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Cognitive offloading refers to the use of physical action and the external environment to simplify mental demand. One form of this—intention offloading—involves the use of external reminders to support delayed intentions. Both beliefs of poor memory ability and a preference to avoid cognitive effort lead to offloading intentions rather than using internal memory. Schizophrenia is a population with deficits in prospective memory and to overcome this difficulty, neuropsychological interventions can propose external aids such as reminders. However, it is unknown what motivates individuals with schizophrenia to spontaneously use reminders. Twenty‐seven individuals with schizophrenia and twenty‐seven non‐clinical individuals were recruited to perform a prospective memory task, with two levels of difficulty, by deciding whether to use reminders or their internal memory. The proportion of reminder use, performance (hits and errors), subjective effort and metacognitive beliefs were recorded. The results show a non‐optimal use of reminders in the schizophrenia group: this group used more reminders than the non‐clinical group when the task was easy but did not increase reminder usage when the task became more difficult. Individuals with schizophrenia perceived the task to be more effortful than the non‐clinical individuals in the easy task, but also had a high estimation of their memory ability. Reminder usage in schizophrenia is atypical and non‐optimal. This may relate to effort and metacognition but the direct influence of these factors remains to be demonstrated. The overall results open perspectives on the neuropsychological treatment of prospective memory in this population. [ABSTRACT FROM AUTHOR]

Schizophrenia is a mental disorder characterized by cognitive impairments, specifically deficits in social recognition memory (SRM). Abnormal hippocampal neurogenesis has been implicated in these deficits. Due to the pathogenetic heterogeneity of schizophrenia, studying the hippocampal neurogenesis and SRM in two models with prenatal and postnatal defects could enhance our understanding of the developmental aspects of the biological susceptibility to schizophrenia. Here, we examined SRM and hippocampal neurogenesis in two developmental models of schizophrenia: gestational exposure to methylazoxymethanol acetate (MAM) and postweaning social isolation (SI). Our findings revealed that gestational MAM exposure induced a decay of social memory while postweaning SI led to impaired social memory formation and decay. In both models, we observed a correlation between impaired SRM and reduced number, and abnormal differentiation and less complex morphology of hippocampal neurons. These results indicate that aberrant hippocampal neurogenesis may contribute to the deficits of SRM in both models, and these abnormalities may be a shared underlying pathogenic factor in developmental models of schizophrenia, regardless of prenatal and postnatal pathogenesis. [ABSTRACT FROM AUTHOR]

Background and Purpose: Antipsychotics such as olanzapine are associated with significant metabolic dysfunction, attributed to gut microbiome dysbiosis. A recent notion that most psychotropics are detrimental to the gut microbiome has arisen from consistent findings of metabolic adverse effects. However, unlike olanzapine, the metabolic effects of lurasidone are conflicting. Thus, this study investigates the contrasting effects of olanzapine and lurasidone on the gut microbiome to explore the hypothesis of 'gut neutrality' for lurasidone exposure. Experimental Approach: Using Sprague–Dawley rats, the effects of olanzapine and lurasidone on the gut microbiome were explored. Faecal and blood samples were collected weekly over a 21‐day period to analyse changes to the gut microbiome and related metabolic markers. Key Results: Lurasidone triggered no significant weight gain or metabolic alterations, instead positively modulating the gut microbiome through increases in mean operational taxonomical units (OTUs) and alpha diversity. This novel finding suggests an underlying mechanism for lurasidone's metabolic inertia. In contrast, olanzapine triggered a statistically significant decrease in mean OTUs, substantial compositional variation and a depletion in short‐chain fatty acid abundance. Microbiome depletion correlated with metabolic dysfunction, producing a 30% increase in weight gain, increased pro‐inflammatory cytokine expression, and increased blood glycaemic and triglyceride levels. Conclusion and Implications: Our results challenge the notion that all antipsychotics disrupt the gut microbiome similarly and highlights the potential benefits of gut‐neutral antipsychotics, such as lurasidone, in managing metabolic side effects. Further research is warranted to validate these findings in humans to guide personalised pharmacological treatment regimens for schizophrenia. [ABSTRACT FROM AUTHOR]

ObjectiveMethodsResultsConclusionsMetacognitive training (MCT) for psychosis is a psychological intervention that blends cognitive behavioural therapy and psychoeducation. Several published systematic reviews and meta‐analyses have provided robust evidence of its efficacy. However, patients' opinions regarding the intervention or their own perception of the changes achieved have been overlooked. This study synthesises the first‐person reports of people with schizophrenia who completed MCT at the Hospital Del Salvador de Valparaiso.This study employed a qualitative methodology. Semi‐structured interviews were conducted with patients who completed MCT. The interviews were reliably transcribed, and a content analysis was performed.All the participants interviewed were positive about MCT, highlighting improvements in various aspects and emphasising factors that contributed to the changes achieved. Four main themes emerged from the analysis: Sowing the seeds of doubt; Significant changes in MCT attendees; Community formation; and What the MCT needs to improve.The results provide an in‐depth report on MCT from the users' perspective and allow reflection on new outcomes to be studied in the future, with quantitative and qualitative methods. [ABSTRACT FROM AUTHOR]

Background Case Presentation Conclusions Ischemic priapism is a rare pathological condition, and delayed intervention can result in irreversible sequelae. Most cases are attributed to the use of antipsychotics. The blockade of α1‐adrenergic receptors is thought to be associated with the disease onset, although data supporting this hypothesis are lacking. No consensus regarding the optimal choice of medication is available.A 59‐year‐old man with schizophrenia, who had been receiving long‐acting injections of risperidone, developed ischemic priapism after receiving paliperidone treatment. Following improvement in ischemic priapism, we administered a combination of aripiprazole and olanzapine, which improved his psychiatric symptoms. We did not observe any recurrence of ischemic priapism.Switching the antipsychotic drug causing ischemic priapism to patients having a relatively low affinity for α1‐adrenergic receptors may enable the treatment of schizophrenia without recurrence of ischemic priapism. In addition to the affinity for α1‐adrenergic receptor, differences in metabolic enzyme types and antipsychotic doses may be involved in the occurrence of ischemic priapism. Accumulating evidence is necessary to establish guidelines for selecting medication of patients with ischemic priapism. [ABSTRACT FROM AUTHOR]

Objective: To define the impact of obesity on inflammatory and oxidative disturbances in antipsychotic‐treated schizophrenia patients. Methods: Several cytokines, inflammatory, metabolic, and oxidative status markers were evaluated in obese (n = 40) and non‐obese (n = 40) antipsychotic‐treated patients and compared with age‐and BMI‐matched controls (n = 80). Results: Schizophrenia patients had higher leptin, TNF‐α, adiponectin, visfatin, resistin, P‐selectin, NPY, BDNF, CD40‐L, MCP‐1, and malondialdehyde, and lower IL‐6, ghrelin, neopterin, and vitamin E levels compared to their respective controls (p < 0.001). Total oxidant status was higher in non‐obese patients compared to controls (p < 0.001), total antioxidant capacity was higher in obese compared to non‐obese patients (p < 0.01), but vitamin A and paraoxonase levels were not different. High sensitive‐CRP levels were higher in obsese controls relative to non‐obese controls (p < 0.05) and in obese patients relative to non‐obese patients (p < 0.001). Fasting glucose, insulin, HbA1c, HOMA‐IR, uric acid, total cholesterol, and triglyceride concentrations were higher in obese patients compared to non‐obese patients. Insulin concentrations and HOMA‐IR were also higher in obese controls than in non‐obese controls. Conclusions: Our results suggest that inflammatory responses and oxidative stress develop independently from obesity in antipsychotic‐treated schizophrenia patients. However, schizophrenia‐induced obesity causes metabolic disturbances; thereby, obese schizophrenia patients are more liable to cardiovascular events and progress of metabolic syndrome than non‐obese patients. [ABSTRACT FROM AUTHOR]

Background: Research has suggested that people diagnosed with schizophrenia experience challenges in their abilities to reflect upon themselves, others and their actions in the world. One emerging approach to addressing these forms of subjective disturbance is Metacognitive Reflection and Insight Therapy (MERIT). Aims: In this study, a randomized delayed trial was conducted to assess the effects of MERIT upon metacognition, psychiatric symptoms and quality of life. Materials and Methods: Following recruitment and randomization, data from 54 adults diagnosed with schizophrenia were analysed. Results: Findings included significant interaction effects between group (immediate intervention or waiting condition) and time (pre‐ and post intervention) with regard to the metacognition general score and its domain of mastery, as well as with regard to negative, positive and cognitive symptoms. Discussion: Participating in MERIT seems to improve one's ability to use reflective knowledge to cope with psychological challenges and to improve, or at least maintain, level of symptomatology. Conclusions: These findings are discussed within the framework of agency as an important aspect of recovery. [ABSTRACT FROM AUTHOR]

Aim: Patients with schizophrenia typically exhibit symptoms of disorganized thought and display concreteness and over‐inclusion in verbal reports, depending on the level of abstraction. While concreteness and over‐inclusion may appear contradictory, the underlying psychopathology that explains these symptoms remains unclear. In the current study, we used functional magnetic resonance imaging with an encoding modeling approach to examine how concepts of various words, represented as brain activity, are anomalously connected at different levels of abstraction in patients with schizophrenia. Methods: Fourteen individuals diagnosed with schizophrenia and 17 healthy controls underwent functional magnetic resonance imaging to measure brain activity representing concepts of various words. We used a persistent homology (PH) method to analyze the topological structures of word representations in schizophrenia patients, healthy controls, and random data, across different levels of abstraction by varying dissimilarity scales in the representation space. Results: The results revealed that patients with schizophrenia exhibited more homogeneous word relationships across different levels of abstraction compared with healthy controls. Additionally, topological structures exhibited a shift toward a random network structure in patients with schizophrenia compared with controls. The PH method successfully distinguished semantic representations of patients with schizophrenia from those of controls. Conclusions: The current results provide an explanation for the mechanisms underlying the deficits in abstraction ability observed in schizophrenia. The isotopic connection of individual concepts reflects both the reduction of contextual connections at a semantically fine‐grained scale and the absence of clear boundaries between related concepts at a coarse scale, which lead to concreteness and over‐inclusion, respectively. [ABSTRACT FROM AUTHOR]

Functions associated with processing reward‐related information are fundamental drivers of motivation, learning, and goal‐directed behavior. Such functions have been classified as the positive valence system under the Research Domain and Criteria (RDoC) criteria and are negatively impacted across a range of psychiatric disorders and mental illnesses. The positive valence system is composed of three comprehensive categories containing related but dissociable functions that are organized into either Reward Responsiveness, Reward Learning, or Reward Valuation. The presence of overlapping behavioral dysfunction across diagnostic mental disorders is in‐part what motivated the RDoC initiative, which emphasized that the study of mental illness focus on investigating relevant behavior and cognitive functions and their underlying mechanisms, rather than separating efforts on diagnostic categories (i.e., transdiagnostic). Moreover, the RDoC approach is well‐suited for preclinical neuroscience research, as the rise in genetic toolboxes and associated neurotechnologies enables researchers to probe specific cellular targets with high specificity. Thus, there is an opportunity to dissect whether behaviors and cognitive functions are supported by shared or distinct neural mechanisms. For preclinical research to effectively inform our understandings of human behavior however, the cognitive and behavioral paradigms should have predictive, neurobiological, and pharmacological predictive validity to the human test. Touchscreen‐based testing systems provide a further advantage for this endeavor enabling tasks to be presented to animals using the same media and task design as in humans. Here, we outline the primary categories of the positive valence system and review the work that has been done cross‐species to investigate the neurobiology and neurochemistry underlying reward‐related functioning. Additionally, we provide clinical tasks outlined by RDoC, along with validity and/or need for further validation for analogous rodent paradigms with a focus on implementing the touchscreen‐based cognitive testing systems. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusions Talk, Understand and Listen for InPatient Settings (TULIPS) was a multi‐centred randomized control trial of an intervention that aimed to increase patient access to psychological therapies on acute mental health wards. This paper aims to: (i) describe a strategy for designing a psychological intervention that is implementable in inpatient mental health settings; (ii) describe methods for assessing the fidelity of interventions within these settings; (iii) report on the extent to which fidelity was achieved in the TULIPS trial.The TULIPS intervention was designed using information from a systematic review, stakeholder interviews, pilot work and a consensus workshop. We assessed fidelity to the model in terms of the delivery and dose of essential elements of the intervention, quality of intervention delivery, engagement of participants with the intervention and differentiation between the intervention and usual care.Although the TULIPS intervention targeted known barriers to the delivery of psychological interventions on mental health wards, we found issues in implementing aspects of the intervention that were dependent upon the participation of members of the multidisciplinary team. Psychologists were able to overcome barriers to delivering individual therapy to patients as this provision was not reliant on the availability of other staff.The intervention period in the study was 6 months. A greater period of time with a critical mass of psychological practitioners is needed to embed psychological interventions on inpatient wards. Our fidelity framework and assessment methods can be used by other researchers implementing and testing psychological therapies within inpatient environments. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusions Intolerance of uncertainty, the tendency to interpret and react negatively to uncertainty, is a transdiagnostic risk factor for anxiety, depression and eating‐related disorders. Given the high comorbidity between anxiety, depression and schizophrenia‐spectrum diagnoses (SSDs), there is potential for intolerance of uncertainty to play a role in modulating psychosis symptoms. To address this gap in our understanding, we conducted the first prospectively registered systematic review on intolerance of uncertainty and psychotic symptoms in both people with SSDs and in the general population.Four databases were searched (PsycINFO, Medline, Web of Science and PubMed), which identified ten studies with a total of 1503 participants that measured intolerance of uncertainty and psychosis symptoms.Key findings suggest the following: (1) Intolerance of uncertainty was associated with total negative psychotic symptoms with small–medium effect sizes; (2) intolerance of uncertainty was higher in individuals with an ‘at‐risk’ mental state for psychosis compared to controls; (3) higher intolerance of uncertainty was associated with more individual psychotic symptoms related to delusions and paranoia within clinical and nonclinical samples; and (4) there was mixed evidence for a relationship between intolerance of uncertainty and auditory hallucinations and intolerance of uncertainty and total positive symptoms in clinical samples.Overall, these findings highlight that intolerance of uncertainty may be an important transdiagnostic dimension and potential treatment target for psychotic symptoms such as delusions and paranoia in people with SSDs. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion Whole‐exome sequencing (WES) studies have revealed that germline de novo variants (gDNVs) contribute to the genetic etiology of schizophrenia. However, the contribution of mosaic DNVs (mDNVs) to the risk of schizophrenia remains to be elucidated. In the present study, we systematically investigated the gDNVs and mDMVs that contribute to the genetic etiology of schizophrenia in a Japanese population.We performed deep WES (depth: 460×) of 73 affected offspring and WES (depth: 116×) of 134 parents from 67 families with schizophrenia. Prioritized rare nonsynonymous gDNV and mDNV candidates were validated using Sanger sequencing and ultra‐deep targeted amplicon sequencing (depth: 71,375×), respectively. Subsequently, we performed a Gene Ontology analysis of the gDNVs and mDNVs to obtain biological insights. Lastly, we selected DNVs in known risk genes for psychiatric and neurodevelopmental disorders.We identified 62 gDNVs and 98 mDNVs. The Gene Ontology analysis of mDNVs implicated actin filament and actin cytoskeleton as candidate biological pathways. There were eight DNVs in known risk genes: splice region gDNVs in AKAP11 and CUL1; a frameshift gDNV in SHANK1; a missense gDNV in SRCAP; missense mDNVs in CTNNB1, GRIN2A, and TSC2; and a nonsense mDNV in ZFHX4.Our results suggest the potential contributions of rare nonsynonymous gDNVs and mDNVs to the genetic etiology of schizophrenia. This is the first report of the mDNVs in schizophrenia trios, demonstrating their potential relevance to schizophrenia pathology. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion To explore the optimal dose of blonanserin transdermal patch (BNS‐P) based on baseline psychiatric symptomatic characteristics during acute schizophrenia.A post hoc cluster analysis was conducted using data from a 6‐week randomized, double‐blind, placebo‐controlled study of BNS‐P (40 or 80 mg/day) in acute schizophrenia. We classified patients into three clusters based on baseline psychiatric symptoms. Efficacy was assessed using the change from baseline to week 6 in the PANSS total score. Safety was assessed by the incidence of adverse events.Among 577 patients, three clusters were identified, characterized by severe psychiatric (Cluster‐S; n = 122), predominant negative (Cluster‐N; n = 191), and predominant positive (Cluster‐P; n = 264) symptoms. In Cluster‐P, both BNS‐P 40 and 80 mg/day reduced PANSS total score significantly more than placebo (p = 0.036, effect size = 0.342; p < 0.001, effect size = 0.687, respectively). In Cluster‐S and ‐N, only BNS‐P 80 mg/day reduced PANSS total score significantly more than placebo (p = 0.045, effect size = 0.497; p = 0.034, effect size = 0.393, respectively). The effect size was greater at 80 mg/day than at 40 mg/day across all clusters. The most common treatment‐emergent adverse events were akathisia and skin‐related adverse events in all clusters.BNS‐P exhibited a dose‐dependent antipsychotic effect in all clusters, particularly highlighting its efficacy in patients with predominant positive symptoms, even at lower doses. These findings provide novel and valuable insights for determining BNS‐P dose tailoring to individual symptomatic characteristics in real‐world practice. [ABSTRACT FROM AUTHOR]

Dopamine D2 receptor occupancy (D2RO) significantly influences the clinical effectiveness and safety of many antipsychotic drugs. Maintaining a D2RO range of 65%–80% provides the best antipsychotic effects while minimizing adverse reactions. Data from a Phase III trial were used to establish an exposure–response relationship for monthly intramuscular Risperidone ISM (75 and 100 mg) or placebo administered to adults with schizophrenia. Pharmacodynamic analysis was based on an Emax model for Positive and Negative Syndrome Scale (PANSS) developed in NONMEM. Plasma concentrations of the active moiety were derived using a previously developed population pharmacokinetic model, which was used for D2RO simulations in conjunction with a published Emax model. The optimal D2RO range (65%–80%) was reached for the median within hours following the first injection of both Risperidone ISM doses. At steady state, median D2RO for both doses remained above 65% throughout the 28‐day dosing period and demonstrated lower variability than oral risperidone. PANSS response did not differ significantly between dose groups, most likely because active moiety concentrations had already reached the plateau of the concentration–response relationship. The pharmacokinetic/pharmacodynamic analysis showed a profound placebo effect (−11.7%), and an additional maximal drug effect (−6.6%) resulting in a total PANSS improvement over time of −18.3%. Pharmacokinetic/pharmacodynamic modeling quantified a PANSS improvement over time after Risperidone ISM administration. The response was not significantly different in either dose group, likely because D2RO was already above the proposed efficacy threshold (65%) within 1 h after the first Risperidone ISM injection and remained above this level following repeated administrations. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim Methods Results Conclusion The study aims to assess the feasibility of developing cognitive tools and integrating the cloud‐enabled mobile‐based technology into routine clinical practice for psychotic patients. Furthermore, it aims to investigate the correlation between the results obtained using developed tools and established clinical measures, offering valuable insights into tools for enhancing the accuracy, efficiency and ease of administration of cognitive evaluation.A total of 160 participants were recruited (83 outpatients with early course of schizophrenia (SZs) and 77 healthy controls [HCs]). The participants were subjected to cognitive assessments, and the data were collected by cognitive assessment digital smart tool (CADST) and PGI memory scale (PGIMS) to assess attention (ATT) and working memory (WM). Outcome measures of these parameters were digit span (score,time) for ATT and delayed recall (score,time) for WM.The total average score in HCs was significantly higher than in SZs for ATT and WM, and CADST was significantly correlated with PGIMS for evaluating ATT and WM. Furthermore, test completion times for ATT and WM were observed more in SZs although most of SZs had achieved scores as high as that of HCs.The potential of CADST as a valuable addition to the conventional cognitive assessment method is highlighted, showing promising feasibility and strong correlations with the established tool. The importance of integrating time parameters suggests broader implications for understanding cognitive function beyond conventional scoring metrics. It demonstrates the effective and accurate approach for large‐scale screening of cognitive parameters in public service settings. [ABSTRACT FROM AUTHOR]

Risperidone extended‐release injectable suspension (R‐ERIS; marketed as RYKINDO) is a novel immediate‐release version of risperidone formulated as extended‐release microspheres for biweekly intramuscular injection to treat schizophrenia in adults. The pharmacokinetics (PK) and safety of R‐ERIS were evaluated in a multicenter, randomized, open‐label, multiple‐dose study in patients with stable schizophrenia or schizoaffective disorder. Eligible patients (N = 108) 18 to 65 years old were randomized (1:1) to receive IM injections of R‐ERIS 25 mg or the comparator, a biweekly risperidone long‐acting injectable (BW‐RLAI; marketed as RISPERDAL CONSTA) 25 mg for a total of 5 injections. The primary objective was to evaluate the relative bioavailability of active moiety (risperidone plus 9‐hydroxyrisperidone) at steady state. Blood samples were analyzed for risperidone and 9‐hydroxyrisperidone using a validated, specific, and sensitive liquid chromatography with tandem mass spectrometry method. Plasma concentration–time data were analyzed using non‐compartmental methods. Pharmacokinetic parameters were calculated based on individual patient PK profiles. Safety was assessed using standard measures. At steady state, mean plasma concentrations of the active moiety were similar for R‐ERIS and BW‐RLAI. R‐ERIS rapidly released risperidone after the injection without apparent lag time. Plasma active moiety levels reached steady state after the second injection of R‐ERIS. The elimination of the drug was completed approximately 2 weeks earlier for R‐ERIS as compared to that for BW‐RLAI. R‐ERIS was safe and well tolerated. Overall, R‐ERIS exhibited a faster onset and offset than BW‐RLAI and statistical analysis of exposure parameters demonstrated bioequivalence at steady state. [ABSTRACT FROM AUTHOR]

α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) ionotropic glutamate receptors (AMPARs) mediate rapid excitatory synaptic transmission in the mammalian brain, primarily driven by the neurotransmitter glutamate. The modulation of AMPAR activity, particularly calcium‐permeable AMPARs (CP‐AMPARs), is crucially influenced by various auxiliary subunits. These subunits are integral membrane proteins that bind to the receptor's core and modify its functional properties, including ion channel kinetics and receptor trafficking. This review comprehensively catalogs all known AMPAR auxiliary proteins, providing vital insights into the biochemical mechanisms governing synaptic modulation and the specific impact of CP‐AMPARs compared to their calcium‐impermeable AMPA receptor (CI‐AMPARs). Understanding the complex interplay between AMPARs and their auxiliary subunits in different brain regions is essential for elucidating their roles in cognitive functions such as learning and memory. Importantly, alterations in these auxiliary proteins' expression, function or interactions have been implicated in various neurological disorders. Aberrant signaling through CP‐AMPARs, in particular, is associated with severe synaptic dysfunctions across neurodevelopmental, neurodegenerative and psychiatric conditions. Targeting the distinct properties of AMPAR‐auxiliary subunit complexes, especially those involving CP‐AMPARs, could disclose new therapeutic strategies, potentially allowing for more precise interventions in treating complex neuronal disorders. [ABSTRACT FROM AUTHOR]

This study examined the association between burnout, psychological distress, ward atmosphere, and working alliance (WA) among mental health workers treating patients with schizophrenia spectrum disorder (SSD). Data were collected from 345 patients with SSD and 151 mental health workers across 98 residential facilities (RFs) as part of the DiAPAson project from October 2020 to October 2021. Participants were excluded from the study if they exhibited patient‐operator matching errors, dropped out, or had many missing Maslach Burnout Inventory (MBI) scores. The final sample included 282 patients and 155 healthcare workers. Burnout was assessed using the MBI. Psychological distress was evaluated with the 12‐item version of the General Health Questionnaire. WA and ward atmosphere were evaluated with the WA Inventory and the Ward Atmosphere Scale, respectively, in both staff and patients. Sociodemographic and clinical data was also collected and analysed. Burnout was associated with a less supportive ward atmosphere, a weaker WA, and higher staff distress. Severe psychiatric symptoms evaluated with Brief Psychiatric Rating Scale in patients were also linked to staff burnout levels. Discrepancies in the perceptions of the ward atmosphere and the WA were observed between staff and patients, with patients reporting better perceptions in both domains. Our findings highlight the complex dynamics of well‐being within psychiatric care settings, emphasizing the importance of role clarity, professional autonomy, and a positive ward atmosphere in mitigating burnout. Interventions focused on such factors may help support mental health professionals involved in SSD patient care. ISRCTN registry ID ISRCTN21141466. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Antipsychotics increase the risk of developing diabetes, but clinical trials are not generalizable with short follow‐up, while observational studies often lack important information, particularly hemoglobin A1c (HbA1c).We followed two Danish cohorts with schizophrenia. First, using Danish nationwide registers, we identified all individuals diagnosed with first‐episode schizophrenia (FES) between 1999 and 2019 (n = 31,856). Exposure was a redeemed prescription for an antipsychotic, and the outcome was diabetes, defined via hospital‐based diagnosis and redeemed prescriptions for glucose‐lowering drugs. Adjusted Cox regression calculated hazard rate ratios (HRR). Second, using data from the Central Denmark Region, we identified all individuals diagnosed with FES from October 2016 to September 2022 (n = 2671). Using a within‐subject design, we analyzed the change in HbA1c during the 2 years after initiation of specific antipsychotics compared to the 2 years before.In the nationwide cohort, 2543 (8.0%) individuals developed diabetes (incidence rate = 9.39 [95% CI = 9.03–9.76] per 1000 person‐years). Antipsychotics, compared to periods without, were associated with an increased risk of developing diabetes (HRR = 2.04, 95% CI = 1.75–2.38). We found a dose–response association, particularly for second‐generation antipsychotics, and different risk rates for specific antipsychotics. In the Central Denmark Region cohort, a total of 9.2% developed diabetes but mean HbA1c levels remained stable at 37 mmol/mol during the 2 years after initiation of antipsychotic medication.This comprehensive real‐world two‐cohort study emphasizes that diabetes affects almost 10% of patients with FES. Antipsychotics increase this risk, while HbA1c deterioration requires longer treatment. These findings are important for clinicians and young patients with FES. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a typical symptom of both neurodegenerative and certain other diseases. In connection with these different pathologies, the etiology and neurological and metabolic changes associated with cognitive impairment must differ. Until these characteristics and differences are understood in greater detail, pharmacological treatment of the different forms of cognitive impairment remains suboptimal. Neurotransmitter receptors, including neuronal nicotinic acetylcholine receptors (nAChRs), dopamine receptors, and glutamine receptors, play key roles in the functions and metabolisms of the brain. Among these, the role of nAChRs in the development of cognitive impairment has attracted more and more attention. The present review summarizes what is presently known concerning the structure, distribution, metabolism, and function of nAChRs, as well as their involvement in major cognitive disorders such as Alzheimer's disease, Parkinson's disease, vascular dementia, schizophrenia, and diabetes mellitus. As will be discussed, the relevant scientific literature reveals clearly that the α4β2 and α7 nAChR subtypes and/or subunits of the receptors play major roles in maintaining cognitive function and in neuroprotection of the brain. Accordingly, focusing on these as targets of drug therapy can be expected to lead to breakthroughs in the treatment of cognitive disorders such as AD and schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Patients with chronic schizophrenia (SZ) have a high risk of suicide, and their cognition function is impaired. We aimed to explore the relationship between attention and suicidal ideation among patients with adult‐onset chronic SZ. Methods: A total of 416 patients with adult‐onset chronic SZ were enrolled in this study. We divided patients into suicidal ideation group and non‐suicidal ideation group according to the evaluation results of the Beck Scale for Suicide Ideation. Psychotic symptoms were measured by Positive and Negative Syndrome Scale (PANSS), and cognitive function was measured by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Insomnia symptoms were measured by Insomnia Severity Index (ISI). Results: Age was significantly different (44.28 ± 10.58 vs. 48.46 ± 12.23, t = 10.64, p = 0.001) between the two groups, and the patients with suicidal ideation were younger than patients without suicidal ideation. The positive symptom scores of the PANSS, the scores of ISI, and attention scores of RBANS were higher in patients with suicidal ideation than patients without suicidal ideation (17.30 ± 5.67 vs. 15.58 ± 4.90, t = 9.633, p = 0.002; 3.00 [1.00–6.00] vs. 2.00 [1.00–3.50], Z = −2.048, p = 0.041; 81.80 ± 14.99 vs. 76.91 ± 13.88, t = 10.101, p = 0.002). In the logistic regression analysis, age (odds ratio [OR], 0.973; 95% confidence interval [95%CI], [0.955–0.992]; p = 0.005), positive symptom scores of PANSS (OR, 1.063; 95%CI, [1.019–1.109]; p = 0.005), ISI scores (OR, 1.098; 95%CI, [1.037–1.163]; p = 0.001), and attention scores of RBANS (OR, 1.029; 95%CI, [1.013–1.047]; p = 0.001) were independently associated with the occurrence of suicidal ideation among patients with adult‐onset chronic SZ. Conclusions: High attention scores of RBANS were a risk factor for suicidal ideation among patients with adult‐onset chronic SZ. [ABSTRACT FROM AUTHOR]

The term "catatonia" was introduced by German psychiatrist Karl Kahlbaum in 1874. Although historically tied to schizophrenia, catatonia exhibits a diverse range of phenotypes and has been observed in various medical and neuropsychiatric conditions. Its intrinsic movement characteristics and association with hypokinetic and hyperkinetic phenomenologies place catatonia within the purview of movement disorders. Despite the presence of catatonia in psychiatry literature for over 150 years, many gaps and controversies persist regarding its etiopathogenesis, phenomenology, diagnostic criteria, and treatment. The current versions of the International Classification of Diseases (ICD‐11) and the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5) require clinicians to identify any three signs of 15 (ICD‐11) or 12 (DSM‐5) for the diagnosis of catatonia. Catalepsy and waxy flexibility are the only motor features with high specificity for the diagnosis. We highlight the gaps and controversies in catatonia as a movement disorder, emphasize the lack of a clear definition, and discuss the inconsistencies in the description of various catatonic signs. We propose the exploration of a bi‐axial classification framework similar to that used for dystonia and tremor to encourage the evaluation of underlying etiologies and to guide therapeutic decisions to improve the outcome of these patients. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Individuals diagnosed with schizophrenia (SZ) demonstrate difficulty distinguishing between internally and externally generated stimuli. These aberrations in "source monitoring" have been theorized as contributing to symptoms of the disorder, including hallucinations and delusions. Altered connectivity within the default mode network (DMN) of the brain has been proposed as a mechanism through which discrimination between self‐generated and externally generated events is disrupted. Source monitoring abnormalities in SZ have additionally been linked to impairments in selective attention and inhibitory processing, which are reliably observed via the N100 component of the event‐related brain potential elicited during an auditory paired‐stimulus paradigm. Given overlapping constructs associated with DMN connectivity and N100 in SZ, the present investigation evaluated relationships between these measures of disorder‐related dysfunction and sought to clarify the nature of task‐based DMN function in SZ. DMN connectivity and N100 measures were assessed using EEG recorded from SZ during their first episode of illness (N = 52) and demographically matched healthy comparison participants (N = 25). SZ demonstrated less evoked theta‐band connectivity within DMN following presentation of pairs of identical auditory stimuli than HC. Greater DMN connectivity among SZ was associated with better performance on measures of sustained attention (p =.03) and working memory (p =.09), as well as lower severity of negative symptoms, though it was not predictive of N100 measures. Together, present findings provide EEG evidence of lower task‐based connectivity among first‐episode SZ, reflecting disruptions of DMN functions that support cognitive processes. Attentional processes captured by N100 appear to be supported by different neural mechanisms. The present study provides evidence of lower connectivity within the brain's default mode network (DMN) among individuals with schizophrenia relative to healthy comparison participants during inhibitory processing. Greater connectivity predicted better cognitive performance and lower symptom severity, implicating DMN in support of these functions and identifying a potential treatment target. Contrary to previous theories that DMN activity interferes with task‐related processing, present findings suggest specific DMN functions may support cognitive processes elicited during task performance. [ABSTRACT FROM AUTHOR]

Exposure to infectious or non‐infectious immune activation during early development is a serious risk factor for long‐term behavioural dysfunctions. Mouse models of maternal immune activation (MIA) have increasingly been used to address neuronal and behavioural dysfunctions in response to prenatal infections. One commonly employed MIA model involves administering poly(I:C) (polyriboinosinic‐polyribocytdilic acid), a synthetic analogue of double‐stranded RNA, during gestation, which robustly induces an acute viral‐like inflammatory response. Using electroencephalography (EEG) and infrared (IR) activity recordings, we explored alterations in sleep/wake, circadian and locomotor activity patterns on the adult male offspring of poly(I:C)‐treated mothers. Our findings demonstrate that these offspring displayed reduced home cage activity during the (subjective) night under both light/dark or constant darkness conditions. In line with this finding, these mice exhibited an increase in non‐rapid eye movement (NREM) sleep duration as well as an increase in sleep spindles density. Following sleep deprivation, poly(I:C)‐exposed offspring extended NREM sleep duration and prolonged NREM sleep bouts during the dark phase as compared with non‐exposed mice. Additionally, these mice exhibited a significant alteration in NREM sleep EEG spectral power under heightened sleep pressure. Together, our study highlights the lasting effects of infection and/or immune activation during pregnancy on circadian activity and sleep/wake patterns in the offspring. [ABSTRACT FROM AUTHOR]

Aim: Cerebello‐cortical functional dysconnectivity plays a key role in the pathology of schizophrenia (SZ). We aimed to investigate the changes in cerebello‐cortical directional connectivity in patients with SZ. Methods: A total of 180 drug‐naïve patients with first‐episode SZ (54 reassessed after 1 year of treatment) and 166 healthy controls (HCs) were included. Resting‐state functional magnetic resonance imaging was used to perform Granger causal analysis, in which each of the nine cerebellar functional systems was defined as a seed. The observed effective connectivity (EC) alterations at baseline were further assessed at follow‐up and were associated with changes in psychotic symptom. Results: We observed increased bottom‐up EC in first‐episode SZ from the cerebellum to the cerebrum (e.g. from the cerebellar attention and cingulo‐opercular systems to the bilateral angular gyri, and from the cerebellar cingulo‐opercular system to the right inferior frontal gyrus). In contrast, decreased top‐down EC in the first‐episode SZ was mainly from the cerebrum to the cerebellum (e.g. from the right inferior temporal gyrus, left middle temporal gyrus, left putamen, and right angular gyrus to the cerebellar language system). After 1 year of antipsychotic treatment, information projections from the cerebrum to the cerebellum were partly restored and positively related to symptom remission. Conclusion: These findings suggest that decreased top‐down EC during the acute phase of SZ may be a state‐dependent alteration related to symptoms and medication. However, increased bottom‐up EC may reflect a persistent pathological trait. [ABSTRACT FROM AUTHOR]

In order to accelerate drug development and avoid unnecessary drug trials in vulnerable pediatric populations, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents. Extrapolation is based on the evidence‐based assumptions that (1) disease characteristics and (2) response to therapy, are similar in adults and adolescents. Whereas the FDA validated the extrapolation approach using data from multiple drug development programs, aripiprazole data are the most relevant to confirm the validity of the extrapolation approach for brexpiprazole, since aripiprazole and brexpiprazole both modulate dopaminergic and serotonergic signaling in the brain. The aims of this analysis were (1) to quantitatively assess the aripiprazole exposure (average steady‐state concentration)–response (Positive and Negative Syndrome Scale total score change from baseline) similarity between adults and adolescents with schizophrenia, (2) to extend the aripiprazole exposure–response modeling to brexpiprazole using adult data, and (3) to use the brexpiprazole model to predict schizophrenia symptom response in adolescents. Disease–drug–dropout models were developed using patient‐level data from clinical studies of aripiprazole (1007 adults, 294 adolescents) and brexpiprazole (1235 adults) in schizophrenia. The aripiprazole model demonstrated similar exposure–response between adults and adolescents with schizophrenia, validating the extrapolation approach. Extrapolation of the brexpiprazole adult exposure–response model to adolescents predicted the efficacy of brexpiprazole in adolescents aged 13‐17 years with schizophrenia. [ABSTRACT FROM AUTHOR]

Aims: Phosphodiesterase 2 (PDE2) regulates intracellular cyclic adenosine monophosphate and guanosine monophosphate (cAMP/cGMP) levels, which contribute to processes crucial for learning and memory. BI 474121, a potent and selective PDE2 inhibitor, is in development for treating cognitive impairment associated with schizophrenia. Methods: The effects of BI 474121 on cGMP concentrations were first assessed in rat cerebrospinal fluid (CSF) to demonstrate central nervous system (CNS) and functional target engagement. Next, a Phase I study in healthy participants assessed the pharmacokinetics of BI 474121 in CSF vs. plasma, the pharmacodynamics of BI 474121 by measuring cGMP concentrations in the CSF, and the safety of BI 474121. Results: In rats, BI 474121 was associated with a dose‐dependent increase (71% at the highest dose tested [3.0 mg kg−1]) in cGMP levels in the CSF relative to vehicle (P < 0.001). In healthy participants, the maximum‐measured concentration CSF‐to‐plasma ratio for BI 474121 exposure was similar following single oral doses of BI 474121 2.5, 10, 20 and 40 mg (dose‐adjusted geometric mean: 8.96% overall). BI 474121 2.5–40 mg administration in healthy participants also increased cGMP levels in CSF (maximum exposure‐related change from baseline ratio, BI 474121: 1.44–2.20 vs. placebo: 1.26). The most common treatment‐emergent adverse event (AE) was mild‐to‐moderate post‐lumbar puncture syndrome, which resolved with standard treatment. No AEs of special interest were observed. Conclusions: BI 474121 crosses the blood–brain barrier to inhibit PDE2, supporting cGMP as a translational marker to monitor CNS target engagement. These findings promote further clinical development of BI 474121. ClinicalTrials.gov number (NCT04672954). [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion People with severe mental illness (SMI) have a higher risk of suicide compared with the general population. However, variations in suicide methods between people with different SMIs have not been examined. The aim of this pre‐registered (PROSPERO CRD42022351748) systematic review was to pool the odds of people with SMI who die by suicide versus those with no SMI, stratified by suicide method.Searches were conducted on December 11, 2023 across PubMed, PsycInfo, CINAHL, and Embase. Eligible studies were those that reported suicide deaths stratified by SMI and suicide methods. Studies were pooled in a random‐effects meta‐analysis, and risk of bias was measured by the Joanna Briggs Institute checklist.After screening, 12 studies were eligible (n = 380,523). Compared with those with no SMI, people with schizophrenia had 3.38× higher odds of jumping from heights (95% CI: 2.08–5.50), 1.93× higher odds of drowning (95% CI: 1.50–2.48). People with bipolar disorder also had 3.2× higher odds of jumping from heights (95% CI: 2.70–3.78). Finally, people with major depression had 3.11× higher odds of drug overdose (95% CI: 1.53–6.31), 2.11× higher odds of jumping from heights (95% CI: 1.93–2.31), and 2.33× lower odds of dying by firearms (OR = 0.43, 95% CI: 0.33–0.56). No studies were classified as high risk of bias, and no outcomes had high levels of imprecision or indirectness.These findings could inform lethal means counselling practices in this population. Additionally individual, clinical, community and public health interventions for people with SMI should prioritise, where feasible, means restriction including access to heights or drugs to overdose. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Materials and Methods Results Conclusions Individuals with schizophrenia present anomalies in the extension and plasticity of the peripersonal space (PPS), the section of space surrounding the body, shaped through motor experiences. A weak multisensory integration in PPS would contribute to an impairment of self‐embodiment processing, a core feature of the disorder linked to specific subjective experiences.In this exploratory study, we aimed at: (1) testing an association between PPS features, psychopathology, and subjective experiences in schizophrenia; (2) describing the PPS profile in individuals with early‐onset schizophrenia.Twenty‐seven individuals with schizophrenia underwent a task measuring the PPS size and boundaries demarcation before and after a motor training with a tool. The Positive And Negative Syndrome Scale (PANSS), the Examination of Anomalous Self Experience scale (EASE) and the Autism Rating Scale (ARS) were used to assess psychopathology. Subsequently, participants were divided into two subgroups, early and adult‐onset schizophrenia. The two groups were compared in regard to their PPS and psychopathological profiles.PPS patterns were associated with psychopathology, particularly positively with PANSS negative scale score, and negatively with subjective experiences of existential reorientation (EASE Domain 5 scores) and of social encounters (ARS scores). Only PPS parameters and ARS scores differentiated between early and adult‐onset participants.Our results, although preliminary and exploratory, can suggest a link between PPS patterns, negative symptoms, and disturbances of the subjective experience, particularly in the intersubjective domain, in schizophrenia. Moreover, they seem to suggest that specific PPS profiles and schizophrenic autism traits could be markers of early‐onset schizophrenia. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Schizophrenia, a debilitating mental disorder, is characterized by persistent negative symptoms such as avolition and anhedonia. Currently, there are no effective treatments available for these symptoms. Thus, our study aims to assess the efficacy of online high‐definition transcranial direct current stimulation (online HD‐tDCS) in addressing the negative symptoms of schizophrenia, utilizing a double‐blind, randomized, sham‐controlled trial design.Fifty‐nine patients with schizophrenia were randomized to receive either active HD‐tDCS or sham stimulation, targeting the left dorsolateral prefrontal cortex. Outcomes were measured by changes in the Positive and Negative Syndrome Scale Factor Score for Negative Symptom (PANSS‐FSNS). Exact low‐resolution electromagnetic tomography was used to assess the functional connectivity.All 59 participants, including 50.84% females with an average age of 43.36 years, completed the trial. In the intention‐to‐treat analysis, patients receiving active HD‐tDCS showed greater improvement in PANSS‐FSNS scores compared to those receiving the sham procedure. The differences were 2.34 (95% confidence interval [CI], 1.28–3.40), 4.28 (95% CI, 2.93–5.62), and 4.91 (95% CI, 3.29–6.52) after the intervention, as well as at 1‐week and 1‐month follow‐ups, respectively. A tingling sensation on the scalp was more common in the active group (63.3%) compared to the sham group (10.3%). Additionally, HD‐tDCS was associated with a decrease in delta‐band connectivity within the default mode network.High‐definition transcranial direct current stimulation was effective and safe in ameliorating negative symptoms in patients with schizophrenia when combined with online functional targeting. [ABSTRACT FROM AUTHOR]

Schizophrenia (SZ) is a highly heritable mental disorder, and genome‐wide association studies have identified the association between deleted in colorectal cancer (DCC) and SZ. Previous study has shown a lowered expression of DCC in the cerebral cortex of SZ patient. In this study, we identified novel single nucleotide polymorphisms (SNPs) of DCC statistically correlated with SZ. Based on these, we generated DCC conditional knockout (CKO) mice and explored behavioral phenotypes in these mice. We observed that deletion of DCC in cortical layer VI but not layer V led to deficits in fear and spatial memory, as well as defective sensorimotor gating revealed by the prepulse inhibition test (PPI). Critically, the defective sensorimotor gating could be restored by olanzapine, an antipsychotic drug. Furthermore, we found that the levels of p‐AKT and p‐GSK3α/β were decreased, which was responsible for impaired PPI in the DCC‐deficient mice. Finally, the DCC‐deficient mice also displayed reduced spine density of pyramidal neurons and disturbed delta‐oscillations. Our data, for the first time, identified and explored downstream substrates and signaling pathway of DCC which supports the hypothesis that DCC is a SZ‐related risky gene and when defective, may promote SZ‐like pathogenesis and behavioral phenotypes in mice. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Recent advances in multivariate pattern recognition have fostered the search for reliable neuroimaging‐based biomarkers in psychiatric conditions, including schizophrenia. These approaches consider the complex pattern of alterations in brain function and structure, overcoming the limitations of traditional univariate methods. To assess the reliability of neuroimaging‐based biomarkers and the contribution of study characteristics in distinguishing individuals with schizophrenia spectrum disorder (SSD) from healthy controls (HCs), we conducted a systematic review of the studies that used multivariate pattern recognition for this objective.We systematically searched PubMed, Scopus, and Web of Science for studies on SSD classification using multivariate pattern analysis on magnetic resonance imaging data. We employed a bivariate random‐effects meta‐analytic model to explore the classification of sensitivity (SE) and specificity (SP) across studies while also evaluating the moderator effects of clinical and non‐clinical variables.A total of 119 studies (with 12,723 patients with SSD and 13,196 HCs) were identified. The meta‐analysis estimated a SE of 79.1% (95% confidence interval [CI], 77.1%–81.0%) and a SP of 80.0% (95% CI, 77.8%–82.0%). In particular, the Positive and Negative Syndrome Scale and the Global Assessment of Functioning scores, age, age of onset, duration of untreated psychosis, deep learning, algorithm type, features selection, and validation methods had significant effects on classification performance.Multivariate pattern analysis reliably identifies neuroimaging‐based biomarkers of SSD, achieving ∼80% SE and SP. Despite clinical heterogeneity, discernible brain modifications effectively differentiate SSD from HCs. Classification performance depends on patient‐related and methodological factors crucial for the development, validation, and application of prospective models in clinical settings. [ABSTRACT FROM AUTHOR]

Background Method Results Conclusion Nonadherence/discontinuation of antipsychotic (AP) medications represents an important clinical issue in patients across psychiatric disorders, including schizophrenia spectrum disorders (SSDs). While antipsychotic‐induced weight gain (AIWG) is a reported contributor to nonadherence, a systematic review of the association between AIWG and medication nonadherence/discontinuation has not been explored previously.A systematic search was conducted in MEDLINE, EMBASE, PsychINFO, CINAHL, and CENTRAL databases, among others, to help identify all studies which explored adherence, study dropouts, AP switching and/or discontinuations attributable to AIWG among individuals with severe mental illness. A meta‐analysis was also completed where applicable.We identified two categories of studies for the meta‐analysis. Category 1 included three studies, which compared measures of AP adherence or discontinuation across BMI classes/degrees of self‐reported weight gain. When compared to normal weight individuals receiving APs or those who did not report AIWG, individuals who were either overweight or obese or reported weight gain in relation to AP use had an increased odds of AP nonadherence (OR 2.37; 95% CI 1.51–3.73; p = 0.0002). Category 2 had 14 studies which compared measures of discontinuation related to weight gain reported as an adverse effect across different APs. Olanzapine was associated with a 3.32 times (95% CI 2.32–4.74; p < 0.00001) increased likelihood of nonadherence or discontinuation when compared to other APs with lower weight gain liabilities. Similarly, APs with moderate weight gain liability (paliperidone, risperidone, and quetiapine) increased the odds of nonadherence or discontinuation by 2.25 (95% CI 1.31–3.87; p = 0.003) when compared to APs considered to have lower weight gain liability (i.e. haloperidol and aripiprazole). The qualitative summary also confirmed these findings.This review and meta‐analysis suggests that AIWG influences medication nonadherence/discontinuation, whereby APs with higher weight gain liability are associated with nonadherence/discontinuation. Additional studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Social dysfunctions are common in various psychiatric disorders, including depression, schizophrenia, and autism, and are long‐lasting and difficult to treat. The development of treatments for social impairment is critical for the treatment of several psychiatric disorders. “Amyloban 3399,” a product extracted from the mushroom Hericium erinaceus, markedly improves social dysfunctions in patients with treatment‐resistant schizophrenia and depression. However, the molecular mechanism(s) through which amyloban ameliorates social impairment remains unclear. To clarify this mechanism, in this study, we aimed to establish a mouse model of social defeat stress (SDS) and investigate the effects of amyloban on social deficits. Amyloban administration ameliorated social deficits and the dopamine system activity in SDS mice. These findings suggest that there is a possibility that amyloban may improve social deficits by suppressing the hyperactivation of the dopaminergic system. Amyloban may be an effective treatment for social dysfunctions associated with various psychiatric disorders. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions Real‐world data (RWD) for paliperidone palmitate (PP) three‐monthly (PP3M) is lacking based on Japan label requirements. This study evaluated the clinical effectiveness of PP3M versus PP once‐monthly (PP1M) in patients with schizophrenia administered according to Japan label requirements.Retrospective analyses were conducted using RWD from Merative™ MarketScan® Multi‐State Medicaid (MDCD) claims database (June 2015–December 2022). Adult patients with schizophrenia switching from PP1M to PP3M were included. Patients transitioning to PP3M were matched with patients who continued with PP1M using propensity score matching (PSM) at 1:1 ratio. Primary hypothesis aimed to investigate non‐inferiority of PP3M versus PP1M in terms of relapse‐free status at 24 months from index PP injection. Outcome measures were proportions of relapse‐free patients at 24 months, time to relapse, treatment persistence, and adherence.Total 4252 eligible adult schizophrenia patients on PP (PP3M:582; PP1M:3670) were identified. After PSM, each PP cohort comprised 562 matched individuals. Estimated proportion of relapse‐free patients was higher in PP3M (85.7%) versus PP1M (77.9%), per Japan PP label. PP3M demonstrated superiority to PP1M after testing for non‐inferiority in terms of achieving relapse‐free status at 24 months, with an estimated difference of 7.8% (95% CI: 1.7%–13.9%). PP3M cohort had lower risk of relapse (HR: 0.605; CI: 0.427–0.856), longer treatment persistence, and higher treatment adherence versus PP1M cohort.Findings suggests that patients who switched to PP3M might be able to reduce risk of relapse compared to those who continued PP1M after aligning particularly with Japan's label requirements. [ABSTRACT FROM AUTHOR]

Aim: People at clinical high risk (CHR) for psychosis are a heterogeneous population in regard to clinical presentation and outcome. It is unclear, however, if their baseline clinical characteristics can be used to construct orthogonal subgroups that differ in their clinical trajectory to provide early identification of individuals in need of tailored interventions. Methods: We used latent profile analysis (LPA) to determine the number of distinct clinical profiles within the CHR population using the NAPLS‐3 dataset, focusing on the clinical features incorporated in the NAPLS psychosis risk calculator (including age, unusual thought content and suspiciousness, processing speed, verbal learning and memory function, social functioning decline, life events, childhood trauma, and family history of psychosis). We then conducted a between‐profile comparisons of clinical trajectories based on psychotic and depressive symptoms as well as substance use disorder (SUD) related features over time. Results: Two distinct profiles emerged. One profile, comprising approximately 25% of the sample, was significantly older, displayed better cognitive performance, experienced more types of traumatic and undesirable life events, exhibited a greater decline in functioning in the past year, and was more likely to have relatives with psychosis. This group showed worse positive symptoms and SUD‐related features over time, although groups did not differ in the proportion of individuals who developed psychosis. Conclusions: LPA results suggest CHRs can be segregated into two profiles with different clinical trajectories. Characterizing individuals within these clinical profiles may help understand the divergent outcomes of this population and ultimately facilitate the development of specialized interventions. [ABSTRACT FROM AUTHOR]

Schizophrenia, as a stressful diagnosis, profoundly impacts the whole family, especially people with schizophrenia and their caregivers. This study tested the potential mediating role of expressed emotion in the association between mental health stigma and quality of life in caregiver‐patient dyads. Using a 2‐wave longitudinal design with a 6‐month interval between assessments, 161 dyads of patients with schizophrenia and their family caregivers (one patient and one caregiver) completed measures of mental health stigma, expressed emotion, and quality of life. The results showed that patients' self‐stigma had no significant actor or partner effect on expressed emotion or quality of life. In contrast, caregivers' stigmatizing attitudes toward patients had a significant partner effect on patients' perception of caregivers' expressed emotion and quality of life. The mediating effect of patients' perception of caregivers' expressed emotion in the association between caregivers' stigmatizing ideas toward patients and patients' quality of life was significant. By focusing on the interdependence of patients and their caregivers, this study highlights the role of caregivers' stigmatizing attitudes toward patients and patients' perception of caregivers' expressed emotion on patients' quality of life. Psychoeducation and interventions should not only aim to reduce the self‐stigma of people with schizophrenia but also their caregivers' stigmatizing ideas toward patients. Family interventions targeted at reducing the EE level of caregivers and patients' perception of caregivers' EE would also benefit the adaptation and quality of life of people with schizophrenia and their caregivers. [ABSTRACT FROM AUTHOR]

Objectives: Stimuli that are separated by a short window of space or time, known as spatial and temporal binding windows (SBW/TBWs), may be perceived as separate. Widened TBWs are evidenced in schizophrenia, although it is unclear if the SBW is similarly affected. The current study aimed to assess if dexamphetamine (DEX) may increase SBWs in a multimodal visuo‐tactile illusion, potentially validating usefulness as an experimental model for multimodal visuo‐tactile hallucinations in schizophrenia, and to examine a possible association between altered binding windows (BWs) and working memory (WM) suggested by previous research. Methods: A placebo‐controlled, double‐blinded, and counter‐balanced crossover design was employed. Permuted block randomisation was used for drug order. Healthy participants received DEX (0.45 mg/kg, PO, b.i.d.) or placebo (glucose powder) in capsules. The Rubber Hand Illusion (RHI) and Wechsler Adult Intelligence Scale Spatial Span was employed to determine whether DEX would alter SBWs and WM, respectively. Schizotypy was assessed with a variety of psychological scales. Results: Most participants did not experience the RHI even under normal circumstances. Bi‐directional and multimodal effects of DEX on individual SBWs and schizotypy were observed, but not on WM. Conclusions: Bidirectional multimodal effects of DEX on the RHI and SBWs were observed in individuals, although not associated with alterations in WM. [ABSTRACT FROM AUTHOR]

Alterations in the white matter have been implicated in schizophrenia. Myelin basic protein (MBP), a component of the myelin sheath, in the cerebrospinal fluid (CSF) has been suggested as a biomarker for white matter damage in demyelinating diseases. This prompted us to examine the CSF‐MBP levels in patients with schizophrenia. We analyzed the CSF‐MBP levels in 152 patients with schizophrenia and 117 age‐ and sex‐matched controls. A significant positive correlation between age and CSF‐MBP levels was observed both in the patients (p < 0.001) and controls (p = 0.014). No significant difference was observed in the CSF‐MBP levels between the two groups. However, among a subsample of the patients (N = 32), a significantly negative correlation was observed between CSF‐MBP and age‐adjusted motor speed score of the brief assessment of cognition in schizophrenia (ρ = −0.59, p < 0.001). Further, among patients who underwent diffusional magnetic resonance imaging of the brain (N = 27), the CSF‐MBP levels showed a significantly negative correlation with the mean kurtosis value in the right temporo‐parietal region (p < 0.001). Our results suggest that the CSF‐MBP level has limited utility as a diagnostic marker; however, higher CSF‐MBP levels are associated with poorer motor speed, which may be associated with regional white matter damage in the brain in patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Constipation is a prevalent gastrointestinal disorder that affects people globally, decreasing their quality of life and life expectancy. Individuals with schizophrenia often suffer from constipation, which could be a result of the illness itself or the side effects of psychotropic medications. However, little research has been conducted on factors contributing to constipation in individuals with schizophrenia. To address this issue, we conducted a survey using self‐administered questionnaires and medical records to identify factors associated with constipation in psychiatric outpatients. This study included 399 patients with schizophrenia, resulting in a high prevalence of constipation (43.4%). The analysis suggested that female gender, the doses of antiparkinsonian medications, and benzodiazepine sleeping pills may be associated with constipation. [ABSTRACT FROM AUTHOR]

Background: In patients with schizophrenia, violent behavior is a clinically important factor that prevents their discharge. Clozapine is an effective antipsychotic medication for treatment‐resistant schizophrenia, and its usefulness for aggressive behavior has also been suggested. Case Presentation: We present the case of a 38‐year‐old male patient diagnosed with schizophrenia who was successfully treated with clozapine after recurrent violent behavior. He was diagnosed with schizophrenia during his adolescence. He was hospitalized for treatment in his teens, but his hallucinations and delusions persisted even after discharge. In his 30s, he became noticeably emotionally unstable, and despite being treated for an adequate period with sufficient doses of several antipsychotics, his symptoms did not improve. This led to repeated hospitalizations triggered by violent behavior toward his parents and siblings within the home. During his fourth hospitalization, clozapine was initiated due to multiple incidents of violence toward nursing staff secondary to hallucinations and delusions. As the dose of clozapine was gradually increased with therapeutic drug monitoring, the patient's hostility, uncooperativeness, and suspiciousness markedly improved, and his aggressive behavior disappeared. He was discharged to a facility on day 194 after starting clozapine and has continued outpatient visits. Conclusion: Clozapine was suggested to be effective for aggressive behavior in patients with treatment‐resistant schizophrenia and should be actively considered. In such cases, regular measurement of blood concentration is useful for adjusting the dosage of clozapine. [ABSTRACT FROM AUTHOR]

Objectives: Metacognitive training (MCT) for psychosis is a group intervention that combines cognitive‐behavioural therapy and psychoeducation. It has proven efficacy in reducing psychotic symptoms and correcting cognitive biases implicated in the development and maintenance of psychotic symptoms. However, other outcomes, such as patient satisfaction with the intervention, have not been well studied despite their importance for adherence and overall success. A systematic review of randomized clinical trials was conducted to assess satisfaction with MCT among adults with psychotic spectrum disorders. Methods: The search was conducted in Ovid Embase, Ovid MEDLINE, PsycINFO and Cochrane Central Register of Controlled Trials (CENTRAL). PRISMA guidelines and the Cochrane Risk of Bias Tool were followed, and certainty of evidence was ascertained using the Grading of Recommendations Assessment, Development and Evaluation framework. The study is registered with PROSPERO (CRD42023418097). Results: Patient satisfaction was considered the primary outcome in 3 of the 10 studies reviewed. Four studies compared MCT with other psychosocial interventions (a newspaper discussion group, cognitive remediation and supportive therapy), two of which found significantly higher satisfaction with MCT. A high percentage of all patients found MCT comprehensible and considered it an important part of their treatment; they would recommend the training to others and found the group setting advantageous. Most participants expressed high subjective satisfaction or acceptance of MCT. Conclusions: The authors found evidence that MCT may be associated with high levels of satisfaction in clinical trials whose main objective is to assess patient satisfaction, but more research is needed to consolidate the findings, especially for the extended version of MCT. [ABSTRACT FROM AUTHOR]

Background: Children of parents with a severe mental illness have an increased risk of developing a lifetime mental illness. We aimed to compare the effects of a preventive family‐based intervention, VIA Family, with treatment as usual (TAU) on these children's global functioning. Methods: Between 2017 and 2021, we conducted a pragmatic, rater‐blinded, two‐arm parallel‐group superiority trial in Denmark. Families with at least one child aged 6–12 years and at least one biological parent with schizophrenia spectrum disorder, bipolar disorder, or recurrent major or moderate depression were included. We randomly allocated 95 families with their 113 children to VIA Family or TAU (ratio 1:1). VIA Family was individually tailored and based on case management. The intervention included options for psychoeducation, parental support, and treatment for emerging child psychiatric symptoms. Blinded raters assessed children and their families at baseline and after 18 months. The primary outcome was the difference in change between groups at end‐of‐treatment in daily global functioning measured with the Children's Global Assessment Scale. Secondary outcomes were emotional and behavioral problems and days absent from school. We analyzed data blinded to allocation. Results: At post‐intervention, differences in mean change from baseline between VIA Family and TAU were non‐significant (CGAS: −1.20, 95% CI = −6.61; 4.21, p = 0.66), as were the differences on the secondary and exploratory outcomes. Conclusion: Contrary to our hypothesis, we did not find a superior effect of VIA Family compared with TAU. The short follow‐up period and large sample heterogeneity might explain the null findings. Therefore, a possible long‐term, preventive treatment effect has yet to be explored. [ABSTRACT FROM AUTHOR]

Schizophrenic individuals display disrupted myelination patterns, altered oligodendrocyte distribution, and abnormal oligodendrocyte morphology. Schizophrenia is linked with dysregulation of a variety of genes involved in oligodendrocyte function and myelin production. Single‐nucleotide polymorphisms (SNPs) and rare mutations in myelination‐related genes are observed in certain schizophrenic populations, representing potential genetic risk factors. Downregulation of myelination‐related RNAs and proteins, particularly in frontal and limbic regions, is consistently associated with the disorder across multiple studies. These findings support the notion that disruptions in myelination may contribute to the cognitive and behavioral impairments experienced in schizophrenia, although further evidence of causation is needed. [ABSTRACT FROM AUTHOR]

Recent studies have highlighted the potential involvement of reactive oxygen species (ROS) and microglia, a major source of ROS, in the pathophysiology of schizophrenia. In our study, we explored how the second‐generation antipsychotic risperidone (RIS) affects ROS regulation and microglial activation in the hippocampus using a mouse ketamine (KET) model of schizophrenia. KET administration resulted in schizophrenia‐like behaviors in male C57BL/6J mice, such as impaired prepulse inhibition (PPI) of the acoustic startle response and hyper‐locomotion. These behaviors were mitigated by RIS. We found that the gene expression level of an enzyme responsible for ROS production (Nox2), which is primarily associated with activated microglia, was lower in KET/RIS‐treated mice than in KET‐treated mice. Conversely, the levels of antioxidant enzymes (Ho‐1 and Gclc) were higher in KET/RIS‐treated mice. The microglial density in the hippocampus was increased in KET‐treated mice, which was counteracted by RIS. Hierarchical cluster analysis revealed three morphological subtypes of microglia. In control mice, most microglia were resting‐ramified (type I, 89.7%). KET administration shifted the microglial composition to moderately ramified (type II, 44.4%) and hyper‐ramified (type III, 25.0%). In KET/RIS‐treated mice, type II decreased to 32.0%, while type III increased to 34.0%. An in vitro ROS assay showed that KET increased ROS production in dissociated hippocampal microglia, and this effect was mitigated by RIS. Furthermore, we discovered that a NOX2 inhibitor could counteract KET‐induced behavioral deficits. These findings suggest that pharmacological inhibition of ROS production by RIS may play a crucial role in ameliorating schizophrenia‐related symptoms. Moreover, modulating microglial activation to regulate ROS production has emerged as a novel avenue for developing innovative treatments for schizophrenia. [ABSTRACT FROM AUTHOR]

Neuropsychiatric conditions represent a major medical and societal challenge. The etiology of these conditions is very complex and combines genetic and environmental factors. The latter, for example, excessive maternal or early postnatal inflammation, as well as various forms of psychotrauma, often act as triggers leading to mental illness after a prolonged latent period (sometimes years). Matrix metalloproteinase‐9 (MMP‐9) is an extracellularly and extrasynaptic operating protease that is markedly activated in response to the aforementioned environmental insults. MMP‐9 has also been shown to play a pivotal role in the plasticity of excitatory synapses, which, in its aberrant form, has repeatedly been implicated in the etiology of mental illness. In this conceptual review, we evaluate the experimental and clinical evidence supporting the claim that MMP‐9 is uniquely positioned to be considered a drug target for ameliorating the adverse effects of environmental insults on the development of a variety of neuropsychiatric conditions, such as schizophrenia, bipolar disorder, major depression, autism spectrum disorders, addiction, and epilepsy. We also identify specific challenges and bottlenecks hampering the translation of knowledge on MMP‐9 into new clinical treatments for the conditions above and suggest ways to overcome these barriers. [ABSTRACT FROM AUTHOR]

Schizophrenia affects identification and disturbs our thinking and motivational capacity. Long‐term use of daidzin (DZN) is evident to enhance attention and memory in experimental animals. This study aimed to investigate the effect of DZN on Swiss mice. To check animals' attention, identification, thinking, and motivational ability, we performed behavioral studies using marble burying, dust removal, and trained swimming protocols. For this, a total of 36 male Swiss albino mice were randomly divided into six groups, consisting of 6 animals in each group, as follows: control (vehicle), DZN‐1.25, DZN‐2.5, DZN‐5 mg/kg, olanzapine (OLN)‐2, and a combination of DZN‐1.25 with OLN‐2. Additionally, in silico studies are also performed to understand the possible molecular mechanisms behind this neurological effect. Findings suggest that DZN dose‐dependently and significantly (p <.05) increased marble burying and removed dust while reducing the time to reach the target point. DZN‐1.25 was found to enhance OLN's effect significantly (p <.05), possibly via agonizing its activity in animals. In silico findings suggest that DZN has strong binding affinities of ‐10.1 and ‐10.4 kcal/mol against human serotonin 2 A (5‐HT2A) and dopamine 2 (D2) receptors, respectively. Additionally, DZN exhibits favorable pharmacokinetic and toxicity properties. We suppose that DZN may exert its attention‐ and memory‐enhancing abilities by interacting with 5‐HT2A and D2 receptors. It may exert a synergistic antischizophrenia‐like effect with the standard drug, OLN. Further studies are required to discover the exact molecular mechanism for this neurological function in animals. [ABSTRACT FROM AUTHOR]

Aims: The cerebellum is involved in higher‐order mental processing as well as sensorimotor functions. Although structural abnormalities in the cerebellum have been demonstrated in schizophrenia, neuroimaging techniques are not yet applicable to identify them given the lack of biomarkers. We aimed to develop a robust diagnostic model for schizophrenia using radiomic features from T1‐weighted magnetic resonance imaging (T1‐MRI) of the cerebellum. Methods: A total of 336 participants (174 schizophrenia; 162 healthy controls [HCs]) were allocated to training (122 schizophrenia; 115 HCs) and test (52 schizophrenia; 47 HCs) cohorts. We obtained 2568 radiomic features from T1‐MRI of the cerebellar subregions. After feature selection, a light gradient boosting machine classifier was trained. The discrimination and calibration of the model were evaluated. SHapley Additive exPlanations (SHAP) was applied to determine model interpretability. Results: We identified 17 radiomic features to differentiate participants with schizophrenia from HCs. In the test cohort, the radiomics model had an area under the curve, accuracy, sensitivity, and specificity of 0.89 (95% confidence interval: 0.82–0.95), 78.8%, 88.5%, and 75.4%, respectively. The model explanation by SHAP suggested that the second‐order size zone non‐uniformity feature from the right lobule IX and first‐order energy feature from the right lobules V and VI were highly associated with the risk of schizophrenia. Conclusion: The radiomics model focused on the cerebellum demonstrates robustness in diagnosing schizophrenia. Our results suggest that microcircuit disruption in the posterior cerebellum is a disease‐defining feature of schizophrenia, and radiomics modeling has potential for supporting biomarker‐based decision‐making in clinical practice. [ABSTRACT FROM AUTHOR]

Mitochondria‐endoplasmic reticulum contacts (MERCs) mediate a close and continuous communication between both organelles that is essential for the transfer of calcium and lipids to mitochondria, necessary for cellular signalling and metabolic pathways. Their structural and molecular characterisation has shown the involvement of many proteins that bridge the membranes of the two organelles and maintain the structural stability and function of these contacts. The crosstalk between the two organelles is fundamental for proper neuronal function and is now recognised as a component of many neurological disorders. In fact, an increasing proportion of MERC proteins take part in the molecular and cellular basis of pathologies affecting the nervous system. Here we review the alterations in MERCs that have been reported for these pathologies, from neurodevelopmental and neuropsychiatric disorders to neurodegenerative diseases. Although mitochondrial abnormalities in these debilitating conditions have been extensively attributed to the high energy demand of neurons, a distinct role for MERCs is emerging as a new field of research. Understanding the molecular details of such alterations may open the way to new paths of therapeutic intervention. [ABSTRACT FROM AUTHOR]

The prevalence of pyramidal cells (PCs) in the mammalian cerebral cortex underscore their value as they play a crucial role in various brain functions, ranging from cognition, sensory processing, to motor output. PC morphology significantly influences brain connectivity and plays a critical role in maintaining normal brain function. Pathological alterations to PC morphology are thought to contribute to the aetiology of neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. This review explores the relationship between abnormalities in PC morphology in key cortical areas and the clinical manifestations in schizophrenia and ASD. We focus largely on human postmortem studies and provide evidence that dendritic segment length, complexity and spine density are differentially affected in these disorders. These morphological alterations can lead to disruptions in cortical connectivity, potentially contributing to the cognitive and behavioural deficits observed in these disorders. Furthermore, we highlight the importance of investigating the functional and structural characteristics of PCs in these disorders to illuminate the underlying pathogenesis and stimulate further research in this area. [ABSTRACT FROM AUTHOR]