HCs (\u003cstrong\u003eTable 2\u003c/strong\u003e). Neither serum MMP-2 concentration (\u003cem\u003eZ\u003c/em\u003e = -1.183, \u003cem\u003eP\u003c/em\u003e = 0.237) nor MMP-2/TIMP-1 ratio (\u003cem\u003eZ\u003c/em\u003e = -1.585, \u003cem\u003eP\u003c/em\u003e = 0.113) differed significantly between groups. However, patients with schizophrenia exhibited significantly higher serum MMP-9 levels than HCs (\u003cem\u003eZ\u003c/em\u003e = -2.067, \u003cem\u003eP\u003c/em\u003e = 0.039). In contrast, serum TIMP-1 concentration was significantly lower in patients than HCs (\u003cem\u003et\u0026nbsp;\u003c/em\u003e= -2.547, \u003cem\u003eP\u003c/em\u003e = 0.012). Consequently, the MMP-9/TIMP-1 ratio was significantly elevated in the patient group (\u003cem\u003eZ\u003c/em\u003e = -2.195, \u003cem\u003eP\u003c/em\u003e = 0.028). Serum IGFBP-1 concentration was also markedly higher in patients with schizophrenia compared to HCs (\u003cem\u003eZ\u003c/em\u003e = -5.994, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001) (\u003cstrong\u003eFigure 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eTable 2. Comparison of serum MMP-2, MMP-9, TIMP-1, and IGFBP-1 concentrations between schizophrenia patients and healthy controls (HCs)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003ePatients (n = 80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHC (n = 59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cem\u003et\u003c/em\u003e/\u003cem\u003eZ\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eMMP-2 (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e30.24 (28.22, 33.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e31.57 (28.77, 34.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-1.183\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e0.237\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eMMP-9 (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e23.93 (11.14, 34.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e17.70 (8.66, 26.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-2.067\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e0.039\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eTIMP-1 (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e32.23\u0026nbsp;\u0026plusmn;\u0026nbsp;7.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e35.54\u0026nbsp;\u0026plusmn;\u0026nbsp;7.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e- 2.547\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eMMP-2/TIMP-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.94 (0.78, 1.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.90 (0.72, 1.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-1.585\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eMMP-9/TIMP-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.74 (0.29, 1.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.55 (0.22, 0.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-2.195\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eIGFBP-1 (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e25.05 (12.64, 47.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e6.95 (3.20, 14.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-5.994\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: MMP-2, matrix metalloproteinase-2; MMP-9, matrix metalloproteinase-9; TIMP-1, tissue inhibitor of metalloproteinase-1; IGFBP-1, insulin-like growth factor binding protein-1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig 1\u003c/strong\u003e. Comparison of serum extracellular matrix biomarker concentrations between patients and healthy controls (HCs). (A) Matrix metalloproteinase-9 (MMP-9). (B) Tissue inhibitor of metalloproteinase-1 (TIMP-1). (C) MMP-9/TIMP-1 ratio. (D) Insulin-like growth factor binding protein-1 (IGFBP-1).\u003c/p\u003e\n\u003cp\u003eGiven the significant difference in BMI between patients and HCs, we evaluated the influence of BMI on group differences in ECM biomarkers by ANCOVA and rank ANCOVA. The group difference in serum TIMP-1 concentration detected by univariate analysis remained significant according to ANCOVA with group as the fixed factor and BMI as the covariate (\u003cem\u003eF\u003c/em\u003e = 6.383, \u003cem\u003eP\u003c/em\u003e = 0.013). Similarly, rank ANCOVA with BMI as the covariate revealed significant group differences in MMP-9 (\u003cem\u003eF\u003c/em\u003e = 4.033, \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.047), MMP-9/TIMP-1 (\u003cem\u003eF\u003c/em\u003e = 4.755, \u003cem\u003eP\u003c/em\u003e = 0.031), and IGFBP-1 (\u003cem\u003eF\u003c/em\u003e = 42.297, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelations of serum ECM marker concentrations with clinical variables\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were no significant correlations between clinical symptom scores as measured by the PANSS and serum MMP-9 concentration, TIMP-1 concentration, MMP-9/TIMP-1 ratio, and IGFBP-1 concentration (all \u003cem\u003eP\u003c/em\u003e \u0026gt; 0.05), nor between clinical symptom scores and clinicodemographic factors smoking status, age of onset, years of education, and chlorpromazine equivalent dose (all \u003cem\u003eP\u003c/em\u003e \u0026gt; 0.05). However, serum TIMP-1 concentration was positively correlated with age (\u003cem\u003er\u003c/em\u003e = 0.257, \u003cem\u003eP\u003c/em\u003e = 0.022) and duration of illness (\u003cem\u003er\u003c/em\u003e = 0.376, \u003cem\u003eP\u003c/em\u003e = 0.001, \u003cstrong\u003eFigure 2\u003c/strong\u003e), while serum IGFBP-1 concentration was negatively correlated with BMI (\u003cem\u003er\u003c/em\u003e = -0.294, \u003cem\u003eP\u003c/em\u003e = 0.008).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig 2\u003c/strong\u003e. Correlation between serum TIMP-1 concentration and duration of illness.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelations of serum ECM marker concentrations with cognitive functions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerum IGFBP-1 concentration was negatively correlated with RBANS immediate memory score (\u003cem\u003er\u003c/em\u003e = - 0.240, \u003cem\u003eP\u003c/em\u003e = 0.024,\u003cstrong\u003e\u0026nbsp;Figure 3\u003c/strong\u003e), while MMP-9, TIMP-1, and MMP-9/TIMP-1 were not significantly correlated with RBANS total score or any subscale score (all \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026gt; 0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig 3.\u0026nbsp;\u003c/strong\u003eCorrelation between serum IGFBP-1 concentration and RBANS immediate memory score.\u003c/p\u003e\n\u003cp\u003eStepwise linear regression analysis revealed that years of education (\u003cem\u003eB\u003c/em\u003e = 1.637, \u003cem\u003e\u0026beta;\u003c/em\u003e = 0.308,\u003cem\u003e\u0026nbsp;t\u0026nbsp;\u003c/em\u003e= 2.906, \u003cem\u003eP\u003c/em\u003e = 0.005) and serum IGFBP-1 concentration (\u003cem\u003eB\u003c/em\u003e = -0.112, \u003cem\u003e\u0026beta;\u003c/em\u003e = -0.213, \u003cem\u003et\u003c/em\u003e = -2.009, \u003cem\u003eP\u003c/em\u003e = 0.048) were independent predictors of immediate memory performance after controlling for age, years of education, smoking status, BMI, duration of illness, age of onset, and chlorpromazine equivalent dose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVariations in serum TIMP-1 concentration with illness duration\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were divided into three illness durations groups, short (\u0026lt;10 years, n = 25), medium (10\u0026ndash;15 years, n = 28), and long (\u0026sup3; 15 years, n = 27), and compared for serum ECM marker concentrations (\u003cstrong\u003eTable 3)\u003c/strong\u003e. One-way ANOVA revealed significant differences in serum TIMP-1 concentration among the three groups (\u003cem\u003eF\u003c/em\u003e = 5.592, \u003cem\u003eP\u003c/em\u003e = 0.005, h\u003csup\u003e2\u003c/sup\u003e = 0.127), and Bonferroni post hoc tests indicated significantly higher serum TIMP-1 concentration in the long duration group compared to both the medium duration group (\u003cem\u003eP\u003c/em\u003e = 0.037) and the short duration group (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.007), while there was no significant difference between medium and short duration groups (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026gt; 0.99).\u003c/p\u003e\n\u003cp\u003eTable 3. Changes in serum TIMP-1 concentration with illness duration\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003eGroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003eDuration (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eTIMP-1 (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cem\u003eF\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003eh\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003eShort duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026lt; 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e29.65\u0026nbsp;\u0026plusmn;\u0026nbsp;5.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e5.592\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e0.127\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003eMedium duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e10\u0026ndash;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e30.94\u0026nbsp;\u0026plusmn;\u0026nbsp;8.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003eLong duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u0026sup3;\u0026nbsp;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e35.95 \u0026plusmn; 6.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eIndependent risk factors for long-term hospitalization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo examine the strengths of these ECM biomarkers as risk factors for chronic schizophrenia, we stratified the entire participant cohort into high and low serum TIMP-1, MMP-9, MMP-9/TIMP-1, and IGFBP-1 subgroups using the median values as cut-offs and conducted modified Poisson regression analysis. Group membership (patient vs. HC) was set as the dependent variable, age, BMI, smoking status, and education level as covariates, and binary ECM biomarker groupings as independent variables. After adjusting for confounding factors, IGFBP-1 above the median was identified as an independent risk factor for long-term hospitalization among male patients with schizophrenia (\u003cem\u003eB\u003c/em\u003e = 0.814, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001, \u003cem\u003eRR\u003c/em\u003e = 2.257, 95% CI: 1.571\u0026ndash;3.243, \u003cstrong\u003eTable 4\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eTable 4. Modified Poisson regression analysis of independent risk factors for long-term hospitalization among male patients with schizophrenia\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003eSE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003eRR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e-0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.800\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.998\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.984\u0026ndash;1.012\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e-0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.516\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.986\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.944\u0026ndash;1.029\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e-0.083\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.526\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.920\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.712\u0026ndash;1.190\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003eEducation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.848\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e1.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.962\u0026ndash;1.049\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003eIGFBP-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.814\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e0.185\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e2.257\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e1.571\u0026ndash;3.243\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study investigated serum concentrations of MMP-2, MMP-9, TIMP-1, and IGFBP-1 as biomarkers of ECM dysregulation in long-term hospitalized male patients with schizophrenia, as well as the associations of these biomarkers with clinical symptoms and cognitive function. The main findings of this study are as follows: 1) Compared to healthy controls, the patient group exhibited lower serum TIMP-1 concentrations, while serum MMP-9 concentration, MMP-9/TIMP-1 ratio, and IGFBP-1 concentration were elevated; 2) Serum IGFBP-1 concentration was negatively correlated with RBANS immediate memory subscore; 3) Serum TIMP-1 concentration was positively correlated with illness duration, with highest levels in the longest duration group (\u0026gt;15 years); 4) Elevated serum IGFBP-1 concentration was identified as an independent risk factor for long-term hospitalization. These findings support ECM dysregulation as a potential pathogenic mechanism underlying schizophrenia progression, and further suggest that serum TIMP-1 and IGFBP-1 may serve as useful prognostic biomarkers, while corresponding brain activities may be effective treatment targets.\u003c/p\u003e\n\u003cp\u003eOur finding that serum MMP-9 concentration was significantly elevated in male chronic schizophrenia patients hospitalized for more than 5 years is consistent with a recent report by Liang et al. [17], and also aligns with our previous findings [30]. However, a systematic review and meta-analysis by Schoretsanitis et al. revealed inconsistent serum MMP-9 alterations across studies of schizophrenia patients [18], hinting that serum MMP-9 may be influenced by disease stage, illness duration, and medication status among other clinical and demographic factors [31]. The elevated serum MMP-9 levels in the current patient population suggests that an ECM remodeling imbalance may persist throughout the course of the disease and contribute to the pathological processes necessitating long-term institutionalization [32, 33].\u003c/p\u003e\n\u003cp\u003eAlternatively, the lower serum TIMP-1 levels among these schizophrenia patients is inconsistent with previous findings by Rahimi et al., who reported no significant difference compared to healthy controls [19], and with Dai et al., who reported that TIMP-1 expression was significantly upregulated in the anterior cingulate cortex of schizophrenia patients and associated with ferroptosis [34]. However, the elevated MMP-9/TIMP-1 ratio in the present patient cohort is consistent with the findings of Rahimi et al[19]. Furthermore, network analysis by Jeffries et al. revealed a strong correlation between TIMP-1 and anti-remodeling protein SERPINE1 expression in patients transitioning to psychosis, whereas this correlation was nearly absent in nonconverters [35], suggesting that dysregulation of ECM remodeling networks may drive psychosis. Compared to individual biomarkers, the MMP-9/TIMP-1 ratio may better reflect a dynamic imbalance of the ECM protease system, with an elevated ratio indicating a shift toward ECM protein degradation [36] and aberrant neuroplastic changes in brain circuits contributing to chronic disease status.\u003c/p\u003e\n\u003cp\u003eSerum IGFBP-1 concentration was also elevated among long-term hospitalized male patients with schizophrenia, while previous studies have reported inconsistent findings, including a series of studies by Melkersson et al. reporting no significant differences in serum IGFBP-1 between schizophrenia patients treated with typical antipsychotics or chlorpromazine and healthy controls, whereas patients treated with olanzapine exhibited significantly lower serum IGFBP-1 [37, 38]. Howes et al. found that serum IGFBP-1 was lower among patients than controls prior to clozapine treatment, and that clozapine treatment did not significantly alter serum IGFBP-1 levels [39]. These inconsistencies may be attributable to differences in antipsychotic medication or other patient characteristics such as metabolic status and disease stage. Elevated IGFBP-1 levels in the current cohort may reflect metabolic disturbances occurring during the chronic course of the illness as IGFBPs not only regulate IGF bioavailability but also possess IGF-independent biological functions [40]. Furthermore, IGFBP-1 has been identified as a substrate for MMP-9 and can be proteolytically cleaved by other MMPs [41]. In the present study, patients exhibited concurrent elevations in serum MMP-9 and IGFBP-1 levels, suggesting complex interactions between the ECM remodeling network and IGF signaling, although the specific mechanistic roles in the chronic progression of schizophrenia require further investigation.\u003c/p\u003e\n\u003cp\u003eSerum IGFBP-1 concentration was negatively correlated with immediate memory performance, consistent with our previous findings in treatment-resistant schizophrenia patients [42] and suggesting that IGFBP-1-dependent processes may disrupt working memory in schizophrenia. Previous studies have reported alterations in the IGF pathway across multiple psychiatric and neurological conditions. Fern\u0026aacute;ndez-Pereira et al. found correlations of IGFBP-3 and IGFBP-5, but not IGFBP-1, with cognitive function [43]. In contrast, significant changes in IGFBP-1 have been observed in elderly male schizophrenia patients [44] and Alzheimer\u0026rsquo;s disease patients [45, 46]. Furthermore, schizophrenia patients with lower IGF-1 levels before treatment showed more pronounced improvement in cognitive deficits following antipsychotic medication [47], in accord with the current findings. These clinical observations, together with findings from animal models [48], indicate that IGF signaling plays an important role in neurodevelopment and cognitive function.\u003c/p\u003e\n\u003cp\u003eSerum TIMP-1 concentration was positively correlated with disease duration and demonstrated relative stability within the first 15 years, followed by a significant increase. This finding is consistent with the neurodevelopmental-progressive hypothesis of schizophrenia [49] and suggests that serum TIMP-1 may reflect cumulative pathological processes involving ECM remodeling, ultimately leading to intractable clinical symptoms. As an acute-phase reactant, TIMP-1 may participate in the persistent low-grade inflammatory state observed in schizophrenia [50, 51]. Longitudinal neuroimaging studies have shown progressive gray matter volume loss and ventricular enlargement in the chronic phase [52-54]. We speculate that chronically elevated peripheral TIMP-1 may reflect neurostructural damage, although the exact mechanisms remain unclear. For instance, imbalances between MMPs and TIMPs may lead to ECM dysregulation and altered neural network architecture [55]. Indeed, the 15-year time point for TIMP-1 elevation observed in our study aligns with the period of accelerated functional decline reported in clinical studies. Alternatively, the relative stability of TIMP-1 in the first 15 years suggests a potential therapeutic window for intervention beyond which neurological changes underlying symptoms are irreversible. Therefore, monitoring of serum TIMP-1 may help identify patients in a state of active disease progression.\u003c/p\u003e\n\u003cp\u003eElevated serum IGFBP-1 levels were identified as an independent risk factor for long-term hospitalization, suggesting that IGFBP-1 may contribute to these pathogenic processes resulting in intractable symptoms. Metabolic disturbances are highly prevalent in schizophrenia patients [56], and elevated IGFBP-1 may reflect this metabolic dysregulation [57]. Further, Cheng et al. identified a negative genetic correlation between plasma IGFBP-6 protein levels and schizophrenia through linkage disequilibrium score regression analysis, suggesting that members of the IGFBP family influence disease susceptibility [58]. Notably, elevated serum IGFBP-1 concentration was associated with alterations in MMP-9 and TIMP-1, suggesting that metabolic dysregulation may contribute to aberrant ECM remodeling and neuroplasticity in long-term schizophrenia patients, leading to a chronic disease condition.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. First, the cross-sectional design precludes causal inferences and tracking of dynamic changes in ECM biomarkers. Second, these findings may only apply to long-term hospitalized male patients with chronic schizophrenia. Larger-scale studies comparing these biomarker changes between clinical groups (e.g., first-episode, patients in remission, etc.) may provide additional support for the contributions of ECM abnormalities to the neurological changes underlying schizophrenia progression. Third, the influences of different antipsychotic medications were not considered in the analysis. Again, future studies should employ longitudinal designs and include more diverse patient populations.\u003c/p\u003e\n\u003cp\u003eThis study revealed that extracellular matrix (ECM) remodeling is dysregulated in male patients with chronic schizophrenia as evidenced by elevated serum MMP-9 levels and MMP-9/TIMP-1 ratio, along with reduced serum TIMP-1. Serum IGFBP-1 was also significantly elevated in patients, correlated with immediate memory impairment, and independently associated with long-term hospitalization. In addition, elevated serum TIMP-1 was associated with longer illness duration due to marked upregulation after 15 years of illness, suggesting that ECM remodeling dysregulation directly contributes to neurological changes underlying chronic pathological progression. These findings identify ECM remodeling as a promising therapeutic target for preventing schizophrenia progression to the chronic state.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank all of the study participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMinggang Jiang and Haidong Yang wrote the manuscript; Xiaobin Zhang and Xiaoyu Sun were responsible for the study design; Haidong Yang and Yubing Han performed the statistical analysis; Yubing Han, Man Yang, and Jing Zhang performed the clinical ratings, recruited the patients, and collected the samples. All authors have contributed to and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was financially supported by the\u0026nbsp;Suzhou Clinical Medical Center for Mood Disorders (grant no. Szlcyxzx202109), Suzhou Key Laboratory (grant no. SZS2024016), Suzhou Multicenter Clinical Research Project on Major Diseases (grant no. DZXYJ202413), Guidance Project of Jiangsu Provincial Health Commission (grant no. Z2023074), and Lianyungang National Natural Science Foundation Reserved Project (General Program) (grant no. K82504). The funding sources of this study had no role in the study design, data collection and analysis, decision to publish, or preparation of the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the results of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe declare that all human experimentation was conducted in accordance with the Declaration of Helsinki and that all procedures were carried out with the adequate understanding and written consent of the subjects. All experimental protocols were approved by the Ethics Committee of Lianyungang Fourth People\u0026rsquo;s Hospital. Informed consent was obtained from all participants and/or their legal guardians. All methods were carried out in accordance with relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Generative AI and AI-assisted Techniques\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eArtificial intelligence (AI) tools were used only for minor language editing (e.g., grammar and style checks). All scientific content, interpretations, and conclusions were generated by the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no competing or potential conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJauhar S, Johnstone M, McKenna PJ. Schizophrenia. Lancet. 2022;399(10323):473\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcCutcheon RA, Keefe RSE, McGuire PK. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Mol Psychiatry. 2023;28(5):1902\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGebreegziabhere Y, Habatmu K, Mihretu A, Cella M, Alem A. Cognitive impairment in people with schizophrenia: an umbrella review. Eur Arch Psychiatry Clin Neurosci. 2022;272(7):1139\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarlati S, Nibbio G, Vita A. Evidence-based psychosocial interventions in schizophrenia: a critical review. Curr Opin Psychiatry. 2024;37(3):131\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeber L, Peter NL, Chiocchia V, Schneider-Thoma J, Siafis S, Bighelli I, Hansen WP, Lin X, Prates-Baldez D, Salanti G, et al. Antipsychotic Drugs and Cognitive Function: A Systematic Review and Network Meta-Analysis. JAMA psychiatry. 2025;82(1):47\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHowes OD, Bukala BR, Beck K. Schizophrenia: from neurochemistry to circuits, symptoms and treatments. Nat reviews Neurol. 2024;20(1):22\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSperanza L, di Porzio U, Viggiano D, de Donato A, Volpicelli F. Dopamine: The Neuromodulator of Long-Term Synaptic Plasticity, Reward and Movement Control. Cells 2021, 10(4).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDzyubenko E, Hermann DM. Role of glia and extracellular matrix in controlling neuroplasticity in the central nervous system. Semin Immunopathol. 2023;45(3):377\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCangalaya C, Sun W, Stoyanov S, Dunay IR, Dityatev A. Integrity of neural extracellular matrix is required for microglia-mediated synaptic remodeling. Glia. 2024;72(10):1874\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBauch J, Faissner A. The Extracellular Matrix Proteins Tenascin-C and Tenascin-R Retard Oligodendrocyte Precursor Maturation and Myelin Regeneration in a Cuprizone-Induced Long-Term Demyelination Animal Model. Cells 2022, 11(11).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQi S, Wang S, Tan Y, Pan C, Bi X. Extracellular Matrix (ECM)-Regulated Molecular Switches: Tissue Inhibitors of Metalloproteinases in Synaptic Formation and Neuropathic Diseases. Cell Mol Neurobiol. 2025;45(1):100.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, Ramirez-Acu\u0026ntilde;a JM, Perez-Romero BA, Guerrero-Rodriguez JF, Martinez-Avila N, Martinez-Fierro ML. The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. \u003cem\u003eInt J Mol Sci\u003c/em\u003e 2020, 21(24).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRibot J, Breton R, Calvo CF, Moulard J, Ezan P, Zapata J, Samama K, Moreau M, Bemelmans AP, Sabatet V, et al. Astrocytes close the mouse critical period for visual plasticity. Science. 2021;373(6550):77\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoates-Park S, Lazaroff C, Gurung S, Rich J, Colladay A, O'Neill M, Butler GS, Overall CM, Stetler-Stevenson WG, Peeney D. Tissue inhibitors of metalloproteinases are proteolytic targets of matrix metalloproteinase 9. Matrix biology: J Int Soc Matrix Biology. 2023;123:59\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerreira AC, Hemmer BM, Philippi SM, Grau-Perales AB, Rosenstadt JL, Liu H, Zhu JD, Kareva T, Ahfeldt T, Varghese M, et al. Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix complexity. Mol Psychiatry. 2023;28(9):3943\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGanguly K, Adhikary K, Acharjee A, Acharjee P, Trigun SK, Mutlaq AS, Ashique S, Yasmin S, Alshahrani AM, Ansari MY. Biological significance and pathophysiological role of Matrix Metalloproteinases in the Central Nervous System. Int J Biol Macromol. 2024;280(Pt 3):135967.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiang Y, Pan H, Yang Z, Yu C, Jiang T, Li Y, Yu H, Qiu M, Zhang S. Alterations in the plasma concentrations of BDNF, proBDNF, and MMP-9 in patients with schizophrenia. Eur J Med Res. 2025;30(1):867.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchoretsanitis G, de Filippis R, Ntogka M, Leucht S, Correll CU, Kane JM. Matrix Metalloproteinase 9 Blood Alterations in Patients With Schizophrenia Spectrum Disorders: A Systematic Review and Meta-Analysis. Schizophr Bull. 2021;47(4):986\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRahimi S, Sayad A, Moslemi E, Ghafouri-Fard S, Taheri M. Blood assessment of the expression levels of matrix metalloproteinase 9 (MMP9) and its natural inhibitor, TIMP1 genes in Iranian schizophrenic patients. Metab Brain Dis. 2017;32(5):1537\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTylec A, Skałecki M, Kocot J, Kurzepa J. Activity of selected metalloproteinases in neurodegenerative diseases of the central nervous system as exemplified by dementia and schizophrenia. Psychiatr Pol. 2021;55(6):1221\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang WB, Aleksic S, Gao T, Weiss EF, Demetriou E, Verghese J, Holtzer R, Barzilai N, Milman S. Insulin-like Growth Factor-1 and IGF Binding Proteins Predict All-Cause Mortality and Morbidity in Older Adults. Cells 2020, 9(6).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaxter RC. Signaling Pathways of the Insulin-like Growth Factor Binding Proteins. Endocr Rev. 2023;44(5):753\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSechrist ZR, Cort\u0026eacute;s JS, Patel NR, Pittman ZJ, Guru Murthy G, Zhu G, Cole CL, Korman BD. Pathologic Signaling and Disease Implications of Insulin-like Growth Factor Binding Proteins in Cancer, Cardiovascular Disease, and Fibrosis. Int J Mol Sci 2025, 26(21).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoppock HA, White A, Aplin JD, Westwood M. Matrix metalloprotease-3 and \u0026ndash;\u0026thinsp;9 proteolyze insulin-like growth factor-binding protein-1. Biol Reprod. 2004;71(2):438\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMa\u0026ntilde;es S, Llorente M, Lacalle RA, G\u0026oacute;mez-Mout\u0026oacute;n C, Kremer L, Mira E, Mart\u0026iacute;nez AC. The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells. J Biol Chem. 1999;274(11):6935\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLim K, Peh OH, Yang Z, Rekhi G, Rapisarda A, See YM, Rashid NAA, Ang MS, Lee SA, Sim K, et al. Large-scale evaluation of the Positive and Negative Syndrome Scale (PANSS) symptom architecture in schizophrenia. Asian J Psychiatr. 2021;62:102732.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIsmail Z, Meehan SR, Farovik A, Miguelez M, Kapadia S, Regnier SA, Zhang Z, Brown TM, Milien M, McIntyre RS. Assessment of patient life engagement in schizophrenia using items from the Positive and Negative Syndrome Scale. Schizophr Res. 2024;274:337\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaudeberg R, Karr JE, Iverson GL, Hammar \u0026Aring;. Examining the repeatable battery for the assessment of neuropsychological status validity indices in people with schizophrenia spectrum disorders. Clin Neuropsychol. 2023;37(1):101\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMisiak B, Piotrowski P, Samochowiec J. Assessment of interrelationships between cognitive performance, symptomatic manifestation and social functioning in the acute and clinical stability phase of schizophrenia: insights from a network analysis. BMC Psychiatry. 2023;23(1):774.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang H, Zhang C, Yang M, Liu J, Zhang Y, Liu D, Zhang X. Variations of plasma oxidative stress levels in male patients with chronic schizophrenia. Correlations with psychopathology and matrix metalloproteinase-9: a case-control study. BMC Psychiatry 2024, 24(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi X, Wang X, Yang Y, Zhou J, Wu X, Zhao J, Zhang J, Guo X, Shao M, Song M, et al. Elevated plasma matrix metalloproteinase 9 in schizophrenia patients associated with poor antipsychotic treatment response and white matter density deficits. Schizophrenia (Heidelb). 2024;10(1):71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBitanihirwe BKY, Woo TW. A conceptualized model linking matrix metalloproteinase-9 to schizophrenia pathogenesis. Schizophr Res. 2020;218:28\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePantazopoulos H, Katsel P, Haroutunian V, Chelini G, Klengel T, Berretta S. Molecular signature of extracellular matrix pathology in schizophrenia. Eur J Neurosci. 2020;53(12):3960\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDai S, Xu Y, Yang T, Wang F, Jiang Y. Identification and Correlation Analysis of Ferroptosis-Related Genes in Three Brain Regions of Patients with Schizophrenia. Actas Esp Psiquiatr. 2024;52(6):800\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJeffries CD, Perkins DO, Fournier M, Do KQ, Cuenod M, Khadimallah I, Domenici E, Addington J, Bearden CE, Cadenhead KS et al. Networks of blood proteins in the neuroimmunology of schizophrenia. Translational Psychiatry 2018, 8(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWłodarczyk L, Cichon N, Karbownik MS, Saluk J, Miller E. Exploring the Role of MMP-9 and MMP-9/TIMP-1 Ratio in Subacute Stroke Recovery: A Prospective Observational Study. Int J Mol Sci 2024, 25(11).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMelkersson KI, Hulting AL, Brismar KE. Different influences of classical antipsychotics and clozapine on glucose-insulin homeostasis in patients with schizophrenia or related psychoses. J Clin Psychiatry. 1999;60(11):783\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMelkersson KI, Hulting AL, Brismar KE. Elevated levels of insulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses. J Clin Psychiatry. 2000;61(10):742\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHowes OD, Gaughran FP, Amiel SA, Murray RM, Pilowsky LS. The effect of clozapine on factors controlling glucose homeostasis. J Clin Psychiatry. 2004;65(10):1352\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFern\u0026aacute;ndez-Pereira C, Ag\u0026iacute;s-Balboa RC. The Insulin-like Growth Factor Family as a Potential Peripheral Biomarker in Psychiatric Disorders: A Systematic Review. Int J Mol Sci 2025, 26(6).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKollet O, Das A, Karamanos N, auf dem Keller U, Sagi I. Redefining metalloproteases specificity through network proteolysis. Trends Mol Med. 2024;30(2):147\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang H, Yang M, Zhang Y, Shi Z, Zhang X, Zhang C. Elevated serum IGFBP-1 levels correlate with cognitive deficits in treatment-resistant and chronic medicated schizophrenia patients. Cytokine 2024, 182.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFern\u0026aacute;ndez-Pereira C, Penedo MA, Rivera-Baltan\u0026aacute;s T, P\u0026eacute;rez-M\u0026aacute;rquez T, Alves-Villar M, Fern\u0026aacute;ndez-Mart\u0026iacute;nez R, Veiga C, Salgado-Barreira \u0026Aacute;, Prieto-Gonz\u0026aacute;lez JM, Ortolano S et al. Protein Plasma Levels of the IGF Signalling System Are Altered in Major Depressive Disorder. Int J Mol Sci 2023, 24(20).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl-Delaimy WK, Von Muhlen D, Barrett-Connor E. Insulinlike Growth Factor-1, Insulinlike Growth Factor Binding Protein-1, and Cognitive Function in Older Men and Women. J Am Geriatr Soc. 2009;57(8):1441\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurialdo G, Barreca A, Nobili F, Rollero A, Timossi G, Gianelli MV, Copello F, Rodriguez G, Polleri A. Relationships between cortisol, dehydroepiandrosterone sulphate and insulin-like growth factor-I system in dementia. J Endocrinol Invest. 2001;24(3):139\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiao J, Zhang Y, Su C, Zheng Q, Guo J. Insulin-Like Growth Factor Signaling in Alzheimer\u0026rsquo;s Disease: Pathophysiology and Therapeutic Strategies. Mol Neurobiol. 2024;62(3):3195\u0026ndash;225.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiong J, Ding Y, Wu X, Zhan J, Wan Q, Wan H, Wei B, Chen H, Yang Y. Association between serum insulin-like growth factor 1 levels and the improvements of cognitive impairments in a subgroup of schizophrenia: Preliminary findings. Schizophr Res. 2024;264:282\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLewitt MS, Boyd GW. Role of the Insulin-like Growth Factor System in Neurodegenerative Disease. Int J Mol Sci 2024, 25(8).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavis J, Eyre H, Jacka FN, Dodd S, Dean O, McEwen S, Debnath M, McGrath J, Maes M, Amminger P, et al. A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis. Neurosci Biobehavioral Reviews. 2016;65:185\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpeers LJ, Bilkey DK. Inflammation in Schizophrenia: The Role of Disordered Oscillatory Mechanisms. Cells 2025, 14(9).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChaves C, Dursun SM, Tusconi M, Hallak JEC. Neuroinflammation and schizophrenia \u0026ndash; is there a link? Front Psychiatry 2024, 15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBelliveau C, Rahimian R, Fakhfouri G, Hosdey C, Simard S, Davoli MA, Mirault D, Giros B, Turecki G, Mechawar N. Evidence of microglial involvement in the childhood abuse-associated increase in perineuronal nets in the ventromedial prefrontal cortex. Brain Behav Immun. 2025;124:321\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAas M, Dieset I, Hope S, Hoseth E, M\u0026oslash;rch R, Reponen E, Steen NE, Laskemoen JF, Ueland T, Aukrust P, et al. Childhood maltreatment severity is associated with elevated C-reactive protein and body mass index in adults with schizophrenia and bipolar diagnoses. Brain Behav Immun. 2017;65:342\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Y, Catts VS, Sheedy D, McCrossin T, Kril JJ, Shannon Weickert C. Cortical grey matter volume reduction in people with schizophrenia is associated with neuro-inflammation. Translational Psychiatry. 2016;6(12):e982\u0026ndash;982.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVujić T, Schvartz D, Furlani IL, Meister I, Gonz\u0026aacute;lez-Ruiz V, Rudaz S, Sanchez J-C. Oxidative Stress and Extracellular Matrix Remodeling Are Signature Pathways of Extracellular Vesicles Released upon Morphine Exposure on Human Brain Microvascular Endothelial Cells. \u003cem\u003eCells\u003c/em\u003e 2022, 11(23).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeng L, Yan G, Wang M, Lei T, Sun L, Zhou T. Prevalence of metabolic syndrome in Chinese patients with schizophrenia: a systematic review and meta-analysis. BMC Psychiatry 2025, 25(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi J, Mao B, Tang X, Zhang Q, Zhao J, Zhang H, Chen W, Cui S. Endocrine and metabolic drivers of sebum dysregulation: Mechanisms and therapeutic strategies. Life Sci. 2025;383:124044.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng S, Guan F, Ma M, Zhang L, Cheng B, Qi X, Liang C, Li P, Kafle OP, Wen Y et al. An atlas of genetic correlations between psychiatric disorders and human blood plasma proteome. Eur Psychiatry 2020, 63(1).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Schizophrenia, extracellular matrix, matrix metalloproteinase-9, insulin-like growth factor binding protein-1, cognitive impairment, illness duration","lastPublishedDoi":"10.21203/rs.3.rs-8288124/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8288124/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eDysregulation of neuroplasticity contributes to the pathogenesis of schizophrenia. Matrix metalloproteinases (MMPs) and endogenous tissue MMP inhibitors (TIMPs) are key regulators of extracellular matrix (ECM) remodeling essential for neuroplasticity, while insulin-like growth factor binding protein-1 (IGFBP-1) modulates ECM dynamics through integrin receptor signaling and MMP-mediated proteolysis. The current study investigated potential abnormalities in serum MMP-9, TIMP-1, and IGFBP-1 concentrations as biomarkers of ECM dysfunction among long-term hospitalized male schizophrenia patients and assessed associations with clinical characteristics.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eSerum MMP-2, MMP-9, TIMP-1, and IGFBP-1 concentrations were compared between 80 male schizophrenia patients hospitalized for \u0026ge;5 years and 59 age-matched healthy male controls. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and cognitive functions using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Correlations between serum measurements and scores on the PANSS and RBANS were assessed while controlling for multiple covariates.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSerum TIMP-1 concentration was significantly lower in the patient group (\u003cem\u003eZ\u003c/em\u003e=-2.547, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012). Conversely, patients exhibited significantly elevated serum MMP-9 (\u003cem\u003eZ\u003c/em\u003e=-2.067, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.039), MMP-9/TIMP-1 ratio (\u003cem\u003eZ\u003c/em\u003e=-2.195, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.028), and IGFBP-1 (\u003cem\u003eZ\u003c/em\u003e=-5.994, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Serum IGFBP-1 concentration negatively correlated with RBANS immediate memory subscore (\u003cem\u003er\u003c/em\u003e=-0.240, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024), and elevated IGFBP-1 was identified as an independent risk factor for long-term hospitalization (\u003cem\u003eRR\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.257, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, 95%CI:1.571\u0026ndash;3.243). Serum TIMP-1 concentration also positively correlated with illness duration (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.376, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eLong-term hospitalized male schizophrenia patients exhibit an ECM remodeling imbalance associated with memory impairment and predictive of chronic disease status. Therefore, molecules regulating ECM dynamics may be effective therapeutic targets for schizophrenia.\u003c/p\u003e","manuscriptTitle":"Altered serum MMP-9, TIMP-1, and IGFBP-1 concentrations in chronic male schizophrenia patients: associations with illness duration and cognitive impairments","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-22 09:47:09","doi":"10.21203/rs.3.rs-8288124/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-02-23T12:47:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-16T19:30:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"177576624552737232590185927209459696484","date":"2026-02-11T19:40:00+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-07T17:25:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"147431089168892611229939047723470367048","date":"2026-02-06T17:19:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"66520031235973190035195627388985566904","date":"2026-01-07T09:44:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"121747111330520485274143974025270019952","date":"2026-01-06T14:03:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"198499922313043288493001819258081351750","date":"2026-01-05T13:24:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-16T10:41:08+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-10T07:30:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-08T10:02:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-08T09:59:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Psychiatry","date":"2025-12-05T13:00:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"32cfbdab-5713-4795-b16c-db3c3d0e7083","owner":[],"postedDate":"December 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-12-22T09:47:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-22 09:47:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8288124","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8288124","identity":"rs-8288124","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}