Correlations of Oxidative Stress Markers with Niacin Sensitivity in Male Patients with Chronic Schizophrenia

Correlations of Oxidative Stress Markers with Niacin Sensitivity in Male Patients with Chronic Schizophrenia | 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 Correlations of Oxidative Stress Markers with Niacin Sensitivity in Male Patients with Chronic Schizophrenia Man Yang, Qing Tian, Xue Yuan, Dongliang Liu, Qiang Shi, Haidong Yang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6906160/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Nov, 2025 Read the published version in BMC Psychiatry → Version 1 posted 11 You are reading this latest preprint version Abstract Background Schizophrenia is a debilitating mental disorder linked to oxidative stress (OS) and inflammatory dysregulation. Emerging evidence suggests impaired niacin sensitivity in schizophrenia patients, potentially reflecting OS and inflammation. This study investigated correlations between OS markers and niacin sensitivity in male chronic schizophrenia patients to elucidate pathophysiological mechanisms and identify biomarkers. Methods The cohort of this cross-sectional study included 80 male chronic schizophrenia patients and 40 matched healthy controls. Blood samples were collected for analysis of nitric oxide (NO), total nitric oxide synthase (TNOS), inducible nitric oxide synthase (iNOS), constitutive nitric oxide synthase (cNOS), total antioxidant capacity (TAC), and vitamin E (VE). Skin niacin sensitivity was assessed via the erythema response to topical niacin. Clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). Statistical analyses ( t -tests, analysis of variance, and logistic regression) were conducted to identify associations. Results TNOS, iNOS, cNOS, TAC, and VE levels were significantly lower in the patient group than in the healthy control group ( p < 0.001). Reduced skin erythema response in patients ( p < 0.001) was correlated with lower TAC activity and VE levels. Plasma NO levels were positively correlated with PANSS positive symptom scores ( r = 0.370, p = 0.004). TAC was a significant predictor of an impaired niacin response (OR = 1.009, p = 0.022). Conclusion Chronic schizophrenia is characterized by disrupted redox balance and diminished niacin sensitivity, implicating oxidative-inflammatory crosstalk in disease pathology. A weakened niacin response, associated with antioxidant deficits, may serve as a biomarker of the severity of OS. These findings underscore the potential of antioxidant therapies to modulate clinical outcomes. Further longitudinal studies are needed to validate causal relationships and therapeutic implications. schizophrenia oxidative stress niacin sensitivity nitric oxide total antioxidant capacity Figures Figure 1 Figure 2 1. Introduction Schizophrenia is a severe and debilitating mental disorder characterized by persistent positive symptoms (e.g., hallucinations, delusions, disorganized thoughts, and speech), negative symptoms (e.g., anhedonia, apathy, and social withdrawal), and cognitive symptoms (inattention, impaired working memory, and dysfunctional executive functions), which affect thoughts, intelligence, and ability to plan [ 1 ]. Emerging evidence suggests that oxidative stress (OS), an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify these harmful byproducts or repair the resulting damage, plays a critical role in the pathophysiology of schizophrenia[ 2 ]. Previous studies have shown that, compared to healthy controls, patients with schizophrenia exhibit reduced sensitivity to niacin [ 3 ], which has been associated with abnormal inflammatory responses[ 1 ], dysregulated OS, and disrupted fatty acid metabolism [ 4 ]. Niacin (vitamin B3) is reported to reduce OS and modulate inflammatory pathways, thereby offering potential therapeutic benefits for psychiatric disorders [ 5 , 6 ]. OS is a normal and complex physiological process involving the production and neutralization of ROS and reactive nitrogen species[ 7 ]. Notably, nitric oxide (NO), a gaseous neurotransmitter, is associated with OS and the production of ROS [ 8 ], while catalase, superoxide dismutase, malondialdehyde, glutathione peroxidase, nitric oxide synthase (NOS), and total antioxidant capacity (TAC) are important parameters of physiological functions[ 9 ]. This redox balance is maintained by both antioxidant enzymes and non-enzymatic antioxidants, such as vitamin C and vitamin E (VE) [ 10 ]. Constitutive nitric oxide synthase (cNOS), which synthesizes NO, is involved in neuronal development and synaptic formation. An overabundance of NO may contribute to neuronal degeneration in the central nervous system[ 11 ]. Inducible nitric oxide synthase (iNOS) plays an essential role in inflammatory processes during damage or infectious impairment of tissues, and NO, generated by iNOS, is involved in pathogenesis of Alzheimer’s diseases, septic shock, multiple sclerosis, and brain ischemia[ 12 ]. While the relationship between OS and schizophrenia has been extensively studied, the interplay between OS markers and niacin sensitivity remains poorly understood, particularly in male patients with chronic schizophrenia[ 13 ]. Since males are often more severely affected by schizophrenia, with earlier onset and poorer outcomes, this population is particularly useful to clarify the correlation between OS and niacin sensitivity to provide valuable insights into the biological mechanisms underlying schizophrenia for the development of personalized therapeutic strategies. 2. Materials and methods 2.1 Participant recruitment and ethical approval The cohort of this cross-sectional study included 80 male chronic schizophrenia patients hospitalized from January to October 2020 at the Lianyungang Psychiatric Hospital Group (including Lianyungang Fourth People's Hospital, Ganyu District Rehabilitation Hospital, Donghai County Psychiatric Hospital, and Guanyun County Psychiatric Hospital) and 40 healthy individuals matched for age, sex, body mass index (BMI), smoking status, and education level as a control group. The inclusion criteria were (1) meeting the Diagnostic and Statistical Manual for Mental Disorders (DSM-V) for schizophrenia, (2) age between 20 and 60 years, (3) Han nationality, (4) diagnosis of schizophrenia of at least 5 years, with stable condition, and (5) consistent dosage of antipsychotic medication for at least 1 year. The exclusion criteria were (1) any severe physical disease, (2) use of non-steroidal anti-inflammatory drugs within the past 10 days, (3) any neurological disease, (4) history of mental illness or substance abuse, and (5) family history of mental illness. The study protocol was approved by the Ethics Committee of the Fourth People’s Hospital of Lianyungang, and written informed consent was obtained from all participants or their legal guardians. All procedures were conducted in accordance with the Declaration of Helsinki. 2.1 Collection of Demographic and Clinical Data A self-made demographic statistical table was used to collect the names, sex, age, smoking status, education levels, height, weight, and BMI of all study participants. For the patient group, additional data collected included age at onset, duration of illness, and medication details, with all medication dosages converted to chlorpromazine equivalent doses. 2.2 Assessment of Clinical Symptom Severity The Positive and Negative Syndrome Scale (PANSS) was utilized to assess the severity of clinical symptoms in the patient group. The PANSS is widely used to measure the severity of psychiatric symptoms in adult schizophrenia patients and includes three independent subscales (Positive, Negative, and General Psychopathology), consisting of 30 items. Each item is scored on a scale from 1 to 7, with the total score ranging from 30 to 210. Higher scores on the PANSS and subscales indicate more severe psychiatric symptoms[ 14 ]. 2.3 Hematological Indices Blood indices measured included NO, total nitric oxide synthase (TNOS), cNOS, iNOS, TAC, and VE. Venous blood samples were collected from participants in the morning after fasting into anticoagulant tubes, centrifuged at 3000 rpm for 15 min, and analyzed by Nanjing Jiancheng Biological Engineering Institute (Nanjing, China). 2.4 Measurement of Skin Niacin Sensitivity Filter paper discs (diameter, 0.9 cm) immersed in four different concentrations of niacin solution (0.0001, 0.001, 0.01, and 0.1 mol/L) were applied to the participants’ forearm up to the elbow in ascending order of concentration and held in place for 1 min. After removal, the erythema response of the skin was observed and recorded at 5, 10, 15, and 20 min, along with photographic documentation. The erythema response of the skin was scored as follows: 0 = no reaction; 1 = partial skin erythema; 2 = complete coverage of the filter paper area by erythema; and 3 = erythema exceeding the filter paper[ 15 ]. The niacin scores obtained at different concentrations and times were summed for a total score. The standard to evaluate the strength of the niacin response was a niacin solution concentration of 0.01 mol/L and 10 min. A score of 0 or 1 was considered a low niacin response, while a sore of 2 or 3 was defined as a high niacin response[ 16 ]. 2.5 Statistical Analysis All statistical analyses were performed using IBM SPSS Statistics for Windows (version 22.0; IBM Corporation, Armonk, NY, USA). The normality of the data was determined using Q-Q plots, the Kolmogorov-Smirnov test, and the Shapiro-Wilk test. Normally distributed measurement data are presented as the mean ± standard deviation. The independent samples t -test was used for comparisons between two groups, while analysis of variance was used for comparisons among multiple groups, followed by post hoc pairwise comparisons. Bonferroni correction was applied to adjust for multiple comparisons. For non-normally distributed measurement data, the Mann–Whitney U test was used for comparisons between two groups and the results are expressed as the median and interquartile range. Categorical data were compared between groups using the χ 2 test and are presented as the frequency and percentage. Pearson correlation analysis was used to assess correlations of TNOS, iNOS, cNOS, TAC, and VE with the total PANSS score and the scores of each subscale. Bonferroni correction was applied to adjust for multiple testing. For example, the Bonferroni corrected probability ( p ) value for each PANSS score was calculated as the original p -value*4. Furthermore, binary logistic regression analysis was employed to identify factors affecting the skin response to niacin. A two-tailed p- value < 0.05 was considered statistically significant. 3. Results 3.1. Comparisons of demographic, clinical characteristics, and skin niacin reaction scores between patients and healthy controls The demographic and clinical characteristics of the patient and control groups are summarized in Table 1 . There were no significant differences in age ( t = 0.905, p = 0.364), education level ( t = -1.301, p = 0.196), BMI ( t = -1.531, p = 0.128), or smoking status ( χ 2 = 2.046, p = 0.121), indicating that the two groups were well matched. In the patient group, the average age at onset was 26.86 ± 8.68 years, the average duration of illness was 13.75 ± 8.01 years, and the average dose of CPZ equivalent administered was 687.14 ± 312.24 mg/day. Compared to the control group, the skin niacin response score (0.01 mmol/L, 10 min) was significantly lower in the patient group ( p < 0.001). Table 1 Demographic and clinical characteristics of male patients with chronic schizophrenia and healthy controls Patients(n = 80) Controls (n = 40) t/Z/χ 2 p Age (years) 40.63 ± 9.80 39.0 ± 7.89 0.905 a 0.364 Education (years) 8.95 ± 3.16 9.68 ± 2.20 -1.301 a 0.196 BMI(kg/m 2 ) 24.51 ± 3.66 25.51 ± 2.66 -1.531 a 0.128 Smoking (n, %) 42 (52.5) 15 (37.5) 2.046 b 0.121 Disease Duration (years) 13.75 ± 8.01 Age of Onset (years) 26.86 ± 8.68 CPZ equivalent Dose (mg/d) 687.14 ± 312.24 PANSS P 11.03 ± 4.55 PANSS N 17.83 ± 7.18 PANSS G 29.24 ± 6.37 PANSS T 58.09 ± 14.90 Skin Niacin Reaction Score [0.01mmol/L, 10min ;M(P25, P75 )] 1 (1, 2) 2 (2, 3) -6.554 c < 0.001 BMI, body mass index; CPZ, chlorpromazine; PANSS, Positive and Negative Syndrome Scale a means independent samples t-test. b means χ 2 test. c means Mann-Whitney U test 3.2. Comparisons of plasma NO, TNOS, iNOS, cNOS, and VE levels, and TAC activity between the patient and healthy control groups OS levels in blood samples from the patient and healthy control groups are summarized in Table 2 . Analysis of covariance (ANCOVA), controlling for age, education level, BMI, and smoking status, revealed significantly lower serum levels of TNOS, iNOS, cNOS, and VE, and TAC activity in the patient group relative to the healthy control group. Table 2 Oxidative stress levels of schizophrenia patients and healthy controls Patients(n = 80) Controls (n = 40) F p NO(µmol/L) 56.49 ± 14.40 61.62 ± 20.71 1.561 ab 0.214 TNOS(U/ml) 2.99 ± 0.81 3.90 ± 0.93 15.713 ab < 0.001 iNOS(U/ml) 1.64 ± 0.54 2.03 ± 0.56 7.225 ab 0.01 cNOS(U/ml) 1.35 ± 0.40 1.87 ± 0.50 19.547 ab < 0.001 TAC(µmol/L) 682.62 ± 125.39 803.14 ± 114.16 23.414 ab < 0.001 VE (µg/mL) 9.28 ± 3.76 13.28 ± 5.42 11.824 ab < 0.001 NO, nitric oxide; TNOS, total nitric oxide synthase; iNOS, inducible nitric oxide synthase; cNOS, constitutive nitric oxide synthase; TAC, total antioxidant capacity; VE, vitamin E; a means independentsamplest-test. b means after controlling for age, education, BMI, smoking status, the difference in OS markers still remained significant. 3.3. Comparison of general demographic and clinical data between the nicotinic acid high-response group, low-response group, and healthy control group The low response group included 36 patients, while the high response group consisted of 44 patients. There were significant differences in TNOS, iNOS, cNOS, and VE levels, as well as TAC activity among the low-response group, high-response group, and control group (all, p 0.05). Following Bonferroni correction, statistically significant differences were observed in the low-response group compared to the healthy control group across multiple OS markers: specifically, TNOS ( p < 0.001), iNOS ( p = 0.01), cNOS ( p < 0.001), and VE levels ( p 0.05). Similarly, comparisons between the high-response group and the healthy control group revealed significant differences in TNOS ( p < 0.001), iNOS ( p = 0.021), cNOS ( p < 0.001), and VE ( p = 0.01) after Bonferroni adjustment. These findings underscore the distinct oxidative stress profiles associated with varying treatment response levels, independent of common confounding factors such as medication dosage or illness duration. The independent samples t -test showed no significant differences in the PANSS total score or subscale scores between the low- and high-response groups (all, p > 0.05) (Table 3 ). Additionally, pairwise comparisons showed significant differences: TAC low-response vs. high-response group ( p < 0.001), low-response vs. control group ( p < 0.001), and high-response vs. control group ( p = 0.013) ( Figure.1 ). Table 3 Comparison of general demographic and clinical characteristics among the niacin low-response group, high-response group, and control group Low-response group(n = 36) High- response group (n = 44) Controls(n = 40) F / χ 2 p Age (years) 42.39 ± 9.57 39.18 ± 9.87 39.0 ± 7.89 1.633 0.200 Education (years) 9.03 ± 3.32 8.89 ± 3.06 9.68 ± 2.20 0.864 0.424 BMI (kg/m 2 ) 24.0 ± 3.80 25.24 ± 3.37 25.51 ± 2.67 2.142 0.122 Smoking (n, %) 19 (52.8) 23 (52.3) 15 (37.5) 5.002 0.287 CPZ equivalent Dose (mg/d) 731.78 ± 336.26 650.61 ± 289.92 1.277 0.250 Disease Duration (years) 14.45 ± 8.43 12.76 ± 7.39 0.861 0.356 AgecOnset (years) 27.19 ± 9.47 26.39 ± 7.53 0.162 0.688 PANSS-P 10.91 ± 4.58 11.18 ± 4.57 0.066 0.798 PANSS-N 17.81 ± 7.11 17.85 ± 7.28 0.001 0.981 PANSS-G 29.15 ± 6.52 29.36 ± 6.25 0.022 0.883 PANSS-T 57.87 ± 14.90 58.39 ± 15.13 0.023 0.879 NO(µmol/L) 54.85 ± 14.50 57.8 ± 14.33 61.62 ± 20.71 1.561 0.214 TNOS(U/ml) 2.85 ± 0.76 b 3.20 ± 0.86 g 3.90 ± 0.93 15.713 < 0.001 iNOS(U/ml) 1.52 ± 0.53 c 1.81 ± 0.51 h 2.03 ± 0.56 7.225 0.001 cNOS(U/ml) 1.33 ± 0.37 d 1.39 ± 0.44 i 1.87 ± 0.50 19.547 < 0.001 TAC(µmol/L) 746.89 ± 115.83 f 591.09 ± 69.43 ak 803.14 ± 114.16 23.414 < 0.001 VE(µg/mL) 8.92 ± 4.09 9.79 ± 3.23 j 13.28 ± 5.42 11.824 < 0.001 Compared with the low - response group, a p < 0.001, b P < 0.001, c p = 0.01, d p < 0.001, e p < 0.001, f p < 0.001; Compared with the control group, g p < 0.001, h p = 0.021, i p < 0.001, j p = 0.01, k p = 0.013; CPZ, chlorpromazine;NO, nitric oxide; TNOS, total nitric oxide synthase; iNOS, inducible nitric oxide synthase; cNOS, constitutive nitric oxide synthase; TAC, total antioxidant capacity; VE, vitamin E; PANSS-P, PANSS positive subscale score; PANSS-N, PANSS negative subscale score; PANSS-G, general psychopathology subscale score; PANSS T, PANSS total scores. a means one-way of analysis of variance; b means χ 2 test; 3.4 Correlation of OS markers with clinical symptoms in schizophrenia patients Other than NO levels, there was no significant correlation of the OS indices and the total PANSS or subscale scores (all, p > 0.05). Notably, serum NO was positively associated with the PANSS subscale scores ( r = 0.370, Bonferroni corrected p = 0.004; Table 4 ). Further stepwise multiple regression analysis with age, education level, smoking status, BMI, age of onset, dose of antipsychotic treatment, duration of illness, and OS markers as covariates found that NO ( β = 0.370, t = 3.513, p = 0.001) influenced the total PANSS score (Fig. 2 ). Table 4 Relationships between oxidative stress markers and psychotic symptom in patients P subscores N subscores G subscoresc PANSS total score NO (µmol/L) r 0.370 0.275 0.091 0.274 p 0.001* 0.014* 0.420 0.014* p b 0.004* 0.056 1.680 0.056 TNOS (U/ml) r 0.176 0.175 0.069 0.162 p 0.118 0.121 0.543 0.152 p b 0.472 0.484 2.172 0.608 iNOS (U/ml) r 0.145 0.155 0.033 0.126 p 0.201 0.170 0.774 0.265 p b 0.804 0.68 3.096 1.06 cNOS (U/ml) r 0.182 0.188 0.055 0.162 p 0.107 0.096 0.626 0.150 p b 0.428 0.384 2.504 0.600 TAC (µmol/L) r 0.203 0.043 0.117 0.137 p 0.070 0.708 0.301 0.227 p b 0.280 2.832 1.204 0.908 VE (µg/mL) r -0.067 -0.134 -0.088 -0.120 p 0.552 0.237 0.437 0.288 p b 2.208 0.948 1.748 1.152 a means Spearman product moment. b means Bonferroni correction was applied in the associations between biomarkers and psychotics symptoms. * means p < 0.05. 3.5 Risk factors for skin niacin reaction in male patients with chronic schizophrenia Using the skin niacin response (assigned as a binary variable, with the low-response group assigned a value of 1 and the high-response group assigned a value of 0) as the dependent variable, logistic regression analysis was conducted with TAC as the independent variable. Additionally, age, education level, BMI, smoking status, disease duration, age of onset, and chlorpromazine equivalent dose were included in the analysis. The results showed that TAC is a risk factor for the skin niacin response in male patients with chronic schizophrenia ( β = 0.008, standard error = 0.004, Wald χ 2 = 5.230, p = 0.022, odds ratio = 1.009 [95% confidence interval: 1.001–1.016]). 4. Discussion This study investigated differences in demographics, clinical characteristics, and skin niacin reaction scores between chronic schizophrenia patients and healthy controls, while also exploring the correlations of OS markers with clinical symptoms. The findings revealed several important insights that contribute to a deeper understanding of the pathophysiological mechanisms underlying schizophrenia: (1) Compared to the healthy controls, serum levels of TNOS, iNOS, cNOS, and VE, as well as TAC activity, were significantly lower in schizophrenia patients receiving psychotropic agents and chronic schizophrenia patients; (2) skin niacin reactivity scores were markedly lower in the patient group as compared to the healthy control group; (3) Plasma NO levels were positively correlated with clinical symptoms; (4) There were significant differences in TNOS, iNOS, cNOS, and VE levels, as well as TAC activity, between the low- and high-response groups as compared to the healthy control group; and (5) In male patients with chronic schizophrenia, plasma CTA activity was identified as a risk factor for the skin niacin response after adjusting for covariates (i.e., age, education level, age of onset, duration of psychosis, and chlorpromazine equivalent dose). Regarding OS markers, serum levels of TNOS, iNOS, and cNOS were significantly lower in the patient group than the healthy control group, suggesting that chronic schizophrenia patients may experience dysfunction of the OS system, which could be linked to the pathophysiological processes of the disorder. Previous studies have found that NOS levels are reduced in the cerebrospinal fluid and post-mortem brain tissue of schizophrenia patients[ 17 ] and animal models (Walton et al.[ 18 ]. Genetic studies have demonstrated that single nucleotide polymorphisms of NOS-related genes are closely associated with the onset of schizophrenia[ 19 , 20 ]. Yang et al.[ 21 ] reported that asymmetric dimethylarginine, an endogenous inhibitor of NOS, is increased in schizophrenia patients, suggesting that NOS activity is suppressed in these individuals. Additionally, serum levels of iNOS are reportedly significantly lower in schizophrenia patients as compared to healthy controls (Peng et al., 2022), consistent with the findings of the present study. Preliminary research suggests that chronic medication use in schizophrenia patients may lead to an imbalance in redox reactions[ 22 ]. In response to inflammatory diseases, iNOS concentrations in the peripheral blood and brain tend to simultaneously increase[ 12 , 23 ]. Further mechanistic studies suggest that the release of cytokines and neurotransmitters may play a significant role in coordinating NOS concentrations in the peripheral blood and brain[ 12 ]. Collectively, these findings indicate that OS is involved in the pathophysiology of schizophrenia. As the primary enzyme responsible for the synthesis of NO, reduced activity of NOS may affect neurotransmitter systems, synaptic plasticity, and neuroinflammation, while iNOS, which is primarily expressed in immune cells, is closely associated with inflammatory responses [ 24 ]. Suppression of NOS activity may weaken the body's antioxidant defense system, further exacerbating OS. Furthermore, changes to NOS activity may also involve regulation of the immune system and chronic inflammation, which are considered important pathological features of schizophrenia[ 25 ]. Although TNOS, iNOS, and cNOS levels were significantly lower in chronic schizophrenia patients than in healthy controls, NO levels showed no significant difference between the two groups. This may be attributed to compensatory mechanisms in the body. For example, previous studies have shown that NO production in schizophrenia patients may be maintained through non-NOS-dependent nitrate reduction pathways [ 26 ]. Additionally, enhanced NO utilization efficiency or clearance capacity may offset the decrease in synthase activity, thereby masking potential NOS functional abnormalities. These compensatory mechanisms may play a role in maintaining the basic level of NO, but the underlying abnormal NOS function and its impact on neurotransmission and neuroinflammation in schizophrenia still need further exploration. Specifically, in accordance with many recent studies, reduced VE levels and TAC activity indicate impaired total antioxidant capacity, potentially leading to increased OS [ 7 , 27 , 28 ]. Hence, oxidative imbalance may contribute to neuronal damage and progression of schizophrenia symptoms[ 29 ]. Notably, certain antipsychotic medications may influence TAC activity and VE metabolism, potentially altering serum levels. The combined effects of these factors could weaken the antioxidant defense system, thereby exacerbating the symptoms of schizophrenia and promoting disease progression. Consequently, in clinical practice, it is crucial to closely monitor the impact of these medications on the patient's antioxidant status and implement appropriate interventions to maintain redox balance. The skin niacin reaction scores were significantly lower in the patient group as compared to the healthy controls, suggesting that the skin niacin response may serve as a potential biomarker for schizophrenia. This finding aligns with previous research indicating that an impaired skin niacin response is a common feature in schizophrenia patients, possibly reflecting underlying abnormalities in inflammatory or OS pathways[ 3 , 4 ]. Further analysis revealed significant differences in TNOS, iNOS, cNOS, TAC, and VE levels between the low and high skin niacin response groups, while no significant differences were observed in other clinical characteristics, suggesting that OS markers may be associated with variations in the skin niacin response, independent of other clinical features. The distinct OS profiles between the response groups highlight the potential role of OS in modulating the skin niacin reaction, which could be a reflection of systemic oxidative imbalance in schizophrenia patients. An abnormal skin niacin response suggests a disturbance in the phospholipase A2-arachidonic acid signaling pathway[ 30 ]. Enhanced antioxidant capacity can counteract the effects of OS, thereby influencing pathways associated with the niacin response. The intensity of the skin niacin response, as an external manifestation of OS status, particularly changes to TNOS, iNO, cNOS, and TAC, indicates that an imbalance in the oxidative-antioxidant-inflammatory system may be a key factor in the pathogenesis of schizophrenia. Correlation analysis showed a positive association between NO levels and PANSS positive symptom scores, indicating that NO may play a significant role in the positive symptoms of schizophrenia. This finding provides a basis for further research into the role of NO in the pathophysiology of schizophrenia. NO is known to influence dopaminergic and glutamatergic neurotransmission, which are recognized as positive symptoms of schizophrenia[ 31 ]. An animal study provided evidence that interactions of the NOX and nNOS redox signaling cascades in the brain affect both cognitive function and social behavior of mice (Walton et al.[ 18 ]. Moreover, elevated NO levels have been positively correlated with positive symptoms and behavioral abnormalities in schizophrenia patients [ 32 ]. Similarly, in the present study, plasma NO levels were significantly positively correlated with PANSS positive symptom scores in schizophrenia patients. Although NO levels were not abnormal, there were significant alterations to TNOS, iNOS, cNOS, and VE levels, as well as TAC activity, possibly due to compensatory mechanisms, NO utilization efficiency, or clearance rates. These correlations suggest that elevated NO levels may exacerbate positive symptoms, possibly through neurotransmitter systems or neuroinflammatory processes. Finally, logistic regression analysis identified TAC as a risk factor for the skin niacin response of male patients with chronic schizophrenia. The skin niacin response is an endogenous prostaglandin D2 release reaction that reflects inflammatory status[ 33 ]. Previous studies have reported that abnormal inflammatory responses may be associated with the pathogenesis of schizophrenia [ 34 ]. Reduced antioxidant capacity can lead to elevated OS levels, further exacerbating inflammatory reactions[ 35 ]. Therefore, schizophrenia patients with altered TAC activity may exhibit a more severe inflammatory state, resulting in a weaker skin niacin response. The finding that TAC activity is associated with the skin niacin response underscores the interplay between OS and inflammatory pathways in schizophrenia and raises the possibility that interventions aimed at enhancing antioxidant capacity could modulate the skin niacin response and potentially improve clinical outcomes for schizophrenia patients. Several limitations should be considered when interpreting our findings. First, although we controlled for age, BMI, and smoking status, other lifestyle variables-such as dietary patterns (e.g., VE intake), alcohol consumption history, and sleep quality-were not assessed which significantly influence OS markers. For instance, plasma VE levels are closely linked to dietary intake; group differences in antioxidant nutrient consumption could confound interpretations of "disease-related antioxidant deficits" versus "nutritional influences." Chronic alcohol consumption modulates key OS markers-including antioxidant capacity and NO pathways-through enhanced ROS generation and glutathione depletion, potentially confounding disease-associated oxidative profiles[ 36 ]. Second, while we identified correlations between TAC and impaired niacin sensitivity, the temporal relationship remains unresolved: it is unclear whether OS drives niacin hyporesponsiveness, or vice versa. Longitudinal tracking of OS markers and niacin responses is needed to establish directionality. Third, while chlorpromazine-equivalent dosing was covaried, OS modulation by antipsychotics may vary across drug classes—notably with clozapine due to its distinct pharmacology—potentially confounding results independent of disease processes[ 37 ]. Fourth, the exclusive focus on male, chronic, medicated, and ethnically Han Chinese patients limits extrapolation to broader schizophrenia populations. Findings may not apply to females (where hormonal influences could alter OS/niacin responses), acute-phase patients, or other ethnic groups. Replication in diverse cohorts is essential. Conclusion Taken together, these findings underscore the critical role of OS markers, particularly TAC activity and NO levels, in chronic schizophrenia and offer new insights into the pathophysiological mechanisms of schizophrenia to develop novel therapeutic strategies. The association between OS and the skin niacin response suggests that oxidative imbalance may be a key factor underlying the impaired niacin response observed in schizophrenia patients. However, further research is necessary to validate these findings and explore potential applications in clinical practice. Longitudinal studies could help determine whether OS markers and the skin niacin response are predictive of disease progression or treatment response, while intervention studies could assess the efficacy of antioxidant therapies to improve clinical symptoms and the skin niacin response in schizophrenia patients. Declarations Acknowledgments We would like to thank all patients who participated in the study. We are grateful to all the psychiatrists and nurses who participated in our current study and those research staff that contributed to the subjects' diagnosis and clinical assessments. Author contributions All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. Xiaobin Zhang, Haidong Yang, Man Yang and Qing Tian were responsible for study design, statistical analysis and writing of the manuscript. Qiang Shi was responsible for laboratorial analysis. Dongliang Liu and Xue Yuan were responsible for recruiting the patients, performing the clinical rating and collecting the samples. All authors have contributed to and have approved the final manuscript. Funding Declaration This study was supported by grants from Medical scientific research project of the Suzhou clinical Medical Center for mood disorders (No. Szlcyxzx202109), Suzhou Key Laboratory (SZS2024016), Multicenter Clinical Research on Major Diseases in Suzhou (DZXYJ202413), Lianyungang Science and Technology Bureau of Social Development Key R&D Projects (SF2319) and Youth Science and Technology Project of Lianyungang Municipal Health Commission (QN202310). The finding sources of this study had no role in study design, data collection and analysis, decision to publish, or preparation of the article. Availability of data and materials All data generated or analysed during this study are included in this published article. Declarations Ethics approval and consent to participate The study protocol was approved by the Institutional Review Committee of Lianyungang Fourth People's Hospital (approval NO. 2019LSYYXLL-P06) and conducted in accordance with the ethical principles for medical research involving human subjects described in the Declaration of Helsinki. Prior to inclusion in this study, informed consent was obtained from all participants and/or guardians. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. References Sabrina H AJFP: Inflammation and JNK's Role in Niacin-GPR109A Diminished Flushed Effect in Microglial and Neuronal Cells With Relevance to Schizophrenia . 2021, 12 (0). Murray A, Rogers J, Katshu M, Liddle P, Upthegrove RJFip: Oxidative Stress and the Pathophysiology and Symptom Profile of Schizophrenia Spectrum Disorders . 2021, 12 :703452. 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Bernstein H, Bogerts B, Keilhoff GJSr: The many faces of nitric oxide in schizophrenia. A review . 2005, 78 (1):69-86. Wadhwa R, Gupta R, Maurya PJCpd: Oxidative Stress and Accelerated Aging in Neurodegenerative and Neuropsychiatric Disorder . 2018, 24 (40):4711-4725. Lushchak VJC-bi: Free radicals, reactive oxygen species, oxidative stress and its classification . 2014, 224 :164-175. Esshili A, Manitz M, Freund N, Juckel GJEntjotECoN: Induction of inducible nitric oxide synthase expression in activated microglia and astrocytes following pre- and postnatal immune challenge in an animal model of schizophrenia . 2020, 35 :100-110. Nasyrova R, Ivashchenko D, Ivanov M, Neznanov NJFip: Role of nitric oxide and related molecules in schizophrenia pathogenesis: biochemical, genetic and clinical aspects . 2015, 6 :139. Zhenlei P, Qiyu J, Junxiong M, Shijie J, Qi M, Xiao L, Zhiguo A, Anqi H, Chuang M, Qizhong YJS: The role of ferroptosis and oxidative stress in cognitive deficits among chronic schizophrenia patients: a multicenter investigation . 2025, 11 (1). S R K, A F, L A OJSB: The positive and negative syndrome scale (PANSS) for schizophrenia . 1987, 13 (2). Liya S, Xuhan Y, Jie J, Xiaowen H, Ying Q, Dandan W, Tianqi Y, Chao Y, Juan Z, Ping Y et al : Identification of the Niacin-Blunted Subgroup of Schizophrenia Patients from Mood Disorders and Healthy Individuals in Chinese Population . 2017, 44 (4). Dan-Dan W, Xiao-Wen H, Jie J, Li-Ya S, Ying Q, Xu-Han Y, Yan G, Gao-Ping C, Ming-Hui L, Peng-Kun W et al : Attenuated and delayed niacin skin flushing in schizophrenia and affective disorders: A potential clinical auxiliary diagnostic marker . 2021, 230 (0). Guoqiang X, Mikulas C, Li-Xin Z, Shutong Y, Robert M PJSR: Decreased calcium-dependent constitutive nitric oxide synthase (cNOS) activity in prefrontal cortex in schizophrenia and depression . 2002, 58 (1). James C W, Balakrishnan S, Zachary M W, Solomon H S, Randy J NJBBR: Neuronal nitric oxide synthase and NADPH oxidase interact to affect cognitive, affective, and social behaviors in mice . 2013, 256 (0). Naomi S W, Holly M, Yungui H, Anna M D, Paul G M, Michelle A C, Marco A A, Jaime M, Jared E H, Anne S B et al : Identification of a schizophrenia-associated functional noncoding variant in NOS1AP . 166 (4). Wei T, Ke H, Ruqi T, Guoquan Z, Chao F, Jing Z, Lingzhen D, Guoying F, Lin H, Yongyong SJIJN: Evidence for association between the 5' flank of the NOS1 gene and schizophrenia in the Chinese population . 2008, 11 (8). Yuan-Jian Y, Jian-Wen X, Ying Z, Jin-Qiong Z, Hai-Bo C, Kun Y, Mao-Rong H, Bin Y, Bo WJPR: Increased plasma asymmetric dimethylarginine is associated with cognitive deficits in patients with schizophrenia . 2016, 246 (0). Man Y, Jin L, Haidong Y, Linya Y, Dongliang L, Lin Z, Xiaobin ZJFP: Cognitive Impairment and Psychopathology Are Related to Plasma Oxidative Stress in Long Term Hospitalized Patients With Chronic Schizophrenia . 2022, 13 (0). Mehdi G, Ali FJNBR: Pathologic role of glial nitric oxide in adult and pediatric neuroinflammatory diseases . 2014, 45 (0). Regina F N, Polina V M, Elena E V, Natalya A S, Nataliya L B, Albert A RJIJMS: Genetic Factors of Nitric Oxide's System in Psychoneurologic Disorders . 2020, 21 (5). Patrick B, Fábio Aparecido B, Angélica Marta L, Isabela da Silva F, Rafael F-F, Camila Ive Ferreira O-B, Tayanne Silva dC, Dorotéia Rossi Silva S, Danilo Grünig Humberto dS, Eduardo Alves dA et al : Oxidative stress biomarkers in treatment-responsive and treatment-resistant schizophrenia patients . 2022, 43 (4). V K, R S K, D A J, K R, C P, G M, J M F, A AJPR: The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway . 2020, 72 (3). Ting X, Qiongwei L, Xingguang L, Li T, Zhiren W, Shuping T, Song C, Guigang Y, Huimei A, Fude Y et al : Plasma total antioxidant status and cognitive impairments in first-episode drug-naïve patients with schizophrenia . 2019, 13 (4). Dag K S, Helge R, Ole A A, Håvard BJAN: A five-year follow-up study of antioxidants, oxidative stress and polyunsaturated fatty acids in schizophrenia . 2019, 31 (4). Dariusz J, Michał D, Joanna R, Napoleon W, Kaja Hanna K, Anna Z, Mateusz M, Hanna K-JJJCM: Pro/Antioxidant State as a Potential Biomarker of Schizophrenia . 2021, 10 (18). Chuangye X, Xuhan Y, Liya S, Tianqi Y, Changqun C, Peng W, Jie J, Ying Q, Xiaowen H, Dandan W et al : An investigation of calcium-independent phospholipase A2 (iPLA2) and cytosolic phospholipase A2 (cPLA2) in schizophrenia . 2019, 273 (0). Rashmi S, Zaffar A, Leena S, Rupesh K SJRPBP: Neuronal Nitric Oxide Synthase (nNOS) in Neutrophils: An Insight . 2021, 180 (0). Minutolo G, Petralia A, Dipasquale S, Aguglia EJEoop: Nitric oxide in patients with schizophrenia: the relationship with the severity of illness and the antipsychotic treatment . 2012, 13 (14):1989-1997. RanPiao G, YuanQiao Z, GuiSen W, JiaHui Z, YeGang H, LiHua X, YanYan W, XiaoChen T, XiaoHua L, HaiChun L et al : Replication of the abnormal niacin response in first episode psychosis measured using laser Doppler flowmeter . 2022, 14 (4). Kyoung-Sae N, Han-Yong J, Yong-Ku KJPNBP: The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia . 2012, 48 (0). Oliver D R, Nieves G C, Rickinder S, Michael B, Seetal DJEIP: Putative neuroprotective pharmacotherapies to target the staged progression of mental illness . 2019, 13 (5). Evangelia Eirini T, Anja PI, Vita DJA: Alcohol-Induced Oxidative Stress and the Role of Antioxidants in Alcohol Use Disorder: A Systematic Review . 2022, 11 (7). Samskruthi M, Sahithi MJBS: Regulation of Reactive Oxygen Species-Mediated Damage in the Pathogenesis of Schizophrenia . 2020, 10 (10). Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial.docx Cite Share Download PDF Status: Published Journal Publication published 17 Nov, 2025 Read the published version in BMC Psychiatry → Version 1 posted Editorial decision: Revision requested 18 Aug, 2025 Reviews received at journal 07 Aug, 2025 Reviews received at journal 24 Jul, 2025 Reviewers agreed at journal 19 Jul, 2025 Reviewers agreed at journal 16 Jul, 2025 Reviewers agreed at journal 15 Jul, 2025 Reviewers agreed at journal 14 Jul, 2025 Reviewers invited by journal 29 Jun, 2025 Editor assigned by journal 23 Jun, 2025 Submission checks completed at journal 22 Jun, 2025 First submitted to journal 22 Jun, 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. 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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-6906160","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":478734913,"identity":"62c21e1d-dff9-457e-9c56-95491709e339","order_by":0,"name":"Man Yang","email":"","orcid":"","institution":"The Fourth People ’ s Hospital of Lianyungang, The Affiliated KangDa College of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Man","middleName":"","lastName":"Yang","suffix":""},{"id":478734914,"identity":"2e0599b8-c513-4be8-b8ae-3422ba5cc60c","order_by":1,"name":"Qing Tian","email":"","orcid":"","institution":"Institute of Mental Health, The Affiliated Guangji Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Qing","middleName":"","lastName":"Tian","suffix":""},{"id":478734915,"identity":"88046eb8-c264-4432-ac83-8c8f1ad82cfe","order_by":2,"name":"Xue Yuan","email":"","orcid":"","institution":"The Fourth People ’ s Hospital of Lianyungang, The Affiliated KangDa College of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xue","middleName":"","lastName":"Yuan","suffix":""},{"id":478734916,"identity":"8771ecf2-cec3-4ea6-bf32-eabefb303ac2","order_by":3,"name":"Dongliang Liu","email":"","orcid":"","institution":"The Fourth People ’ s Hospital of Lianyungang, The Affiliated KangDa College of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Dongliang","middleName":"","lastName":"Liu","suffix":""},{"id":478734917,"identity":"8775431c-46e2-4048-a368-fc4ddad8fe06","order_by":4,"name":"Qiang Shi","email":"","orcid":"","institution":"The Fourth People ’ s Hospital of Lianyungang, The Affiliated KangDa College of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qiang","middleName":"","lastName":"Shi","suffix":""},{"id":478734918,"identity":"9bc1c4f8-6fe6-4c05-b84f-bb5cdc06dd00","order_by":5,"name":"Haidong Yang","email":"","orcid":"","institution":"The Fourth People ’ s Hospital of Lianyungang, The Affiliated KangDa College of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Haidong","middleName":"","lastName":"Yang","suffix":""},{"id":478734919,"identity":"b5bda032-a308-4693-897d-d19d86348598","order_by":6,"name":"Xiaobin B. Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYDACCRgpwdjA8MHAxo40LYwzCtKSidUCYTDzfDgEtIsAkJ/d/Ozh1zYLeX7p5tbNNgYHmBnYDx/dgE8L45xj5sYyZyQMZ8452HY7x+AOHwNPWtoNfFqYJRLMpCUqJBg33EgEaXnGzCDBY4ZXC5tE+jdpCQMJe7AWC4PDjA2EtPBI5JhJfqiQSARrYSBGi4RETpk0wxmJZJBfbvYYpCWzEfKL/Iz0bZI/2+ps+6Xbn9348cfGjp/98DG8WkCAmQfFd4SUgwDjD2JUjYJRMApGwcgFAKG5SbW4k6SEAAAAAElFTkSuQmCC","orcid":"","institution":"Institute of Mental Health, The Affiliated Guangji Hospital of Soochow University","correspondingAuthor":true,"prefix":"","firstName":"Xiaobin","middleName":"B.","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-06-16 13:38:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6906160/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6906160/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12888-025-07560-2","type":"published","date":"2025-11-17T15:58:42+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85918064,"identity":"011ade9d-41f5-44d2-a8b5-3bb9758340a2","added_by":"auto","created_at":"2025-07-03 07:19:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":44973,"visible":true,"origin":"","legend":"\u003cp\u003eDifferences in TAC activity among low-response groups, high-response groups and the control groups.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6906160/v1/86a2c9ce1c3a068ba74c1175.png"},{"id":85918065,"identity":"53f889ec-0c1c-4e41-a7c0-a9ac7003e27d","added_by":"auto","created_at":"2025-07-03 07:19:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":32811,"visible":true,"origin":"","legend":"\u003cp\u003eRelationship between NO levels and PANSS positive subscores among patients.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6906160/v1/13f104dd62dd2c53b742a14a.png"},{"id":96650206,"identity":"a4012af1-dcd2-4f8f-b2eb-e4e4c5bf3e1f","added_by":"auto","created_at":"2025-11-24 16:09:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2828905,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6906160/v1/172496e8-9eed-428d-be41-7c9aede683c7.pdf"},{"id":85917566,"identity":"5af9d25c-0a6b-4462-b65b-9246cbd66dbc","added_by":"auto","created_at":"2025-07-03 07:11:04","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":17985,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-6906160/v1/091d6750e79ed507f8e73a5d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Correlations of Oxidative Stress Markers with Niacin Sensitivity in Male Patients with Chronic Schizophrenia","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eSchizophrenia is a severe and debilitating mental disorder characterized by persistent positive symptoms (e.g., hallucinations, delusions, disorganized thoughts, and speech), negative symptoms (e.g., anhedonia, apathy, and social withdrawal), and cognitive symptoms (inattention, impaired working memory, and dysfunctional executive functions), which affect thoughts, intelligence, and ability to plan [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Emerging evidence suggests that oxidative stress (OS), an imbalance between the production of reactive oxygen species (ROS) and the body\u0026rsquo;s ability to detoxify these harmful byproducts or repair the resulting damage, plays a critical role in the pathophysiology of schizophrenia[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Previous studies have shown that, compared to healthy controls, patients with schizophrenia exhibit reduced sensitivity to niacin [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], which has been associated with abnormal inflammatory responses[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], dysregulated OS, and disrupted fatty acid metabolism [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Niacin (vitamin B3) is reported to reduce OS and modulate inflammatory pathways, thereby offering potential therapeutic benefits for psychiatric disorders [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOS is a normal and complex physiological process involving the production and neutralization of ROS and reactive nitrogen species[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Notably, nitric oxide (NO), a gaseous neurotransmitter, is associated with OS and the production of ROS [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], while catalase, superoxide dismutase, malondialdehyde, glutathione peroxidase, nitric oxide synthase (NOS), and total antioxidant capacity (TAC) are important parameters of physiological functions[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This redox balance is maintained by both antioxidant enzymes and non-enzymatic antioxidants, such as vitamin C and vitamin E (VE) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Constitutive nitric oxide synthase (cNOS), which synthesizes NO, is involved in neuronal development and synaptic formation. An overabundance of NO may contribute to neuronal degeneration in the central nervous system[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Inducible nitric oxide synthase (iNOS) plays an essential role in inflammatory processes during damage or infectious impairment of tissues, and NO, generated by iNOS, is involved in pathogenesis of Alzheimer\u0026rsquo;s diseases, septic shock, multiple sclerosis, and brain ischemia[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile the relationship between OS and schizophrenia has been extensively studied, the interplay between OS markers and niacin sensitivity remains poorly understood, particularly in male patients with chronic schizophrenia[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Since males are often more severely affected by schizophrenia, with earlier onset and poorer outcomes, this population is particularly useful to clarify the correlation between OS and niacin sensitivity to provide valuable insights into the biological mechanisms underlying schizophrenia for the development of personalized therapeutic strategies.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Participant recruitment and ethical approval\u003c/h2\u003e \u003cp\u003eThe cohort of this cross-sectional study included 80 male chronic schizophrenia patients hospitalized from January to October 2020 at the Lianyungang Psychiatric Hospital Group (including Lianyungang Fourth People's Hospital, Ganyu District Rehabilitation Hospital, Donghai County Psychiatric Hospital, and Guanyun County Psychiatric Hospital) and 40 healthy individuals matched for age, sex, body mass index (BMI), smoking status, and education level as a control group. The inclusion criteria were (1) meeting the Diagnostic and Statistical Manual for Mental Disorders (DSM-V) for schizophrenia, (2) age between 20 and 60 years, (3) Han nationality, (4) diagnosis of schizophrenia of at least 5 years, with stable condition, and (5) consistent dosage of antipsychotic medication for at least 1 year. The exclusion criteria were (1) any severe physical disease, (2) use of non-steroidal anti-inflammatory drugs within the past 10 days, (3) any neurological disease, (4) history of mental illness or substance abuse, and (5) family history of mental illness.\u003c/p\u003e \u003cp\u003e The study protocol was approved by the Ethics Committee of the Fourth People\u0026rsquo;s Hospital of Lianyungang, and written informed consent was obtained from all participants or their legal guardians. All procedures were conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Collection of Demographic and Clinical Data\u003c/h2\u003e \u003cp\u003eA self-made demographic statistical table was used to collect the names, sex, age, smoking status, education levels, height, weight, and BMI of all study participants. For the patient group, additional data collected included age at onset, duration of illness, and medication details, with all medication dosages converted to chlorpromazine equivalent doses.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Assessment of Clinical Symptom Severity\u003c/h2\u003e \u003cp\u003eThe Positive and Negative Syndrome Scale (PANSS) was utilized to assess the severity of clinical symptoms in the patient group. The PANSS is widely used to measure the severity of psychiatric symptoms in adult schizophrenia patients and includes three independent subscales (Positive, Negative, and General Psychopathology), consisting of 30 items. Each item is scored on a scale from 1 to 7, with the total score ranging from 30 to 210. Higher scores on the PANSS and subscales indicate more severe psychiatric symptoms[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Hematological Indices\u003c/h2\u003e \u003cp\u003eBlood indices measured included NO, total nitric oxide synthase (TNOS), cNOS, iNOS, TAC, and VE. Venous blood samples were collected from participants in the morning after fasting into anticoagulant tubes, centrifuged at 3000 rpm for 15 min, and analyzed by Nanjing Jiancheng Biological Engineering Institute (Nanjing, China).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Measurement of Skin Niacin Sensitivity\u003c/h2\u003e \u003cp\u003e Filter paper discs (diameter, 0.9 cm) immersed in four different concentrations of niacin solution (0.0001, 0.001, 0.01, and 0.1 mol/L) were applied to the participants\u0026rsquo; forearm up to the elbow in ascending order of concentration and held in place for 1 min. After removal, the erythema response of the skin was observed and recorded at 5, 10, 15, and 20 min, along with photographic documentation. The erythema response of the skin was scored as follows: 0\u0026thinsp;=\u0026thinsp;no reaction; 1\u0026thinsp;=\u0026thinsp;partial skin erythema; 2\u0026thinsp;=\u0026thinsp;complete coverage of the filter paper area by erythema; and 3\u0026thinsp;=\u0026thinsp;erythema exceeding the filter paper[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The niacin scores obtained at different concentrations and times were summed for a total score. The standard to evaluate the strength of the niacin response was a niacin solution concentration of 0.01 mol/L and 10 min. A score of 0 or 1 was considered a low niacin response, while a sore of 2 or 3 was defined as a high niacin response[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical Analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using IBM SPSS Statistics for Windows (version 22.0; IBM Corporation, Armonk, NY, USA). The normality of the data was determined using Q-Q plots, the Kolmogorov-Smirnov test, and the Shapiro-Wilk test. Normally distributed measurement data are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. The independent samples \u003cem\u003et\u003c/em\u003e-test was used for comparisons between two groups, while analysis of variance was used for comparisons among multiple groups, followed by post hoc pairwise comparisons. Bonferroni correction was applied to adjust for multiple comparisons. For non-normally distributed measurement data, the Mann\u0026ndash;Whitney U test was used for comparisons between two groups and the results are expressed as the median and interquartile range. Categorical data were compared between groups using the \u003cem\u003eχ\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e test and are presented as the frequency and percentage. Pearson correlation analysis was used to assess correlations of TNOS, iNOS, cNOS, TAC, and VE with the total PANSS score and the scores of each subscale. Bonferroni correction was applied to adjust for multiple testing. For example, the Bonferroni corrected probability (\u003cem\u003ep\u003c/em\u003e) value for each PANSS score was calculated as the original \u003cem\u003ep\u003c/em\u003e-value*4. Furthermore, binary logistic regression analysis was employed to identify factors affecting the skin response to niacin. A two-tailed \u003cem\u003ep-\u003c/em\u003evalue\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Comparisons of demographic, clinical characteristics, and skin niacin reaction scores between patients and healthy controls\u003c/h2\u003e \u003cp\u003eThe demographic and clinical characteristics of the patient and control groups are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. There were no significant differences in age (\u003cem\u003et\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.905, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.364), education level (\u003cem\u003et\u003c/em\u003e = -1.301, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.196), BMI (\u003cem\u003et\u003c/em\u003e = -1.531, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.128), or smoking status (\u003cem\u003eχ\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;2.046, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.121), indicating that the two groups were well matched. In the patient group, the average age at onset was 26.86\u0026thinsp;\u0026plusmn;\u0026thinsp;8.68 years, the average duration of illness was 13.75\u0026thinsp;\u0026plusmn;\u0026thinsp;8.01 years, and the average dose of CPZ equivalent administered was 687.14\u0026thinsp;\u0026plusmn;\u0026thinsp;312.24 mg/day. Compared to the control group, the skin niacin response score (0.01 mmol/L, 10 min) was significantly lower in the patient group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and clinical characteristics of male patients with chronic schizophrenia and healthy controls\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients(n\u0026thinsp;=\u0026thinsp;80)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControls (n\u0026thinsp;=\u0026thinsp;40)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003et/Z/χ\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40.63 \u0026plusmn; 9.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39.0 \u0026plusmn; 7.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.905 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.364\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEducation (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.95 \u0026plusmn; 3.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.68 \u0026plusmn; 2.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-1.301 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.196\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI(kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.51 \u0026plusmn; 3.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.51 \u0026plusmn; 2.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-1.531 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.128\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (52.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.046 \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.121\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease Duration (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.75 \u0026plusmn; 8.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge of Onset (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.86 \u0026plusmn; 8.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCPZ equivalent Dose (mg/d)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e687.14 \u0026plusmn; 312.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePANSS P\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.03 \u0026plusmn; 4.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePANSS N\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17.83 \u0026plusmn; 7.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePANSS G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.24 \u0026plusmn; 6.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePANSS T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58.09 \u0026plusmn; 14.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin Niacin Reaction Score [0.01mmol/L, 10min ;M(P25, P75 )]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1, 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2, 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-6.554 \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBMI, body mass index; CPZ, chlorpromazine; PANSS, Positive and Negative Syndrome Scale\u003c/p\u003e \u003cp\u003e \u003csup\u003ea\u003c/sup\u003e means independent samples t-test.\u003c/p\u003e \u003cp\u003e \u003csup\u003eb\u003c/sup\u003e means \u003cem\u003eχ\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e test.\u003c/p\u003e \u003cp\u003e \u003csup\u003ec\u003c/sup\u003e means Mann-Whitney U test\u003c/p\u003e \u003cp\u003e \u003cb\u003e3.2. Comparisons of plasma NO, TNOS, iNOS, cNOS, and VE levels, and TAC activity between the patient and healthy control groups\u003c/b\u003e \u003c/p\u003e \u003cp\u003eOS levels in blood samples from the patient and healthy control groups are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Analysis of covariance (ANCOVA), controlling for age, education level, BMI, and smoking status, revealed significantly lower serum levels of TNOS, iNOS, cNOS, and VE, and TAC activity in the patient group relative to the healthy control group.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOxidative stress levels of schizophrenia patients and healthy controls\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients(n\u0026thinsp;=\u0026thinsp;80)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControls (n\u0026thinsp;=\u0026thinsp;40)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eF\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO(\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e56.49 \u0026plusmn; 14.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e61.62 \u0026plusmn; 20.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.561 \u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.214\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNOS(U/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.99 \u0026plusmn; 0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3.90 \u0026plusmn; 0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15.713 \u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eiNOS(U/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.64 \u0026plusmn; 0.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e2.03 \u0026plusmn; 0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.225 \u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecNOS(U/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.35 \u0026plusmn; 0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.87 \u0026plusmn; 0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19.547 \u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTAC(\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e682.62 \u0026plusmn; 125.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e803.14 \u0026plusmn; 114.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23.414 \u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVE (\u0026micro;g/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.28\u0026thinsp;\u0026plusmn;\u0026thinsp;3.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.28\u0026thinsp;\u0026plusmn;\u0026thinsp;5.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.824 \u003csup\u003eab\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNO, nitric oxide; TNOS, total nitric oxide synthase; iNOS, inducible nitric oxide synthase; cNOS, constitutive nitric oxide synthase; TAC, total antioxidant capacity; VE, vitamin E;\u003c/p\u003e \u003cp\u003e \u003csup\u003ea\u003c/sup\u003e means independentsamplest-test.\u003c/p\u003e \u003cp\u003e \u003csup\u003eb\u003c/sup\u003e means after controlling for age, education, BMI, smoking status, the difference in OS markers still remained significant.\u003c/p\u003e \u003cp\u003e \u003cb\u003e3.3. Comparison of general demographic and clinical data between the nicotinic acid high-response group, low-response group, and healthy control group\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe low response group included 36 patients, while the high response group consisted of 44 patients. There were significant differences in TNOS, iNOS, cNOS, and VE levels, as well as TAC activity among the low-response group, high-response group, and control group (all, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), but not in age, education level, BMI, smoking status, NO level, chlorpromazine equivalent dose, disease duration, or age of onset among the three groups (all, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Following Bonferroni correction, statistically significant differences were observed in the low-response group compared to the healthy control group across multiple OS markers: specifically, TNOS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), iNOS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01), cNOS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and VE levels (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In contrast, no significant differences were detected in chlorpromazine equivalent dose, disease duration, or age at onset (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Similarly, comparisons between the high-response group and the healthy control group revealed significant differences in TNOS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), iNOS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021), cNOS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and VE (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01) after Bonferroni adjustment. These findings underscore the distinct oxidative stress profiles associated with varying treatment response levels, independent of common confounding factors such as medication dosage or illness duration. The independent samples \u003cem\u003et\u003c/em\u003e-test showed no significant differences in the PANSS total score or subscale scores between the low- and high-response groups (all, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Additionally, pairwise comparisons showed significant differences: TAC low-response vs. high-response group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), low-response vs. control group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and high-response vs. control group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013) (\u003cb\u003eFigure.1\u003c/b\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of general demographic and clinical characteristics among the niacin low-response group, high-response group, and control group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow-response group(n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHigh- response group (n\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControls(n\u0026thinsp;=\u0026thinsp;40)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eF\u003c/em\u003e/\u003cem\u003eχ\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42.39\u0026thinsp;\u0026plusmn;\u0026thinsp;9.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39.18\u0026thinsp;\u0026plusmn;\u0026thinsp;9.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.633\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.200\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEducation (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.03\u0026thinsp;\u0026plusmn;\u0026thinsp;3.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.89\u0026thinsp;\u0026plusmn;\u0026thinsp;3.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.68\u0026thinsp;\u0026plusmn;\u0026thinsp;2.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.864\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.424\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.24\u0026thinsp;\u0026plusmn;\u0026thinsp;3.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.51\u0026thinsp;\u0026plusmn;\u0026thinsp;2.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.122\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (52.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (52.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.287\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCPZ equivalent Dose (mg/d)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e731.78\u0026thinsp;\u0026plusmn;\u0026thinsp;336.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e650.61\u0026thinsp;\u0026plusmn;\u0026thinsp;289.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.277\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.250\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease Duration (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.45\u0026thinsp;\u0026plusmn;\u0026thinsp;8.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.76\u0026thinsp;\u0026plusmn;\u0026thinsp;7.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.861\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.356\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAgecOnset (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.19\u0026thinsp;\u0026plusmn;\u0026thinsp;9.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.39\u0026thinsp;\u0026plusmn;\u0026thinsp;7.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.162\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.688\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePANSS-P\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.91\u0026thinsp;\u0026plusmn;\u0026thinsp;4.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.18\u0026thinsp;\u0026plusmn;\u0026thinsp;4.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.798\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePANSS-N\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17.81\u0026thinsp;\u0026plusmn;\u0026thinsp;7.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.85\u0026thinsp;\u0026plusmn;\u0026thinsp;7.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.981\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePANSS-G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.15\u0026thinsp;\u0026plusmn;\u0026thinsp;6.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.36\u0026thinsp;\u0026plusmn;\u0026thinsp;6.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.883\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePANSS-T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57.87\u0026thinsp;\u0026plusmn;\u0026thinsp;14.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58.39\u0026thinsp;\u0026plusmn;\u0026thinsp;15.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.879\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO(\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54.85\u0026thinsp;\u0026plusmn;\u0026thinsp;14.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57.8\u0026thinsp;\u0026plusmn;\u0026thinsp;14.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61.62\u0026thinsp;\u0026plusmn;\u0026thinsp;20.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.561\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.214\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNOS(U/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.85\u0026thinsp;\u0026plusmn;\u0026thinsp;0.76\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.86\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e15.713\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eiNOS(U/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.53\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003csup\u003eh\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.225\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecNOS(U/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.37\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.44\u003csup\u003ei\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e19.547\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTAC(\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e746.89\u0026thinsp;\u0026plusmn;\u0026thinsp;115.83\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e591.09\u0026thinsp;\u0026plusmn;\u0026thinsp;69.43 \u003csup\u003eak\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e803.14\u0026thinsp;\u0026plusmn;\u0026thinsp;114.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e23.414\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVE(\u0026micro;g/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.92\u0026thinsp;\u0026plusmn;\u0026thinsp;4.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.79\u0026thinsp;\u0026plusmn;\u0026thinsp;3.23\u003csup\u003ej\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.28\u0026thinsp;\u0026plusmn;\u0026thinsp;5.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11.824\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCompared with the low - response group, \u003csup\u003ea\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001, \u003csup\u003eb\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001, \u003csup\u003ec\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e = 0.01, \u003csup\u003ed\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001, \u003csup\u003ee\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001, \u003csup\u003ef\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001; Compared with the control group, \u003csup\u003eg\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001, \u003csup\u003eh\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e = 0.021, \u003csup\u003ei\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001, \u003csup\u003ej\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e = 0.01, \u003csup\u003ek\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e = 0.013; CPZ, chlorpromazine;NO, nitric oxide; TNOS, total nitric oxide synthase; iNOS, inducible nitric oxide synthase; cNOS, constitutive nitric oxide synthase; TAC, total antioxidant capacity; VE, vitamin E; PANSS-P, PANSS positive subscale score; PANSS-N, PANSS negative subscale score; PANSS-G, general psychopathology subscale score; PANSS T, PANSS total scores.\u003c/p\u003e \u003cp\u003e \u003csup\u003ea\u003c/sup\u003e means one-way of analysis of variance; \u003csup\u003eb\u003c/sup\u003e means \u003cem\u003eχ\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e test;\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Correlation of OS markers with clinical symptoms in schizophrenia patients\u003c/h2\u003e \u003cp\u003eOther than NO levels, there was no significant correlation of the OS indices and the total PANSS or subscale scores (all, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Notably, serum NO was positively associated with the PANSS subscale scores (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.370, Bonferroni corrected \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004; Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Further stepwise multiple regression analysis with age, education level, smoking status, BMI, age of onset, dose of antipsychotic treatment, duration of illness, and OS markers as covariates found that NO (\u003cem\u003eβ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.370, \u003cem\u003et\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.513, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) influenced the total PANSS score (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRelationships between oxidative stress markers and psychotic symptom in patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP subscores\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN subscores\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG subscoresc\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePANSS total score\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNO (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.370\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.275\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.274\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.014*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.420\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.014*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.004*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.680\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNOS (U/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.175\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.162\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.543\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.152\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.472\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.484\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.172\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.608\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eiNOS (U/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.155\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.126\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.201\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.170\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.774\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.265\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.804\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.096\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecNOS (U/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.188\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.055\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.162\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.096\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.626\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.150\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.428\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.384\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.504\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.600\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTAC (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.043\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.137\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.070\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.708\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.227\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.280\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.832\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.204\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.908\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVE (\u0026micro;g/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.088\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.120\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.552\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.237\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.437\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.288\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.948\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.748\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.152\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003ea\u003c/sup\u003e means Spearman product moment.\u003c/p\u003e \u003cp\u003e \u003csup\u003eb\u003c/sup\u003e means Bonferroni correction was applied in the associations between biomarkers and\u003c/p\u003e \u003cp\u003epsychotics symptoms.\u003c/p\u003e \u003cp\u003e* means \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Risk factors for skin niacin reaction in male patients with chronic schizophrenia\u003c/h2\u003e \u003cp\u003eUsing the skin niacin response (assigned as a binary variable, with the low-response group assigned a value of 1 and the high-response group assigned a value of 0) as the dependent variable, logistic regression analysis was conducted with TAC as the independent variable. Additionally, age, education level, BMI, smoking status, disease duration, age of onset, and chlorpromazine equivalent dose were included in the analysis. The results showed that TAC is a risk factor for the skin niacin response in male patients with chronic schizophrenia (\u003cem\u003eβ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008, standard error\u0026thinsp;=\u0026thinsp;0.004, Wald \u003cem\u003eχ\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;5.230, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022, odds ratio\u0026thinsp;=\u0026thinsp;1.009 [95% confidence interval: 1.001\u0026ndash;1.016]).\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study investigated differences in demographics, clinical characteristics, and skin niacin reaction scores between chronic schizophrenia patients and healthy controls, while also exploring the correlations of OS markers with clinical symptoms. The findings revealed several important insights that contribute to a deeper understanding of the pathophysiological mechanisms underlying schizophrenia: (1) Compared to the healthy controls, serum levels of TNOS, iNOS, cNOS, and VE, as well as TAC activity, were significantly lower in schizophrenia patients receiving psychotropic agents and chronic schizophrenia patients; (2) skin niacin reactivity scores were markedly lower in the patient group as compared to the healthy control group; (3) Plasma NO levels were positively correlated with clinical symptoms; (4) There were significant differences in TNOS, iNOS, cNOS, and VE levels, as well as TAC activity, between the low- and high-response groups as compared to the healthy control group; and (5) In male patients with chronic schizophrenia, plasma CTA activity was identified as a risk factor for the skin niacin response after adjusting for covariates (i.e., age, education level, age of onset, duration of psychosis, and chlorpromazine equivalent dose).\u003c/p\u003e \u003cp\u003eRegarding OS markers, serum levels of TNOS, iNOS, and cNOS were significantly lower in the patient group than the healthy control group, suggesting that chronic schizophrenia patients may experience dysfunction of the OS system, which could be linked to the pathophysiological processes of the disorder. Previous studies have found that NOS levels are reduced in the cerebrospinal fluid and post-mortem brain tissue of schizophrenia patients[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and animal models (Walton et al.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Genetic studies have demonstrated that single nucleotide polymorphisms of NOS-related genes are closely associated with the onset of schizophrenia[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Yang et al.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] reported that asymmetric dimethylarginine, an endogenous inhibitor of NOS, is increased in schizophrenia patients, suggesting that NOS activity is suppressed in these individuals. Additionally, serum levels of iNOS are reportedly significantly lower in schizophrenia patients as compared to healthy controls (Peng et al., 2022), consistent with the findings of the present study. Preliminary research suggests that chronic medication use in schizophrenia patients may lead to an imbalance in redox reactions[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In response to inflammatory diseases, iNOS concentrations in the peripheral blood and brain tend to simultaneously increase[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Further mechanistic studies suggest that the release of cytokines and neurotransmitters may play a significant role in coordinating NOS concentrations in the peripheral blood and brain[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Collectively, these findings indicate that OS is involved in the pathophysiology of schizophrenia. As the primary enzyme responsible for the synthesis of NO, reduced activity of NOS may affect neurotransmitter systems, synaptic plasticity, and neuroinflammation, while iNOS, which is primarily expressed in immune cells, is closely associated with inflammatory responses [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Suppression of NOS activity may weaken the body's antioxidant defense system, further exacerbating OS. Furthermore, changes to NOS activity may also involve regulation of the immune system and chronic inflammation, which are considered important pathological features of schizophrenia[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Although TNOS, iNOS, and cNOS levels were significantly lower in chronic schizophrenia patients than in healthy controls, NO levels showed no significant difference between the two groups. This may be attributed to compensatory mechanisms in the body. For example, previous studies have shown that NO production in schizophrenia patients may be maintained through non-NOS-dependent nitrate reduction pathways [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Additionally, enhanced NO utilization efficiency or clearance capacity may offset the decrease in synthase activity, thereby masking potential NOS functional abnormalities. These compensatory mechanisms may play a role in maintaining the basic level of NO, but the underlying abnormal NOS function and its impact on neurotransmission and neuroinflammation in schizophrenia still need further exploration.\u003c/p\u003e \u003cp\u003eSpecifically, in accordance with many recent studies, reduced VE levels and TAC activity indicate impaired total antioxidant capacity, potentially leading to increased OS [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Hence, oxidative imbalance may contribute to neuronal damage and progression of schizophrenia symptoms[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Notably, certain antipsychotic medications may influence TAC activity and VE metabolism, potentially altering serum levels. The combined effects of these factors could weaken the antioxidant defense system, thereby exacerbating the symptoms of schizophrenia and promoting disease progression. Consequently, in clinical practice, it is crucial to closely monitor the impact of these medications on the patient's antioxidant status and implement appropriate interventions to maintain redox balance.\u003c/p\u003e \u003cp\u003eThe skin niacin reaction scores were significantly lower in the patient group as compared to the healthy controls, suggesting that the skin niacin response may serve as a potential biomarker for schizophrenia. This finding aligns with previous research indicating that an impaired skin niacin response is a common feature in schizophrenia patients, possibly reflecting underlying abnormalities in inflammatory or OS pathways[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurther analysis revealed significant differences in TNOS, iNOS, cNOS, TAC, and VE levels between the low and high skin niacin response groups, while no significant differences were observed in other clinical characteristics, suggesting that OS markers may be associated with variations in the skin niacin response, independent of other clinical features. The distinct OS profiles between the response groups highlight the potential role of OS in modulating the skin niacin reaction, which could be a reflection of systemic oxidative imbalance in schizophrenia patients. An abnormal skin niacin response suggests a disturbance in the phospholipase A2-arachidonic acid signaling pathway[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Enhanced antioxidant capacity can counteract the effects of OS, thereby influencing pathways associated with the niacin response. The intensity of the skin niacin response, as an external manifestation of OS status, particularly changes to TNOS, iNO, cNOS, and TAC, indicates that an imbalance in the oxidative-antioxidant-inflammatory system may be a key factor in the pathogenesis of schizophrenia.\u003c/p\u003e \u003cp\u003eCorrelation analysis showed a positive association between NO levels and PANSS positive symptom scores, indicating that NO may play a significant role in the positive symptoms of schizophrenia. This finding provides a basis for further research into the role of NO in the pathophysiology of schizophrenia. NO is known to influence dopaminergic and glutamatergic neurotransmission, which are recognized as positive symptoms of schizophrenia[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. An animal study provided evidence that interactions of the NOX and nNOS redox signaling cascades in the brain affect both cognitive function and social behavior of mice (Walton et al.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Moreover, elevated NO levels have been positively correlated with positive symptoms and behavioral abnormalities in schizophrenia patients [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Similarly, in the present study, plasma NO levels were significantly positively correlated with PANSS positive symptom scores in schizophrenia patients. Although NO levels were not abnormal, there were significant alterations to TNOS, iNOS, cNOS, and VE levels, as well as TAC activity, possibly due to compensatory mechanisms, NO utilization efficiency, or clearance rates. These correlations suggest that elevated NO levels may exacerbate positive symptoms, possibly through neurotransmitter systems or neuroinflammatory processes.\u003c/p\u003e \u003cp\u003eFinally, logistic regression analysis identified TAC as a risk factor for the skin niacin response of male patients with chronic schizophrenia. The skin niacin response is an endogenous prostaglandin D2 release reaction that reflects inflammatory status[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Previous studies have reported that abnormal inflammatory responses may be associated with the pathogenesis of schizophrenia [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Reduced antioxidant capacity can lead to elevated OS levels, further exacerbating inflammatory reactions[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Therefore, schizophrenia patients with altered TAC activity may exhibit a more severe inflammatory state, resulting in a weaker skin niacin response. The finding that TAC activity is associated with the skin niacin response underscores the interplay between OS and inflammatory pathways in schizophrenia and raises the possibility that interventions aimed at enhancing antioxidant capacity could modulate the skin niacin response and potentially improve clinical outcomes for schizophrenia patients.\u003c/p\u003e \u003cp\u003eSeveral limitations should be considered when interpreting our findings. First, although we controlled for age, BMI, and smoking status, other lifestyle variables-such as dietary patterns (e.g., VE intake), alcohol consumption history, and sleep quality-were not assessed which significantly influence OS markers. For instance, plasma VE levels are closely linked to dietary intake; group differences in antioxidant nutrient consumption could confound interpretations of \"disease-related antioxidant deficits\" versus \"nutritional influences.\" Chronic alcohol consumption modulates key OS markers-including antioxidant capacity and NO pathways-through enhanced ROS generation and glutathione depletion, potentially confounding disease-associated oxidative profiles[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Second, while we identified correlations between TAC and impaired niacin sensitivity, the temporal relationship remains unresolved: it is unclear whether OS drives niacin hyporesponsiveness, or vice versa. Longitudinal tracking of OS markers and niacin responses is needed to establish directionality. Third, while chlorpromazine-equivalent dosing was covaried, OS modulation by antipsychotics may vary across drug classes—notably with clozapine due to its distinct pharmacology—potentially confounding results independent of disease processes[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Fourth, the exclusive focus on male, chronic, medicated, and ethnically Han Chinese patients limits extrapolation to broader schizophrenia populations. Findings may not apply to females (where hormonal influences could alter OS/niacin responses), acute-phase patients, or other ethnic groups. Replication in diverse cohorts is essential.\u003c/p\u003e "},{"header":"Conclusion","content":"\u003cp\u003eTaken together, these findings underscore the critical role of OS markers, particularly TAC activity and NO levels, in chronic schizophrenia and offer new insights into the pathophysiological mechanisms of schizophrenia to develop novel therapeutic strategies. The association between OS and the skin niacin response suggests that oxidative imbalance may be a key factor underlying the impaired niacin response observed in schizophrenia patients. However, further research is necessary to validate these findings and explore potential applications in clinical practice. Longitudinal studies could help determine whether OS markers and the skin niacin response are predictive of disease progression or treatment response, while intervention studies could assess the efficacy of antioxidant therapies to improve clinical symptoms and the skin niacin response in schizophrenia patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe would like to thank all patients who participated in the study. We are grateful to all the psychiatrists and nurses who participated in our current study and those research staff that contributed to the subjects\u0026apos; diagnosis and clinical assessments.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. Xiaobin Zhang, Haidong Yang, Man Yang and Qing Tian were responsible for study design, statistical analysis and writing of the manuscript. Qiang Shi was responsible for laboratorial analysis. Dongliang Liu and Xue Yuan were responsible for recruiting the patients, performing the clinical rating and collecting the samples. All authors have contributed to and have approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Declaration\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was supported by grants from Medical scientific research project of the Suzhou clinical Medical Center for mood disorders (No. Szlcyxzx202109), Suzhou Key Laboratory (SZS2024016), Multicenter Clinical Research on Major Diseases in Suzhou (DZXYJ202413), Lianyungang Science and Technology Bureau of Social Development Key R\u0026amp;D Projects (SF2319) and Youth Science and Technology Project of Lianyungang Municipal Health Commission (QN202310). The finding sources of this study had no role in study design, data collection and analysis, decision to publish, or preparation of the article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations Ethics approval and consent to participate\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Institutional Review Committee of Lianyungang Fourth People\u0026apos;s Hospital (approval NO. 2019LSYYXLL-P06) and conducted in accordance with the ethical principles for medical research involving human subjects described in the Declaration of Helsinki. Prior to inclusion in this study, informed consent was obtained from all participants and/or guardians.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSabrina H AJFP: \u003cstrong\u003eInflammation and JNK\u0026apos;s Role in Niacin-GPR109A Diminished Flushed Effect in Microglial and Neuronal Cells With Relevance to Schizophrenia\u003c/strong\u003e. 2021, \u003cstrong\u003e12\u003c/strong\u003e(0).\u003c/li\u003e\n\u003cli\u003eMurray A, Rogers J, Katshu M, Liddle P, Upthegrove RJFip: \u003cstrong\u003eOxidative Stress and the Pathophysiology and Symptom Profile of Schizophrenia Spectrum Disorders\u003c/strong\u003e. 2021, \u003cstrong\u003e12\u003c/strong\u003e:703452.\u003c/li\u003e\n\u003cli\u003eErik MJPLEFA: \u003cstrong\u003eThe niacin response biomarker as a schizophrenia endophenotype: A status update\u003c/strong\u003e. 2017, \u003cstrong\u003e136\u003c/strong\u003e(0).\u003c/li\u003e\n\u003cli\u003eSergej N, Suzana J, Vesna \u0026Scaron;J, Alena B-TJPLEFA: \u003cstrong\u003eAn association between niacin skin flush response and plasma triglyceride levels in patients with schizophrenia\u003c/strong\u003e. 2020, \u003cstrong\u003e155\u003c/strong\u003e(0).\u003c/li\u003e\n\u003cli\u003eMichael B, David C, Olivia D, Kristy L, Sue J, Ian S, Murray A-H, Fiona J, Fiona K, Paul K\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eN-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial\u003c/strong\u003e. 2008, \u003cstrong\u003e64\u003c/strong\u003e(5).\u003c/li\u003e\n\u003cli\u003eMoylan S, Berk M, Dean O, Samuni Y, Williams L, O\u0026apos;Neil A, Hayley A, Pasco J, Anderson G, Jacka F\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eOxidative \u0026amp; nitrosative stress in depression: why so much stress?\u003c/strong\u003e 2014, \u003cstrong\u003e45\u003c/strong\u003e:46-62.\u003c/li\u003e\n\u003cli\u003eHaidong Y, Wenxi S, Man Y, Jin L, Jing Z, Xiaobin ZJS: \u003cstrong\u003eVariations to plasma H(2)O(2) levels and TAC in chronical medicated and treatment-resistant male schizophrenia patients: Correlations with psychopathology\u003c/strong\u003e. 2024, \u003cstrong\u003e10\u003c/strong\u003e(1).\u003c/li\u003e\n\u003cli\u003eBernstein H, Bogerts B, Keilhoff GJSr: \u003cstrong\u003eThe many faces of nitric oxide in schizophrenia. 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associated with cognitive deficits in patients with schizophrenia\u003c/strong\u003e. 2016, \u003cstrong\u003e246\u003c/strong\u003e(0).\u003c/li\u003e\n\u003cli\u003eMan Y, Jin L, Haidong Y, Linya Y, Dongliang L, Lin Z, Xiaobin ZJFP: \u003cstrong\u003eCognitive Impairment and Psychopathology Are Related to Plasma Oxidative Stress in Long Term Hospitalized Patients With Chronic Schizophrenia\u003c/strong\u003e. 2022, \u003cstrong\u003e13\u003c/strong\u003e(0).\u003c/li\u003e\n\u003cli\u003eMehdi G, Ali FJNBR: \u003cstrong\u003ePathologic role of glial nitric oxide in adult and pediatric neuroinflammatory diseases\u003c/strong\u003e. 2014, \u003cstrong\u003e45\u003c/strong\u003e(0).\u003c/li\u003e\n\u003cli\u003eRegina F N, Polina V M, Elena E V, Natalya A S, Nataliya L B, Albert A RJIJMS: \u003cstrong\u003eGenetic Factors of Nitric Oxide\u0026apos;s System in Psychoneurologic Disorders\u003c/strong\u003e. 2020, 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phospholipase A2 (cPLA2) in schizophrenia\u003c/strong\u003e. 2019, \u003cstrong\u003e273\u003c/strong\u003e(0).\u003c/li\u003e\n\u003cli\u003eRashmi S, Zaffar A, Leena S, Rupesh K SJRPBP: \u003cstrong\u003eNeuronal Nitric Oxide Synthase (nNOS) in Neutrophils: An Insight\u003c/strong\u003e. 2021, \u003cstrong\u003e180\u003c/strong\u003e(0).\u003c/li\u003e\n\u003cli\u003eMinutolo G, Petralia A, Dipasquale S, Aguglia EJEoop: \u003cstrong\u003eNitric oxide in patients with schizophrenia: the relationship with the severity of illness and the antipsychotic treatment\u003c/strong\u003e. 2012, \u003cstrong\u003e13\u003c/strong\u003e(14):1989-1997.\u003c/li\u003e\n\u003cli\u003eRanPiao G, YuanQiao Z, GuiSen W, JiaHui Z, YeGang H, LiHua X, YanYan W, XiaoChen T, XiaoHua L, HaiChun L\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eReplication of the abnormal niacin response in first episode psychosis measured using laser Doppler flowmeter\u003c/strong\u003e. 2022, \u003cstrong\u003e14\u003c/strong\u003e(4).\u003c/li\u003e\n\u003cli\u003eKyoung-Sae N, Han-Yong J, Yong-Ku KJPNBP: \u003cstrong\u003eThe role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia\u003c/strong\u003e. 2012, \u003cstrong\u003e48\u003c/strong\u003e(0).\u003c/li\u003e\n\u003cli\u003eOliver D R, Nieves G C, Rickinder S, Michael B, Seetal DJEIP: \u003cstrong\u003ePutative neuroprotective pharmacotherapies to target the staged progression of mental illness\u003c/strong\u003e. 2019, \u003cstrong\u003e13\u003c/strong\u003e(5).\u003c/li\u003e\n\u003cli\u003eEvangelia Eirini T, Anja PI, Vita DJA: \u003cstrong\u003eAlcohol-Induced Oxidative Stress and the Role of Antioxidants in Alcohol Use Disorder: A Systematic Review\u003c/strong\u003e. 2022, \u003cstrong\u003e11\u003c/strong\u003e(7).\u003c/li\u003e\n\u003cli\u003eSamskruthi M, Sahithi MJBS: \u003cstrong\u003eRegulation of Reactive Oxygen Species-Mediated Damage in the Pathogenesis of Schizophrenia\u003c/strong\u003e. 2020, \u003cstrong\u003e10\u003c/strong\u003e(10).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"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, oxidative stress, niacin sensitivity, nitric oxide, total antioxidant capacity","lastPublishedDoi":"10.21203/rs.3.rs-6906160/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6906160/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSchizophrenia is a debilitating mental disorder linked to oxidative stress (OS) and inflammatory dysregulation. Emerging evidence suggests impaired niacin sensitivity in schizophrenia patients, potentially reflecting OS and inflammation. This study investigated correlations between OS markers and niacin sensitivity in male chronic schizophrenia patients to elucidate pathophysiological mechanisms and identify biomarkers.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe cohort of this cross-sectional study included 80 male chronic schizophrenia patients and 40 matched healthy controls. Blood samples were collected for analysis of nitric oxide (NO), total nitric oxide synthase (TNOS), inducible nitric oxide synthase (iNOS), constitutive nitric oxide synthase (cNOS), total antioxidant capacity (TAC), and vitamin E (VE). Skin niacin sensitivity was assessed via the erythema response to topical niacin. Clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). Statistical analyses (\u003cem\u003et\u003c/em\u003e-tests, analysis of variance, and logistic regression) were conducted to identify associations.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eTNOS, iNOS, cNOS, TAC, and VE levels were significantly lower in the patient group than in the healthy control group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Reduced skin erythema response in patients (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) was correlated with lower TAC activity and VE levels. Plasma NO levels were positively correlated with PANSS positive symptom scores (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.370, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004). TAC was a significant predictor of an impaired niacin response (OR\u0026thinsp;=\u0026thinsp;1.009, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eChronic schizophrenia is characterized by disrupted redox balance and diminished niacin sensitivity, implicating oxidative-inflammatory crosstalk in disease pathology. A weakened niacin response, associated with antioxidant deficits, may serve as a biomarker of the severity of OS. These findings underscore the potential of antioxidant therapies to modulate clinical outcomes. Further longitudinal studies are needed to validate causal relationships and therapeutic implications.\u003c/p\u003e","manuscriptTitle":"Correlations of Oxidative Stress Markers with Niacin Sensitivity in Male Patients with Chronic Schizophrenia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-03 07:10:59","doi":"10.21203/rs.3.rs-6906160/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-18T16:37:25+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-07T12:04:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-24T14:02:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"215658348589128660133990552522779073330","date":"2025-07-19T07:51:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"245331354702783097453887265656711607514","date":"2025-07-16T10:46:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"62283656150970674397942782153596191361","date":"2025-07-15T17:18:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"212116631727735255599116140251226809303","date":"2025-07-14T06:41:32+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-29T22:59:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-23T12:37:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-22T07:50:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Psychiatry","date":"2025-06-22T07:47:16+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":"e397234b-2e83-4c0b-bc56-14b407f39530","owner":[],"postedDate":"July 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-24T16:04:18+00:00","versionOfRecord":{"articleIdentity":"rs-6906160","link":"https://doi.org/10.1186/s12888-025-07560-2","journal":{"identity":"bmc-psychiatry","isVorOnly":false,"title":"BMC Psychiatry"},"publishedOn":"2025-11-17 15:58:42","publishedOnDateReadable":"November 17th, 2025"},"versionCreatedAt":"2025-07-03 07:10:59","video":"","vorDoi":"10.1186/s12888-025-07560-2","vorDoiUrl":"https://doi.org/10.1186/s12888-025-07560-2","workflowStages":[]},"version":"v1","identity":"rs-6906160","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6906160","identity":"rs-6906160","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}