Hospital admissions and community health service contacts for mental illness following self-reported child maltreatment: Results from the Childhood Adversity and Lifetime Morbidity (CALM) study.

BACKGROUND: Child maltreatment (CM) includes neglect, and several types of abuse, including physical, emotional, and sexual. CM has been associated with a wide range of mental illnesses. Literature examining these illnesses in mid-life is scarce, and the impact of these illnesses on mental health service use is currently unknown. OBJECTIVE: To examine associations between self-reported CM and subsequent hospital admissions for mental illnesses, and/or community mental health service contacts. SETTING: Birth cohort study data linked to administrative health data, including hospital admissions and community mental health service contacts, up to the age of 40. METHODS: Associations between hospital admissions for mental health and community mental health contacts and CM subtypes (neglect, physical abuse, emotional abuse and sexual abuse) were examined using multivariate logistic regression. RESULTS: Adjusted analyses showed that all subtypes of CM were significantly (p < 0.05) associated with admissions to hospital for any type of mental illness (aOR range 1.87-3.61), non-psychotic mental disorders (aOR range 1.98-3.61), alcohol and/or substance use (aOR range 2.83-5.43), and community mental health service contacts (aOR range 2.44-3.13). Hospital admissions for psychotic mental disorders were significantly associated with physical abuse, emotional abuse, and sexual abuse (aOR range 2.14-3.93). CONCLUSIONS: The results of this study confirm the current knowledge around CM and subsequent mental health illnesses up to the age of 40, and extend this knowledge to hospital and mental health service use.

Experiences of individuals presenting to the emergency department for mental health reasons: A systematic mixed studies review.

OBJECTIVE: Emergency departments the world over have seen substantial increases in the number of individuals presenting for mental health reasons. However, we have a limited understanding of their experiences of care. The aim of this review was to systematically examine and synthesise literature relating to the experiences of individuals presenting to emergency department for mental health reasons. METHODS: We followed Pluye and Hong's seven-step approach to conducting a systematic mixed studies review. Studies were included if they investigated adult mental health experiences in emergency department from the users' perspective. Studies describing proxy, carer/family or care provider experiences were excluded. RESULTS: Sixteen studies were included. Thematic synthesis identified three themes and associated subthemes. Theme 1 - ED staff can make-or-break and ED experience - comprised: Feeling understood and heard; Engaging in judgement-free interactions; Receiving therapeutic support; Being actively and passively invalidated for presenting to the ED; and Once a psych patient, always a psych patient. Theme 2 - Being in the ED environment is counter-therapeutic - comprised: Waiting for an 'extremely' long time; and Lacking privacy. Theme 3 was Having nowhere else to go. CONCLUSIONS: The experiences described by individuals presenting to emergency department for mental health reasons were mostly poor. The results illustrate a need for increased mental health education and training for all emergency department staff. Employment of specialist and lived experience workers should also be prioritised to support more therapeutic relationships and emergency department environments. In addition, greater investment in mental health systems is required to manage the current crisis and ensure future sustainability.

Emergency Department Presentations for Injuries Following Agency-Notified Child Maltreatment: Results From the Childhood Adversity and Lifetime Morbidity (CALM) Study.

Child maltreatment (CM) is associated with negative health outcomes in adulthood, including deliberate self-harm (DSH), suicidal behaviours, and victimisation. It is unknown if associations extend to emergency department (ED) presentations for non-DSH related injuries. Birth cohort study data was linked to administrative health data, including ED presentations for non DSH related injuries and agency-reported and substantiated notifications for CM. Adjusted analyses (n = 6087) showed that any type of agency-reported notification for CM was significantly associated with increased odds of ED presentation for injuries (aOR = 1.57; 95% CI 1.32-1.87). In moderation analyses, women yielded significantly higher odds of notified and substantiated physical abuse, substantiated emotional abuse, and being subject to more than one type of substantiated abuse than males. ED presentations for injuries could be a proxy for risky behaviours, disguised DSH/suicidal behaviours, or physical abuse. The consistent findings in women may point to victimisation via interpersonal violence.

Overcoming clozapine's adverse events: a narrative review of systematic reviews and meta-analyses.

INTRODUCTION: Clozapine is the gold standard treatment for treatment-resistant schizophrenia, however adverse events remain a clinical challenge. AREAS COVERED: This review presents a narrative synthesis of systematic reviews and meta-analyses that have reported the onset, incidence, prevalence, and management of clozapine's adverse events. We conducted a systematic literature search using PubMed, Embase, PsycINFO, OvidMEDLINE, CINAHL, and the Cochrane Database of Systematic Reviews from inception to April 2024. EXPERT OPINION: Effective management of clozapine's adverse events necessitates multi-faceted, individualized, and shared-decision strategies. Despite a lack of high-quality systematic evidence, expert inter-disciplinary solutions are provided to help address a critical need for clinical guidance. This 35-year update offers an evidence-based framework to assist clinicians, patients, and caregivers navigate the adverse events associated with clozapine therapy.

Clozapine is an important medication for people with schizophrenia who do not respond to other treatments. It has been used for over 30 years and provides relief from symptoms and improves quality of life. However, it has side effects that can be daunting for both healthcare workers and people taking clozapine. This article summarizes the latest research on clozapine's side effects into an easy-to-use guide to help understand the side effects better. With the right knowledge and a team approach involving healthcare workers, patients, their families and carers, the risks of clozapine's side effects can be managed. Proactive and careful monitoring for side effects, education on what to do if they occur, open conversations, and regular health checkups can significantly reduce the risk that side effects become a problem.

Associations between child maltreatment and hospital admissions for alcohol and other substance use-related disorders up to 40 years of age: Results from the Childhood Adversity and Lifetime Morbidity study.

BACKGROUND AND AIMS: Evidence on the associations between child maltreatment (CM), alcohol use disorders (AUDs) and other substance use disorders (SUDs) comes largely from retrospective studies. These rely on self-reported data, which may be impacted by recall bias. Using prospective CM reports to statutory agencies, we measured associations between CM notifications and inpatient admissions for AUDs and SUDs up to 40 years of age. DESIGN, SETTING AND PARTICIPANTS: Observational study linking administrative health data from Queensland, Australia to prospective birth cohort data comprising both agency-reported and substantiated notifications of CM. MEASUREMENTS: Outcomes were inpatient admissions for AUDs and SUDs based on ICD-10-Australian modification (AM)-coded primary diagnoses. Unadjusted and adjusted logistic regression analyses were undertaken. FINDINGS: Ten per cent (n = 609) of the cohort had a history of agency-reported or substantiated CM notifications before age 15. These individuals had higher adjusted odds of being admitted for AUDs and SUDs. For AUDs, the adjusted odds of inpatient admission were 2.86 [95% confidence interval (CI) = 1.73-4.74] greater where there was any previous agency-reported CM and 3.38 (95% CI = 1.94-5.89) greater where there was any previous substantiated CM. For SUDs, the adjusted odds of inpatient admission were 3.34 (95% CI = 2.42-4.61) greater where there was any previous agency-reported CM and 2.98 (95% CI = 2.04-4.36) greater where there was any previous substantiated CM. CONCLUSIONS: People with a history of child maltreatment appear to have significantly higher odds of inpatient admissions for alcohol use disorders and other substance use disorders up to 40 years of age compared to people with no history of child maltreatment.

Association of symptom severity and cerebrospinal fluid alterations in recent onset psychosis in schizophrenia-spectrum disorders - An individual patient data meta-analysis.

Neuroinflammation and blood-cerebrospinal fluid barrier (BCB) disruption could be key elements in schizophrenia-spectrum disorders(SSDs) etiology and symptom modulation. We present the largest two-stage individual patient data (IPD) meta-analysis, investigating the association of BCB disruption and cerebrospinal fluid (CSF) alterations with symptom severity in first-episode psychosis (FEP) and recent onset psychotic disorder (ROP) individuals, with a focus on sex-related differences. Data was collected from PubMed and EMBASE databases. FEP, ROP and high-risk syndromes for psychosis IPD were included if routine basic CSF-diagnostics were reported. Risk of bias of the included studies was evaluated. Random-effects meta-analyses and mixed-effects linear regression models were employed to assess the impact of BCB alterations on symptom severity. Published (6 studies) and unpublished IPD from n = 531 individuals was included in the analyses. CSF was altered in 38.8 % of individuals. No significant differences in symptom severity were found between individuals with and without CSF alterations (SMD = -0.17, 95 %CI -0.55-0.22, p = 0.341). However, males with elevated CSF/serum albumin ratios or any CSF alteration had significantly higher positive symptom scores than those without alterations (SMD = 0.34, 95 %CI 0.05-0.64, p = 0.037 and SMD = 0.29, 95 %CI 0.17-0.41p = 0.005, respectively). Mixed-effects and simple regression models showed no association (p > 0.1) between CSF parameters and symptomatic outcomes. No interaction between sex and CSF parameters was found (p > 0.1). BCB disruption appears highly prevalent in early psychosis and could be involved in positive symptoms severity in males, indicating potential difficult-to-treat states. This work highlights the need for considering BCB breakdownand sex-related differences in SSDs clinical trials and treatment strategies.

Prevalence of multimorbidity in people with and without severe mental illness: a systematic review and meta-analysis.

BACKGROUND: People with severe mental illness, such as schizophrenia-spectrum disorder and bipolar disorder, face poorer health outcomes from multiple chronic illnesses. Physical multimorbidity, the coexistence of two or more chronic physical conditions, and psychiatric multimorbidity, the coexistence of three or more psychiatric disorders, are both emerging concepts useful in conceptualising disease burden. However, the prevalence of physical and psychiatric multimorbidity in this cohort is unknown. This study aimed to estimate the absolute prevalence of both physical and psychiatric multimorbidity in people with severe mental illness, and also compare the odds of physical multimorbidity prevalence against people without severe mental illness. METHODS: We searched CINAHL, EMBASE, PubMed, and PsycINFO from inception until Feb 15, 2024, for observational studies that measured multimorbidity prevalence. To be included, studies had to have an observational study design, be conducted in an adult population (mean age ≥18 years) diagnosed with either schizophrenia-spectrum disorder or bipolar disorder, and include a measurement of occurrence of either physical multimorbidity (≥2 physical health conditions) or psychiatric multimorbidity (≥3 psychiatric conditions total, including the severe mental illness). From control studies, a random-effects meta-analysis compared odds of physical multimorbidity between people with and without severe mental illness. Absolute prevalence of physical and psychiatric multimorbidity in people with severe mental illness was also calculated. Sensitivity and meta-regression analyses tested an array of demographic, diagnostic, and methodological variables. FINDINGS: From 11 144 citations we included 82 observational studies featuring 1 623 773 individuals with severe mental illness (specifically schizophrenia-spectrum disorder or bipolar disorder), of which 21 studies featured 13 235 882 control individuals without severe mental illness (descriptive data for the entire pooled cohorts were not available for numbers of males and females, age, and ethnicity). This study did not feature involvement of people with lived experience. The odds ratio (OR) of physical multimorbidity between people with and without severe mental illness was 2·40 (95% CI 1·57-3·65, k=11, p=0·0009). This ratio was higher in younger severe mental illness populations (mean age ≤40 years, OR 3·99, 95% CI 1·43-11·10) compared with older populations (mean age >40 years, OR 1·55, 95% CI 0·96-2·51; subgroup differences p=0·0013). For absolute prevalence, 25% of those with severe mental illness have physical multimorbidity (95% CI 0·19-0·32, k=29) and 14% have psychiatric multimorbidity (95% CI 0·08-0·23, k=21). INTERPRETATION: This is the first meta-analysis to estimate physical alongside psychiatric multimorbidity prevalence, showing that these are common in people with schizophrenia-spectrum disorder and bipolar disorder. The greater burden of physical multimorbidity in people with severe mental illness compared with those without is higher for younger cohorts, reflecting a need for earlier intervention. Our findings speak to the utility of multimorbidity for characterising the disease burden associated with severe mental illness, and the importance of facilitating integrated physical and mental health care. FUNDING: None.

Admissions for psychosis following agency-notified child maltreatment at 40-year-follow-up: Results from the Childhood Adversity and Lifetime Morbidity (CALM) cohort.

There is substantial evidence of an association between self-reported child maltreatment (CM) and subsequent psychosis in retrospective data. Such findings may be affected by recall bias. Prospective studies of notifications to statutory agencies address recall bias but are less common and subject to attrition bias. These studies may therefore be underpowered to detect significant associations for some CM types such as sexual abuse. This study therefore linked administrative health data to a large birth cohort that included notifications to child protection agencies. We assessed psychiatric outcomes of CM as measured by inpatient admissions for non-affective psychoses (ICD10 codes F20-F29) to both public and private hospitals in Brisbane, Australia. Follow-up was up to 40 years old. There were 6087 cohort participants whose data could be linked to the administrative health data. Of these, 10.1 % had been the subject of a CM notification. Seventy-two participants (1.2 %) had been admitted for non-affective psychosis by 40-year follow-up. On adjusted analysis, all notified and substantiated types of CM were associated with admissions for non-affective psychosis. This included neglect, physical, sexual or emotional abuse, as well as notifications for multiple CM types. For instance, there was a 2.72-fold increase in admissions following any agency notification (95 % CI = 1.53-4.85). All maltreatment types therefore show a significant association with subsequent admissions for psychosis up to the age of 40. Screening for CM in individuals who present with psychosis is, therefore, indicated, as well as greater awareness that survivors of CM may be at higher risk of developing psychotic symptoms.

Inflammatory cerebrospinal fluid markers in schizophrenia spectrum disorders: A systematic review and meta-analysis of 69 studies with 5710 participants.

BACKGROUND: There is increasing evidence of immune dysregulation and neuroinflammation occurring in schizophrenia. The aim of this study is to combine studies on routine CSF parameters, as well as cytokines and inflammatory proteins, in individuals with schizophrenia spectrum disorders. METHODS: CSF parameters were summated and inverse variance meta-analyses using a random effects model were performed comparing mean difference or odds ratios. Between study heterogeneity was assessed using the I2 statistic. Quality assessment and sensitivity analyses were performed. RESULTS: There were 69 studies of 5710 participants, including 3180 individuals with schizophrenia spectrum disorders. Averaged CSF parameters were within normal limits, however, between 3.1 % and 23.5 % of individual cases with schizophrenia spectrum disorders had an abnormal CSF result: Protein (abnormal in 23.5 % cases), albumin (in 18.5 %), presence of oligoclonal bands (in 9.3 %), white blood cell count (in 3.6 %), and IgG levels (3.1 %). Meta-analysis of 55 studies with non-psychiatric controls demonstrated a significant increase in CSF total protein (MD: 3.50, CI: 0.12-6.87), albumin ratio (MD: 0.55, CI: 0.02-0.09), white cell count (MD: 0.25, CI: 0.05-0.46), IL-6 (SMD: 0.53, CI: 0.29 to 0.77) and IL-8 (SMD: 0.56, CI: 0.11 to 1.01). Sensitivity analysis did not alter findings. CONCLUSION: Abnormal CSF parameters, cytokines and inflammatory proteins were found in a significant proportion of individuals with schizophrenia spectrum disorders. This may indicate alterations to blood brain barrier function and permeability, CSF flow dynamics or neuroinflammation. Further research is needed to explore these potential mechanisms.

The effectiveness and tolerability of pharmacotherapy for psychosis in 22q11.2 Deletion Syndrome: A systematic review.

OBJECTIVE: The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion in humans with over 180 phenotypic expressions. Approximately 30-40% of affected individuals will develop psychosis and 25% meet the criteria for schizophrenia. Despite this, pharmacotherapy for managing psychosis in 22q11.2DS is poorly understood and 22q11.2DS psychosis is frequently labelled as treatment resistant. The objectives of this paper are to evaluate the effectiveness and tolerability of pharmacotherapy for 22q11.2DS psychosis and evaluate the evidence for treatment resistance. METHOD: A systematic search was performed using CINAHL, The Cochrane Library (Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials and Cochrane Clinical Answers), EMBASE, PsycINFO, PubMed, Scopus and Web of Science Core Collection from inception to December 2022. It yielded 39 case reports, 6 case series and 1 retrospective study which met the inclusion criteria. RESULTS: Based on the current literature, individuals with 22q11.2DS psychosis experience a greater rate of medical co-morbidities such as cardiac arrhythmias, seizures and movement disorders, which complicate pharmacotherapy. Poor tolerability rather than poor clinical response motivates the switching of antipsychotics, which may explain the labelling of treatment resistance in the literature. CONCLUSION: There are insufficient data to recommend a single antipsychotic for 22q11.2DS psychosis. Nonetheless, with proactive management of co-morbidities, antipsychotic medication in 22q11.2DS psychosis is an effective treatment commonly resulting in improvement in quality of life.

Making meaning of multimorbidity and severe mental illness: A viewpoint.

People living with severe mental illness, such as schizophrenia and bipolar affective disorder, frequently experience poorer physical health compared to those without mental illness. This issue has hitherto been approached through the disease-centred construct of comorbidity, where subsequent conditions are viewed as secondary to an 'index condition'. In contrast, this Viewpoint sets out to explain why multimorbidity, a patient-centred concept that instead refers to the coexistence of multiple chronic illnesses, is a more versatile and robust framework for tackling the issue of poor physical health in people with severe mental illness. In establishing this argument, this Viewpoint has sought to address three key areas. First, this article will discuss the epidemiology of both physical and psychiatric multimorbidity, with respect to how they manifest at greater frequency and at younger ages in people with severe mental illness. Second, the profound consequences of this multimorbidity burden will be explored, with respect to the 'three D's' of death (premature mortality), disability (functional impacts) and deficit (health-economic impacts). Finally, the utility of multimorbidity as a framework will be illustrated through a proposal for a three-dimensional multimorbidity construct composed of (1) quantity, (2) severity and (3) duration of an individual's chronic illnesses. Consequently, this Viewpoint aims to capture why it is necessary for modern psychiatry to grasp the concept of multimorbidity to facilitate holistic healthcare for people living with severe mental illness.

Evaluating the epidemiology of clozapine-associated neutropenia among people on clozapine across Australia and Aotearoa New Zealand: a retrospective cohort study.

BACKGROUND: Clozapine is associated with the risk of serious neutropenia. However, this risk might decrease over time, meaning that indefinite absolute neutrophil count (ANC) monitoring could be unnecessary. We aimed to determine the epidemiology and timing of clozapine-associated neutropenia outcomes, to investigate variables that might contribute to the odds of neutropenia, and to determine risk of competing neutropenic events during clozapine treatment. METHODS: We performed a retrospective analysis of the Australian and New Zealand Viatris Pharmacovigilance system (one of two monitoring databases for these two countries) between June 6, 1990, and Oct 25, 2022. Patients were excluded from analysis if they commenced clozapine before 1990, did not have a haematology test within 2 weeks of commencement date, or had no follow-up. We measured minor neutropenia (ANC 1·0-1·5 × 109 per L) and serious neutropenia (ANC <1·0 × 109 per L) leading to cessation of clozapine within 6 weeks of the neutropenic event. We determined the rates of minor and serious neutropenia and calculated odds ratios (ORs) for the likelihood of neutropenia leading to cessation. For serious neutropenia leading to cessation, we used time-to-event to calculate rolling weekly averages and to perform competing risk analysis of outcomes using Cox proportional hazards models and a Fine-Gray subdistribution hazards regression model. For the subset of data where information on previous clozapine use was available, we did an analysis for participants who did and did not have previous clozapine exposure. FINDINGS: We included 26 630 people, with 2·6 million ANC values. Within the total cohort, 17 585 people (66%) were male, 9025 (33·9%) female, and 20 (0·1%) other gender, and the mean age was 36·1 years (SD 13·7). We did not have data on race or ethnicity. Of the 26 630 people taking clozapine, 1146 (4·3%) had minor neutropenia, 313 (1·2%) had serious neutropenia leading to cessation, and 223 (0·8%) had serious neutropenia unrelated to clozapine without cessation. In people with no previous exposure to clozapine (n=15 973), the cumulative incidence of serious neutropenia leading to cessation was 0·9% at 18 weeks and 1·4% at 2 years; the weekly incidence rate for serious neutropenia leading to cessation peaked at 9 weeks (0·128%) and fell to a rolling average weekly incidence of 0·001% by 2 years. For minor neutropenia, the cumulative incidence was 1·7% at 18 weeks and 3·5% at 2 years; the weekly incidence rate peaked at 9 weeks (0·218%) and fell to a stable rolling average of 0·01%. The median time to a serious neutropenic event leading to cessation was 17 weeks (IQR 9·96-102). Previous clozapine exposure reduced the risk of serious neutropenia leading to cessation (OR 0·19, 95% CI 0·12-0·31; p <0·0001). INTERPRETATION: Most serious neutropenia leading to clozapine cessation occurs within 18 weeks of treatment and becomes negligible after 2 years. Weekly haematological monitoring after the first 18 weeks could be safely reduced to once every 4 weeks and ceased after 2 years unless clinically indicated. Clozapine retrial after interruption with 2 cumulative years of unremarkable testing might not require further haematological monitoring. A serious neutropenia ANC threshold of ≤1·0 × 109 per L could be used in more jurisdictions. FUNDING: None.

Glucose-6-phosphate dehydrogenase deficiency and psychotic disorders: A systematic review.

OBJECTIVES: Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD) is the most common enzymopathy globally. Early studies suggested an association with severe psychotic illness; however, changes to laboratory testing and diagnostic classification renders the association unclear. This study aims to explore the interaction between G6PD deficiency and psychotic symptoms, in particular to identify specific patterns of presentation or impact on outcomes. METHODS: Pubmed, Embase, and PsycInfo databases were searched from inception to May 2023. Descriptive statistics and narrative review of were used to synthesise data on demographics, mental and physical health diagnoses, investigations, treatment, and outcomes. RESULTS: No clear link was found in published data (eight case reports, case series of n = 29) with a high rate (63%) of haemolytic crisis at the time of psychiatric presentation suggested delirium as an alternative diagnosis. Four case control studies found no significant difference in the prevalence of G6PD deficiency. However, catatonic presentation was reported in 40% of the case series and a higher prevalence of G6PD deficiency in catatonic schizophrenia was noted in case control studies. CONCLUSIONS: Based on the information available there was no clear association between G6PD deficiency and psychotic illness or treatment resistance, although paucity of studies and risk of bias limit strong conclusions.

Prevalence of frailty in severe mental illness: findings from the UK Biobank.

BACKGROUND: Severe mental illness (SMI) is associated with significant morbidity. Frailty combines biological ageing, comorbidity and psychosocial factors and can predict adverse health outcomes. Emerging evidence indicates that frailty is higher in individuals with SMI than in the general population, although studies have been limited by sample size. AIMS: To describe the prevalence of frailty in people with SMI in a large cohort using three different frailty measures and examine the impact of demographic and sociodemographic variables. METHOD: The UK Biobank survey data, which included individuals aged 37-73 years from England, Scotland and Wales from 2006 to 2010, with linked in-patient hospital episodes, were utilised. The prevalence of frailty in individuals with and without SMI was assessed through three frailty measures: frailty index, physical frailty phenotype (PFP) and Hospital Frailty Risk Score (HFRS). Stratified analysis and dichotomous logistic regression were conducted. RESULTS: A frailty index could be calculated for 99.5% of the 502 412 UK Biobank participants and demonstrated greater prevalence of frailty in women and an increase with age. The prevalence of frailty for those with SMI was 3.19% (95% CI 3.0-3.4), 4.2% (95% CI 3.8-4.7) and 18% (95% CI 15-23) using the frailty index, PFP and HFRS respectively. The prevalence ratio was between 3 and 18 times higher than in those without SMI. CONCLUSIONS: As a measure, frailty captures the known increase in morbidity associated with SMI and may potentially allow for earlier identification of those who will benefit from targeted interventions.

A guide to support trainee's success in the psychotherapy written case submission.

OBJECTIVE: Many trainees find the Psychotherapy Written Case (PWC) requirement of the Royal Australian and New Zealand College of Psychiatrists training program challenging. The skills developed and assessed through this experience are critical to the competencies expected of a psychiatrist. However, the process of psychodynamic psychotherapy is often dramatically different from the expectations associated with early clinical placements in acute psychiatric settings. To support trainees in achieving success in the PWC, a guide to the written report was developed based on a review of existing resources and various stakeholder perspectives. CONCLUSIONS: The submission should reflect a training case rather than an idealised or fictionalised story attempting to demonstrate the therapist's competence. The PWC submission must meet the requirements of a general psychiatric report and provide a considered reflection on the experience of the novice therapist.

Verbal and visual learning ability in patients with treatment-resistant schizophrenia: A 1-year follow-up study.

Objective: In the general population, repeated cognitive testing produces learning effects with potential for improved test performance. It is currently unclear whether the same effect of repeated cognitive testing on cognition pertains to people living with schizophrenia, a condition often associated with significant cognitive impairments. This study aims to evaluate learning ability in people with schizophrenia and-considering the evidence that antipsychotic medication can additionally impair cognitive performance-explore the potential impact of anticholinergic burden on verbal and visual learning. Method: The study included 86 patients with schizophrenia, treated with clozapine, who had persisting negative symptoms. They were assessed at baseline, weeks 8, 24 and 52 using Positive and Negative Syndrome Scale, Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-R (BVMT-R). Results: There were no significant improvements in verbal or visual learning across all measurements. Neither the clozapine/norclozapine ratio nor anticholinergic cognitive burden significantly predicted participants' total learning. Premorbid IQ was significantly associated with verbal learning on the HVLT-R. Conclusions: These findings advance our understanding of cognitive performance in people with schizophrenia and demonstrate limited learning performance in individuals with treatment-refractory schizophrenia.

Alteration patterns of peripheral concentrations of cytokines and associated inflammatory proteins in acute and chronic stages of schizophrenia: a systematic review and network meta-analysis.

BACKGROUND: Immune system dysfunction is considered to play an aetiological role in schizophrenia spectrum disorders, with substantial alterations in the concentrations of specific peripheral inflammatory proteins, such as cytokines. However, there are inconsistencies in the literature over which inflammatory proteins are altered throughout the course of illness. Through conducting a systematic review and network meta-analysis, this study aimed to investigate the patterns of alteration that peripheral inflammatory proteins undergo in both acute and chronic stages of schizophrenia spectrum disorders, relative to a healthy control population. METHODS: In this systematic review and meta-analysis, we searched PubMed, PsycINFO, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials from inception to March 31, 2022, for published studies reporting peripheral inflammatory protein concentrations in cases of people with schizophrenia-spectrum disorders and healthy controls. Inclusion criteria were: (1) observational or experimental design; (2) a population consisting of adults diagnosed with schizophrenia-spectrum disorders with a specified indicator of acute or chronic stage of illness; (3) a comparable healthy control population without mental illness; (4) a study outcome measuring the peripheral protein concentration of a cytokine, associated inflammatory marker, or C-reactive protein. We excluded studies that did not measure cytokine proteins or associated biomarkers in blood. Mean and SDs of inflammatory marker concentrations were extracted directly from full-text publshed articles; articles that did not report data as results or supplementary results were excluded (ie, authors were not contacted) and grey literature and unpublished studies were not sought. Pairwise and network meta-analyses were done to measure the standardised mean difference in peripheral protein concentrations between three groups: individuals with acute schizophrenia-spectrum disorder, individuals with chronic schizophrenia-spectrum disorder, and healthy controls. This protocol was registered on PROSPERO, CRD42022320305. FINDINGS: Of 13 617 records identified in the database searches, 4492 duplicates were removed, 9125 were screened for eligibility, 8560 were excluded after title and abstract screening, and three were excluded due to limited access to the full-text article. 324 full-text articles were then excluded due to inappropriate outcomes, mixed or undefined schizophrenia cohorts, or duplicate study populations, five were removed due to concerns over data integrity, and 215 studies were included in the meta-analysis. 24 921 participants were included, with 13 952 adult cases of schizophrenia-spectrum disorder and 10 969 adult healthy controls (descriptive data for the entire cohort were not available for age, numbers of males and females, and ethnicity). Concentration of interleukin (IL)-1ß, IL-1 receptor antagonist (IL-1RA), soluble interleukin-2 receptor (sIL-2R), IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, and C-reactive protein were consistently elevated in both individuals with acute schizophrenia-spectrum disorder and chronic schizophrenia-spectrum disorder, relative to healthy controls. IL-2 and interferon (IFN)-γ were significantly elevated in acute schizophrenia-spectrum disorder, while IL-4, IL-12, and IFN-γ were significantly decreased in chronic schizophrenia-spectrum disorder. Sensitivity and meta-regression analyses revealed that study quality and a majority of the evaluated methodological, demographic, and diagnostic factors had no significant impact on the observed results for most of the inflammatory markers. Specific exceptions to this included: methodological factors of assay source (for IL-2 and IL-8), assay validity (for IL-1ß), and study quality (for transforming growth factor-ß1); demographic factors of age (for IFN-γ, IL-4, and IL-12), sex (for IFN-γ and IL-12), smoking (for IL-4), and BMI (for IL-4); and diagnostic factors including diagnostic composition of schizophrenia-spectrum cohort (for IL-1ß IL-2, IL-6, and TNF-α), antipsychotic-free cases (for IL-4 and IL-1RA), illness duration (for IL-4), symptom severity (for IL-4), and subgroup composition (for IL-4). INTERPRETATION: Results suggest that people with schizophrenia-spectrum disorders have a baseline level of inflammatory protein alteration throughout the illness, as reflected by consistently elevated pro-inflammatory proteins, hypothesised here as trait markers (eg, IL-6), while those with acute psychotic illness might have superimposed immune activity with increased concentrations of hypothesised state markers (eg, IFN-γ). Further research is required to determine whether these peripheral alterations are reflected within the central nervous system. This research facilitates an entry point in understanding how clinically relevant inflammatory biomarkers might one day be useful to the diagnosis and prognostication of schizophrenia-spectrum disorders. FUNDING: None.