Xanomeline and trospium chloride (X/T) reduced symptoms and was generally well tolerated in two phase 3, 5-week, randomized, double-blind, placebo-controlled trials in adults with schizophrenia. The authors evaluated the long-term safety, tolerability, and efficacy of X/T in an open-label extension of the two phase 3 trials. EMERGENT-4 was a 52-week open-label extension trial of participants who completed the EMERGENT-2 and EMERGENT-3 acute trials. Between February 2021 and October 2023, 152 participants initiated twice-daily oral doses of xanomeline 50 mg/trospium 20 mg and titrated to a maximum dosage of twice-daily oral xanomeline 125 mg/trospium 30 mg. The primary endpoint was the proportion of participants reporting a treatment-emergent adverse event (TEAE). Efficacy measures included Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions severity scale (CGI-S). A total of 156 (42.6%) of the 366 participants who completed EMERGENT-2 or EMERGENT-3 enrolled in EMERGENT-4; of these 34 (21.8%) enrolled participants completed the 52-week treatment period. Overall, 81 (53.3%) of 152 treated participants experienced at least one TEAE. Consistent with the acute trials, the most common treatment-related adverse events were gastrointestinal disorders (e.g., nausea, vomiting, dyspepsia, dry mouth) that were mild or moderate in intensity and resolved with continued treatment. No new safety or tolerability issues were observed. X/T was not associated with clinically meaningful motor symptoms, hyperprolactinemia, weight gain, or adverse effects on metabolic parameters. X/T was associated with continued symptom improvement over the trial duration. Mean changes in PANSS total score from acute trial baseline to week 52 were -33.8 and -31.3 in the treatment groups receiving X/T and placebo, respectively, in the acute trials. Similar patterns of continued improvement were observed for scores on the CGI-S, PANSS positive subscale, and PANSS negative subscale. Long-term treatment with X/T over 52 weeks was safe, generally well tolerated, and associated with durable symptom improvement in people with schizophrenia.

Oxidative stress is associated with the pathophysiology of schizophrenia. Peripheral non-enzymatic antioxidants can reflect the degree of oxidative stress and antioxidant levels, and can be used as markers of oxidative stress. However, the relationships between these markers and the clinical phenotypes of first -episode adolescent-onset schizophrenia (AOS) is unclear. This study aimed to elucidate the impact of peripheral non - enzymatic antioxidants on male AOS patients and their association with clinical symptoms. Serum albumin (ALB), total bilirubin (TBIL), and uric acid (UA) of 59 first-episode AOS patients and 55 healthy controls were measured respectively. Furthermore, schizophrenia-related clinical symptoms were evaluated using the five-factor model of the Positive and Negative Syndrome Scale (PANSS). In Han Chinese first-episode male AOS patients, levels of TBIL and UA were significantly increased (p < 0.05), while ALB decreased (p < 0.01) compared with healthy controls. Furthermore, multivariate logistic regression showed that UA, ALB, and TBIL (all p < 0.01) were independently associated with AOS. Moreover, correlation analysis revealed that ALB was positively correlated with the PANSS total, cognitive and excited factor scores (all p < 0.05); TBIL was positively correlated with the excited factor score (p < 0.01); UA was positively correlated with the PANSS total, negative, cognitive and excited factor scores (all p < 0.05). In addition, Receiver operating characteristics assessment indicated that ALB and TBIL could effectively distinguish AOS patients from healthy controls. This study confirms the association of peripheral non-enzymatic antioxidants (ALB, TBIL, and UA) with clinical manifestations and pathophysiology in schizophrenia. ALB and TBIL may serve as potential biomarkers for oxidative stress and symptom severity in AOS, particularly in males, providing insights for diagnostic and therapeutic strategies.

Disentangling violence in schizophrenia: Interactions between symptom trajectories, conduct disorder, and pharmacotherapy.

Efficacy of glutamate-GABA modulator riluzole for the treatment of cognitive and psychotic symptoms in 22q11.2 deletion syndrome: A placebo-controlled crossover trial.

Efficacy of high-frequency transcranial magnetic stimulation to improve negative symptoms in patients with Schizophrenia: A meta-analysis of randomized controlled trials.

Right orbitofrontal cortex rTMS targets anxiety, not depressive, symptoms in first-episode schizophrenia.

Schizophrenia (SCZ) shows marked biological heterogeneity, with negative symptoms linked to poor outcomes and hypothesized immune dysregulation. This study examined whether a peripheral cytokine-long non-coding RNA (lncRNA) panel could distinguish patients with SCZ and Brief Negative Symptom Scale (BNSS)-defined subgroups from healthy controls (HC). Forty-one hospitalized patients with SCZ completed the BNSS and the Positive and Negative Syndrome Scale (PANSS). Twenty HCs, frequency-matched for age and sex, served as comparison samples. Severe negative-symptom subgroups were defined using two BNSS criteria: a broader (SNS1) and a more restrictive (SNS2) threshold. Serum cytokines-interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10)-and leukocyte lncRNAs (MALAT1, NEAT1, MEG3) were quantified by enzyme-linked immunosorbent assay and quantitative RT-PCR. Covariate-adjusted logistic and multinomial models (adjusting for age, sex, body mass index, and smoking) assessed discrimination using area under the receiver-operating-characteristic curve (AUC) and interquartile-range odds ratios (OR_IQR). IL-6 correlated with PANSS Total (ρ = .48, p = .001) and Negative (ρ = .34, p = .032) scores and was higher in SCZ than HC (p = .033), with further increases in SNS subgroups. NEAT1 was significantly reduced only within BNSS-defined subgroups (p ≤ .025). The dual-marker pattern (IL-6 ↑, NEAT1 ↓) showed the strongest discrimination for SNS1 versus HC (AUC = 0.85) and the steepest multinomial contrasts for SNS2 (IL-6 OR_IQR = 4.98; NEAT1 OR_IQR = 0.11). Elevated IL-6 and decreased NEAT1 define a peripheral signature linked to negative-symptom severity in SCZ and may support biologically informed stratification and longitudinal research.

While individuals with schizophrenia (SZ) exhibit deficits in social cognition, the specific profile of these deficits across multiple domains and their relationship with clinical symptoms warrants further characterization. This study aimed to systematically assess key social-cognitive domains-theory of mind (ToM), emotion recognition, attributional style, and social perception-and examine their associations with psychopathology in SZ. Sixty-eight individuals with SZ and 68 matched healthy controls (HC) completed a comprehensive battery of social-cognitive measures, including the false-belief task (assessing first- and second-order ToM), the Faux Pas task, the emotional recognition task, the attributional style questionnaire, and the social perception scale. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Compared to HC, individuals with SZ showed significant deficits across all social-cognitive measures. Specifically, the SZ group exhibited deficits in emotion recognition for all negative emotions (fear, anger, sadness, disgust) but not for happiness, and in attributional style for positive but not negative events. Correlation analyses identified a statistically significant inverse relationship between attributional stability for negative events (i.e., the tendency to attribute the causes of negative events to factors that are persistent over time) and PANSS general psychopathology scores (τ = -0.25, P < 0.043). Furthermore, no other social-cognitive domains (ToM, emotion recognition, social perception) showed significant correlations with any PANSS symptom dimensions. Network analysis further characterized second-order ToM as the core deficit, exhibiting the highest strength and centrality within the social-cognitive network, with mediation effects most pronounced for sadness and happiness recognition. These findings highlight second-order ToM as a core deficit in individuals with schizophrenia and suggest that a stable attributional style may be associated with a lower overall burden of general psychopathology. These social-cognitive domains may represent promising targets for future cognitive remediation interventions for people living with schizophrenia.

The PANSS Autism Severity Score (PAUSS) has recently become a popular measure of autistic features in psychosis populations, but evidence on its longitudinal reliability and factor configuration is poor. The aims of this investigation were to examine psychometric characteristics of the PAUSS in young patients with First Episode Psychosis (FEP) treated in an early intervention service, with primary interest for its long-term stability across 2 years of follow-up and factor configuration. All FEP participants completed the Positive And Negative Syndrome Scale (PANSS) and Autism Quotient (AQ) at baseline and across the follow-up. Statistical analysis mainly included Cronbach's α to examine internal consistency of the PAUSS, Cohen's k statistics and Spearman's ρ correlation coefficients for its longitudinal stability and convergent validity with AQ scores, and exploratory factor analysis to explore its dimensions' configuration. 301 FEP participants were recruited (170 with Schizophrenia Spectrum Disorder [SSD]). Cronbach's α value for the PAUSS was 0.806, but with unacceptable inter-item correlations for PANSS G5 and G15 items. K value for examining PAUSS convergent validity with AQ score was unacceptable (0.295), as well as ρ and k values to quantify long-term test-retest reliability (< 0.750 and < 0.600, respectively). No long-term stability of the PAUSS scores across the follow-up was also found using Wilcoxon's test for repeated measure. Our EFA found a 2-factor model in the FEP total sample and a 3-factor configuration in the SSD subgroup. Our results suggest that the PAUSS does not represent a valid instrument to assess autistic features in FEP and SSD. Indeed, the it probably captures psychotic symptom severity rather than autistic features, especially reflecting negative symptom load.

Accumulating evidence suggests that oxidative stress (OS) contributes to the onset and progression of schizophrenia (SCZ). However, the pattern of OS alterations in first-episode, drug-naïve patients and their associations with clinical and cognitive features remain unclear. In this study, 98 first-episode SCZ patients and 96 matched healthy controls were recruited. Plasma levels of total antioxidant capacity (TAC), malondialdehyde (MDA), lipid peroxidation (LPO), NADPH oxidase (NOX), glutathione S-transferase (GST), and glutathione reductase (GR) were measured. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), and cognitive performance was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Compared with controls, patients exhibited significantly higher TAC, MDA, and LPO levels but lower NOX levels, while GST and GR showed no significant differences. RBANS total and subscale scores were markedly reduced in patients, indicating generalized cognitive impairment. Correlation analyses revealed that GST was positively correlated with total PANSS scores, GR with negative symptoms, and LPO with overall cognition, attention, and delayed recall. These findings indicate that first-episode SCZ patients display an imbalance between oxidative and antioxidant systems, and specific OS markers are linked to symptom severity and cognitive dysfunction. OS alterations may serve as potential early biomarkers and therapeutic targets for schizophrenia.

The corpus callosum (CC) is critical for inter-hemispheric integration, and its structural abnormalities have been implicated in the neurobiology of schizophrenia (SCZ). Approximately 20-35% of SCZ patients exhibit resistance to antipsychotics and are classified as treatment-resistant schizophrenia (TRS). To date, no studies have specifically analyzed CC morphology in TRS compared to healthy controls (HCs) and treatment-responsive SCZ patients (non-TRS). The study included 75 HCs and 97 SCZ patients (39 TRS and 58 non-TRS, including cannabis users and non-users). Participants underwent cross-sectional assessment using the Neurological Evaluation Scale (NES), the Brief Assessment of Cognition in Schizophrenia, and the Positive and Negative Syndrome Scale (PANSS). CC volume was measured via MRI and analyzed with a novel artificial intelligence program (MRI-AI) for single-subject assessment, with findings confirmed through group-level voxel-based morphometry (VBM). TRS patients exhibited significantly higher total PANSS (p < 0.001) and NES (p < 0.001) scores and performed worse on working memory tasks compared to non-TRS patients. MRI-AI identified CC volume reduction in 55.88% of TRS patients (TRS CC: 3.02 mL vs. non-TRS with cannabis use: 3.69 mL; without cannabis use: 3.28 mL; p = 0.002). VBM confirmed significant CC volume reduction in TRS patients relative to HCs (p = 0.004). Cannabis use in non-TRS patients did not significantly affect CC volume or cognitive performance. TRS is associated with pronounced neurological, cognitive, and clinical dysfunctions. Aberrant CC volume may contribute to TRS pathogenesis and executive function deficits. MRI-AI provides a robust, single-subject approach for characterizing CC abnormalities in schizophrenia, offering potential for personalized clinical assessment.

BackgroundFormal thought disorder (FTD) is a core symptom of schizophrenia spectrum disorders (SSDs). As a key representational dimension of FTD, speech features have been shown in previous studies to hold potential as diagnostic biomarkers for SSD. However, relevant research remains limited, and such speech features have not yet been applied clinically for SSD diagnosis.ObjectiveThe aim of this research is to establish a Chinese speech database for multidimensional analysis of speech characteristics, quantify these high-dimensional linguistic features using natural language processing (NLP), and ultimately develop objective biomarkers for diagnosing and assessing the severity of SSD.MethodsThis will be a single-center, prospective, observational study. In accordance with the DSM-5 criteria, a total of 300 inpatients or outpatients meeting the diagnostic criteria for SSD are planned to be included. Healthy controls with no history of intellectual disability will subsequently be matched. Each participant will undergo a 1-to-2-hour task-guided interview conducted by a psychiatrist, which includes an app-based assessment of the PANSS(Positive and Negative Syndrome Scale), short passage reading, an animal fluency test, a pseudosentence reading task, a symptom severity rating task, an inner-world expression task, and a picture description task. All the interviews will be audio-recorded. After the interview, clinical rating scales will assess psychiatric symptom severity, social functioning, and thought-language disorders. During the study, at an interval of 2 weeks.DiscussionBy multidimensionally quantifying these speech characteristics and integrating machine learning, this study aims to screen highly discriminative speech feature combinations specific to SSD, thereby providing technical and theoretical support for the precise diagnosis and personalized intervention of SSD. These findings will deepen psychiatrists’ understanding of the linguistic pathological mechanisms underlying SSD and promote the development of diagnostic tools and intervention protocols based on novel biomarkers.

This prospective 12-week randomized controlled trial tested an adherence promotion approach called Customized Adherence Enhancement in schizophrenia (CAE-S) vs. Enhanced Treatment as Usual (eTAU) in 36 poorly adherent individuals. Patients were randomized to either CAE-S or eTAU at baseline and were assessed at 12-week follow-up. Primary outcomes were program attendance, patient satisfaction and change in schizophrenia symptoms as measured by the Positive and Negative Syndrome Scale (PANSS). Additional evaluations were adherence measured by the Tablets Routine Questionnaire (TRQ), Clinical Global Impression (CGI), Short Form Health Survey (SF-12), Global Assessment of Functioning (GAF), and Strauss-Carpenter Level of Functioning Scale (SCLFS). Mean age was 44.9 (Standard deviation/SD 12) years. 12-week attrition was 19.4%. At screening, mean past 7-day TRQ (proportion of days with missed dose) was 29.7% (SD 23.8) for CAE and 41.7% (SD 26.5) for eTAU. By baseline, mean TRQ improved to 11.3% (SD 15.8) in CAE-S, and to 19.3% (SD 25.7) in eTAU. Mean session attendance (out of a maximum of 6) was 4.89 (SD 1.9) for CAE and 3.88 (SD 2.5) for ETAU. CAE and ETAU satisfaction were both high. From baseline to 12 weeks, mean PANSS improved significantly in both CAE-S (p < .05) and eTAU (p < .01) with no difference between arms. There was no significant change in TRQ, while CGI and GAF improved significantly in both arms with no significant difference between arms. Mean SCLFS improved in both arms, with results favoring CAE (p < .001). Telehealth CAE-S is feasible and acceptable among poorly adherent patients with schizophrenia. Adherence improved rapidly with monitoring, which could explain improvement in schizophrenia symptoms and largely similar outcomes across intervention arms.

The challenges in measuring symptoms of schizophrenia: An exploratory graph analysis of the Positive and Negative Syndrome Scale (PANSS).

Social isolation, social cognition and symptom severity in Chilean patients with Schizophrenia: A mediational model.

Distinct neuroimaging signatures of OSSO compared to schizophrenia and healthy controls using graph theoretical analysis.

Objective:Second-generation antipsychotics can lead to metabolic problems. This study investigated whether an herbal compound with green tea, Persian borage, and purslane extracts could help in antipsychotic-induced weight management in schizophrenia patients.Materials and Methods: This triple-blind, placebo-controlled study at Hijazi Psychiatry Hospital in Mashhad, Iran, involved 73 schizophrenia patients. Participants received either an herbal compound or a placebo, alongside their antipsychotic medication. The primary outcome was changes in body mass index (BMI), with secondary outcomes including waist-to-hip ratio (WHR), fasting blood sugar (FBS), HbA1c, lipid profile, blood pressure, appetite, quality of life, and psychotic symptom severity.Results:The herbal compound significantly reduced BMI (p<0.001), WHR (p<0.001), HbA1c (p=0.042), low-density lipoprotein (LDL) concentration (p=0.009), and systolic blood pressure (p=0.015) compared to the placebo. No significant differences were observed in FBS or lipid profile (except LDL) between the two groups. The intervention group had significantly lower appetite levels than the placebo group at weeks four and eight (p=0.001). There was no significant difference between the two groups in the Positive and Negative Syndrome Scale (PANSS) score at any time. Participants reported no serious adverse effects.Conclusion:Adding herbal compound to antipsychotics significantly lowered BMI, WHR, HbA1c, LDL levels, systolic blood pressure, and appetite in schizophrenia patients.

Does insight improve during the course of psychosis?

ABSTRACTBackground and HypothesisIn people with psychotic disorders, exercise is known to improve psychotic symptoms; however, the mechanisms underlying these effects are unclear. In the network approach, mental disorders are conceptualised as complex systems of interacting symptoms. In this context, exercise interventions could modify the dynamic of psychotic symptoms within the network. Using data from two independent clinical trials using exercise, the aim was to investigate the impact of exercise interventions on network connectivity, then compare the network structure pre and post intervention.Study DesignCombined data from two clinical trials on exercise with a total of 106 participants with a diagnosis of psychotic disorder were included. The Positive and Negative Syndrome Scale (PANSS) was used to assess symptom severity using semi‐structured interviews. Networks analyses were performed to compare before and after exercise.Study ResultsAt baseline, the PANSS network was densely connected with several strong positive connections. Symptoms being most central were negative symptoms. After exercise, the network was less dense and less connected, and the connections were different. When the networks before and after exercise were compared, they were significantly different in terms of structure, but not global strength.ConclusionThis study is the first to show that exercise seems to favour a disconnection between psychotic symptoms and could modify the network structure, providing a first mechanism of action which would require more investigation.

Examining clinical symptoms in schizophrenia based on visual-spatial working memory and resting-state EEG.