Immunoinflammatory features and cognitive function in treatment-resistant schizophrenia: unraveling distinct patterns in clozapine-resistant patients.

Patients with treatment-resistant schizophrenia (TRS), particularly those resistant to clozapine (CTRS), pose a clinical challenge due to limited response to standard antipsychotic treatments. Inflammatory factors like tumor necrosis factor-alpha (TNF-α), interleukin 2 (IL-2), and interleukin 6 (IL-6) are implicated in schizophrenia's pathophysiology. Our study examines cognitive function, psychopathological symptoms and inflammatory factors in TRS patients, focusing on differences between CTRS and non-CTRS individuals, as well as healthy controls. A cohort of 115 TRS patients and 84 healthy controls were recruited, assessing IL-2, IL-6 and TNF-α. The Positive and Negative Syndrome Scale (PANSS) was applied to assess psychopathological symptoms, while the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was applied to assess cognitive functioning. CTRS patients showed lower visuospatial constructional score (p = 0.015), higher PANSS scores, higher levels of IL-2 and reduced TNF-α than non-CTRS patients (p < 0.05). Notably, IL-2 was independently associated with psychopathology symptoms in CTRS patients (Beta = 0.268, t = 2.075, p = 0.042), while IL-6 was associated with psychopathology symptoms in non-CTRS patients (Beta = - 0.327, t = - 2.109, p = 0.042). Sex-specific analysis in CTRS patients revealed IL-2 associations with PANSS total and positive symptoms in females, and TNF-α associations with PANSS positive symptoms in males. Furthermore, IL-2, IL-6, and TNF-α displayed potential diagnostic value in TRS patients and CTRS patients (p < 0.05). Clozapine­resistant symptoms represent an independent endophenotype in schizophrenia with distinctive immunoinflammatory characteristics, potentially influenced by sex.

Sex difference in the interrelationship between TNF-α and oxidative stress status in first-episode drug-naïve schizophrenia.

BACKGROUND: Increasing evidence indicates that dysregulated TNF-α and oxidative stress (OxS) contribute to the pathophysiology of schizophrenia. Additionally, previous evidence has demonstrated sex differences in many aspects of schizophrenia including clinical characteristics, cytokines, and OxS markers. However, to the best of our knowledge, there is no study investigating sex differences in the association between TNF-α, the OxS system, and their interaction with clinical symptoms in schizophrenia patients, especially in first-episode drug-naïve (FEDN) patients. METHODS: A total of 119 FEDN schizophrenia patients and 135 healthy controls were recruited for this study. Serum TNF-α, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA) were measured. The Positive and Negative Syndrome Scale (PANSS) was applied to evaluate psychotic symptoms. Two-way ANOVA, partial correlation analysis, and multivariate regression analysis were performed. RESULTS: A sex difference in MDA levels was demonstrated only in healthy controls (F = 7.06, pBonferroni = 0.045) and not seen in patients. Furthermore, only male patients had higher MDA levels than male controls (F = 8.19, pBonferroni = 0.03). Additionally, sex differences were observed in the association of TNF-α and MDA levels with psychotic symptoms (all pBonferroni < 0.05). The interaction of TNF-α and MDA was only associated with general psychopathology symptom in male patients (B = - 0.07, p = 0.02). CONCLUSION: Our results demonstrate the sex difference in the relationship between TNF-α, MDA, and their interaction with psychopathological symptoms of patients with schizophrenia.

Disturbance of Oxidative Stress Parameters in Treatment-Resistant Bipolar Disorder and Their Association With Electroconvulsive Therapy Response.

OBJECTIVE: Electroconvulsive therapy (ECT) is an effective option for treatment-resistant bipolar disorder (trBD). However, the mechanisms of its effect are unknown. Oxidative stress is thought to be involved in the underpinnings of BD. Our study is the first, to our knowledge, to report the association between notable oxidative stress parameters (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], catalase [CAT], and malondialdehyde [MDA]) levels and ECT response in trBD patients. METHODS: A total 28 trBD patients and 49 controls were recruited. Six-week ECT and naturalistic follow-up were conducted. SOD, GSH-Px, CAT, and MDA levels were measured by enzyme-linked immunosorbent assay, and the 17-item Hamilton Depression Rating Scale and Young Mania Rating Scale were administered at baseline and the end of the 6th week. MANCOVA, ANCOVA, 2 × 2 ANCOVA, and a multiple regression model were conducted. RESULTS: SOD levels were lower in both trBD mania and depression (P = .001; P = .001), while GSH-Px (P = .01; P = .001) and MDA (P = .001; P = .001) were higher in both trBD mania and depression compared with controls. CAT levels were positively associated with 17-item Hamilton Depression Rating Scale scores in trBD depression (radjusted = 0.83, P = .005). MDA levels in trBD decreased after 6 weeks of ECT (P = .001). Interestingly, MDA levels decreased in responders (P = .001) but not in nonresponders (P > .05). CONCLUSIONS: Our study indicates that decreased SOD could be a trait rather than a state in trBD. Oxidative stress levels are associated with illness severity and ECT response. This suggests that the mechanism of oxidative stress plays a crucial role in the pathophysiology of trBD.

Association of cytokines levels, psychopathology and cognition among CR-TRS patients with metabolic syndrome.

Clozapine-resistant treatment-refractory schizophrenia (CR-TRS) patients face significant clinical challenges. While links between metabolic syndrome (MetS) and inflammatory cytokines in schizophrenia have been established, the relationship between MetS and cytokine levels in CR-TRS patients remains unexplored. This study aimed to investigate the relationship between cytokines levels, clinical symptoms and cognitive impairments in CR-TRS patients, both with and without MetS. The study included 69 CR-TRS patients (31with MetS and 38 without MetS) and 84 healthy controls. The levels of IL-2, IL-6, TNF-α and routine biochemical parameters were measured. Psychopathological symptoms and cognitive function were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), respectively. We found that CR-TRS patients with MetS displayed lower cognitive function scores compared to those without MetS, even when accounting for potential confounders. TNF-α levels were significantly higher in CRTRS patients with MetS compared to those without MetS, demonstrating substantial pathophysiological potential for CR-TRS patients with MetS via receiver operating characteristic curve (ROC). In CR-TRS patients without MetS, IL-2 independently contributed to the total score and general psychopathology subscore of PANSS. Additionally, IL-6 exhibited an independent contribution to the positive subscore of PANSS. In terms of cognition function, IL-6 independently contributed to the delayed memory of RBANS in CR-TRS patients without MetS. TNF-α could potentially serve as a predictive marker for distinguishing between CR-TRS patients with/without MetS, while IL-2 and IL-6 could independently contribute to psychopathological symptoms or cognitive function in CRTRS patients without MetS. Our study provided insights into the potential interplay between cytokines, clinical symptoms and cognitive impairments in CR-TRS patients with/without MetS.

Reduction of intracortical inhibition (ICI) correlates with cognitive performance and psychopathology symptoms in schizophrenia.

Cognitive impairment is a core symptom of schizophrenia (SZ), with GABAergic dysfunction in the brain potentially serving as a critical pathological mechanism underlying this condition. Intracortical inhibition (ICI), which includes short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI), can be used to assess the inhibitory function of cortical GABAergic neurons. The aim of this study was to investigate the relationship between ICI and cognitive function, as well as psychopathological symptoms, in SZ patients. We recruited 130 SZ patients and 105 healthy controls (HCs). All subjects underwent paired-pulse transcranial magnetic stimulation (ppTMS) measurements, which included resting motor threshold (RMT), SICI and LICI. The cognitive function of all subjects was assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). The psychopathological symptoms of the SZ group were assessed using the Positive and Negative Syndrome Scale (PANSS). We examined group differences in MCCB scores, RMT, SICI, and LICI. Within the SZ group, we assessed the relationship between ICI and cognitive function, as well as psychopathological symptoms. Two-way ANOVA, Mann-Whitney U test, Receiver operating characteristic (ROC) curves, and partial Spearman correlation analysis were performed. The SZ group showed a worse cognitive score in all 6 cognitive dimensions of the MCCB compared to the HC group (all p < 0.05). The SZ group had lower degree of SICI and LICI compared to the HC group (both p < 0.05). ROC curves analysis showed that SICI and LICI all displayed good performance in differentiating SZ patients and HCs (both p < 0.05), and SICI exhibited a better performance, yielding an area under the curve (AUC) of 0.856 (95% CI 0.807-0.904). Furthermore, in the SZ group, SICI demonstrated a significant negative correlation with PANSS positive score, negative score, general psychopathology score, and total score (all pBonferroni < 0.05), and LICI demonstrated a significant negative correlation with PANSS positive score, general psychopathology score and total score (all pBonferroni < 0.05). Additionally, in the SZ group, SICI demonstrated a significant positive correlation with speed of processing score, working memory score, verbal learning score, visual learning score, and reasoning and problem-solving score of the MCCB (all pBonferroni < 0.05), while LICI was only weakly positive correlated with speed of processing score of the MCCB (r = 0.247, p = 0.005, pBonferroni = 0.03). Our results demonstrate that the reduction of ICI could serve as a trait-dependent in-vivo biomarker of GABAergic deficits for SZ and related cognitive impairments.

Adverse childhood experiences in patients with schizophrenia: related factors and clinical implications.

The relationship between adverse childhood experiences (ACEs) and the development of psychotic symptoms is not well understood. Therefore, this study aimed to investigate the frequency and distribution of ACEs among patients with schizophrenia and their potential correlation with symptomatology and personality pathology. We conducted a cross-sectional study involving 571 patients with schizophrenia in Shanghai, China. Symptomatology was assessed using the Positive and Negative Symptoms Scale (PANSS) and personality pathology was assessed using the Personality Diagnostic Questionnaire Fourth Edition Plus (PDQ-4+). ACEs were assessed using the Child Trauma Questionnaire-Short Form (CTQ-SF). ACEs were highly prevalent, with 80.8% of the patients with schizophrenia reporting at least one ACE. The three most common types of ACE were physical neglect (69.8%), emotional neglect (28.2%), and emotional abuse (22.9%). For specific ACE, emotional abuse was significantly associated with PD traits, whereas emotional and physical neglect types of ACE was significantly associated with negative symptoms. A higher level of physical abuse was more commonly reported by men, younger individuals, and those with a higher level of antisocial PD traits. Higher levels of physical neglect were associated with more severe negative symptoms. ACEs are commonly observed in patients with schizophrenia. Therefore, it is strongly recommended that this clinical population be provided with a comprehensive assessment and individualized intervention for those exposed to specific ACEs.

Effectiveness of accelerated intermittent theta burst stimulation for social cognition and negative symptoms among individuals with schizophrenia: A randomized controlled trial.

BACKGROUND: Social cognitive and negative symptoms impairment may increase the risk of mental disability in individuals with schizophrenia. However, randomized controlled studies on the effectiveness of accelerated intermittent theta burst stimulation (iTBS) for social cognition and negative symptoms in individuals with schizophrenia are very limited. METHODS: A total of 125 individuals with schizophrenia were recruited, 66 of whom were randomly divided into an active iTBS group (n=34) and sham iTBS group (n=32) by stratified sampling. Participants received either active iTBS or sham iTBS targeting the left dorsolateral prefrontal cortex (DLPFC) 20 sessions for 4 weeks under navigation. The Facial Emotion Recognition Test (FERT), Hinting Task (HT), and Positive and Negative Syndrome Scale (PANSS) were measured at baseline, 2 weeks, and 4 weeks. The trial protocol was registered with the Chinese Clinical Trial Registry (ChiCTR2100051984). RESULTS: Sixty patients (90.90%) completed the intervention and the 4-week follow-up, including 29 women (43.94%) and 37 men (56.06%) with a mean (SD) age of 47.53 (10.17) years. The primary outcomes showed FERT scores (week 2; 0.27 [95% CI, 0.09 to 0.45]; P< .01; ES 0.14) (week 4; 0.63 [95% CI, 0.45 to 0.80]; P< .001; ES 0.47) and HT scores (week 2; 1.00 [95% CI, -0.02 to 1.98]; P< .05; ES 0.67) (week 4; 2.13 [95% CI, 1.21 to 3.06]; P< .001; ES 0.27) in the active iTBS group were significantly different from those in the sham iTBS group at 2 and 4 weeks of follow-up. The secondary outcome showed that the negative symptom score (-3.43 [95% CI, -4.85 to -2.01]; P< .001; ES 0.29) of the active iTBS group was significantly different from that of the sham iTBS group at the 4th week of follow-up. CONCLUSIONS: Accelerated iTBS can effectively ameliorate the social cognition and negative symptoms of individuals with schizophrenia. These results suggest that accelerated iTBS may be a safe and effective neuromodulation technique to improve the overall functional recovery of individuals with schizophrenia, and has a good clinical application prospect.

Amisulpride augmentation therapy improves cognitive performance and psychopathology in clozapine-resistant treatment-refractory schizophrenia: a 12-week randomized, double-blind, placebo-controlled trial.

BACKGROUND: Although clozapine is an effective option for treatment-resistant schizophrenia (TRS), there are still 1/3 to 1/2 of TRS patients who do not respond to clozapine. The main purpose of this randomized, double-blind, placebo-controlled trial was to explore the amisulpride augmentation efficacy on the psychopathological symptoms and cognitive function of clozapine-resistant treatment-refractory schizophrenia (CTRS) patients. METHODS: A total of 80 patients were recruited and randomly assigned to receive initial clozapine plus amisulpride (amisulpride group) or clozapine plus placebo (placebo group). Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Clinical Global Impression (CGI) scale scores, Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Treatment Emergent Symptom Scale (TESS), laboratory measurements, and electrocardiograms (ECG) were performed at baseline, at week 6, and week 12. RESULTS: Compared with the placebo group, amisulpride group had a lower PANSS total score, positive subscore, and general psychopathology subscore at week 6 and week 12 (PBonferroni < 0.01). Furthermore, compared with the placebo group, the amisulpride group showed an improved RBANS language score at week 12 (PBonferroni < 0.001). Amisulpride group had a higher treatment response rate (P = 0.04), lower scores of CGI severity and CGI efficacy at week 6 and week 12 than placebo group (PBonferroni < 0.05). There were no differences between the groups in body mass index (BMI), corrected QT (QTc) intervals, and laboratory measurements. This study demonstrates that amisulpride augmentation therapy can safely improve the psychiatric symptoms and cognitive performance of CTRS patients. CONCLUSION: This study indicates that amisulpride augmentation therapy has important clinical significance for treating CTRS to improve clinical symptoms and cognitive function with tolerability and safety. Trial registration Clinicaltrials.gov identifier- NCT03652974. Registered August 31, 2018, https://clinicaltrials.gov/ct2/show/NCT03652974.

A Feasibility Study on Smart Mattresses to Improve Sleep Quality.

Good sleep quality is essential, especially for clinical users. Sleep disorders not only impair the success rate of treatment but also delay recovery. They can seriously interfere with treatment outcomes and even endanger a user's life. In this study, we created a smart mattress containing 10 × 18 air packs and control units. Each air pack contains a set of pressure and height sensors and two air valves. Each row control unit can detect and adjust the pressure and height of each air bag in the row. When the bed body is turned on, it automatically initializes, adjusts the state of each air bag to the same height and pressure, and enters a slow scanning state. When perceived objects or people are lying on the bed, the bed automatically perceives the human body structure and body pressure matrix, increases the scanning speed for more timely and accurate measurements of the digital matrix and forming pressure by matrix-normalized processing, and then uses local pressure variance detection to automatically adjust to the sleeping position of the human body and thus achieve a uniform force distribution and a comfortable state. Finally, pressure matrix binarization was used to match sleeping position templates to identify the best template for automatic recognition of the sleeping position. The experimental results show that the sleeping position recognition method has high accuracy, recall, and precision. Our mattress is designed with interfaces for external devices. In future research, the smart mattress can connect to an auxiliary part of a smart ecosystem consisting of a smart pill box, a smart lighting system, and a microclimate system, which is expected to yield a more comprehensive intelligent ward to explore the possibility of improving sleep quality.

Predicting individual responses to lithium with oxidative stress markers in drug-free bipolar disorder.

Objectives: This is the first study to investigate the oxidative stress (OxS) levels in drug-free bipolar disorder (BD) patients and their association with lithium response.Methods: A total of 61 drug-free BD patients and 49 controls were included. Patients treated with lithium were followed-up for 6 weeks. The levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and malondialdehyde (MDA) were measured at baseline and at the end of the sixth week.Results: Compared to controls, the SOD levels were lower, whereas the MDA were higher in the BD-depression (BD-D) group (both P < 0.001). GSH-Px levels were higher in both the BD-D and the BD-mania (BD-M) group (both P < 0.001). Both GSH-Px and MDA levels in the BD (P = 0.009, P < 0.001) and the BD-D subgroup (P = 0.006, P = 0.001) decreased significantly after the 6-week treatment with lithium. Interestingly, both GSH-Px and MDA levels decreased in responders (P = 0.03, P = 0.002) but not in the non-responders of BD-D (both p > 0.05). Moreover, the reduction in the MDA levels were associated with lithium response (B = 1.47, Wald statistic = 5.94, P = 0.015, odds ratio = 4.35, 95% confidence interval 1.33-14.20).Conclusions: Our study demonstrates an imbalance of OxS in drug-free BD, especially BD-D. Lithium reduces the GSH-Px and MDA levels in BD patients. The reduction in MDA levels may predict individual responsiveness to lithium.

The interaction of NOS1AP, DISC1, DAOA, and GSK3B confers susceptibility of early-onset schizophrenia in Chinese Han population.

Although many major breakthrough had identificated potential susceptibility genes for schizophrenia, the aetiology of schizophrenia is still unknown. In the present study, we focused on the N-methyl-Daspartate receptors related genes nitric oxide synthase 1 adaptor gene (NOS1AP), disrupted in schizophrenia 1 gene (DISC1), d-amino acid oxidase activator gene (DAOA), and glycogen synthase kinase 3-beta gene (GSK3B). A family-based genetic association study (459 Han Chinese subjects in 153 nuclear families) using 3 single nucleotide polymorphisms in NOS1AP, 2 in DISC1, 1 in DAOA and 1 in GSK3B was conducted. We found rs12742393 have just positive trend with schizophrenia (SCZ) (p=0.07) after FDR correction. NOS1AP mRNA and serum levels were significantly elevated in SCZ patients (p<0.001; p<0.001) compared with healthy control. However, expression Quantitative Trait Loci (eQTL) analysis have demonstrated that rs12742393 genotype were not significantly associated with the NOS1AP mRNA expression. GMDR identified a significant seven-locus interaction model involving (NOS1AP-rs348624, rs12742393, rs1415263, DISC1-rs821633, rs1000731, DAOA-rs2391191and GSK3B- rs6438552) with a good testing accuracy (0.72). Our finding suggested statistically significant role of interaction of NOS1AP, DISC1, DAOA, and GSK3B polymorphisms (NOS1AP-rs348624, rs12742393, rs1415263, DISC1-rs821633, rs1000731, DAOA-rs2391191and GSK3B-rs6438552) in EOS susceptibility.

Association of schizophrenia with the rs821633 polymorphism in the DISC1 gene among Han Chinese.

BACKGROUND: Previous studies report that various single nucleotide polymorphisms (SNP) in the Disrupted-in Schizophrenia 1 (DISC1) gene are closely associated with schizophrenia, but there are no studies that assess the relationship of age of onset of schizophrenia with these SNPs. OBJECTIVE: Investigate the relationship between the rs821633 SNP in the DISC1 gene and the occurrence and age of onset of schizophrenia in Han Chinese. METHODS: We used the TaqMan genotyping technology to examine the rs821633 SNP in the DISC1 gene among 315 individuals who developed schizophrenia prior to 19 years of age ('early-onset'), 407 individuals who developed schizophrenia when 19 years of age or older ('late-onset'), and 482 healthy controls. We used survival analyses to investigate the relationship between the rs821633(C) risk allele and the age of onset of schizophrenia. RESULTS: Compared to the prevalence in healthy controls, the prevalence of the C/C genotype of rs821633 and of the C allele in rs821633 were significantly greater in individuals with early-onset schizophrenia (X (2)=7.17, df=1, p=0.007; X (2)=7.20, df=2, p=0.032) and significantly greater in individuals with late-onset schizophrenia (X (2)=5.36, df=1, p=0.022; X (2)=6.58, df=2, p=0.041). However, there were no significant differences in the prevalence of the C/C genotype or the C allele between individuals with early-onset and late-onset schizophrenia. Kaplan-Meier survival analyses found no significant association between the rs821633(C) risk allele and age of onset in schizophrenia. CONCLUSION: We confirm the association of polymorphism in the rs821633 SNP in the DISC1 gene with schizophrenia among Han Chinese, but we found no association between the rs821633(C) risk allele and the age of onset in individuals with schizophrenia.