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Psychosis is one of the most disabling psychiatric disorders. Pediatric traumatic brain injury (pTBI) has been cited as a developmental risk factor for psychosis, however this association has never been assessed meta-analytically.
A systematic review and meta-analysis of the association between pTBI and subsequent psychotic disorders/symptoms was performed. The study was pre-registered (CRD42022360772) adopting a random-effects model to estimate meta-analytic odds ratio (OR) and 95% confidence interval (CI) using the Paule–Mandel estimator. Subgroup (study location, study design, psychotic disorder v. subthreshold symptoms, assessment type, and adult v. adolescent onset) and meta-regression (quality of evidence) analyses were also performed. The robustness of findings was assessed through sensitivity analyses. The meta-analysis is available online as a computational notebook with an open dataset.
We identified 10 relevant studies and eight were included in the meta-analysis. Based on a pooled sample size of 479686, the pooled OR for the association between pTBI and psychosis outcomes was 1.80 (95% CI 1.11–2.95). There were no subgroup effects and no outliers. Both psychotic disorder and subthreshold symptoms were associated with pTBI. The overall association remained robust after removal of low-quality studies, however the OR reduced to 1.43 (95% CI 1.04–1.98). A leave-one-out sensitivity analysis showed the association was robust to removal of all but one study which changed the estimate to marginally non-significant.
We report cautious meta-analytic evidence for a positive association between pTBI and future psychosis. New evidence will be key in determining long-term reliability of this finding.
In Continental Philosophy of Psychiatry: The Lure of Madness Alastair Morgan surveys the contributions of a loosely conceived school of psychiatrists, philosophers and social theorists to understanding and responding to madness during the years 1910–1980. Taking my cue from him, I highlight some of the contributors discussed in Morgan's book and reflect that although madness may be difficult or even impossible to articulate effectively in discourse it remains a ‘limit experience’ which demarcates and illuminates the contours of other thinking and being, including reason and activism. I discuss social and cultural factors that have dulled clinicians’ sensitivities to the sounds of madness in recent decades and advocate the need for a reappraisal of our expertise and for a new activism today. What may at first appear as a failed clinical-philosophical tradition remains of professional relevance in today's rapidly transforming circumstances of practice both as inspiration and as cautionary tale.
The use of digital technologies as a method of delivering health behaviour change (HBC) interventions is rapidly increasing across the general population. However, the role in severe mental illness (SMI) remains overlooked. In this study, we aimed to systematically identify and evaluate all of the existing evidence around digital HBC interventions in people with an SMI. A systematic search of online electronic databases was conducted. Data on adherence, feasibility, and outcomes of studies on digital HBC interventions in SMI were extracted. Our combined search identified 2196 titles and abstracts, of which 1934 remained after removing duplicates. Full-text screening was performed for 107 articles, leaving 36 studies to be included. From these, 14 focused on physical activity and/or cardio-metabolic health, 19 focused on smoking cessation, and three concerned other health behaviours. The outcomes measured varied considerably across studies. Although over 90% of studies measuring behavioural changes reported positive changes in behaviour/attitudes, there were too few studies collecting data on mental health to determine effects on psychiatric outcomes. Digital HBC interventions are acceptable to people with an SMI, and could present a promising option for addressing behavioural health in these populations. Feedback indicated that additional human support may be useful for promoting adherence/engagement, and the content of such interventions may benefit from more tailoring to specific needs. While the literature does not yet allow for conclusions regarding efficacy for mental health, the available evidence to date does support their potential to change behaviour across various domains.
Little information is available on the association between gender nonconformity during adolescence and subsequent mental health. While the distress related to gender nonconformity may be socially produced rather than attributed to individual-level factors, further research is needed to better understand the role of psychosocial factors in this context.
We analyzed data from the Tokyo Teen Cohort, obtained through random sampling of adolescents born between 2002 and 2004. We used inverse probability weighting to examine the association of gender nonconformity at ages 12 and 14 as a time-varying variable with subsequent mental health at age 16, while accounting for time-fixed and time-varying confounders. Furthermore, we used a weighting approach to investigate the mediating role of modifiable psychosocial factors in this association, addressing exposure-mediator and mediator–mediator interactions.
A total of 3171 participants were analyzed. Persistent gender nonconforming behavior at ages 12 and 14 was associated with subsequent depression (β = 2.02, 95% confidence interval [CI] 0.85 to 3.19) and psychotic experiences (β = 0.33, 95% CI 0.14 to 0.52) at age 16. The results remained robust in sensitivity analyses. Approximately 30% of the association between gender nonconformity and depression was consistently mediated by a set of psychosocial factors, namely loneliness, bullying victimization, and relationships with mother, father, and friends.
Persistent gender nonconformity during adolescence is associated with subsequent mental health. Psychosocial factors play a vital mediating role in this association, highlighting the essential need for social intervention and change to reduce stigmatization and ameliorate mental health challenges.
Childhood trauma has been linked to increased risk of schizophrenia and social dysfunction, and oxytocin and its receptor gene have been implicated in regulating social behavior. This study investigated the potential role of oxytocin and oxytocin receptor gene (OXTR) in mediating the effects of childhood trauma on social functioning in schizophrenia.
The study consisted of 382 patients with schizophrenia and 178 healthy controls who were assessed using the Taiwanese version of the Childhood Trauma Questionnaire (CTQ-SF), the Social Functioning Scale (SFS), and plasma oxytocin levels. DNA was extracted to genotype the OXTR and ten single-nucleotide polymorphisms (SNPs; rs2254298, rs237885, rs237887, rs237899, rs53576, rs9840864, rs13316193, rs7632287, rs1042778, and rs237895) were selected.
Patients with schizophrenia showed higher CTQ-SF scores (t = 12.549, p < 0.001), lower SFS scores (t = −46.951, p < 0.001), and lower plasma oxytocin levels (t = −5.448, p < 0.001) compared to healthy controls. The study also found significant differences in OXTR SNPs between both groups, with risk alleles being more prevalent in patients with schizophrenia (t = 2.734, p = 0.006). Results indicated a significant moderated mediation effect, with oxytocin and the OXTR SNPs partially mediating the relationship between childhood trauma exposure and social functioning in patients with schizophrenia (index of mediation = 0.038, 95% CI [0.033–0.044]).
The findings suggest that oxytocin and its receptor gene may be promising targets for interventions aimed at improving social functioning in patients with a history of childhood trauma and schizophrenia. However, further research is needed to fully understand these effects and the potential of oxytocin-based interventions in this population.
Individuals with serious mental illness have a markedly shorter life expectancy. A major contributor to premature death is cardiovascular disease (CVD). We investigated associations of (genetic liability for) depressive disorder, bipolar disorder and schizophrenia with a range of CVD traits and examined to what degree these were driven by important confounders.
We included participants of the Dutch Lifelines cohort (N = 147 337) with information on self-reported lifetime diagnosis of depressive disorder, bipolar disorder, or schizophrenia and CVD traits. Employing linear mixed-effects models, we examined associations between mental illness diagnoses and CVD, correcting for psychotropic medication, demographic and lifestyle factors. In a subsample (N = 73 965), we repeated these analyses using polygenic scores (PGSs) for the three mental illnesses.
There was strong evidence that depressive disorder diagnosis is associated with increased arrhythmia and atherosclerosis risk and lower heart rate variability, even after confounder adjustment. Positive associations were also found for the depression PGSs with arrhythmia and atherosclerosis. Bipolar disorder was associated with a higher risk of nearly all CVD traits, though most diminished after adjustment. The bipolar disorder PGSs did not show any associations. While the schizophrenia PGSs was associated with increased arrhythmia risk and lower heart rate variability, schizophrenia diagnosis was not. All mental illness diagnoses were associated with lower blood pressure and a lower risk of hypertension.
Our study shows widespread associations of (genetic liability to) mental illness (primarily depressive disorder) with CVD, even after confounder adjustment. Future research should focus on clarifying potential causal pathways between mental illness and CVD.
The structure of negative symptoms of schizophrenia is still a matter of controversy. Although a two-dimensional model (comprising the expressive deficit dimension and the motivation and pleasure dimension) has gained a large consensus, it has been questioned by recent investigations.
To investigate the latent structure of negative symptoms and its stability over time in people with schizophrenia using network analysis.
Negative symptoms were assessed in 612 people with schizophrenia using the Brief Negative Symptom Scale (BNSS) at baseline and at 4-year follow-up. A network invariance analysis was conducted to investigate changes in the network structure and strength of connections between the two time points.
The network analysis carried out at baseline and follow-up, supported by community detection analysis, indicated that the BNSS's items aggregate to form four or five distinct domains (avolition/asociality, anhedonia, blunted affect and alogia). The network invariance test indicated that the network structure remained unchanged over time (network invariance test score 0.13; P = 0.169), although its overall strength decreased (6.28 at baseline, 5.79 at follow-up; global strength invariance test score 0.48; P = 0.016).
The results lend support to a four- or five-factor model of negative symptoms and indicate overall stability over time. These data have implications for the study of pathophysiological mechanisms and the development of targeted treatments for negative symptoms.
A patient developed fever, raised inflammatory markers and a maculopapular rash following commencement of clozapine for treatment of his schizoaffective disorder. Skin biopsy confirmed Sweet's syndrome. Identification of the cause was challenging, with a number of possible considerations including infection, malignancy and various potential drug triggers.
This case highlights the difficulties in the diagnosis of Sweet's syndrome, as well as in identifying the original trigger, which can have significant consequences for management. Withdrawal of potentially causative drugs must be balanced with their benefits, and decisions must be made in the best interests of the patient. Following two courses of prednisolone and withdrawal of clozapine, the patient's rash and systemic symptoms resolved. This confirmed the diagnosis of drug-induced Sweet's syndrome, with clozapine as the offending agent. His mental state stabilised on an alternative antipsychotic.
Schizophrenia (SZ) is a severe, complex, and common mental disorder with high heritability (80%), an adult age of onset, and high discordance (∼50%) in monozygotic twins (MZ). Extensive studies on familial and non-familial cases have implicated a number of segregating mutations and de novo changes in SZ that may include changes to the mitochondrial genome. Yet, no single universally causal variant has been identified, highlighting its extensive genetic heterogeneity. This report specifically focuses on the assessment of changes in the mitochondrial genome in a unique set of monozygotic twins discordant (MZD) for SZ using blood. Genomic DNA from six pairs of MZD twins and two sets of parents (N = 16) was hybridized to the Affymetrix Human SNP Array 6.0 to assess mitochondrial DNA copy number (mtDNA-CN). Whole genome sequencing (WGS) and quantitative polymerase chain reaction (qPCR) was performed for a subset of MZD pairs and their parents and was also used to derive mtDNA-CN estimates. The WGS data were further analyzed to generate heteroplasmy (HP) estimates. Our results show that mtDNA-CN estimates for within-pair and mother-child differences were smaller than comparisons involving unrelated individuals, as expected. MZD twins showed discordance in mtDNA-CN estimates and displayed concordance in directionality of differences for mtDNA-CN across all technologies. Further, qPCR performed better than Affymetrix in estimating mtDNA-CN based on relatedness. No reliable differences in HP were detected between MZD twins. The within-MZD differences in mtDNA-CN observed represent postzygotic somatic changes that may contribute to discordance of MZ twins for diseases, including SZ.
Clinical implementation of risk calculator models in the clinical high-risk for psychosis (CHR-P) population has been hindered by heterogeneous risk distributions across study cohorts which could be attributed to pre-ascertainment illness progression. To examine this, we tested whether the duration of attenuated psychotic symptom (APS) worsening prior to baseline moderated performance of the North American prodrome longitudinal study 2 (NAPLS2) risk calculator. We also examined whether rates of cortical thinning, another marker of illness progression, bolstered clinical prediction models.
Participants from both the NAPLS2 and NAPLS3 samples were classified as either ‘long’ or ‘short’ symptom duration based on time since APS increase prior to baseline. The NAPLS2 risk calculator model was applied to each of these groups. In a subset of NAPLS3 participants who completed follow-up magnetic resonance imaging scans, change in cortical thickness was combined with the individual risk score to predict conversion to psychosis.
The risk calculator models achieved similar performance across the combined NAPLS2/NAPLS3 sample [area under the curve (AUC) = 0.69], the long duration group (AUC = 0.71), and the short duration group (AUC = 0.71). The shorter duration group was younger and had higher baseline APS than the longer duration group. The addition of cortical thinning improved the prediction of conversion significantly for the short duration group (AUC = 0.84), with a moderate improvement in prediction for the longer duration group (AUC = 0.78).
These results suggest that early illness progression differs among CHR-P patients, is detectable with both clinical and neuroimaging measures, and could play an essential role in the prediction of clinical outcomes.
Although disconnectivity among brain regions has been one of the main hypotheses for schizophrenia, the superficial white matter (SWM) has received less attention in schizophrenia research than the deep white matter (DWM) owing to the challenge of consistent reconstruction across subjects.
We obtained the diffusion magnetic resonance imaging (dMRI) data of 223 healthy controls and 143 patients with schizophrenia. After harmonising the raw dMRIs from three different studies, we performed whole-brain two-tensor tractography and fibre clustering on the tractography data. We compared the fractional anisotropy (FA) of white matter tracts between healthy controls and patients with schizophrenia. Spearman’s rho was adopted for the associations with clinical symptoms measured by the Positive and Negative Syndrome Scale (PANSS). The Bonferroni correction was used to adjust multiple testing.
Among the 33 DWM and 8 SWM tracts, patients with schizophrenia had a lower FA in 14 DWM and 4 SWM tracts than healthy controls, with small effect sizes. In the patient group, the FA deviations of the corticospinal and superficial–occipital tracts were negatively correlated with the PANSS negative score; however, this correlation was not evident after adjusting for multiple testing.
We observed the structural impairments of both the DWM and SWM tracts in patients with schizophrenia. The SWM could be a potential target of interest in future research on neural biomarkers for schizophrenia.
The incidence of psychotic disorders varies in different geographic areas. As there has been no report from Turkey, this study aimed to provide the treated incidence rate of first-episode psychosis (FEP) in a defined area.
All individuals, aged 15–64 years, presenting with FEP (ICD-10 F20-29, F30-33) to mental health services in a defined catchment-area in Sinop which is located in the Black Sea region of the northern Turkey were recorded over a 4-year period (2009 to 2012). Incidence rates of psychotic disorders and their 95% confidence intervals (CIs) were estimated. Poisson regression was applied to estimate the differences in incidence rate ratio (IRR) by age, sex, and urbanicity.
One hundred and fifteen FEP participants were identified during the 4 years. Crude incidence rates of all psychoses, schizophrenia, other psychotic disorders, and affective psychotic disorders were respectively 38.5 (95% CI 27.1–49.9), 10.7 (95% CI 6.6–14.8), 10.0 (95% CI 5.7–14.3) and 17.7 (95% CI 11.3–24.2) per 100 000 person-years. After age-sex standardisation the rates increased slightly. There were no gender differences in the incidence rates. IRR of any psychotic disorder was highest in the youngest age group (15–24 years) compared to the oldest age group (55–64 years), 7.9 (95% CI 2.8–30.5). In contrast with previous studies, the incidence rate of any psychotic disorder was not significantly increased in urban areas compared with rural areas.
The current study, the first of its kind from Turkey, indicates that the risk of schizophrenia and other psychotic disorders in a lowly urbanised area of Turkey is comparable to those reported in Western European cities.
Chapter 7 shows that abstract concepts are inner/cognitive tools. Inner speech is potent in enhancing our cognition, imagination, and motivation. In this chapter, I propose that we use inner speech more extensively with more abstract concepts, during both their acquisition and use, while monitoring our knowledge during their processing and referring to others to complement and enrich it. I review several studies with children and adults showing that the mouth motor system is more engaged during abstract concept acquisition and elaboration. This mouth activation suggests that language is implicitly activated during abstract language processing. Also, while low numbers engage the hand effector more, the processing of larger numbers might involve language, hence the mouth, more extensively. I overview research on the neural underpinning of abstract concepts, which confirms the importance of linguistic and social neural networks for their representation. Finally, I illustrate studies on abstractness in conditions characterized by impairments in social interaction and inner and overt speech abilities, such as autism, schizophrenia, and aphasia. Overall, the studies reviewed support the idea of a determinant role of language as an inner tool supporting the acquisition and use of abstract concepts.
Women and gender-diverse people with early psychosis are at risk for suboptimal sexual health outcomes, yet little research has explored their sexual health experiences.
This study explored sexual health experiences and related priorities among women and gender-diverse people with early psychosis, to identify opportunities for improvements in sexual health and well-being.
Semi-structured individual qualitative interviews explored how patient participants (n = 19, aged 18–31 years, cisgender and transgender women and non-binary individuals) receiving clinical care from early psychosis programmes in Ontario, Canada, experienced their sexual health, including sexual function and behaviour. Thematic analysis was conducted, with triangulation from interviews/focus groups with clinicians (n = 36) who provide sexual and mental healthcare for this population.
Three key themes were identified based on patient interviews: theme 1 was the impact of psychotic illness and its treatments on sexual function and activity, including variable changes in sex drive, attitudes and behaviours during acute psychosis, vulnerability to trauma and medications; theme 2 related to intimacy and sexual relationships in the context of psychosis, with bidirectional effects between relationships and mental health; and theme 3 comprised autonomy, identity and intersectional considerations, including gender, sexuality, culture and religion, which interplay with psychosis and sexual health. Clinicians raised each of these priority areas, but emphasised risk prevention relative to patients’ more holistic view of their sexual health and well-being.
Women and non-binary people with early psychosis have wide-ranging sexual health priorities, affecting many facets of their lives. Clinical care should incorporate this knowledge to optimise sexual health and well-being in this population.
Clinical guidelines recommend providing physical activity interventions (PAIs) to people with schizophrenia or bipolar disorder for weight management. However, the cost-effectiveness of PAIs is unknown.
To evaluate the availability and methodological quality of economic evaluations of PAIs for people with schizophrenia or bipolar disorder.
Four databases (MEDLINE, Embase, PsycInfo and Scopus) were searched on 5 July 2022. Based on the retrieved studies, forward and backward citation searches were conducted. Two reviewers independently selected studies for inclusion. Study quality was assessed using the Drummond checklist. Review results were presented using narrative synthesis.
Fourteen articles reporting nine studies were included. All included studies assessed PAIs within a multicomponent lifestyle intervention. Mixed findings were reported on the cost-effectiveness of multicomponent lifestyle intervention: three studies reported it as cost-effective; four studies reported it as not cost-effective; and two studies did not conclude whether it was cost-effective or not. Very limited evidence suggests that certain patient subgroups might be more likely to benefit from multicomponent lifestyle interventions with a PAI component: men; individuals with comorbid type 2 diabetes; and individuals who have been psychiatric hospital in-patients for ≥1 year. The quality of included studies ranged from moderate to high.
The current economic evidence suggests that not all modalities of multicomponent lifestyle intervention including a PAI component are cost-effective for people with schizophrenia or bipolar disorder; and not all people with schizophrenia or bipolar disorder would benefit equally from the intervention. Future research is urgently needed to identify the cost-effective modality of PAI for different patient subgroups.
Life engagement represents a holistic concept that encompasses outcomes reflecting life-fulfilment, well-being and participation in valued and meaningful activities, which is recently gaining attention and scientific interest. Despite its conceptual importance and its relevance, life engagement represents a largely unexplored domain in schizophrenia. The aims of the present study were to independently assess correlates and predictors of patient life engagement in a large and well-characterized sample of schizophrenia patients.
To assess the impact of different demographic, clinical, cognitive and functional parameters on life engagement in a large sample of patients with schizophrenia, data from the social cognition psychometric evaluation project were analyzed.
Overall schizophrenia and depressive symptom severity, premorbid IQ, neurocognitive performance, social cognition performance both in the emotion processing and theory of mind domains, functional capacity, social skills performance and real-world functioning in different areas all emerged as correlates of patient life engagement. Greater symptom severity and greater impairment in real-world interpersonal relationships, social skills, functional capacity and work outcomes emerged as individual predictors of greater limitations in life engagement.
Life engagement in people living with schizophrenia represents a holistic and complex construct, with several different clinical, cognitive and functional correlates. These features represent potential treatment targets to improve the clinical condition and also facilitate the process of recovery and the overall well-being of people living with schizophrenia.
Schizophrenia (SZ) and autism spectrum disorders (ASD) are characterized by difficulties in theory of mind (ToM). We examined group differences in performance on a ToM-related test and associations with an estimated IQ.
Participants [N = 1227, SZ (n = 563), ASD (n = 159), and controls (n = 505), 32.2% female] completed the Reading the Mind in the Eyes Test (RMET) and assessments of cognitive ability. Associations between IQ and group on RMET were investigated with regression analyses.
SZ (d = 0.73, p < 0.001) and ASD (d = 0.37, p < 0.001) performed significantly worse on the RMET than controls. SZ performed significantly worse than ASD (d = 0.32, p = 0.002). Adding IQ to the model, SZ (d = 0.60, p < 0.001) and ASD (d = 0.44, p < 0.001) continued to perform significantly worse than controls, but no longer differed from each other (d = 0.13, p = 0.30). Small significant negative correlations between symptom severity and RMET performance were found in SZ (PANSS positive: r = −0.10, negative: r = −0.11, both p < 0.05). A small non-significant negative correlation was found for Autism Diagnostic Observation Schedule scores and RMET in ASD (r = −0.08, p = 0.34).
SZ and ASD are characterized by impairments in RMET. IQ contributed significantly to RMET performance and accounted for group differences in RMET between SZ and ASD. This suggests that non-social cognitive ability needs to be included in comparative studies of the two disorders.
People with schizophrenia die almost 20 years earlier than the general population, most commonly from avertable cardiometabolic disease. Existing pharmacological weight-loss agents including metformin have limited efficacy. Recently available glucagon-like peptide (GLP-1) receptor agonists such as semaglutide have shown promise for weight loss but have yet to be trialled in this population.
To examine the efficacy of semaglutide to ameliorate antipsychotic-induced obesity in people with schizophrenia who have been treated with clozapine for more than 18 weeks.
This is a 36-week, double-blinded, randomised placebo-controlled trial. We will recruit 80 clozapine-treated patients with schizophrenia or schizoaffective disorder, aged 18–64 years, with a baseline body mass index ≥26 kg/m2, who will be randomised to subcutaneous semaglutide of 2.0 mg once a week or placebo for 36 weeks. The primary endpoint will be percentage change in body weight from baseline.
This trial will assess the efficacy and side-effects of the GLP-1 receptor agonist semaglutide on body weight and provide evidence on the possible clinical utility of semaglutide in patients with inadequate response to metformin. The study is registered with the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) with clinical trial registration number ACTRN12621001539820.
This research could benefit individuals with schizophrenia who experience significant health issues, leading to premature mortality, owing to antipsychotic-induced weight gain. Study findings will be disseminated through peer-reviewed publications and conference presentations.
Substantial evidence indicates structural abnormalities in the cerebral cortex of patients with schizophrenia (SCZ), although their clinical implications remain unclear. Previous case-control studies have investigated group-level differences in structural abnormalities, although the study design cannot account for interindividual differences. Recent research has focused on the association between the heterogeneity of the cerebral cortex morphometric features and clinical heterogeneity.
We used neuroimaging data from 420 healthy controls and 695 patients with SCZ from seven studies. Four cerebral cortex measures were obtained: surface area, gray matter volume, thickness, and local gyrification index. We calculated the coefficient of variation (CV) and person-based similarity index (PBSI) scores and performed group comparisons. Associations between the PBSI scores and cognitive functions were evaluated using Spearman's rho test and normative modeling.
Patients with SCZ had a greater CV of surface area and cortical thickness than those of healthy controls. All PBSI scores across cortical measures were lower in patients with SCZ than in HCs. In the patient group, the PBSI scores for gray matter volume and all cortical measures taken together positively correlated with the full-scale IQ scores. Patients with deviant PBSI scores for gray matter volume and all cortical measures taken together had lower full-scale IQ scores than those of other patients.
The cerebral cortex in patients with SCZ showed greater regional and global structural variability than that in healthy controls. Patients with deviant similarity of cortical structural profiles exhibited a lower general intelligence than those exhibited by the other patients.