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Introduction: Childhood trauma and adversities (CTA) and aberrant salience (AS) have a pivotal role in schizophrenia development, but their interplay with psychotic symptoms remains vague. We explored the mediation performed by AS between CTA and psychotic symptomatology in schizophrenia. Methods: We approached 241 adults suffering from schizophrenia spectrum disorders (SSDs), who have been in the unit for at least 12 consecutive months, excluding the diagnosis of dementia, and recent substance abuse disorder, and cross-sectional evaluated through the Aberrant Salience Inventory (ASI), Childhood Trauma Questionnaire Short-Form (CTQ-SF), and Positive and Negative Symptom Scale (PANSS). We tested a path-diagram where AS mediated the relationship between CTA and psychosis, after verifying each measure one-dimensionality through confirmatory factor analysis. Results: The final sample comprised 222 patients (36.9% female), with a mean age of 42.4 (± 13.3) years and an average antipsychotic dose of 453.6 (± 184.2) mg/day (chlorpromazine equivalents). The mean duration of untreated psychosis was 1.8 (± 2.0) years while the mean onset age was 23.9 (± 8.2) years. Significant paths were found from emotional abuse to ASI total score (β = 0.39; p

Objective markers which can reliably predict psychosis transition among individuals with at-risk mental state (ARMS) are warranted. In this study, sixty-five ARMS subjects [of whom 17 (26.2%) later developed psychosis] were recruited, and we performed supervised linear support vector machine (SVM) with a variety of combinations of.modalities (clinical features, cognition, structural magnetic resonance imaging, eventrelated.potentials, and polyunsaturated fatty acids) to predict future psychosis onset. While single-modality SVMs showed a poor to fair accuracy, multi-modal SVMs revealed better predictions, up to 0.88 of the balanced accuracy, suggesting the advantage of multi-modal machine-learning methods for forecasting psychosis onset in ARMS.

Language impairments often appear in patients with schizophrenia and are potential targets for rehabilitation. Clinical practice and research should be intimately connected. The aim was to perform a narrative review of the assessment and intervention tools that have been used for the rehabilitation of schizophrenia patients with language and communication impairments. Two types of tools, general and specific, were developed for both purposes. General tools include the Positive and Negative Syndrome Scale for assessment, and the Integrated Psychological Therapy for intervention. The specific tools used to evaluate language and communication impairments include the Scale for the Assessment of Thought, Language and Communication, the Formal Thought Disorder scales (for caregivers and patients), and the Thought and Language Disorder scale. The most recent language-specific intervention tools include the Cognitive Pragmatic Treatment, Conecta-2, Let's talk! Multimodal Speech-Gesture training, Speech Therapy Intervention Group, and PragmaCom. These tools primarily involve psychopathology/psychiatry, psychology, linguistics, speech and language therapy, and nursing. In conclusion, a wide range of assessment and intervention tools are available for the rehabilitation of language and communication impairments associated with schizophrenia. An integrative and interdisciplinary approach should always be considered for rehabilitation of language and communication in patients with schizophrenia throughout their lifetime.

Introduction: A first psychotic episode may be related to neurological diseases, especially encephalitis of infectious or autoimmune origin. It is remarkable that an immune-mediated encephalitis triggered by a confirmed subacute bacterial meningitis is documented, and this is the case we will present. Clinical case: A 22-year-old woman with no previous medical history, immunocompetent, with three months of behavioral, affective and cognitive symptoms with subsequent compromise of sensory perception and psychosis. Examination of cerebrospinal fluid showed inflammatory signs with positive FilmArray© for Streptococcus pneumoniae. She received anti-psychotic and antibiotic treatment for 2 weeks without clinical improvement. Postencephalitic syndrome with immune-mediated psychosis was considered as a diagnosis, and immunosuppressive management with corticosteroid and plasmapheresis was initiated with complete resolution of symptoms. After one year of follow-up no neurological relapse has been identified. Discussion: Encephalitis is a neurological syndrome due to brain parenchymal damage that can result in psychiatric symptoms including psychosis and behavioral changes. Its causes are usually infectious (usually viral) or autoimmune (Anti NMDA, AMPA, LGI1 or others). A psychiatric condition in bacterial meningitis without improvement with antibiotic treatment is remarkable, its presence should suggest an immune-mediated post-infectious syndrome that may respond to the use of immunomodulators even in the absence of identification of autoimmune encephalitis-associated antibodies. No similar cases have been reported in the literature. Conclusion: Immune-mediated psychosis may be a manifestation of post-encephalitic syndrome associated with bacterial meningitis and its treatment with immunosuppressants may offer benefit in cases where the use of antipsychotics and antibiotics shows no improvement.

Background: Stigmatization toward psychosis is persistent among mental health professionals (MHPs) and negatively impacts the patients' outcomes. One suggested way of reducing stigmatization is to expose MHPs to simulations of psychotic symptoms. This approach has been associated with an increase in empathy, but also with an increase in the desire of social distance. The addition of an empathic task (ET) has been suggested to neutralize this effect on social distance. The present study aims to (1) examine the effect of a remotely administered 360° immersive video (360IV) simulation on empathy and stigma among psychology students and (2) replicate the neutralizing effect of an ET on social distance. Finally, the potential role of immersive properties on changes will also be explored. Methods: A 360IV simulating auditory hallucinations was constructed in collaboration with patient partners. 121 psychology students were allocated to one of three conditions: (i) exposure to the 360IV, (ii) exposure to the 360IV and to an ET (360IV + ET), and (iii) no exposure (control). Measures of empathy and stigma (stereotypes and social distance) were collected before and after the interventions. Results: An increase of empathy was observed in the 360IV and 360IV + ET conditions compared to the control condition. There was an increase of stereotypes in all conditions and no effect on social distance. Conclusions: This study confirms the effectiveness of a 360IV simulation intervention in increasing empathy in psychology students but questions its efficacy in reducing stigma.

Background: Despite advancements in the treatment of psychosis, many patients continue to experience persistent symptoms and relapses during antipsychotic treatment, particularly when they fail to adhere to prescribed medications. Ayurveda explains psychotic disorders as “Unmada” and describes various treatment protocols. Although these therapies and methods have been in practice for several years, systematic evidence has not been generated for the same. Thus, in the current review an attempt has been made to illustrate currently available clinical trials on Ayurveda management of psychosis. Methods: We identified 23 studies by literature search in PubMed Central, Cochrane Library and AYUSH Research portal. Out of these, 21 were retrieved after systematic deduplication. After excluding nine studies, 12 studies were included for review. Results: Total of 12 articles comprising 10 clinical trials and 2 case reports were reviewed. Most of the studies demonstrated significant improvement in psychopathology assessed through various symptom rating scales. Discussion: The role of Ayurveda, in the treatment of psychosis is least explored. Currently available studies on the effect of Ayurveda treatment on psychosis are very less in number to draw a valuable conclusion. Hence there is a large scope for conducting neurobiologically informed clinical research in the management of psychotic disorders using Ayurvedic approaches.

Effective interventions for treating social anxiety in psychosis, and understanding mechanisms between social anxiety to paranoia are limited. This study investigated stigma, internal and external shame, social rank appraisals, self-esteem and safety behaviours as mediators between social anxiety and paranoia in cross-cultural Thai and UK samples. Participants aged ≥18-year-old completed a cross-sectional internet-delivered survey. Social anxiety, paranoia, depression, and hypothesised mediating variables were measured. Both of the Thailand and UK samples were analysed separately to explore cultural differences. Associations between social anxiety and paranoia were calculated by linear regression. Mediation analysis was used to test the indirect effects of mediators. Eight-hundred and forty-two people completed the survey (427 from Thailand: 415 from the UK). Linear relationships between social anxiety and paranoia were found across both countries. In multiple mediation analyses, the social anxiety-paranoia relationship controlling for depression was significantly mediated by external shame and safety behaviours in both countries. Self-esteem was also significant, but only in the UK. External shame and safety behaviours were significant mediators, cross-culturally, explaining the indirect pathway of the social anxiety-paranoia relationship. Interventions targeting external shame and safety behaviours should be tested in clinical population to guide intervention for psychosis. Hypothesised potential factors were discussed.

Background: The aim of the study was to validate the course and outcome of treatment in patients with schizophrenic disorders and to compare it with those of patients with depression using a multidimensional assessing approach measuring psychopathological, social and cognitive levels of functioning. Methods: We recruited N = 86 chronically ill patients, n = 41 with schizophrenic disorders and n = 45 with depression and examined them by means of the ASSESS battery with 5 measuring points within one year. Results: Psychopathological symptoms and cognitive functioning changed over time, but still remained. Furthermore, changes in functional ability in the psychosocial area were observed in the overall collective. The course of the patients with schizophrenic disorders differed especially from that of the patients with depression in relation to the domain personal relationships. In both groups, symptoms of the disease correlated negatively with cognition and psychosocial functioning. Cognitive deficits were associated with a reduced level of psychosocial functioning. Discussion: The ASSESS battery proved to be a practicable measuring instrument for complex assessment of the course of the disease in patients with schizophrenic disorders as well as depression. The stable course of symptoms in both disorders as well as psychosocial differences would have to be further confirmed in long term studies to derive necessary treatment recommendations.

Cardiometabolic disorders have known inflammatory implications, and peripheral measures of inflammation and cardiometabolic disorders are common in persons with psychotic disorders. Inflammatory signatures are also related to neurobiological and behavioral changes in psychosis. Relationships between systemic inflammation and cardiometabolic genetic risk in persons with psychosis have not been examined. Thirteen peripheral inflammatory markers and genome-wide genotyping were assessed in 122 participants (n ​= ​86 psychosis, n ​= ​36 healthy controls) of European ancestry. Cluster analyses of inflammatory markers classified higher and lower inflammation subgroups. Single-trait genetic risk scores (GRS) were constructed for each participant using previously reported GWAS summary statistics for the following traits: schizophrenia, bipolar disorder, major depressive disorder, coronary artery disease, type-2 diabetes, low-density lipoprotein, high-density lipoprotein, triglycerides, and waist-to-hip ratio. Genetic correlations across traits were quantified. Principal component (PC) analysis of the cardiometabolic GRSs generated six PC loadings used in regression models to examine associations with inflammation markers. Functional module discovery explored biological mechanisms of the inflammation association of cardiometabolic GRS genes. A subgroup of 38% persons with psychotic disorders was characterized with higher inflammation status. These higher inflammation individuals had lower BACS scores (p ​= ​0.038) compared to those with lower inflammation. The first PC of the cardiometabolic GRS matrix was related to higher inflammation status in persons with psychotic disorders (OR ​= ​2.037, p ​= ​0.001). Two of eight modules within the functional interaction network of cardiometabolic GRS genes were enriched for immune processes. Cardiometabolic genetic risk may predispose some individuals with psychosis to elevated inflammation which adversely impacts cognition associated with illness.

The immune and antioxidant systems are intimately connected and their role in the etiology of major psychiatric disorders is currently under study. The aim of this study was to evaluate the potential associations between inflammatory/antioxidant peripheral markers and presence of psychotic symptoms or severity of illness in patients affected by major psychiatric disorders.One hundred and twenty-six drug-free patients were included. A blood sample was collected to measure total/B/T lymphocytes and plasma levels of albumin, total bilirubin, uric acid, C-reactive protein, and vitamins A and E. Severity of illness was assessed using psychometric scales. Groups of patients divided according to diagnosis were compared in terms of measured markers using multivariate analyses of variance (MANOVAs). Linear and logistic regression analyses were performed to investigate the potential association between markers and severity of illness or presence/absence of psychotic symptoms.Albumin plasma levels were higher in patients with substance-induced psychotic disorder (SIPD) than subjects affected by schizophrenia (F ​= ​4.923; p ​= ​0.003). Lower vitamin E (OR ​= ​0.81; p ​= ​0.014) and T lymphocyte (OR ​= ​0.99; p ​= ​0.048) plasma levels were predictive of lifetime psychotic symptoms. Lower vitamin A levels were associated with higher Montgomery-Åsberg Depression Rating Scale scores (β ​= ​-24.26; p ​= ​0.029), independent of diagnosis.Patients with SIPD may be less vulnerable to oxidative stress. The severity of depressive symptoms, inversely associated with vitamin A plasma levels, is likely to be modulated by the degree of inflammation. Patients presenting with lifetime psychotic symptoms may be more vulnerable to oxidative stress and may have a higher activation of humoral immunity.

Objective: Cannabis sativa is a recreational drug commonly consumed in Europe and is getting popularity for both recreational and therapeutic use. In some individuals, the use of cannabis leads to psychotic disorders. This systematic review summarizes the current evidence linking genetic polymorphisms and inter-individual susceptibility to psychosis induced by cannabis. Method: Studies published from 2005 to 2020 were identified through Medline using PubMed, Web of Science and Scopus database and searches were conducted according to PRISMA guidelines. Initial search was performed with terms: “cannabis induced psychosis” AND “genetics”. Results: From the initial group of 108 papers, 18 studies met our inclusion criteria. Many of the findings revealed associations with genetic polymorphisms modulations of genes involved directly (COMT, DRD2 and DAT) or indirectly (AKT1) to dopamine pathways. The most consistent finding was with COMT rs4680, where the presence of the Val allele was associated with a higher risk for cannabis-induced psychosis. This higher susceptibility was also reported for AKT1 (rs2494732) with the CC genotype. Of note, the only genome-wide association study identified a significant signal close to the cholinergic receptor muscarinic 3 represented by rs115455482 and rs74722579 predisposing to cannabis-induced hallucinations and remarkably no dopaminergic target was found. Conclusion: Actual evidence supports the role of dopamine in cannabis induced psychosis. However, most of genetic polymorphism studies have as a starting point the pre-existing dopaminergic theoretical basis for psychosis. This alerts to the importance of more broad genetic studies. Integrate genetic results into biological systems may enhance our knowledge of cannabis induced psychosis and could help in the prevention and treatment of these patients.

Introduction: It has been shown that public stigma towards people with schizophrenia hinders their psychosocial integration. Public stigma expresses itself through lexical labels used in the print media and social networks, heightening the internalization of stigma in this population, a phenomenon known as internalised stigma or self-stigma. This paper analyses the diffusion in the mass media of two dimensions of stigma: public stigma and self-stigma., Methods: For public stigma, we searched for the lexical labels "schizophrenia", "schizophrenic", "psychosis" and "psychotic" in Chilean newspapers from 2010 to 2020, and for self-stigma, we used semi-structured interviews with people with a diagnosis of schizophrenia who are users of mental health services in Santiago de Chile. The findings were organised into four categories per stigma dimension. Lexical frequencies and semantic relationships were then analysed using the UAM Corpus tool and AntConc software., Results: The results showed frequent use of stigmatising labels in the written press, with harmful semantic associations such as violence, delinquency, unpredictability and danger., Conclusions: Such labels tend to be accepted by those affected, evidence of their internalisation of the stigma towards the disease, and create a barrier to integration and inclusion., (Copyright © 2022 Elsevier España, S.L.U. Todos los derechos reservados. Published by Elsevier España, S.L.U. All rights reserved.)

Evidence suggests a remarkable shared genetic susceptibility between psychiatric disorders. However, sex-dependent differences have been less studied. We explored the contribution of schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) polygenic scores (PGSs) on the risk for psychotic disorders and whether sex-dependent differences exist (CIBERSAM sample: 1826 patients and 1372 controls). All PGSs were significantly associated with psychosis. Sex-stratified analyses showed that the variance explained in psychotic disorders risk was significantly higher in males than in females for all PGSs. Our results confirm the shared genetic architecture across psychotic disorders and demonstrate sex-dependent differences in the vulnerability to psychotic disorders., Competing Interests: Author disclosures CA has been a consultant to or has received honoraria or grants from Abbot, Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion, Takeda and Teva. JB received consulting fees from Takeda as members of the Advisory Board. JB received research grants and served as consultant, advisor, or speaker within the last 3 years for: AB-Biotics, Acadia Pharmaceuticals, Alkermes, Angelini, Ambrosetti-Angelini, Biogen, Casen Recordati, D&A Pharma, Exeltis, Gilead, Indivior, GW Pharmaceuticals, Janssen-Cilag, Jazz Pharmaceuticals, Lundbeck, Otsuka, Pfizer, Roche, Sage Therapeutics, Servier, Shire, Takeda. In addition, JB received research funding from the Spanish Ministry of Economy and Competitiveness—Centro de Investigación Biomedica en Red area de Salud Mental (CIBERSAM), and Instituto de Salud Carlos III, Spanish Ministry of Health. AG-P has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen-Cilag, Lundbeck, Otsuka, Alter, Angelini, Novartis, Rovi, Takeda, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), the Basque Government, and the European Framework Program of Research. The rest of the authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Unlike high-income countries (HICs), there are few early intervention services for psychosis in low-and middle-income countries (LAMICs). In HICs, research spurred the growth of such services. Little is known about the state of EIP research in LAMICs, which we address by examining their research output and collaborations vis-à-vis that of HICs., Methods: We conducted a search in Scopus database for early psychosis publications in scientific journals since 1980. Data from each record, including title, author affiliation, and date, were downloaded. For HIC-LAMIC collaborations, data on first, corresponding and last authors' affiliations, and funding were manually extracted. Descriptive statistics and social network analysis were conducted., Results: Globally, early psychosis publications increased from 24 in 1980 to 1297 in 2022. Of 16,942 included publications, 16.1 % had LAMIC authors. 71.3 % involved authors from a single country (regardless of income level). 21.9 % were collaborations between HICs, 6.6 % between HICs and LAMICs, and 0.2 % among LAMICs. For research conducted in LAMICs and involving HIC-LAMIC collaborations, the first, last, and corresponding authors were LAMIC-based in 71.8 %, 60.7 %, and 63.0 %, respectively. These positions were dominated (80 %) by authors from four LAMICs. 29.4 % of the HIC-LAMIC subset was funded solely by LAMIC funders, predominantly two LAMICs., Conclusions: LAMICs are starkly underrepresented in the otherwise flourishing body of early psychosis research. They have far fewer collaborations and less funding than HICs. Closing these gaps in LAMICs where most of the world's youth live is imperative to generate the local knowledge needed to strengthen early psychosis services that are known to improve outcomes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A substantial portion of schizophrenia spectrum disorder (SSD) patients exhibit resistance to antipsychotic treatments, emphasizing the need for reliable treatment response biomarkers. Previous magnetic resonance imaging (MRI) studies have identified various imaging predictors in SSD. This study focuses on evaluating the effectiveness of diffusion MRI sequences, diffusion tensor imaging (DTI) and diffusion-weighted imaging (DWI), in predicting antipsychotic response in SSD patients. A systematic search for relevant articles was conducted in PubMed, Embase, Scopus, and Web of Science on February 11, 2024. Twelve studies involving a total of 742 patients were systematically reviewed. The baseline DTI/DWI biomarkers revealed significant associations with antipsychotic treatment response. Notably a consistent negative link was found between response and baseline fractional anisotropy (FA) in fronto-temporo-limbic white matter tracts, specifically the superior longitudinal fasciculus, providing moderate-level evidence. In addition, weak-level evidence was found for the negative association between the treatment response and baseline FA in the corpus callosum, internal, and external capsule tracts. Collectively, this review demonstrated that obtaining pre-treatment brain diffusion MRI scans, particularly from white matter tracts of fronto-temporo-limbic network, can assist in delineating the treatment response trajectory in patients with SSD. However, additional larger randomized controlled trials are required to further substantiate these findings., Competing Interests: Declaration of competing interest No potential conflict of interests is declared., (Copyright © 2024. Published by Elsevier B.V.)

Ghrelin is a peptide released by the endocrine cells of the stomach and the neurons in the arcuate nucleus of the hypothalamus. It modulates both peripheral and central functions. Although ghrelin has emerged as a potent stimulator of growth hormone release and as an orexigenic neuropeptide, the wealth of literature suggests its involvement in the pathophysiology of affective disorders including depression. Ghrelin exhibits a dual role through the advancement and reduction of depressive behavior with nervousness in the experimental animals. It modulates depression-related signals by forming neuronal networks with various neuropeptides and classical neurotransmitter systems. The present review emphasizes the integration and signaling of ghrelin with other neuromodulatory systems concerning depressive disorders. The role of ghrelin in the regulation of neurosynaptic transmission and depressive illnesses implies that the ghrelin system modulation can yield promising antidepressive therapies.

Background: Compulsory Community Treatment Orders (CTOs) are contentious because they impose severe restrictions on individuals in community settings. The existing evidence for CTOs is constrained by ethical and methodological limitations and may not support usual clinical practise. This study examines the effectiveness of CTOs using routine data in the New Zealand context. Methods: Ministry of Health, New Zealand databases provided demographic, service use, and medication dispensing data for all individuals placed on a CTO between 2009 and 2018. We examined the effectiveness of CTOs through a comparison of psychiatric endpoints identified as useful in the literature according to CTO status. Further analyses examined the moderating influences of age, sex, ethnicity, and diagnosis on outcome. Findings: 14,726 patients were placed under a CTO over the 10 year period between 1 January 2009 and 31 December 2018. Patients on CTOs experienced a reduced frequency of admissions (rate ratio of 0∙94, 95% CI 0.93-0.95, p

Background: Schizophrenia and white blood cell counts (WBC) are both complex and polygenic traits. Previous evidence suggests that increased WBC are associated with higher all-cause mortality, and other studies have found elevated WBC in first-episode psychosis and chronic schizophrenia. However, these observational findings may be confounded by antipsychotic exposures and their effects on WBC. Mendelian randomization (MR) is a useful method for examining the directions of genetically-predicted relationships between schizophrenia and WBC., Methods: We performed a two-sample MR using summary statistics from genome-wide association studies (GWAS) conducted by the Psychiatric Genomics Consortium Schizophrenia Workgroup (N = 130,644) and the Blood Cell Consortium (N = 563,946). The MR methods included inverse variance weighted (IVW), MR Egger, weighted median, MR-PRESSO, contamination mixture, and a novel approach called mixture model reciprocal causal inference (MRCI). False discovery rate was employed to correct for multiple testing., Results: Multiple MR methods supported bidirectional genetically-predicted relationships between lymphocyte count and schizophrenia: IVW (b = 0.026; FDR p-value = 0.008), MR Egger (b = 0.026; FDR p-value = 0.008), weighted median (b = 0.013; FDR p-value = 0.049), and MR-PRESSO (b = 0.014; FDR p-value = 0.010) in the forward direction, and IVW (OR = 1.100; FDR p-value = 0.021), MR Egger (OR = 1.231; FDR p-value < 0.001), weighted median (OR = 1.136; FDR p-value = 0.006) and MRCI (OR = 1.260; FDR p-value = 0.026) in the reverse direction. MR Egger (OR = 1.171; FDR p-value < 0.001) and MRCI (OR = 1.154; FDR p-value = 0.026) both suggested genetically-predicted eosinophil count is associated with schizophrenia, but MR Egger (b = 0.060; FDR p-value = 0.010) and contamination mixture (b = -0.013; FDR p-value = 0.045) gave ambiguous results on whether genetically predicted liability to schizophrenia would be associated with eosinophil count. MR Egger (b = 0.044; FDR p-value = 0.010) and MR-PRESSO (b = 0.009; FDR p-value = 0.045) supported genetically predicted liability to schizophrenia is associated with elevated monocyte count, and the opposite direction was also indicated by MR Egger (OR = 1.231; FDR p-value = 0.045). Lastly, unidirectional genetic liability from schizophrenia to neutrophil count were proposed by MR-PRESSO (b = 0.011; FDR p-value = 0.028) and contamination mixture (b = 0.011; FDR p-value = 0.045) method., Conclusion: This MR study utilised multiple MR methods to obtain results suggesting bidirectional genetic genetically-predicted relationships for elevated lymphocyte counts and schizophrenia risk. In addition, moderate evidence also showed bidirectional genetically-predicted relationships between schizophrenia and monocyte counts, and unidirectional effect from genetic liability for eosinophil count to schizophrenia and from genetic liability for schizophrenia to neutrophil count. The influence of schizophrenia to eosinophil count is less certain. Our findings support the role of WBC in schizophrenia and concur with the hypothesis of neuroinflammation in schizophrenia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: While genetic and cohort studies suggest immune and reduction/oxidation (redox) alterations occur in psychosis, less is known about potential alterations in children and adolescents., Methods: We conducted a systematic review to identify immune and redox biomarker studies in children and adolescents (mean age ≤ 18 years old) across the psychosis spectrum: from psychotic like experiences, which are common in children, to threshold psychotic disorders like schizophrenia. We conducted meta-analyses when at least three studies measured the same biomarker., Results: The systematic review includes 38 pediatric psychosis studies. The meta-analyses found that youth with threshold psychotic disorders had higher neutrophil/lymphocyte ratio (Hedge's g = 0.40, 95 % CI 0.17 - 0.64), tumor necrosis factor (Hedge's g = 0.38, 95 % CI 0.06 - 0.69), C-reactive protein (Hedge's g = 0.38, 95 % CI 0.05 - 0.70), interleukin-6 (Hedge's g = 0.35; 95 % CI 0.11 - 0.64), and total white blood cell count (Hedge's g = 0.29, 95 % CI 0.12 - 0.46) compared to youth without psychosis. Other immune and oxidative stress meta-analytic findings were very heterogeneous., Conclusion: Results from several studies are consistent with the hypothesis that signals often classified as "proinflammatory" are elevated in threshold pediatric psychotic disorders. Data are less clear for immune markers in subthreshold psychosis and redox markers across the subthreshold and threshold psychosis spectrum. Immune and redox biomarker intervention studies are lacking, and research investigating interventions targeting the immune system in threshold pediatric psychosis is especially warranted., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Barzilay reports serving on the scientific boards of Taliaz Health and Zynerba Pharmaceuticals and owning stock in Taliaz Health outside the submitted work. All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Increased peripheral cytokine levels have been observed in patients with psychotic disorders; however, large high-quality studies with individually matched healthy controls have been lacking regarding cytokines in cerebrospinal fluid (CSF) of individuals with psychotic disorders., Methods: Patients diagnosed with a non-organic, non-affective psychotic disorder (ICD-10: F20/22-29) within a year prior to inclusion and individually age- and sex-matched healthy controls were included by identical in- and exclusion criteria's except for the psychiatric diagnoses. All participants were aged 18-50 years and individuals with neurological or immunological disorders were excluded. CSF cytokines were analyzed with MesoScale V-PLEX neuroinflammation panel. Co-primary outcomes were CSF interleukin-6 (IL-6) and IL-8., Results: We included 104 patients and 104 healthy controls, matching on age, sex and BMI. No significant differences were found for the primary outcomes IL-6 (relative mean difference (MD): 0.97, 95 %CI: 0.84-1.11, p = 0.637) or IL-8 (MD: 1.01, 95 %CI: 0.93-1.09, p = 0.895). Secondary analyses found patients to have higher IL-4 (MD: 1.30, 95 %CI: 1.04-1.61, p = 0.018), a trend towards higher IFN-γ (MD: 1.26, 95 %CI: 0.99-1.59, p = 0.056), and lower IL-16 (MD: 0.83, 95 %CI: 0.74-0.94, p = 0.004) than healthy controls, though not significant after correction for multiple testing. IL-8 and IL-16 were found positively associated with CSF white blood cells and CSF/serum albumin ratio. The study was limited by 77.9 % of the patients being on antipsychotic treatment at time of intervention, and that levels of nine of the 26 cytokines were below lower limit of detection (LLOD) in >50 % of samples; however, for the primary outcomes IL-6 and IL-8 more than 99.5 % of the samples were above LLOD and for IL-8 all samples exceeded the lower limit of quantification (LLOQ)., Conclusions: We found no evidence of increased IL-6 and IL-8 in patients with recent-onset psychotic disorders in contrary to previous findings in meta-analyses of CSF cytokines. Secondary analyses found indication of higher IL-4, decreased IL-16, and borderline increased IFN-γ in patients, neither of which have previously been reported on in CSF analyses of individuals with psychotic disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

There is a need to maximize understanding of conditions under which officers are most likely to use lethal force when interacting with persons with severe mental illness (SMI) and whether utilization of a mental health professional (MHP) serves to reduce use of force (UoF) severity. Using a mixed methods concurrent triangulation design framework, this exploratory study examined UoF with individuals exhibiting signs of psychosis and whether police-MHP partnerships decrease UoF severity. Findings indicate officers use more severe forms of force with armed individuals displaying signs of psychosis and that MHP presence did not reduce force severity in such cases. Qualitative themes provide context for these findings and include (1) concerns for MHP safety, (2) planned collaborations support safety, and (3) MHPs support de-escalation. Discussion highlights a need for increased officer education on SMI, appropriate de-escalation strategies, co-created engagement/disengagement protocols for MHPs, and defined standards of practice for police-mental health collaborations., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Ltd.)

Background: The associations between COVID-19 vaccination and post-COVID psychiatric disorders are unclear. Furthermore, it is uncertain if these associations differ depending on the dominant SARS-CoV-2 variant at the time of infection. This retrospective cohort study aimed to clarify the associations between COVID-19 vaccination and incident psychiatric disorders after breakthrough infection according to the different variant periods in Japan., Methods: Medical claims data, COVID-19 case-related information, and vaccination records were collected from three Japanese municipalities. The study population comprised public insurance enrollees aged ≥65 years who developed COVID-19 between June 2021 and December 2022. The study exposure was each participant's vaccination status 14 days before infection, and the outcomes were the occurrence of psychiatric disorders within three months of infection. Multivariable logistic regression analyses were performed to calculate the odds ratios (ORs) and 95 % confidence intervals (CIs) of vaccination for the occurrence of psychiatric disorders. Analyses were conducted for the Delta period (June to December 2021), Omicron BA.1/BA.2 period (January to June 2022), and Omicron BA.5 period (July to December 2022)., Results: We analyzed 270 participants (vaccinated: 149) in the Delta period, 2,963 participants (vaccinated: 2,699) in the Omicron BA.1/BA.2 period, and 7,723 participants (vaccinated: 7,159) in the Omicron BA.5 period. During the Delta period, vaccinated participants had significantly lower odds for psychotic disorders (OR: 0.23, 95 % CI: 0.06-0.88, P = 0.032) than unvaccinated participants. During the Omicron BA.5 period, vaccinated participants had significantly lower odds for organic mental disorders (OR: 0.54, 95 % CI: 0.30-0.95, P = 0.033), psychotic disorders (OR: 0.31, 95 % CI: 0.19-0.53, P < 0.001), mood disorders (OR: 0.53, 95 % CI: 0.29-0.99, P = 0.046), and insomnia (OR: 0.48, 95 % CI: 0.32-0.72, P < 0.001) than unvaccinated participants. There were no significant differences in psychiatric disorders between the vaccinated and unvaccinated groups during the Omicron BA.1/BA.2 period., Conclusions: This is the first study to demonstrate that the associations between COVID-19 vaccination and post-COVID psychiatric disorders vary among the different variant periods. Future studies on these associations should be conducted with consideration to the prevalent circulating variants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Recent evidence has implicated complement component (C) 4A in excessive elimination of synapses in schizophrenia. C4A is believed to contribute to physiological synapse removal through signaling within the C1q initiated classical activation axis of the complement system. So far, a potential involvement of C1q in the pathophysiology of schizophrenia remains unclear. In this study, we first utilized large-scale gene expression datasets (n = 586 patients with schizophrenia and n = 986 controls) to observe lower C1QA mRNA expression in prefrontal cortex tissue of individuals with schizophrenia (P = 4.8x10 -05 ), while C1QA seeded co-expression networks displayed no enrichment for schizophrenia risk variants beyond C4A. We then used targeted liquid chromatography-mass spectrometry (LS-MS) to measure cerebrospinal fluid (CSF) levels of C1qA in 113 individuals with first-episode psychosis (FEP), among which 66 individuals was later diagnosed with schizophrenia, and 87 healthy controls. CSF concentrations of C1qA were lower in individuals diagnosed with FEP (P = 0.0001), also after removing subjects with a short-term prescription of an antipsychotic agent (P = 0.0005). We conclude that C1q mRNA and protein levels are lower in schizophrenia and that further experimental studies are needed to understand the functional implications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The gut microbiome has been implicated in the pathogenesis of mental disorders where the gut-brain axis acts as a bidirectional communication network., Methods: Herein, we investigated the compositional and functional differences of gut microbiome between patients with first-episode psychosis (FEP) (n = 26) and healthy control participants (n = 22) using whole-genome shotgun sequencing. In addition, we assessed the oral microbiome in patients with FEP (n = 13) and listed their taxonomic diversity., Results: Our findings suggest that there is a dysbiosis of gut microbiota in patients with FEP. Relative abundance of Bifidobacterium adolescentis, Prevotella copri, and Turicibacter sanguinis was markedly increased (linear discriminant analysis scores [log 10 ] > 1, and Mann-Whitney U test; false discovery rate-adjusted p values < .05) in the FEP group compared with the healthy control participants. Pathway analysis indicated that several metabolic pathways, particularly deoxyribonucleotide biosynthesis, branched-chain amino acid biosynthesis, tricarboxylic acid cycle, and fatty acid elongation and biosynthesis, were dysregulated in the FEP group compared with the healthy control group. In addition, this preliminary study was able to identify specific gut microbes (at baseline) that were predictive of weight gain in the FEP group at a 1-year follow-up. Bacteroides dorei, Bifidobacterium adolescentis, Turicibacter sanguinis, Roseburia spp., and Ruminococcus lactaris were positively associated (eXtreme gradient boosting, XGBoost regression model, Shapley additive explanations, R 2  = 0.82) with weight gain., Conclusions: Our findings may suggest the involvement of gut microbiota in the pathogenesis of psychosis. The benefit of modulation of the gut microbiome in the treatment of psychotic disorders should be explored further., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: New treatments with new mechanisms are urgently needed for people with schizophrenia. Xanomeline is a dual M 1 and M 4 -preferring muscarinic receptor agonist that does not block D 2 dopamine receptors, unlike all currently approved treatments for schizophrenia. Xanomeline-trospium (KarXT) combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride with the goal of ameliorating xanomeline-related adverse events associated with peripheral muscarinic receptors. The EMERGENT-2 trial aimed to assess the efficacy and safety of KarXT in people with schizophrenia experiencing acute psychosis., Methods: EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3 trial in people with schizophrenia. Participants were adults aged 18-65 years with a diagnosis of schizophrenia who had a recent worsening of psychosis warranting hospital admission, a Positive and Negative Syndrome Scale (PANSS) score of 80 or higher, and a Clinical Global Impression-Severity score of 4 or higher. The participants were recruited from 22 inpatient sites in the USA, and were randomly assigned (1:1) to KarXT or placebo twice per day. Participants randomly assigned to KarXT received 50 mg xanomeline and 20 mg trospium twice per day for the first 2 days and then 100 mg xanomeline and 20 mg trospium twice per day for days 3-7. Beginning on day 8, KarXT dosing was flexible with an optional increase to 125 mg xanomeline and 30 mg trospium twice per day and the option to return to 100 mg xanomeline and 20 mg trospium based on tolerability. The primary endpoint was change from baseline to week 5 in PANSS total score. Efficacy analyses used the modified intention-to-treat population (all randomly assigned participants who received at least one trial medication dose and had at least one post-baseline PANSS assessment). Least squares mean change from baseline, SE, and least squares mean difference between the KarXT and placebo groups at week 5, along with the 95% CI and two-sided p values were calculated for the primary and secondary continuous efficacy endpoints. Safety analyses included all participants receiving at least one trial medication dose and used descriptive statistics. This trial is registered with ClinicalTrials.gov (NCT04659161)., Findings: From Dec 16, 2020, to April 13, 2022, of 407 people who were screened, 252 participants meeting enrolment criteria were randomly assigned to the KarXT (n=126) or placebo (n=126). Baseline PANSS total scores were 98·3 (KarXT; n=126) and 97·9 (placebo; n=125). The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favoured KarXT (-21·2 points, SE 1·7) versus placebo (-11·6 points, 1·6; least squares mean difference -9·6; 95% CI -13·9 to -5·2; p<0·0001, Cohen's d effect size=0·61). All secondary endpoints were also met, and favoured KarXT versus placebo (p<0·05). The most common adverse events with KarXT versus placebo were constipation (27 [21%] vs 13 [10%]), dyspepsia (24 [19%] vs 10 [8%]), headache (17 [14%] vs 15 [12%]), nausea (24 [19%] vs seven [6%]), vomiting (18 [14%] vs one [1%]), hypertension (12 [10%] vs one [1%]), dizziness (11 [9%] vs four [3%]), gastro-oesophageal reflux disease (eight [6%] vs zero [0%]), and diarrhoea (seven [6%] vs four [3%]). Treatment-emergent adverse event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]), weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%])., Interpretation: In the EMERGENT-2 trial, KarXT was effective in reducing positive and negative symptoms and was generally well tolerated. These results support the potential for KarXT to represent a new class of effective and well tolerated antipsychotic medicines based on activating muscarinic receptors, not the D 2 dopamine receptor-blocking mechanism of all current antipsychotic medications. Results from additional trials, including the identical EMERGENT-3 trial and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional information on the efficacy and safety of KarXT in people with schizophrenia., Funding: Karuna Therapeutics., Competing Interests: Declaration of interests CUC has been a consultant, advisor, or both consultant and advisor to or has received honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo Pharma, Biogen, Boehringer Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, Intra-Cellular Therapies, Janssen or Johnson & Johnson, Karuna Therapeutics, LB Pharma, Lundbeck, MedAvante-ProPhase, MedinCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine Biosciences, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, ROVI, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris; provided expert testimony for Janssen and Otsuka; served on a data safety monitoring board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, ROVI, Sage, Supernus, Tolmar, and Teva; has received grant support from Janssen and Takeda; received royalties from UpToDate; and is a stock option holder of Cardio Diagnostics, LB Pharma, Mindpax, PsiloSterics, and Quantic. AB has been a consultant, advisor, or both consultant and advisor for Arrivo Sirtsei, BioXcel, Karuna Therapeutics, Neumarker, and Perception Neuroscience, and holds equity in Karuna Therapeutics and Perception Neuroscience. SMP is an employee of Karuna Therapeutics, is in a leadership or fiduciary role at Karuna Therapeutics, Sage Therapeutics, and Voyager Therapeutics, and holds equity in Eli Lilly Pharmaceuticals, Karuna Therapeutics, Sage Therapeutics, and Voyager Therapeutics. IK, SS, HZ, ACM, and SKB are employees of and hold equity in Karuna Therapeutics. RK was a principal investigator for the EMERGENT-2 study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Early identification and intervention of individuals with an increased risk for bipolar disorder (BD) may improve the course of illness and prevent long‑term consequences. Early-BipoLife, a multicenter, prospective, naturalistic study, examined risk factors of BD beyond family history in participants aged 15-35 years. At baseline, positively screened help-seeking participants (screenBD at-risk) were recruited at Early Detection Centers and in- and outpatient depression and attention-deficit/hyperactivity disorder (ADHD) settings, references (Ref) drawn from a representative cohort. Participants reported sociodemographics and medical history and were repeatedly examined regarding psychopathology and the course of risk factors. N = 1,083 screenBD at-risk and n = 172 Ref were eligible for baseline assessment. Within the first two years, n = 31 screenBD at-risk (2.9 %) and none of Ref developed a manifest BD. The cumulative transition risk was 0.0028 at the end of multistep assessment, 0.0169 at 12 and 0.0317 at 24 months (p = 0.021). The transition rate with a BD family history was 6.0 %, 4.7 % in the Early Phase Inventory for bipolar disorders (EPIbipolar), 6.6 % in the Bipolar Prodrome Interview and Symptom Scale-Prospective (BPSS-FP) and 3.2 % with extended Bipolar At-Risk - BARS criteria). In comparison to help-seeking young patients from psychosis detection services, transition rates in screenBD at-risk participants were lower. The findings of Early-BipoLife underscore the importance of considering risk factors beyond family history in order to improved early detection and interventions to prevent/ameliorate related impairment in the course of BD. Large long-term cohort studies are crucial to understand the developmental pathways and long-term course of BD, especially in people at- risk., Competing Interests: Declaration of Competing Interest JM, KLB, CB, KL, CS, JM, GJ, AJF, ML, AB, AR, SM, TS, TK, IF, AJ, UD, SKÖ, PFP, LMH, PR, SB, PM, BM and AP state to have no conflict of interest. SKS has received author's and advisory honoraria from Takeda/Shire and Medice Arzneimittel Pütter GmbH in the last 3 years. AR serves on advisory boards and receives speaker's honoraria from Medice, Shire/Takeda, Janssen, neuraxpharm, Servier and SAGE. MB has received grant support from the Deutsche Forschungsgemeinschaft, the Bundesministerium für Bildung und Forschung, and the European Commission. He served as a consultant to GH Research, Janssen-Cilag, neuraxpharm, Novartis, Shire International, Sunovion, and Takeda, and received fees from Aristo, Hexal, Janssen-Cilag, and Sunovion. CU Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic., (Copyright © 2023. Published by Elsevier B.V.)

Oxidative stress may contribute to declining course and poor outcomes in psychosis. However, in vivo Magnetic Resonance Spectroscopy studies yield disparate results due to clinical stage, sample demographics, neuroanatomical focus, sample size, and acquisition method variations. We investigated glutathione in brain regions from participants with psychosis, and the relation of glutathione to clinical features and spectroscopy protocols. Meta-analysis comprised 21 studies. Glutathione levels did not differ between total psychosis patients (N = 639) and controls (N = 704) in the Medial Prefrontal region (k = 21, d = -0.09, CI = -0.28 to 0.10, p = 0.37). Patients with stable schizophrenia exhibited a small but significant glutathione reduction compared to controls (k = 14, d = -0.20, CI = -0.40 to -0.00, p = 0.05). Meta-regression showed older studies had greater glutathione reductions, possibly reflecting greater accuracy related to spectroscopy advancements in more recent studies. No significant effects of methodological variables, such as voxel size or echo time were found. Reduced glutathione in patients with stable established schizophrenia may provide novel targets for precision medicine. Standardizing MRS acquisition methods in future studies may help address discrepancies in glutathione levels., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Emerging adults who endorse more positive psychotic-like experiences (PLEs; bizarre experiences, delusional ideations) may experience greater cannabis-related impairments in executive function. Negative and depressive PLEs are also associated with cannabis use, however, less is known about their relation to executive functioning. Here, we hypothesize that high positive PLEs and cannabis use are associated with worse performance on computerized versions of the Iowa Gambling Task (IGT) and the Card Sorting Task (CST); exploratory analyses are conducted with negative and depressive PLEs., Methods: We recruited university students (N = 543) who completed an online study consisting of self-report measures of problematic cannabis use (Cannabis Use Disorder Identification Test; CUDIT-R) and PLEs (Community Assessment of Psychotic Experiences; CAPE). Of these, n=270 completed the CST and n=251 completed the IGT., Results: Problematic cannabis use and high endorsement of positive PLEs related to significantly worse performance on the IGT and greater perseverative errors on the CST. In addition, people who endorsed high levels of positive PLEs were also significantly more likely to complete the IGT with less money relative to those who endorsed fewer PLEs, regardless of cannabis use. Further analyses based on negative PLEs revealed a similar pattern for perseverative errors on the CST; depressive PLEs were not related to task performance., Conclusion: Findings highlight that problematic cannabis use and more frequent and distressing positive PLEs are associated with poorer executive functioning. Thus, executive functioning may have implications for intervention among those high on both attributes, who are at high risk of onset of psychosis., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Cannabis is a risk factor in the onset and persistence of psychotic disorders. There is concern that non-medical cannabis legalization in Canada may have population-level impacts on psychotic disorders. We sought to examine changes in health service use and incident cases of psychotic disorder following cannabis legalization, during a period of tight restrictions on retail stores and product types., Methods: We conducted a cross-sectional interrupted time-series analysis using linked population-based health administrative data from Ontario (Canada) from January 2014 to March 2020. We identified psychosis-related outpatient visits, emergency department visits, hospitalizations, and inpatient length of stay, as well as incident cases of psychotic disorders, among people aged 14 to 60 years., Results: We did not find evidence of increases in health service use or incident cases of psychotic disorders over the short-term (17 month) period following cannabis legalization. However, we found clear increasing trends in health service use and incident cases of substance-induced psychotic disorders over the entire observation window (2014-2020)., Conclusion: Our findings suggest that the initial period of tight market restriction following legalization of non-medical cannabis was not associated with an increase in health service use or frequency of psychotic disorders. A longer post-legalization observation period, which includes expansion of the commercial cannabis market, is needed to fully understand the population-level impacts of non-medical cannabis legalization; thus, it would be premature to conclude that the legalization of non-medical cannabis did not lead to increases in health service use and incident cases of psychotic disorder., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lena Palaniyappan reports personal fees for serving as chief editor from the Canadian Medical Association Journals, speaker/consultant fees from Janssen Canada and Otsuka Canada (2019), SPMM Course Limited, UK, Canadian Psychiatric Association; book royalties from Oxford University Press; investigator-initiated educational grants from Janssen Canada, Sunovion and Otsuka Canada outside the submitted work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Early stress increases the risk for psychiatric disorders. Glucocorticoids are stress mediators that regulate transcriptional activity and morphology in the hippocampus, which is implicated in the pathophysiology of multiple psychiatric conditions. We aimed to establish the relevance of hippocampal glucocorticoid-induced transcriptional activity as a mediator of the effects of early life on later psychopathology in humans., Methods: RNA sequencing was performed with anterior and posterior hippocampal dentate gyrus from adult female macaques (n = 12/group) that were chronically treated with betamethasone (glucocorticoid receptor agonist) or vehicle. Coexpression network analysis identified a preserved gene network in the posterior hippocampal dentate gyrus that was strongly associated with glucocorticoid exposure. The single nucleotide polymorphisms in the genes in this network were used to create an expression-based polygenic score in humans., Results: The expression-based polygenic score significantly moderated the association between early adversity and psychotic disorders in adulthood (UK Biobank, women, n = 44,519) and on child peer relations (ALSPAC [Avon Longitudinal Study of Parents and Children], girls, n = 1666 for 9-year-olds and n = 1594 for 11-year-olds), an endophenotype for later psychosis. Analyses revealed that this network was enriched for glucocorticoid-induced epigenetic remodeling in human hippocampal cells. We also found a significant association between single nucleotide polymorphisms from the expression-based polygenic score and adult brain gray matter density., Conclusions: We provide an approach for the use of transcriptomic data from animal models together with human data to study the impact of environmental influences on mental health. The results are consistent with the hypothesis that hippocampal glucocorticoid-related transcriptional activity mediates the effects of early adversity on neural mechanisms implicated in psychiatric disorders., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

This research aims to explore roles and challenges faced by Indonesian community pharmacists in mental healthcare management. A sequential mixed method study was conducted. This study found that drug counselling as a pharmaceutical care service that is often given to patients with mental disorder. Nonetheless, inadequate training and concern of psychotropic drug abused were identified as a major barrier hindering effective service delivery. These finding suggests that there is a need for pharmacists to gain additional education and training in mental health, as well as implement a system that integrates patient medical records across all healthcare settings., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Background: Involuntary admission is widely used in psychiatry, usually requiring that the patient present an imminent danger to himself or others. Previous studies have established several predictors for involuntary admission, but they have been almost exclusively conducted in Western European or North American countries. By contrast, data on this topic from Eastern European countries is virtually absent. Historically, involuntary admission has been often used as a tool for political repression in Romania before the fall of the communist regime. While there have been significant changes in the legal framework in the last 30 years, there is still no real-world data to build upon., Methods: We analyzed a sample of 177 patients admitted to the "Alexandru Obregia" psychiatric hospital in Bucharest between November 2022 and January 2023, of which 49.7% (88) were involuntary hospitalizations. We collected socio-demographic and clinical data by both by direct interview, and by consulting patient records, attending physicians and relatives., Results: Socio-demographic factors predictive for involuntary admission were unemployment, lower income, and urban living. Of the clinical variables analyzed, diagnosis of psychosis or mania on admission carried increased risk of involuntary hospitalization, as did nonadherence to treatment, higher disease severity and aggression. Hospital presentation by police or ambulance carried significant additional risk compared to self-referral., Conclusion: Certain categories of patients are considerably more likely to be involuntarily hospitalized and there appears to be considerable interrelatedness between the identified risk factors., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Individuals with bipolar disorder (BD) and schizophrenia (SCZ) show aberrant brain dynamics (i.e., altered recruitment or traversal through different brain states over time). Existing investigations of brain dynamics typically assume that one dominant brain state characterizes each time point. However, as multiple brain states likely are engaged at any given moment, this approach can obscure alterations in less prominent but critical brain states. Here, we examined brain dynamics in BD and SCZ by implementing a novel framework that simultaneously assessed the engagement of multiple brain states., Methods: Four recurring brain states were identified by applying nonlinear manifold learning and k-means clustering to the Human Connectome Project task-based functional magnetic resonance imaging data. We then assessed moment-to-moment state engagement in 2 independent samples of healthy control participants and patients with BD or SCZ using resting-state (N = 336) or task-based (N = 217) functional magnetic resonance imaging data. Relative state engagement and state engagement variability were extracted and compared across groups using multivariate analysis of covariance, controlling for site, medication, age, and sex., Results: Our framework identified dynamic alterations in BD and SCZ, while a state discretization approach revealed no significant group differences. Participants with BD or SCZ showed reduced state engagement variability, but not relative state engagement, across multiple brain states during resting-state and task-based functional magnetic resonance imaging. We found decreased state engagement variability in older participants and preliminary evidence suggesting an association with avolition., Conclusions: Assessing multiple brain states simultaneously can reflect the complexity of aberrant brain dynamics in BD and SCZ, providing a more comprehensive understanding of the neural mechanisms underpinning these conditions., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Competing Interests: I report grants from the US National Institutes of Health (R01MH131022), Start-up Emerging Research Award from the University of Cape Town, and the Carnegie Developing Emerging Academic Leaders Award from the Carnegie Corporation New York, NY, USA.

Alterations in the complement system have been reported in some people with psychotic disorder, including in pre-psychotic individuals, suggesting that complement pathway dysregulation may be a feature of the early psychosis phenotype. Measurement of complement protein expression in psychosis has been largely restricted to the blood from patients with established illness who were taking antipsychotic medication. The present study examined a range of complement proteins in blood and cerebrospinal fluid (CSF) derived from individuals at clinical high-risk for psychosis (CHR), antipsychotic-naïve first-episode psychosis (FEP) and healthy controls. A panel of complement proteins (C1q, C3, C3b/iC3b, C4, factor B and factor H) were quantified in serum and matched CSF in 72 participants [n = 23 individuals at CHR, n = 24 antipsychotic-naïve FEP, n = 25 healthy controls] using a multiplex immunoassay. Analysis of covariance was used to assess between-group differences in complement protein levels in serum and CSF. Pearson's correlation was used to assess the relationship between serum and CSF proteins, and between complement proteins and symptom severity. In serum, all proteins, except for C3, were significantly higher in FEP and CHR. While a trend was observed, protein levels in CSF did not statistically differ between groups and appeared to be impacted by BMI and sample storage time. Across the whole sample, serum and CSF protein levels were not correlated. In FEP, higher levels of serum classical and alternative grouped pathway components were correlated with symptom severity. Our exploratory study provides evidence for increased activity of the peripheral complement system in the psychosis spectrum, with such elevations varying with clinical severity. Further study of complement in CSF is warranted. Longitudinal investigations are required to elucidate whether complement proteins change peripherally and/or centrally with progression of psychotic illness., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The primary objective is to analyse the impact of the COVID-19 pandemic on the triggers of psychopathology and on the delusional content of patients with psychotic symptoms treated during the first three months of the pandemic in a tertiary hospital in Madrid., Methods: We conducted a cross-sectional, observational and retrospective study of all patients attending the psychiatric emergency room (ER) between 11th March and 11th June 2020. Sociodemographic and clinical variables were included. The chi-squared test or Fisher's exact test were performed to compare categorical variables. The level of statistical significance was set at P<.05., Results: In the first month of the pandemic, COVID-19 conditioned the delirious content of 38.5% of the admitted patients and acted as a direct trigger for 46.2% of consultations. In the second week it affected 100.0% of the patients in both cases. Subsequently, a progressive and significant decrease was observed, with COVID-19 being the triggering factor for 17.6% and 11.5% of consultations in the second and third months of the pandemic respectively. Similarly, it was the main determinant of the delusional content in 13.7% and 3.8% of cases respectively., Conclusions: The current pandemic affects delirium's pathoplasty. The delusional content of patients admitted with psychotic symptoms is quickly conditioned, which may be related to the radical change in their life, without transition or prior preparation. The patient's environmental context and events have a huge impact on the dynamics and characteristics of mental disorders., (Copyright © 2021 Asociación Colombiana de Psiquiatría. Published by Elsevier España, S.L.U. All rights reserved.)

Research suggests higher neighbourhood ethnic minority density to be associated with lessened chances of ethnic group illness. We focus on the density effect on psychosis, arguing that (at higher ethnic concentrations) it acts as a contextual influence attenuating the compositional influence whereby minority ethnicity is associated with higher psychosis risk. In terms of ecological disease regression, the ethnic density effect will then be apparent in nonlinear impacts of minority concentration. Contextual effects may also be evident in spatially varying regression coefficient models for psychosis. Nonlinearity or heterogeneity may be associated with other contextual processes where geography modifies demography (e.g. deprivation amplification). We illustrate these issues with an analysis of psychosis prevalence in 4835 London neighbourhoods. The data are collected in primary care (during 2019/20) using clinical diagnosis (e.g. based on referrals to specialists or psychosis hospitalisation), and refer to patients currently under care: such care may extend retrospectively over several years. The data offer a complete population perspective in contrast to survey data, which typically offer limited geographic perspectives. We consider impacts on psychosis prevalence of non-white ethnicity, as well as those of deprivation, social fragmentation and urbanicity. We find evidence suggesting nonlinear impacts of non-white ethnicity on psychosis (essentially flat risk above a threshold concentration), but find no evidence for deprivation amplification., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Author. Published by Elsevier Ltd.. All rights reserved.)

Background: Familial, obstetric, and early-life environmental risks for schizophrenia spectrum disorder (SSD) alter normal cerebral development, leading to the formation of characteristic brain deficit patterns prior to onset of symptoms. We hypothesized that the insidious effects of these risks may increase brain similarity to adult SSD deficit patterns in prepubescent children., Methods: We used data collected by the Adolescent Brain Cognitive Development (ABCD) Study (N = 8940, age = 9.9 ± 0.1 years, 4307/4633 female/male), including 727 (age = 9.9 ± 0.1 years, 351/376 female/male) children with family history of SSD, to evaluate unfavorable cerebral effects of ancestral SSD history, pre/perinatal environment, and negative early-life environment. We used a regional vulnerability index to measure the alignment of a child's cerebral patterns with the adult SSD pattern derived from a large meta-analysis of case-control differences., Results: In children with a family history of SSD, the regional vulnerability index captured significantly more variance in ancestral history than traditional whole-brain and regional brain measurements. In children with and without family history of SSD, the regional vulnerability index also captured more variance associated with negative pre/perinatal environment and early-life experiences than traditional brain measurements., Conclusions: In summary, in a cohort in which most children will not develop SSD, familial, pre/perinatal, and early developmental risks can alter brain patterns in the direction observed in adult patients with SSD. Individual similarity to adult SSD patterns may provide an early biomarker of the effects of genetic and developmental risks on the brain prior to psychotic or prodromal symptom onset., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Clozapine presents immunoregulatory properties not well understood. To address this issue, we performed this systematic review to evaluate the immune alterations induced by clozapine and its relationship with the drug's clinical response and compare it with other antipsychotics. Our systematic review has selected nineteen studies meeting the inclusion criteria, from which eleven were included in the meta-analysis, totalizing 689 subjects distributed over three different comparisons. The results revealed that clozapine treatment activates the compensatory immune-regulatory system (CIRS) (Hedges's g = +1.049; CI +0.62 - +1.47, p < 0.001) but has no effects on the immune-Inflammatory Response System (IRS) (Hedges's g= -0.27; CI -1.76 - +1.22, p = 0.71), M1 macrophage (Hedges's g= -0.32; CI -1.78 - +1.14, p = 0.65) and Th1 (Hedge's g = 0.86; CI -0.93 - +1.814, p = 0.07) profiles. Comparing clozapine-treated patients with other anti-psychotics-treated, plasma levels of interleukin (IL)-6 were greater in the clozapine group (Hedge's g = 0.75; CI 0.35 - 1.15, p<0.001). In addition, higher IL-6 plasma levels after four weeks of clozapine treatment were related to the development of clozapine-induced fever; however, IL-6 levels recovered to baseline in 6-10 weeks due to an unexplained compensatory mechanism. In conclusion, our results show that clozapine treatment causes a time-dependent mixed immune profile characterized by increased IL-6 levels and CIRS activation, which may contribute to this drug mechanism of action and adverse effects. Future studies must be designed to investigate the relationship between clozapine-induced immune alterations and symptom remission, treatment resistance, and adverse effects, given the importance of this drug for treating resistant schizophrenia., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests, (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)