Paranoia is higher in minority group individuals, especially those reporting intersecting aspects of difference. High negative and low positive self and other beliefs, and low social rank, are predictive of paranoia overtime; however, data are typically from majority group participants. This study examined whether social defeat or healthy cultural mistrust best characterizes paranoia in minority groups.

Using cross-sectional, survey design, with a large (n = 2510) international sample, moderation analyses (PROCESS) examined whether self and other beliefs, and perceived social rank, operate similarly or differently in minority vs majority group participants. Specifically, we tested whether beliefs moderated the influence of minority group, and intersecting aspects of difference, on paranoia.

Paranoia was consistently higher in participants from minority vs majority groups and level of paranoid thinking was significantly higher at each level of the intersectionality index. Negative self/other beliefs were associated with elevated paranoia in all participants. However, in support of the notion of healthy cultural mistrust, low social rank, and low positive self/other beliefs were significantly associated with paranoia in majority group participants but unrelated to paranoia in respective minority group members.

Although mixed, our findings signal the need to consider healthy cultural mistrust when examining paranoia in minority groups and bring into question whether “paranoia” accurately describes the experiences of marginalized individuals, at least at low levels of severity. Further research on paranoia in minority groups is crucial to developing culturally appropriate ways of understanding people’s experiences in the context of victimization, discrimination, and difference.

Deficits in performing and interpreting communicative nonverbal behaviors, such as gesture, have been linked to varied psychopathology and dysfunction. Some evidence suggests that individuals at risk for psychosis have deficits in gesture interpretation and performance; however, individuals with internalizing disorders (eg, depression) may have similar deficits. No previous studies have examined whether gesture deficits in performance and interpretation are specific to those at risk for psychosis. Additionally, the underlying mechanisms (eg, cognition) and consequences (eg, functioning) of these deficits are poorly understood.

This study examined self-reported gesture interpretation (SRGI) and performance (SRGP) in those at clinical high risk for psychosis (CHR; N = 88), those with internalizing disorders (INT; N = 51), and healthy controls (HC; N = 53). Participants completed questionnaires, clinical interviews, and neurocognitive tasks.

Results indicated that the CHR group was characterized by significantly lower SRGI scores than the HC or INT groups (d = 0.41); there were no differences among groups in SRGP. Within CHR participants, greater deficits in SRGP were associated with lower verbal learning and memory (r = -.33), but not general intelligence or processing speed. Furthermore, gesture deficits were associated with higher cross-sectional risk for conversion to a full psychotic disorder in the CHR group.

Overall, these findings suggest that specific subdomains of gesture may reflect unique vulnerability for psychosis, self-report may be a viable assessment tool in understanding these phenomena, and gesture dysfunction may signal risk for transition to psychosis.

Tauopathies are neurodegenerative diseases that involve the pathological accumulation of tau proteins; in this family are Alzheimer disease, corticobasal degeneration, and chronic traumatic encephalopathy, among others. Hypothesizing that reducing this accumulation could mitigate pathogenesis, we performed a cross-species genetic screen targeting 6,600 potentially druggable genes in human cells and Drosophila. We found and validated 83 hits in cells and further validated 11 hits in the mouse brain. Three of these hits (USP7, RNF130, and RNF149) converge on the C terminus of Hsc70-interacting protein (CHIP) to regulate tau levels, highlighting the role of CHIP in maintaining tau proteostasis in the brain. Knockdown of each of these three genes in adult tauopathy mice reduced tau levels and rescued the disease phenotypes. This study thus identifies several points of intervention to reduce tau levels and demonstrates that reduction of tau levels via regulation of this pathway is a viable therapeutic strategy for Alzheimer disease and other tauopathies.

Empathic function is essential for the well-being of social species. Empathy loss is associated with various brain disorders and represents arguably the most distressing feature of frontotemporal dementia (FTD), a leading form of presenile dementia. The neural mechanisms are unknown. We established an FTD mouse model deficient in empathy and observed that aged somatic transgenic mice expressing GGGGCC repeat expansions in C9orf72, a common genetic cause of FTD, exhibited blunted affect sharing and failed to console distressed conspecifics by affiliative contact. Distress-induced consoling behavior activated the dorsomedial prefrontal cortex (dmPFC), which developed profound pyramidal neuron hypoexcitability in aged mutant mice. Optogenetic dmPFC inhibition attenuated affect sharing and other-directed consolation in wild-type mice, whereas chemogenetically enhancing dmPFC excitability rescued empathy deficits in mutant mice, even at advanced ages when substantial cortical atrophy had occurred. These results establish cortical hypoexcitability as a pathophysiological basis of empathy loss in FTD and suggest a therapeutic strategy.

The clinical definition of neurodegenerative diseases is based on symptoms that reflect terminal damage of specific brain regions. This is misleading as it tells little about the initial disease processes. Circuitry failures that underlie the clinical symptomatology are themselves preceded by clinically mostly silent, slowly progressing multicellular processes that trigger or are triggered by the accumulation of abnormally folded proteins such as Aβ, Tau, TDP-43, and α-synuclein, among others. Methodological advances in single-cell omics, combined with complex genetics and novel ways to model complex cellular interactions using induced pluripotent stem (iPS) cells, make it possible to analyze the early cellular phase of neurodegenerative disorders. This will revolutionize the way we study those diseases and will translate into novel diagnostics and cell-specific therapeutic targets, stopping these disorders in their early track before they cause difficult-to-reverse damage to the brain.

Cognitive impairment is a debilitating side effect experienced by patients with cancer treated with systemically administered anticancer therapies. With around 19.3 million new cases of cancer worldwide in 2020 and the five year survival rate growing from 50% in 1970 to 67% in 2013, an urgent need exists to understand enduring side effects with severe implications for quality of life. Whereas cognitive impairment associated with chemotherapy is recognized in patients with breast cancer, researchers have started to identify cognitive impairment associated with other treatments such as immune, endocrine, and targeted therapies only recently. The underlying mechanisms are diverse and therapy specific, so further evaluation is needed to develop effective therapeutic interventions. Drug and non-drug management strategies are emerging that target mechanistic pathways or the cognitive deficits themselves, but they need to be rigorously evaluated. Clinically, consistent use of objective diagnostic tools is necessary for accurate diagnosis and clinical characterization of cognitive impairment in patients treated with anticancer therapies. This should be supplemented with clinical guidelines that could be implemented in daily practice. This review summarizes the recent advances in the mechanisms, clinical characterization, and novel management strategies of cognitive impairment associated with treatment of non-central nervous system cancers.

In neurodegenerative diseases, proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. However, there is a need to rapidly identify amyloid conformations in situ. Here, we use machine learning on the full information available in fluorescent excitation/emission spectra of amyloid-binding dyes to identify six distinct different conformational strains in vitro, as well as amyloid-β (Aβ) deposits in different transgenic mouse models. Our EMBER (excitation multiplexed bright emission recording) imaging method rapidly identifies conformational differences in Aβ and tau deposits from Down syndrome, sporadic and familial Alzheimer’s disease human brain slices. EMBER has in situ identified distinct conformational strains of tau inclusions in astrocytes, oligodendrocytes, and neurons from Pick’s disease. In future studies, EMBER should enable high-throughput measurements of the fidelity of strain transmission in cellular and animal neurodegenerative diseases models, time course of amyloid strain propagation, and identification of pathogenic versus benign strains.

To explore the housing trajectory, personal recovery, functional level, and quality of life of clients at discharge and 1 year after completing Projet Réaffiliation Itinérance Santé Mentale (PRISM), a shelter-based mental health and rehabilitation program intended to provide individuals experiencing homelessness and severe mental illness with transition housing and to reconnect them with mental health and social services.

Housing status, psychiatric follow-up trajectory, personal recovery (Canadian Personal Recovery Outcome Measure), functional level (Multnomah Community Ability Scale), and quality of life (Lehman Quality of Life Interview) were assessed at program entry, at program discharge and 1 year later.

Of the 50 clients who participated in the study from May 31, 2018, to December 31, 2019, 43 completed the program. Of these, 76.7% were discharged to housing modalities and 78% were engaged with psychiatric follow-up at the program’s end. Housing stability, defined as residing at the same permanent address since discharge, was achieved for 62.5% of participants at 1-year follow-up. Functional level and quality of life scores improved significantly both at discharge and at 1-year follow-up from baseline.

Admission to PRISM helped clients secure long-term stable housing and appropriate psychiatric follow-up. Stable housing was maintained for most clients at 1-year follow-up, and they benefited from sustained functional and quality of life outcomes in long-term follow-up.

Children exposed to socioenvironmental adversities (eg, urbanicity, pollution, neighborhood deprivation, crime, and family disadvantage) are more likely to subsequently develop subclinical psychotic experiences during adolescence (eg, hearing voices, paranoia). However, the pathways through which this occurs have not been previously investigated. We hypothesized that cognitive ability and inflammation would partly explain this association.

Data were utilized from the Environmental-Risk Longitudinal Twin Study, a cohort of 2232 children born in 1994-1995 in England and Wales and followed to age 18. Socioenvironmental adversities were measured from birth to age 10 and classified into physical risk (defined by high urbanicity and air pollution) and socioeconomic risk (defined by high neighborhood deprivation, neighborhood disorder, and family disadvantage). Cognitive abilities (overall, crystallized, fluid, and working memory) were assessed at age 12; and inflammatory markers (C-reactive protein, interleukin-6, soluble urokinase plasminogen activator receptor) were measured at age 18 from blood samples. Participants were interviewed at age 18 regarding psychotic experiences.

Higher physical risk and socioeconomic risk were associated with increased odds of psychotic experiences in adolescence. The largest mediation pathways were from socioeconomic risk via overall cognitive ability and crystallized ability, which accounted for ~11% and ~19% of the association with psychotic experiences, respectively. No statistically significant pathways were found via inflammatory markers in exploratory (partially cross-sectional) analyses.

Cognitive ability, especially crystallized ability, may partly explain the association between childhood socioenvironmental adversity and adolescent psychotic experiences. Interventions to support cognitive development among children living in disadvantaged settings could buffer them against developing subclinical psychotic phenomena.

People with schizophrenia and other serious mental illnesses (SMI) represent a concerning health disparity population, with 10-30 fewer years of life compared to the general population, mainly from high rates of cardiovascular disease (CVD). Preventing CVD is possible with exercise and diet interventions, but only 50 % of participants in clinical trials achieve reduction in CVD risk. This study assessed whether cash incentives improved weight loss, cardiovascular endurance, and/or mortality risk when added to one of four healthy lifestyle programs (gym membership, Weight Watchers membership, the InSHAPE program, InSHAPE + Weight Watchers).

From 2012 to 2015, 1348 overweight or obese adults with SMI enrolled in a study using equipoise stratified randomization. Participants were randomly assigned to intervention, then to cash incentives, or not, for participation (gym and/or Weight Watchers), with baseline and quarterly assessments for 12 months. We examined effects of the interventions, key covariates, and incentives, using generalized linear models.

Main effects of randomization to receive cash incentives was not significant for any outcome; whereas total amount of incentives was significantly associated with all three primary outcomes (weight loss, cardiovascular endurance, mortality risk), mainly for participants in the InSHAPE+WW group who received additional cash incentives.

Incentives may be effective at preventing CVD and improving health outcomes for people with SMI, especially in the context of intensive support for healthy lifestyle behaviors. Policy changes are required to increase access to healthy lifestyle programming and more research is needed to establish the optimal amount of incentives for people with SMI.

ClinicalTrials.gov identifier: NCT02515981.

Roluperidone has antagonist properties for 5-HT_2A, sigma₂, α_1A– and α_1B-adrenergic receptors, but no dopaminergic binding affinities. In 2 randomized controlled trials (RCT), treatment improved negative symptoms of schizophrenia and social functioning among patients with moderate to severe negative symptoms. We report results of the protocol specified analysis of 2 open-label extension studies of 24 and 40 weeks investigating whether improvement of negative symptoms was sustained without significant adverse effects or worsening of psychosis. Following 12-week double-blind phase of both RCTs, patients were eligible to receive monotherapy roluperidone 32 mg/day or 64 mg/day for 24 weeks (trial 1) or 40 weeks (trial 2) in open-label extension study. Trial 1 included 244 patients of whom 142 entered 24-week open-label extension and trial 2 included 513 patients of whom 341 entered 40-week open-label extension. Trial 1 had PANSS negative factor score of Pentagonal Structure Model as primary outcome. Trial 2 had Marder Negative Symptoms Factor Score as primary outcome measure and Personal and Social Performance (PSP) Total score as secondary outcome. During open-label extensions, continued improvements in negative symptoms and on PSP were observed. Overall rate of symptomatic worsening requiring discontinuation of roluperidone and treatment with an antipsychotic was <10 %. Roluperidone was well tolerated with no meaningful changes in vital signs, laboratory values, weight gain, metabolic indices, or extrapyramidal symptoms. Results of 2 open-label extension trials support roluperidone as a treatment of negative symptoms and social functioning deficits in patients with moderate to severe negative symptoms of schizophrenia.

Schizotypy has become an increasingly important construct for elaborating psychotic disorders that vary along the schizophrenic spectrum. However, different schizotypy inventories vary in conceptual approach and measurement. In addition, commonly used schizotypy scales have been seen as qualitatively different from screening instruments for prodromal schizophrenia like the Prodromal Questionnaire-16 (PQ-16). Our study investigated the psychometric properties of three schizotypy questionnaires (the Schizotypal Personality Questionnaire-Brief, Oxford-Liverpool Inventory of Feelings and Experiences, and the Multidimensional Schizotypy Scale) as well as the PQ-16 in a cohort of 383 non-clinical subjects. We initially evaluated their factor structure using Principal Component Analysis (PCA) and used Confirmatory Factor Analysis (CFA) to test a newly proposed composition of factors. PCA results support a three-factor structure of schizotypy that accounts for 71 % of the total variance, but also shows cross-loadings of some schizotypy subscales. CFA of the newly composed schizotypy factors (together with an added neuroticism factor) shows good fit. Analyses including the PQ-16 indicate considerable overlap with measures of trait schizotypy, suggesting that the PQ-16 might not be quantitatively or qualitatively different from schizotypy measurements. Taken together, results indicate that there is good support for a three-factor structure of schizotypy but also that different schizotypy measurements grasp facets of schizotypy differently. This points towards the need for an integrative approach for assessing the construct of schizotypy.

Catatonia is a neuropsychiatric syndrome associated with both psychiatric disorders and medical conditions. Understanding of the pathophysiology of catatonia remains limited, and the role of the environment is unclear. Although seasonal variations have been shown for many of the disorders underlying catatonia, the seasonality of this syndrome has not yet been adequately explored.

Clinical records were screened to identify a cohort of patients suffering from catatonia and a control group of psychiatric inpatients, from 2007 to 2016 in South London. In a cohort study, the seasonality of presentation was explored fitting regression models with harmonic terms, while the effect of season of birth on subsequent development of catatonia was analyzed using regression models for count data. In a case-control study, the association between month of birth and catatonia was studied fitting logistic regression models.

In total, 955 patients suffering from catatonia and 23,409 controls were included. The number of catatonic episodes increased during winter, with a peak in February. Similarly, an increasing number of cases was observed during summer, with a second peak in August. However, no evidence for an association between month of birth and catatonia was found.

The presentation of catatonia showed seasonal variation in accordance with patterns described for many of the disorders underlying catatonia, such as mood disorders and infections. We found no evidence for an association between season of birth and risk of developing catatonia. This may imply that recent triggers may underpin catatonia, rather than distal events.

Suicidal ideation (SI) is prevalent among individuals at clinical high-risk for psychosis (CHR). Natural language processing (NLP) provides an efficient method to identify linguistic markers of suicidality. Prior work has demonstrated that an increased use of “I”, as well as words with semantic similarity to “anger”, “sadness”, “stress” and “lonely”, are correlated with SI in other cohorts. The current project analyzes data collected in an SI supplement to an NIH R01 study of thought disorder and social cognition in CHR. This study is the first to use NLP analyses of spoken language to identify linguistic correlates of recent suicidal ideation among CHR individuals. The sample included 43 CHR individuals, 10 with recent suicidal ideation and 33 without, as measured by the Columbia-Suicide Severity Rating Scale, as well as 14 healthy volunteers without SI. NLP methods include part-of-speech (POS) tagging, a GoEmotions-trained BERT Model, and Zero-Shot Learning. As hypothesized, individuals at CHR for psychosis who endorsed recent SI utilized more words with semantic similarity to “anger” compared to those who did not. Words with semantic similarity to “stress”, “loneliness”, and “sadness” were not significantly different between the two CHR groups. Contrary to our hypotheses, CHR individuals with recent SI did not use the word “I” more than those without recent SI. As anger is not characteristic of CHR, findings have implications for the consideration of subthreshold anger-related sentiment in suicidal risk assessment. As NLP is scalable, findings suggest that language markers may improve suicide screening and prediction in this population.

The quantity and quality of social contacts have been related to self-esteem, and both social relationships and self-esteem have been implicated in the pathways to paranoia. However, how social relationships interplay with self-esteem to trigger paranoia is not well understood. This study aims to investigate whether different measures of social connectedness (social support, loneliness, and desired friendship), as well as the frequency of social contact, impact paranoia and other positive and negative psychotic-like experiences (PLE) through the indirect effect of self-esteem. Data from a sample of 169 nonclinically ascertained participants oversampled for schizotypy scores were analyzed using two different approaches: retrospective trait-like and ecological momentary measures of social connectedness. Results showed that self-esteem mediates the pathways from poor social support and social longing, but not from loneliness, to paranoia and other cognitive PLE. In contrast, pathways from social connectedness to perceptual PLE and negative PLE were not mediated by self-esteem. Results were consistent across trait-like and momentary measures. Finally, self-esteem was not implicated in the pathways from the frequency of social contact and paranoia or other forms of PLE. These results provide a comprehensive picture of how social connectedness drives specific symptoms of psychosis through self-esteem. Findings underscore the need to explore separately the quality and quantity of social relationships and suggest that the subjective experience of meaningful social bonds is key social determinants of mental health. Therefore, addressing inadequacies of social connectedness could substantially improve symptomatic and functional outcomes of psychosis.

Previous research showed that the Global Financial Crisis (GFC) was associated with a widening disparity in suicide rates between lower-class occupations and the highest-class occupations in Australia. There has been no research investigating whether this trend continued post-GFC.

This study aimed to investigate suicide rates by occupational class among employed Australians aged 15 years and over, between 2007 and 2018.

A population-level retrospective mortality study was conducted using data from the National Coronial Information System. Adjusted suicide rates were calculated over the period 2007 to 2018. Negative binomial regression models were used to assess the relationship between occupational class, gender and time, comparing post-GFC years (2010-2012, 2013-2015 and 2016-2018) with GFC years (2007-2009).

Relative to the GFC period of 2007-2009, a significant reduction in suicide disparity between managers and other occupation groups was only observed among male labourers (rate ratios (RR) = 0.65, 95% CI 0.49-0.86) and male technicians/trades workers (RR = 0.73, 95% CI 0.56-0.96) for the period 2013-2015.

Skilled manual and lower-skilled occupational classes remain at elevated risk of suicide in Australia. While a decreasing divergence in suicide rates was only observed between labourer and manager occupational classes post-GFC, this trend was not maintained over the later part of the study period (2016-2018). There is a need to further understand the relationship between contextual factors associated with suicide among the employed population, especially during periods of economic downturn.

Cognitive impairment is the strongest predictor of functional outcomes in schizophrenia and is hypothesized to result from synaptic dysfunction. However, targeting synaptic plasticity and cognitive deficits in patients remains a significant clinical challenge. A comprehensive understanding of synaptic plasticity and the molecular basis of learning and memory in a disease context can provide specific targets for the development of novel therapeutics targeting cognitive impairments in schizophrenia. Here, we describe the role of synaptic plasticity in cognition, summarize evidence for synaptic dysfunction in schizophrenia and demonstrate the use of patient derived induced-pluripotent stem cells for studying synaptic plasticity in vitro. Lastly, we discuss current advances and future technologies for bridging basic science research of synaptic dysfunction with clinical and translational research that can be used to predict treatment response and develop novel therapeutics.

Ribosome-associated quality control (RQC) pathway is responsible for degradation of nascent polypeptides in aberrantly stalled ribosomes, and its defects may lead to neurological diseases. However, the underlying molecular mechanism of how RQC dysfunction elicits neurological disorders remains poorly understood. Here we revealed that neurons with knockout (KO) of ubiquitin ligase LTN1, a key gene in the RQC pathway, show developmental defects in neurons via upregulation of TTC3 and UFMylation signaling proteins. The abnormally enhanced TTC3 protein in Ltn1 KO neurons reduced further accumulation of translationally arrested products by preventing translation initiation of selective genes. However, the overaccumulated TTC3 protein in turn caused dendritic abnormalities and reduced surface-localized GABA_A receptors during neuronal development. Ltn1 KO mice showed behavioral deficits associated with cognitive disorders, a subset of which were restored by TTC3 knockdown in medial prefrontal cortex. Together, the overactivated cellular compensatory mechanism against defective RQC through TTC3 overaccumulation induced synaptic and cognitive deficits. More broadly, these findings represent a novel cellular mechanism underlying neuronal dysfunctions triggered by exaggerated cellular stress response to accumulated abnormal translation products in neurons.

Complexity and lack of standardization have mostly limited the use of event-related potentials (ERPs) and quantitative EEG (QEEG) biomarkers in drug development to small early phase trials. We present results from a clinical study on healthy volunteers (HV) and patients with schizophrenia (SZ) that assessed test-retest, group differences, variance, and correlation with functional assessments for ERP and QEEG measures collected at clinical and commercial trial sites with standardized instrumentation and methods, and analyzed through an automated data analysis pipeline.

81 HV and 80 SZ were tested at one of four study sites. Subjects were administered two ERP/EEG testing sessions on separate visits. Sessions included a mismatch negativity paradigm, a 40 Hz auditory steady-state response paradigm, an eyes-closed resting state EEG, and an active auditory oddball paradigm. SZ subjects were also tested on the Brief Assessment of Cognition (BAC), Positive and Negative Syndrome Scale (PANSS), and Virtual Reality Functional Capacity Assessment Tool (VRFCAT).

Standardized ERP/EEG instrumentation and methods ensured few test failures. The automated data analysis pipeline allowed for near real-time analysis with no human intervention. Test-retest reliability was fair-to-excellent for most of the outcome measures. SZ subjects showed significant deficits in ERP and QEEG measures consistent with published academic literature. A subset of ERP and QEEG measures correlated with functional assessments administered to the SZ subjects.

With standardized instrumentation and methods, complex ERP/EEG testing sessions can be reliably performed at clinical and commercial trial sites to produce high-quality data in near real-time.

Mentalizing impairment in schizophrenia has been linked to altered neural responses. This study aimed to replicate previous findings of altered activation of the mentalizing network in schizophrenia and investigate its possible association with impaired domain-general cognition.

We analyzed imaging data from two large multi-centric German studies including 64 patients, 64 matched controls and a separate cohort of 300 healthy subjects, as well as an independent Australian study including 46 patients and 61 controls. All subjects underwent functional magnetic resonance imaging while performing the same affective mentalizing task and completed a cognitive assessment battery. Group differences in activation of the mentalizing network were assessed by classical as well as Bayesian two-sample t-tests. Multiple regression analysis was performed to investigate effects of neurocognitive measures on activation of the mentalizing network.

We found no significant group differences in activation of the mentalizing network. Bayes factors indicate that these results provide genuine evidence for the null hypothesis. We found a positive association between verbal intelligence and activation of the medial prefrontal cortex, a key region of the mentalizing network, in three independent samples. Finally, individuals with low verbal intelligence showed altered activation in areas previously implicated in mentalizing dysfunction in schizophrenia.

Mentalizing activation in patients with schizophrenia might not differ compared to large well-matched groups of healthy controls. Verbal intelligence is an important confounding variable in group comparisons, which should be considered in future studies of the neural correlates of mentalizing dysfunction in schizophrenia.

Microvascular and inflammatory mechanisms have been hypothesized to be involved in the pathophysiology of psychotic spectrum disorders (PSDs). However, data evaluating these hypotheses remain limited.

We applied a three-compartment intravoxel incoherent motion free water imaging (IVIM-FWI) technique that estimates the perfusion fraction (PF), free water fraction (FW), and anisotropic diffusion of tissue (FAt) to examine microvascular and microstructural changes in gray and white matter in 55 young adults with a PSD compared to 37 healthy controls (HCs).

We found significantly increased PF, FW, and FAt in gray matter regions, and significantly increased PF, FW, and decreased FAt in white matter regions in the PSD group versus HC. Furthermore, in patients, but not in the HC group, increased PF, FW, and FAt in gray matter and increased PF in white matter were significantly associated with poor performance on several cognitive tests assessing memory and processing speed. We additionally report significant associations between IVIM-FWI metrics and myo-inositol, choline, and N-acetylaspartic acid magnetic resonance spectroscopy imaging metabolites in the posterior cingulate cortex, which further supports the validity of PF, FW, and FAt as microvascular and microstructural biomarkers of PSD. Finally, we found significant relationships between IVIM-FWI metrics and the duration of psychosis in gray and white matter regions.

The three-compartment IVIM-FWI model provides metrics that are associated with cognitive deficits and may reflect disease progression.

Dynamics of the distributed sets of functionally synchronized brain regions, known as large-scale networks, are essential for the emotional state and cognitive processes. However, few studies were performed to elucidate the aberrant dynamics across the large-scale networks across multiple psychiatric disorders. In this paper, we aimed to investigate dynamic aspects of the aberrancy of the causal connections among the large-scale networks of the multiple psychiatric disorders.

We applied dynamic causal modeling (DCM) to the large-sample multi-site dataset with 739 participants from 4 imaging sites including 4 different groups, healthy controls, schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD), to compare the causal relationships among the large-scale networks, including visual network, somatomotor network (SMN), dorsal attention network (DAN), salience network (SAN), limbic network (LIN), frontoparietal network, and default mode network.

DCM showed that the decreased self-inhibitory connection of LIN was the common aberrant connection pattern across psychiatry disorders. Furthermore, increased causal connections from LIN to multiple networks, aberrant self-inhibitory connections of DAN and SMN, and increased self-inhibitory connection of SAN were disorder-specific patterns for SCZ, MDD, and BD, respectively.

DCM revealed that LIN was the core abnormal network common to psychiatric disorders. Furthermore, DCM showed disorder-specific abnormal patterns of causal connections across the 7 networks. Our findings suggested that aberrant dynamics among the large-scale networks could be a key biomarker for these transdiagnostic psychiatric disorders.

Currently there is no first-line treatment recommended for the negative symptoms of schizophrenia. Psychosocial and behavioural interventions are widely used to reduce the burden of negative symptoms. Meta-analytic studies have summarised the evidence for specific approaches but not compared evidence quality and benefit.

To review and evaluate the evidence from meta-analytic studies of psychosocial and behavioural interventions for the negative symptoms of schizophrenia.

A systematic literature search was undertaken to identify all meta-analyses evaluating psychosocial and behavioural interventions reporting on negative symptom outcomes in people with schizophrenia. Data on intervention, study characteristics, acceptability and outcome were extracted. Risk of bias was evaluated. Results were summarised descriptively, and evidence ranked on methodological quality.

In total, 31 systematic reviews met the inclusion criteria evaluating the efficacy of negative symptom interventions on 33 141 participants. Exercise interventions showed effect sizes (reduction in negative symptoms) ranging from -0.59 to -0.24 and psychological interventions ranging from -0.65 to -0.04. Attrition ranged between 12% to 32%. Across the studies considered heterogeneity varied substantially (range 0-100). Most of the reviews were of very low to low methodological quality. Methodological quality ranking suggested that the effect size for cognitive remediation and exercise therapy may be more robust compared with other approaches.

Most of the interventions considered had a small-to-moderate effect size, good acceptability levels but very few had negative symptoms as the primary intervention target. To improve the confidence of these effect sizes being replicated in clinical settings future studies should minimise risk of bias.

Little is still known about the long-term impact of childhood and adolescent persistent depression and anxiety in adulthood.

To investigate the impact of persistent anxiety, depression, and comorbid anxiety and depression across childhood and adolescence on the development of multiple adverse outcomes in young adulthood.

This study used data from 8122 participants in the Avon Longitudinal Study of Parents and Children cohort. The Development and Well-Being Assessment (DAWBA) examined child anxiety and depression symptomatology. The DAWBA generalised anxiety and mood subscales at 8, 10 and 13 years were selected, and a measure of comorbid anxiety and depression symptoms was created at each time point. Further, several mental and physical health, substance misuse and education/employment problems were assessed at 24 years. Latent class growth analyses were used to detect trajectories of anxiety, depression and comorbid anxiety and depression; and logistic regression to examine how persistent anxiety, depression or both were associated with adverse outcomes at 24 years.

All three classes with persistent anxiety, depression or both were significantly associated with presenting with any mental health problems and any education/employment problem. Persistent high levels of depression and high levels of comorbid anxiety and depression, but not persistent high anxiety, were significantly associated with any physical health problem. High levels of comorbid anxiety and depression was the only DAWBA domain significantly associated with substance misuse; and overall, this was the domain that exerted the greatest negative impact, as it presented the highest odd ratio values.

Children and adolescents with comorbid anxiety and depression are at the highest risk for having more adverse outcomes at 24 years.

Governments and non-governmental organisations are increasingly adopting a ‘zero-suicide’ goal, but what such a goal precisely involves is unclear. Ostensibly it strongly prioritises the prevention and elimination of all suicide. We argue that, so understood, a societal goal of zero suicide risks contravening several ethical principles. In terms of beneficence and non-maleficence, a ‘zero-suicide’ goal risks being inefficient and may burden or harm many people. Autonomy-wise, a blanket ban on all suicide is excessive. As regards social justice, zero suicide risks focusing on the symptoms of social malaise instead of the structures causing it. With respect to transparency, a ‘zero’ goal that cannot be met makes these authorities look detached and risks frustration, distrust and, worse, stigmatisation of suicide and of mental health conditions. Instead, we propose a middle path for suicide prevention, founded on harm reduction, ‘soft group paternalism’ and efforts directed at increased quality of life for disadvantaged groups. Although soft group paternalism respects autonomy, this approach permits coercive interferences in certain circumstances. We hope that the justificatory framework tying together these largely familiar elements is novel and sensible.

Treatment response to specific antipsychotic medications is difficult to predict on clinical grounds alone. The current study hypothesizes that the baseline complement pathway activity predicts the treatment response and investigates the relationship between baseline plasma biomarkers with treatment response to antipsychotic medications.

Baseline plasma samples were collected from first episode of psychosis patients (n = 243) from a multi-center clinical trial. The participants were treated with amisulpride for 4 weeks. Levels of complement and coagulation proteins at baseline were measured using both data-dependent and data-independent mass spectrometry approaches. The primary outcome was remission status at 4 weeks and the secondary outcomes included change in psychotic and functional symptoms over the period of treatment. In addition, immunoassays were performed at baseline for complement C1R, as well as for activation markers C4a and sC5b-9.

The plasma level of complement variant C4A was significantly associated with remission at 4 weeks. Moreover, higher levels of several complement and coagulation pathway proteins were associated with a reduction in psychotic symptoms and an improvement in functioning. Immunoassays showed an association of baseline levels of C1R and C4a as well as complement activation marker sC5b-9 levels with treatment response.

The results demonstrated that the response to antipsychotic treatment might be related to pre-treatment levels of plasma complement and coagulation pathway proteins. This is consistent with independent evidence associating immune dysfunction with the pathophysiology of psychosis. Moreover, these results inform the development of novel therapeutic approaches that target the complement system for psychosis.

Grandiose delusions may entail difficult responsibilities and detrimental actions for patients. Recognition of these consequences by patients may provide an avenue for engagement in treatment. Furthermore, when patients carry out actions within the delusional system (“immersion behaviors”) or spend considerable time thinking about their grandiose beliefs this may contribute to the persistence of the grandiosity and further harmful consequences. We, therefore, investigated grandiose-related subjective harm, immersion behaviors, and perseverative thinking.

A cross-sectional study with 798 patients with psychosis (375 of whom had grandiose delusions) and 4518 nonclinical adults. Factor analyses using data from participants scoring highly on grandiosity were used to form 3 scales: subjective harm from exceptional experiences questionnaire; immersion behaviors questionnaire; and thinking about exceptional experiences questionnaire. Associations with grandiosity were tested using structural equation modeling.

A total of 268 (77.9%) patients with grandiose delusions identified grandiose-related harms in the past 6 months and 199 (55.1%) wanted help. Immersion behaviors and perseverative thinking were highly prevalent, and explained 39.5% and 20.4% of the variance in grandiosity, respectively. Immersion behaviors and perseverative thinking were significantly associated with subjective harm, even when severity of grandiosity was controlled. Requests for help were associated with higher levels of subjective harm, use of immersion behaviors, and perseverative thinking but not severity of grandiosity.

Acting on grandiose delusions, including harmful behaviors and excessive thinking about grandiose delusions, may be routes for clinicians to engage patients in treatment. This could be a starting point for targeted psychological interventions for grandiose delusions.

Game theory paradigms, such as the Prisoner’s Dilemma Game (PDG), have been used to study nonclinical paranoia, though research using clinical populations has been scarce. We test our novel theoretical model that schizophrenia leads to competitiveness in interpersonal interactions, and that this link is serially mediated by trait paranoia, state paranoia, and distrust.

In this quasi-experimental study, individuals with schizophrenia spectrum diagnoses with current persecutory delusions (n = 46) and a nonclinical control group (n = 43) played the PDG, and completed measures of trait paranoia, state paranoia, and distrust.

Individuals with schizophrenia competed more in the PDG than the control group. Supporting our theoretical model, all direct effects were significant: schizophrenia was associated with higher trait paranoia (H1); trait paranoia predicted state paranoia in the PDG (H2); state paranoia in the PDG predicted distrust of the opponent in the PDG (H3); and distrust predicted competition in the PDG (H4). The hypothesized indirect effect of schizophrenia on competition in the PDG via trait paranoia, state paranoia, and distrust was supported in a serial mediation model (H5).

The findings make clear theoretical and methodological contributions. We provide the first evidence for a theoretical process model by which schizophrenia leads to competitiveness in interpersonal interactions via trait paranoia, state paranoia, and distrust. Game theory paradigms, and the PDG in particular, are important for advancing theory and research on paranoia as it occurs in both clinical and nonclinical populations.

Fibrils formed by the 42-residue amyloid-β peptide (Aβ42), a main component of amyloid deposits in Alzheimer’s disease (AD), are known to be polymorphic, i.e., to contain multiple possible molecular structures. Previous studies of Aβ42 fibrils, including fibrils prepared entirely in vitro or extracted from brain tissue and using solid-state NMR (ssNMR) or cryogenic electron microscopy (cryo-EM) methods, have found polymorphs with differences in amino acid sidechain orientations, lengths of structurally ordered segments, and contacts between cross-β subunit pairs within a single filament. Despite these differences, Aβ42 molecules adopt a common S-shaped conformation in all previously described high-resolution Aβ42 fibril structures. Here we report two cryo-EM-based structures of Aβ42 fibrils that are qualitatively different, in samples derived from AD brain tissue by seeded growth. In type A fibrils, residues 12 to 42 adopt a ν-shaped conformation, with both intra-subunit and intersubunit hydrophobic contacts to form a compact core. In type B fibrils, residues 2 to 42 adopt an υ-shaped conformation, with only intersubunit contacts and internal pores. Type A and type B fibrils have opposite helical handedness. Cryo-EM density maps and molecular dynamics simulations indicate intersubunit K16-A42 salt bridges in type B fibrils and partially occupied K28-A42 salt bridges in type A fibrils. The coexistence of two predominant polymorphs, with differences in N-terminal dynamics, is supported by ssNMR data, as is faithful propagation of structures from first-generation to second-generation brain-seeded Aβ42 fibril samples. These results demonstrate that Aβ42 fibrils can exhibit a greater range of structural variations than seen in previous studies.

The neuronal mechanisms that underlie deficits in effort cost computation in schizophrenia (SZ) are poorly understood. Given the role of frontostriatal circuits in valence-oriented motivation, we hypothesized that these circuits are either dysfunctional in SZ or do not appropriately predict behavior in SZ when task conditions are difficult and good performance is rewarded.

A total of 52 people with recent onset SZ-spectrum disorders and 48 healthy controls (HCs) performed a 3T fMRI task with 2 valence conditions (rewarded vs neutral) and 2 difficulty conditions. Frontostriatal connectivity was extracted during the cue (anticipatory) phase. Individual behavior was fit using a drift-diffusion model, allowing the performance parameter, drift rate (DR), to vary between task conditions. Three models were examined: A group × condition model of DR, a group × condition model of connectivity, and a regression model of connectivity predicting DR depending on group and condition.

DRs showed the expected positive correlation with accuracy and a negative association with reaction time. The SZ group showed a deficit in DR but did not differ in overall connectivity or show a valence-specific deficit in connectivity. Significant group × valence × difficulty interactions, however, were observed on the relationship between right dorsolateral prefrontal (DLPFC)-striatal connectivity and DR (DLPFC-Caudate: F = 10.92, PFDR = .004; DLPFC-Putamen: F = 5.14, PFDR = .048) driven by more positive relationships between DR and connectivity during cues for the difficult-rewarded condition in HCs compared to SZ.

These findings suggest that frontostriatal connectivity is less predictive of performance in SZ when task difficulty is increased and a reward incentive is applied.

There is a lack of consensus about the effect of the COVID-19 pandemic on the mental health of children and adolescents. We aimed to compare rates of paediatric emergency department visits for attempted suicide, self-harm, and suicidal ideation during the pandemic with those before the pandemic.

For this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO for studies published between Jan 1, 2020, and Dec 19, 2022. Studies published in English with data on paediatric (ie, those aged <19 years) emergency department visits before and during the COVID-19 pandemic were included. Case studies and qualitative analyses were excluded. Changes in attempted suicide, self-harm, suicidal ideation, and other mental-illness indicators (eg, anxiety, depression, and psychosis) were expressed as ratios of the rates of emergency department visits during the pandemic compared with those before the pandemic, and we analysed these with a random-effects meta-analysis. This study was registered with PROSPERO, CRD42022341897.

10 360 non-duplicate records were retrieved, which yielded 42 relevant studies (with 130 sample-estimates) representing 11·1 million emergency department visits for all indications of children and adolescents across 18 countries. The mean age of the samples of children and adolescents across studies was 11·7 years (SD 3·1, range 5·5-16·3), and there were on average 57·6% girls and 43·4% boys as a proportion of emergency department visits for any health reasons (ie, physical and mental). Only one study had data related to race or ethnicity. There was good evidence of an increase in emergency department visits for attempted suicide during the pandemic (rate ratio 1·22, 90% CI 1·08-1·37), modest evidence of an increase in emergency department visits for suicidal ideation (1·08, 0·93-1·25), and good evidence for only a slight change in self-harm (0·96, 0·89-1·04). Rates of emergency department visits for other mental-illness indications showed very good evidence of a decline (0·81, 0·74-0·89), and paediatric visits for all health indications showed strong evidence of a reduction (0·68, 0·62-0·75). When rates for attempted suicide and suicidal ideation were combined as a single measure, there was good evidence of an increase in emergency department visits among girls (1·39, 1·04-1·88) and only modest evidence of an increase among boys (1·06, 0·92-1·24). Self-harm among older children (mean age 16·3 years, range 13·0-16·3) showed good evidence of an increase (1·18, 1·00-1·39), but among younger children (mean age 9·0 years, range 5·5-12·0) there was modest evidence of a decrease (0·85, 0·70-1·05).

The integration of mental health support within community health and the education system-including promotion, prevention, early intervention, and treatment-is urgently needed to increase the reach of mental health support that can mitigate child and adolescent mental distress. In future pandemics, increased resourcing in some emergency department settings would help to address their expected increase in visits for acute mental distress among children and adolescents.

None.

This study aimed to analyse whether intelligence quotient (IQ) improves, declines, or remains stable over 10 years among FEP patients and healthy subjects.

A group of FEP patients enrolled in a Program of First Episode Psychosis in Spain called PAFIP, and a sample of Healthy Controls (HC) completed the same neuropsychological battery at baseline and approximately 10 years later, which included the WAIS vocabulary subtest to estimate premorbid IQ and 10-year IQ. Cluster analysis was performed separately in the patient group and the HC group to determine their profiles of intellectual change.

One hundred and thirty-seven FEP patients were grouped into five clusters: “Improved low IQ” (9.49 % of patients), “Improved average IQ” (14.6 %), “Preserved low IQ” (17.52 %), “Preserved average IQ” (43.06 %), and “Preserved high IQ” (15.33 %). Ninety HC were grouped into three clusters: “Preserved low IQ” (32.22 % of the HC), “Preserved average IQ” (44.44 %), and “Preserved high IQ” (23.33 %). The first two clusters of FEP patients, characterized by a low IQ, earlier age at illness onset, and lower educational attainment, showed a substantial cognitive improvement. The remaining clusters demonstrated cognitive stability.

The FEP patients showed intellectual improvement or stability, but no decline post-onset of psychosis. However, their profiles of intellectual change are more heterogeneous than that of HC over 10 years. Particularly, there is a subgroup of FEP patients with a significant potential for long-term cognitive enhancement.

The left dorsolateral prefrontal cortex is a prime target for repetitive transcranial magnetic stimulation (TMS) to treat neuropsychiatric disorders; thus, abundant efficacy data from controlled trials are available. A cross-diagnostic meta-analysis was conducted to identify the symptom domains susceptible to repetitive TMS to the left dorsolateral prefrontal cortex.

This systematic review and meta-analysis investigated the effects of repetitive TMS to the left dorsolateral prefrontal cortex on neuropsychiatric symptoms presenting across diagnoses. We searched , MEDLINE, Embase, Web of Science, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform for randomised and sham controlled trials published from inception to Aug 17, 2022. Included studies assessed symptoms using clinical measures and reported sufficient data to calculate effect sizes pooled with a random effects model. Two independent reviewers conducted screening and used the Cochrane risk-of-bias tool for quality assessment. Summary data were extracted from published reports. The main outcome was the therapeutic effects of repetitive TMS of the left dorsolateral prefrontal cortex on distinct symptom domains. This study is registered with PROSPERO (CRD42021278458).

Of 9056 studies identified (6704 from databases and 2352 from registers), 174 were included in the analysis including 7905 patients. 163 of 174 studies reported gender data; 3908 (52·35%) of 7465 patients were male individuals, and 3557 (47·65%) were female individuals. Mean age was 44·63 years (range 19·79-72·80). Ethnicity data were mostly not available. Effect size was large for craving (Hedges’g -0·803 [95% CI -1·099 to -0·507], p<0·0001; I=82·40%), medium for depressive symptoms (-0·725 [-0·889 to -0·561], p<0·0001; I=85·66%), small for anxiety, obsessions or compulsions, pain, global cognition, declarative memory, working memory, cognitive control, and motor coordination (Hedges’g -0·198 to -0·491), and non-significant for attention, suicidal ideation, language, walking ability, fatigue, and sleep.

The cross-diagnostic meta-analysis shows the efficacy of repetitive TMS of the left dorsolateral prefrontal cortex on distinct symptom domains, providing a novel framework for assessing target or efficacy interactions of repetitive TMS, and informing personalised applications for conditions for which regular trials are uninformative.

The University Grants Committee of Hong Kong and the Mental Health Research Center, The Hong Kong Polytechnic University.

There exist few direct studies of delusional content in psychosis across geo-cultural contexts, especially those in which treatment protocols and measures are comparable. To directly examine an illness outcome that is potentially culturally mediated, this study investigated the baseline presentation and longitudinal trajectory of delusions in first-episode psychosis (FEP) across 2 similar treatment settings in Montréal (Canada) and Chennai (India).

Patients entering an early intervention program for FEP in Chennai (N = 168) and Montréal (N = 165) were compared on site-level differences in the presentation of delusions across specific time points over 2 years of treatment. Delusions were measured using the Scale for Assessment of Positive Symptoms. Chi-square and regression analyses were conducted.

At baseline, delusions were more frequent in Montréal than in Chennai (93% vs 80%, respectively; X2(1) = 12.36, P < .001). Thematically, delusions of grandiosity, religiosity, and mind reading were more common in Montréal than in Chennai (all P < .001); however, these baseline differences did not persist over time. Regression revealed a significant time-by-site interaction in the longitudinal course of delusions, which differs from the trajectory of other FEP-positive symptom domains.

To the best of our knowledge, this is the first direct comparison of delusions in similar programs for FEP across 2 different geo-cultural contexts. Our findings support the notion that delusion themes follow consistent ordinal patterns across continents. Future work is needed to unpack the differences in severity that present at baseline and minor differences in content.

To synthesise results of mental health outcomes in cohorts before and during the covid-19 pandemic.

Systematic review.

Medline, PsycINFO, CINAHL, Embase, Web of Science, China National Knowledge Infrastructure, Wanfang, medRxiv, and Open Science Framework Preprints.

Studies comparing general mental health, anxiety symptoms, or depression symptoms assessed from 1 January 2020 or later with outcomes collected from 1 January 2018 to 31 December 2019 in any population, and comprising ≥90% of the same participants before and during the covid-19 pandemic or using statistical methods to account for missing data. Restricted maximum likelihood random effects meta-analyses (worse covid-19 outcomes representing positive change) were performed. Risk of bias was assessed using an adapted Joanna Briggs Institute Checklist for Prevalence Studies.

As of 11 April 2022, 94 411 unique titles and abstracts including 137 unique studies from 134 cohorts were reviewed. Most of the studies were from high income (n=105, 77%) or upper middle income (n=28, 20%) countries. Among general population studies, no changes were found for general mental health (standardised mean difference (SMD)_change 0.11, 95% confidence interval -0.00 to 0.22) or anxiety symptoms (0.05, -0.04 to 0.13), but depression symptoms worsened minimally (0.12, 0.01 to 0.24). Among women or female participants, general mental health (0.22, 0.08 to 0.35), anxiety symptoms (0.20, 0.12 to 0.29), and depression symptoms (0.22, 0.05 to 0.40) worsened by minimal to small amounts. In 27 other analyses across outcome domains among subgroups other than women or female participants, five analyses suggested that symptoms worsened by minimal or small amounts, and two suggested minimal or small improvements. No other subgroup experienced changes across all outcome domains. In three studies with data from March to April 2020 and late 2020, symptoms were unchanged from pre-covid-19 levels at both assessments or increased initially then returned to pre-covid-19 levels. Substantial heterogeneity and risk of bias were present across analyses.

High risk of bias in many studies and substantial heterogeneity suggest caution in interpreting results. Nonetheless, most symptom change estimates for general mental health, anxiety symptoms, and depression symptoms were close to zero and not statistically significant, and significant changes were of minimal to small magnitudes. Small negative changes occurred for women or female participants in all domains. The authors will update the results of this systematic review as more evidence accrues, with study results posted online (https://www.depressd.ca/covid-19-mental-health).

PROSPERO CRD42020179703.

Despite unregulated amphetamine use increasing, there are limited data on related emergency department (ED) visits in Canada. Our primary objective was to examine trends in amphetamine-related ED visits over time in Ontario, including by age and sex. Secondary objectives were to examine whether patient characteristics were associated with ED revisit within 6 months.

Using administrative claims and census data, we calculated annual patient- and encounter-based rates of amphetamine-related ED visits from 2003 to 2020 among individuals 18+ years of age. We also performed a retrospective cohort study of individuals with amphetamine-related ED visits between 2019 and 2020 to determine whether select factors were associated with ED revisit within 6 months. Multivariable logistic regression modelling was used to measure associations.

The population-based rate of amphetamine-related ED visits increased nearly 15-fold between 2003 (1.9/100,000 Ontarians) and 2020 (27.9/100,000 Ontarians). Seventy-five percent of individuals returned to the ED for any reason within 6 months. Psychosis and use of other substances were both independently associated with ED revisit for any reason within 6 months (psychosis: AOR = 1.54, 95% CI = 1.30-1.83; other substances: AOR = 1.84, 95% CI = 1.57-2.15), whereas having a primary care physician was negatively associated with ED revisit (AOR = 0.77, 95% CI = 0.60-0.98).

Increasing rates of amphetamine-related ED visits in Ontario are cause for concern. Diagnoses of psychosis and the use of other substances may serve to identify individuals who are most likely to benefit from both primary and substance-specific care.

Overdose risk during a course of treatment with medication for opioid use disorder (MOUD) has not been clearly delineated. The authors sought to address this gap by leveraging a new data set from three large pragmatic clinical trials of MOUD.

Adverse event logs, including overdose events, from the three trials (N=2,199) were harmonized, and the overall risk of having an overdose event in the 24 weeks after randomization was compared for each study arm (one methadone, one naltrexone, and three buprenorphine groups), using survival analysis with time-dependent Cox proportional hazard models.

By week 24, 39 participants had ≥1 overdose event. The observed frequency of having an overdose event was 15 (5.30%) among 283 patients assigned to naltrexone, eight (1.51%) among 529 patients assigned to methadone, and 16 (1.15%) among 1,387 patients assigned to buprenorphine. Notably, 27.9% of patients assigned to extended-release naltrexone never initiated the medication, and their overdose rate was 8.9% (7/79), compared with 3.9% (8/204) among those who initiated naltrexone. Controlling for sociodemographic and time-varying medication adherence variables and baseline substance use, a proportional hazard model did not show a significant effect of naltrexone assignment. Significantly higher probabilities of experiencing an overdose event were observed among patients with baseline benzodiazepine use (hazard ratio=3.36, 95% CI=1.76, 6.42) and those who either were never inducted on their assigned study medication (hazard ratio=6.64, 95% CI=2.12, 19.54) or stopped their medication after initial induction (hazard ratio=4.04, 95% CI=1.54, 10.65).

Among patients with opioid use disorder seeking medication treatment, the risk of overdose events over the next 24 weeks is elevated among those who fail to initiate or discontinue medication and those who report benzodiazepine use at baseline.

Negative symptoms are a primary cause of disability in schizophrenia for which there are no established pharmacotherapies. This study evaluated a novel psychosocial intervention that combined two evidence-based practices-motivational interviewing and cognitive-behavioral therapy (MI-CBT)-for the treatment of motivational negative symptoms.

Seventy-nine participants with schizophrenia and moderate to severe negative symptoms were included in a randomized controlled trial comparing the 12-session MI-CBT treatment with a mindfulness control condition. Participants were assessed at three time points through the study period, which included 12 weeks of active treatment and 12 weeks of follow-up. The primary outcome measures were motivational negative symptoms and community functioning; the secondary outcomes included a posited biomarker of negative symptoms: pupillometric response to cognitive effort.

Compared with the control group, participants in the MI-CBT group showed significantly greater improvements in motivational negative symptoms over the acute treatment period. Their gains relative to baseline were maintained at follow-up, although the differential benefit relative to control subjects was attenuated. There were nonsignificant effects toward improvements in community functioning and differential change in the pupillometric markers of cognitive effort.

The results show that combining motivational interviewing with CBT yields improvements in negative symptoms, a feature of schizophrenia generally thought of as resistant to intervention. Motivational negative symptoms not only responded to the novel treatment, but the gains were maintained over the follow-up period. Implications for future studies and for improving the generalization of the negative symptom gains to daily functioning domains are discussed.

Sleep disturbances and cognitive impairment are both persistent and common features of schizophrenia. Accumulating evidence indicates that sleep-dependent memory consolidation might be impaired in patients with schizophrenia compared to healthy controls. The current systematic review was performed in accordance with PRISMA guidelines. A random-effects model was used to calculate effect sizes (Hedge’s g). In the quantitative review, three separate meta-analyses were conducted for procedural memory in healthy controls, schizophrenia, and comparison between healthy controls and schizophrenia. Additionally, separate meta-analyses were conducted for the studies using finger tapping motor sequence task, as it is the most commonly used task. The current systematic review included 14 studies including 304 patients with schizophrenia and 209 healthy controls. The random-effects model analyses for sleep-dependent procedural memory consolidation resulted in a small effect size in schizophrenia (g = 0.26), a large effect size in healthy controls (g = 0.98), a moderate effect size in healthy controls vs schizophrenia (g = 0.64). For the studies using finger tapping motor sequence task, meta-analyses resulted in a small effect size in schizophrenia (g = 0.19), a large effect size in healthy controls (g = 1.07), a moderate effect size in healthy controls vs schizophrenia (g = 0.70). In the qualitative review, there was also impaired sleep-dependent declarative memory consolidation in schizophrenia compared to healthy controls. Current findings support that sleep improves memory consolidation in healthy adults, but there is a deficit in sleep-dependent memory consolidation in people with schizophrenia. Future studies investigating sleep-dependent consolidation of different memory subtypes with polysomnography in different stages of psychotic disorders are needed.

Aberrant resting-state functional connectivity (FC) of anterior cingulate cortex (ACC) has been implicated in the pathophysiology of schizophrenia and bipolar disorder (BP). This study investigated the subregional FC of ACC across schizophrenia and psychotic (PBP) and nonpsychotic BP (NPBP) and the relationship between brain functional alterations and clinical manifestations. A total of 174 first-episode medication-naive patients with schizophrenia (FES), 80 patients with PBP, 77 patients with NPBP and 173 demographically matched healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. Brain-wide FC of ACC subregions was computed for each individual, and compared between the groups. General intelligence was evaluated using the short version of the Wechsler Adult Intelligence Scale. Relationships between FC and various clinical and cognitive variables were estimated using the skipped correlation. The FES, PBP and NPBP groups showed differing connectivity patterns in the left caudal, dorsal and perigenual ACC. Transdiagnostic dysconnectivity was found in the subregional ACC associated with cortical, limbic, striatal and cerebellar regions. Disorder-specific dysconnectivity in FES was identified between the left perigenual ACC and bilateral orbitofrontal cortex, and the left caudal ACC coupling with the default mode network (DMN) and visual processing region was correlated with psychotic symptoms. In the PBP group, FC between the left dorsal ACC and the right caudate was correlated with psychotic symptoms, and FC connected with the DMN was associated with affective symptoms. The current findings confirmed that subregional ACC dysconnectivity could be a key transdiagnostic feature and associated with differing clinical symptomology across schizophrenia and PBP.

Women who experience depression during or within a year of pregnancy are at increased risk of morbidity and mortality. Although those living in low- and middle-income countries are thought to be at increased risk of perinatal depression, the true prevalence remains unclear.

To determine the prevalence of depression among individuals living in low- and middle-income countries during pregnancy and up 1 year post partum.

MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and the Cochrane Library were searched from database inception until April 15, 2021.

Studies were included that reported the prevalence of depression using a validated method during pregnancy or up to 12 months post partum in countries defined by the World Bank as low, lower-middle, and upper-middle income.

This study followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Two reviewers independently assessed study eligibility, extracted data, and assessed studies for bias. Prevalence estimates were calculated using a random-effects meta-analysis model. Subgroup analyses were performed among women who were considered at increased risk of developing perinatal depression.

Point prevalence of perinatal depression was the main outcome measured as percentage point estimates with corresponding 95% CIs.

The search identified 8106 studies, of which data were extracted from 589 eligible studies reporting outcomes of 616 708 women from 51 countries. The pooled prevalence of perinatal depression across all studies was 24.7% (95% CI, 23.7%-25.6%). The prevalence of perinatal depression varied slightly by country income status. The highest prevalence was found in lower-middle-income countries, with a pooled prevalence of 25.5% (95% CI, 23.8%-27.1%; 197 studies from 23 countries including 212 103 individuals). In upper-middle-income countries, the pooled prevalence was 24.7% (95% CI, 23.6%-25.9%; 344 studies from 21 countries including 364 103 individuals) and in low-income countries, the pooled prevalence was 20.7% (95% CI, 18.4%-23.0%; 50 studies from 7 countries including 40 502 individuals). The East Asia and the Pacific region had the lowest prevalence of perinatal depression at 21.4% (95% CI, 19.8%-23.1%) and was significantly increased in the Middle East and North Africa at 31.5% (95% CI, 26.9%-36.2%; between-group comparison: P < .001). In subgroup analyses, the highest prevalence of perinatal depression was found among women who experienced intimate partner violence, at 38.9% (95% CI, 34.1%-43.6%). revalence of depression was also high among women with HIV (35.1% [95% CI, 29.6%-40.6%]) and those who had experienced a natural disaster (34.8% [95% CI, 29.4%-40.2%]).

This meta-analysis found that depression was common in low- and middle-income countries, affecting 1 in 4 perinatal women. Accurate estimates of the prevalence of perinatal depression in low- and middle-income countries are essential in informing policy, allocating scarce resources, and directing further research to improve outcomes for women, infants, and families.

Distinguishing delusions and hallucinations from unusual beliefs and experiences has proven challenging.

The advent of neural network and generative modeling approaches to big data offers a challenge and an opportunity; healthy individuals with unusual beliefs and experiences who are not ill may raise false alarms and serve as adversarial examples to such networks.

Explicitly training predictive models with adversarial examples should provide clearer focus on the features most relevant to casehood, which will empower clinical research and ultimately diagnosis and treatment.

Down syndrome (DS) is a neurological disorder with multiple immune-related symptoms; however, crosstalk between the CNS and peripheral immune system remains unexplored. Using parabiosis and plasma infusion, we found that blood-borne factors drive synaptic deficits in DS. Proteomic analysis revealed elevation of β2-microglobulin (B2M), a major histocompatibility complex class I (MHC-I) component, in human DS plasma. Systemic administration of B2M in wild-type mice led to synaptic and memory defects similar to those observed in DS mice. Moreover, genetic ablation of B2m or systemic administration of an anti-B2M antibody counteracts synaptic impairments in DS mice. Mechanistically, we demonstrate that B2M antagonizes NMDA receptor (NMDAR) function through interactions with the GluN1-S2 loop; blocking B2M-NMDAR interactions using competitive peptides restores NMDAR-dependent synaptic function. Our findings identify B2M as an endogenous NMDAR antagonist and reveal a pathophysiological role for circulating B2M in NMDAR dysfunction in DS and related cognitive disorders.

Hepatic encephalopathy (HE) is a common decompensating event in patients with cirrhosis. Because of the aging population of patients with cirrhosis, differentiating HE from nonhepatic etiologies of cognitive impairment, such as dementia, is increasingly important.

Veterans with cirrhosis were identified via International Classification of Diseases -10 codes between October 1, 2019, and September 30, 2021, using the VA Corporate Data Warehouse. Baseline characteristics were compared between cohorts based on the presence vs absence of dementia. Factors associated with having a diagnosis of dementia were evaluated using multivariate logistic regression models, adjusting for demographics, comorbid illnesses, cirrhosis etiology, and cirrhosis complications.

A total of 71,552 veterans with cirrhosis were identified, of which, 5,647 (7.89%) veterans had a diagnosis of dementia. Veterans with dementia were older, more frequently White, urban located, and diagnosed with alcohol-related cirrhosis, metabolic syndrome, brain trauma, and cerebrovascular disease more frequently. On multivariable analysis, the presence of any decompensating event was associated with dementia. Multivariable analysis of individual decompensating events revealed HE to be associated with a dementia diagnosis, but not ascites, independent of other risk factors analyzed.

Dementia is commonly diagnosed in patients with cirrhosis and correlates with a diagnosis of HE, independent of alcohol use, brain injury, age, and other metabolic risk factors. Dementia did not correlate with other decompensating events. Increased awareness of the overlap between dementia and HE, as well as reliable diagnostic and treatment strategies, is needed for the aging population of veterans with cirrhosis.

Autism spectrum disorder (ASD) is a highly heterogeneous disorder, yet transcriptomic profiling of bulk brain tissue has identified substantial convergence among dysregulated genes and pathways in ASD. However, this approach lacks cell-specific resolution. We performed comprehensive transcriptomic analyses on bulk tissue and laser-capture microdissected (LCM) neurons from 59 postmortem human brains (27 ASD and 32 controls) in the superior temporal gyrus (STG) of individuals ranging from 2 to 73 years of age. In bulk tissue, synaptic signaling, heat shock protein-related pathways, and RNA splicing were significantly altered in ASD. There was age-dependent dysregulation of genes involved in gamma aminobutyric acid (GABA) (GAD1 and GAD2) and glutamate (SLC38A1) signaling pathways. In LCM neurons, AP-1-mediated neuroinflammation and insulin/IGF-1 signaling pathways were upregulated in ASD, while mitochondrial function, ribosome, and spliceosome components were downregulated. GABA synthesizing enzymes GAD1 and GAD2 were both downregulated in ASD neurons. Mechanistic modeling suggested a direct link between inflammation and ASD in neurons, and prioritized inflammation-associated genes for future study. Alterations in small nucleolar RNAs (snoRNAs) associated with splicing events suggested interplay between snoRNA dysregulation and splicing disruption in neurons of individuals with ASD. Our findings supported the fundamental hypothesis of altered neuronal communication in ASD, demonstrated that inflammation was elevated at least in part in ASD neurons, and may reveal windows of opportunity for biotherapeutics to target the trajectory of gene expression and clinical manifestation of ASD throughout the human lifespan.

Due to limited existing literature available on the presentation and treatment of catatonia in the peripartum, this retrospective descriptive cohort study aimed to examine demographic data, catatonic features, diagnoses pre- and post-catatonic episodes, treatment and the presence of obstetric complications.

Individuals with catatonia were identified in a previous study using anonymised electronic healthcare records from a large mental health trust in South-East London. The presence of features from the Bush-Francis Catatonia Screening Instrument was coded by the investigators and longitudinal data were extracted from structured fields and free text.

21 individuals were identified from the larger cohort, each of whom experienced one episode of catatonia in the postpartum period, and all had had an inpatient psychiatric admission. 13 patients (62 %) presented after their first pregnancy and 12 (57 %) experienced obstetric complications. 11 (53 %) attempted breastfeeding and 10 (48 %) received a diagnosis of a depressive disorder following the episode of catatonia. The majority presented with immobility or stupor, mutism, staring and withdrawal. All were treated with antipsychotics and 19 (90 %) received benzodiazepines.

This study suggests that signs and symptoms of catatonia during the peripartum are similar to other catatonic presentations. However, the postpartum may be a period of high risk for catatonia and obstetric factors, such as birth complications, may be relevant.

Cognitive remediation (CR) benefits cognition and functioning in psychosis but we do not know the optimal level of therapist contact, so we evaluated the potential benefits of different CR modes.

A multi-arm, multi-center, single-blinded, adaptive trial of therapist-supported CR. Participants from 11 NHS early intervention psychosis services were independently randomized to Independent, Group, One-to-One, or Treatment-as-usual (TAU). The primary outcome was functional recovery (Goal Attainment Scale [GAS]) at 15-weeks post randomization. Independent and TAU arms were closed after an interim analysis, and three informative contrasts tested (Group vs One-to-One, Independent vs TAU, Group + One-to-One vs TAU). Health economic analyses considered the cost per Quality Adjusted Life Year (QALY). All analyses used intention-to-treat principles.

We analyzed 377 participants (65 Independent, 134 Group, 112 One-to-One, 66 TAU). GAS did not differ for Group vs One-to-One: Cohen’s d: 0.07, -0.25 to 0.40 95% CI, P = .655; Independent vs TAU: Cohen’s d: 0.07, -0.41 to 0.55 95% CI, P = .777. GAS and the cognitive score improved for Group + One-to-One vs TAU favoring CR (GAS: Cohen’s d: 0.57, 0.19-0.96 95% CI, P = .003; Cognitive score: Cohens d: 0.28, 0.07-0.48 95% CI, P = .008). The QALY costs were £4306 for Group vs TAU and £3170 for One-to-One vs TAU. Adverse events did not differ between treatment methods and no serious adverse events were related to treatment.

Both active therapist methods provided cost-effective treatment benefiting functional recovery in early psychosis and should be adopted within services. Some individuals benefited more than others so needs further investigation.

ISRCTN14678860 https://doi.org/10.1186/ISRCTN14678860Now closed.

Risk-taking in specific contexts can be beneficial, leading to rewarding outcomes. Schizophrenia is associated with disadvantageous decision-making, as subjects pursue uncertain risky rewards less than controls. However, it is unclear whether this behavior is associated with more risk sensitivity or less reward incentivization. Matching on demographics and intelligence quotient (IQ), we determined whether risk-taking was more associated with brain activation in regions affiliated with risk evaluation or reward processing.

Subjects (30 schizophrenia/schizoaffective disorder, 30 controls) completed a modified, fMRI Balloon Analogue Risk Task. Brain activation was modeled during decisions to pursue risky rewards and parametrically modeled according to risk level.

The schizophrenia group exhibited less risky-reward pursuit despite previous adverse outcomes (Average Explosions; F(1,59) = 4.06, P = .048) but the comparable point at which risk-taking was volitionally discontinued (Adjusted Pumps; F(1,59) = 2.65, P = .11). Less activation was found in schizophrenia via whole brain and region of interest (ROI) analyses in the right (F(1,59) = 14.91, P < 0.001) and left (F(1,59) = 16.34, P < 0.001) nucleus accumbens (NAcc) during decisions to pursue rewards relative to riskiness. Risk-taking correlated with IQ in schizophrenia, but not controls. Path analyses of average ROI activation revealed less statistically determined influence of anterior insula upon dorsal anterior cingulate bilaterally (left: χ2 = 12.73, P < .001; right: χ2 = 9.54, P = .002) during risky reward pursuit in schizophrenia.

NAcc activation in schizophrenia varied less according to the relative riskiness of uncertain rewards compared to controls, suggesting aberrations in reward processing. The lack of activation differences in other regions suggests similar risk evaluation. Less insular influence on the anterior cingulate may relate to attenuated salience attribution or inability for risk-related brain region collaboration to sufficiently perceive situational risk.

Schizotypy is a multidimensional construct that captures a continuum of risk for developing schizophrenia-spectrum psychopathology. Existing 3-factor models of schizotypy, consisting of positive, negative, and disorganized dimensions have yielded mixed evidence of genetic continuity with schizophrenia using polygenic risk scores. Here, we propose an approach that involves splitting positive and negative schizotypy into more specific subdimensions that are phenotypically continuous with distinct positive symptoms and negative symptoms recognized in clinical schizophrenia. We used item response theory to derive high-precision estimates of psychometric schizotypy using 251 self-report items obtained from a non-clinical sample of 727 (424 females) adults. These subdimensions were organized hierarchically using structural equation modeling into 3 empirically independent higher-order dimensions enabling associations with polygenic risk for schizophrenia to be examined at different levels of phenotypic generality and specificity. Results revealed that polygenic risk for schizophrenia was associated with variance specific to delusional experiences (γ = 0.093, P = .001) and reduced social interest and engagement (γ = 0.076, P = .020), and these effects were not mediated via the higher-order general, positive, or negative schizotypy factors. We further fractionated general intellectual functioning into fluid and crystallized intelligence in 446 (246 females) participants that underwent onsite cognitive assessment. Polygenic risk scores explained 3.6% of the variance in crystallized intelligence. Our precision phenotyping approach could be used to enhance the etiologic signal in future genetic association studies and improve the detection and prevention of schizophrenia-spectrum psychopathology.

Doxycycline and minocycline are brain-penetrant tetracycline antibiotics, which recently gained interest because of their immunomodulatory and neuroprotective properties. Observational studies have suggested that exposure to these drugs may decrease the risk to develop schizophrenia, but results are inconsistent. The aim of this study was to investigate the potential association between doxycycline use and later onset of schizophrenia.

We used data from 1 647 298 individuals born between 1980 and 2006 available through Danish population registers. 79 078 of those individuals were exposed to doxycycline, defined as redemption of at least 1 prescription. Survival analysis models stratified for sex with time-varying covariates were constructed to assess incidence rate ratios (IRRs) for schizophrenia (ICD-10 code F20.xx), with adjustment for age, calendar year, parental psychiatric status, and educational level.

In the non-stratified analysis, there was no association between doxycycline exposure and schizophrenia risk. However, men who redeemed doxycycline had a significantly lower incidence rate for schizophrenia onset compared to men that did not (IRR 0.70; 95% CI 0.57-0.86). By contrast, women had a significantly higher incidence rate for schizophrenia onset, compared to women that did not redeem doxycycline prescriptions (IRR 1.23; 95% CI 1.08, 1.40). The effects were not found for other tetracycline antibiotics (IRR 1.00; 95% CI 0.91, 1.09).

Doxycycline exposure is associated with a sex-dependent effect on schizophrenia risk. The next steps are replication of the results in independent well-characterized population cohorts, as well as preclinical studies to investigate sex-specific effects of doxycycline on biological mechanisms implicated in schizophrenia.

Social and nonsocial cognition are defined as distinct yet related constructs. However, the relative independence of individual variables-and whether specific tasks directly depend on performance in other tasks-is still unclear. The current study aimed to answer this question by using a Bayesian network approach to explore directional dependencies among social and nonsocial cognitive domains.

The study sample comprised 173 participants with schizophrenia (71.7% male; 28.3% female). Participants completed 5 social cognitive tasks and the MATRICS Consensus Cognitive Battery. We estimated Bayesian networks using directed acyclic graph structures to examine directional dependencies among the variables.

After accounting for negative symptoms and demographic variables, including age and sex, all nonsocial cognitive variables depended on processing speed. More specifically, attention, verbal memory, and reasoning and problem solving solely depended on processing speed, while a causal chain emerged between processing speed and visual memory (processing speed → attention → working memory → visual memory). Social processing variables within social cognition, including emotion in biological motion and empathic accuracy, depended on facial affect identification.

These results suggest that processing speed and facial affect identification are fundamental domains of nonsocial and social cognition, respectively. We outline how these findings could potentially help guide specific interventions that aim to improve social and nonsocial cognition in people with schizophrenia.

Neurocognitive and social cognitive abilities are important contributors to functional outcomes in schizophrenia spectrum disorders (SSDs). An unanswered question of considerable interest is whether neurocognitive and social cognitive deficits arise from overlapping or distinct white matter impairment(s).

We sought to fill this gap, by harnessing a large sample of individuals from the multi-center Social Processes Initiative in the Neurobiology of the Schizophrenia(s) (SPINS) dataset, unique in its collection of advanced diffusion imaging and an extensive battery of cognitive assessments. We applied canonical correlation analysis to estimates of white matter microstructure, and cognitive performance, across people with and without an SSD.

Our results established that white matter circuitry is dimensionally and strongly related to both neurocognition and social cognition, and that microstructure of the uncinate fasciculus and the rostral body of the corpus callosum may assume a “privileged role” subserving both. Further, we found that participant-wise estimates of white matter microstructure, weighted by cognitive performance, were largely consistent with participants’ categorical diagnosis, and predictive of (cross-sectional) functional outcomes.

The demonstrated strength of the relationship between white matter circuitry and neurocognition and social cognition underscores the potential for using relationships among these variables to identify biomarkers of functioning, with potential prognostic and therapeutic implications.

Impairments in the expression, experience, and recognition of emotion are common in early psychosis (EP). Computational accounts of psychosis suggest disrupted top-down modulation by the cognitive control system (CCS) on perceptual circuits underlies psychotic experiences, but their role in emotional deficits in EP is unknown.

The affective go/no-go task was used to probe inhibitory control during the presentation of calm or fearful faces in young persons with EP and matched controls. Computational modeling of functional magnetic resonance imaging (fMRI) data were performed using dynamic causal modeling (DCM). The influence of the CCS on perceptual and emotional systems was examined using parametric empirical bayes.

When inhibiting motor response to fearful faces, EP participants showed higher brain activity in the right posterior insula (PI). To explain this, we used DCM to model effective connectivity between the PI, regions from the CCS activated during inhibition (dorsolateral prefrontal cortex [DLPFC] and anterior insula [AI]), and a visual input region, the lateral occipital cortex (LOC). EP participants exerted a stronger top-down inhibition from the DLPFC to the LOC than controls. Within the EP cohort, increased top-down connectivity between the LOC and AI was associated with a higher burden of negative symptoms.

Young persons with a recent onset of psychosis show a disturbance in the cognitive control of emotionally salient stimuli and the suppression of irrelevant distractors. These changes are associated with negative symptoms, suggesting new targets for the remediation of emotional deficits in young persons with EP.

The term central sleep apnoea (CSA) encompasses diverse clinical situations where a dysfunctional drive to breathe leads to recurrent respiratory events, namely apnoea (complete absence of ventilation) and hypopnoea sleep (insufficient ventilation) during sleep. Studies have demonstrated that CSA responds to some extent to pharmacological agents with distinct mechanisms, such as sleep stabilisation and respiratory stimulation. Some therapies for CSA are associated with improved quality of life, although the evidence on this association is uncertain. Moreover, treatment of CSA with non-invasive positive pressure ventilation is not always effective or safe and may result in a residual apnoea-hypopnoea index.

To evaluate the benefits and harms of pharmacological treatment compared with active or inactive controls for central sleep apnoea in adults.

We used standard, extensive Cochrane search methods. The latest search date was 30 August 2022.

We included parallel and cross-over randomised controlled trials (RCTs) that evaluated any type of pharmacological agent compared with active controls (e.g. other medications) or passive controls (e.g. placebo, no treatment or usual care) in adults with CSA as defined by the International Classification of Sleep Disorders 3rd Edition. We did not exclude studies based on the duration of intervention or follow-up. We excluded studies focusing on CSA due to periodic breathing at high altitudes.

We used standard Cochrane methods. Our primary outcomes were central apnoea-hypopnoea index (cAHI), cardiovascular mortality and serious adverse events. Our secondary outcomes were quality of sleep, quality of life, daytime sleepiness, AHI, all-cause mortality, time to life-saving cardiovascular intervention, and non-serious adverse events. We used GRADE to assess certainty of evidence for each outcome.

We included four cross-over RCTs and one parallel RCT, involving a total of 68 participants. Mean age ranged from 66 to 71.3 years and most participants were men. Four trials recruited people with CSA associated with heart failure, and one study included people with primary CSA. Types of pharmacological agents were acetazolamide (carbonic anhydrase inhibitor), buspirone (anxiolytic), theophylline (methylxanthine derivative) and triazolam (hypnotic), which were given for between three days and one week. Only the study on buspirone reported a formal evaluation of adverse events. These events were rare and mild. No studies reported serious adverse events, quality of sleep, quality of life, all-cause mortality, or time to life-saving cardiovascular intervention. Carbonic anhydrase inhibitors versus inactive control Results were from two studies of acetazolamide versus placebo (n = 12) and acetazolamide versus no acetazolamide (n = 18) for CSA associated with heart failure. One study reported short-term outcomes and the other reported intermediate-term outcomes. We are uncertain whether carbonic anhydrase inhibitors compared to inactive control reduce cAHI in the short term (mean difference (MD) -26.00 events per hour, 95% CI -43.84 to -8.16; 1 study, 12 participants; very low certainty). Similarly, we are uncertain whether carbonic anhydrase inhibitors compared to inactive control reduce AHI in the short term (MD -23.00 events per hour, 95% CI -37.70 to 8.30; 1 study, 12 participants; very low certainty) or in the intermediate term (MD -6.98 events per hour, 95% CI -10.66 to -3.30; 1 study, 18 participants; very low certainty). The effect of carbonic anhydrase inhibitors on cardiovascular mortality in the intermediate term was also uncertain (odds ratio (OR) 0.21, 95% CI 0.02 to 2.48; 1 study, 18 participants; very low certainty). Anxiolytics versus inactive control Results were based on one study of buspirone versus placebo for CSA associated with heart failure (n = 16). The median difference between groups for cAHI was -5.00 events per hour (IQR -8.00 to -0.50), the median difference for AHI was -6.00 events per hour (IQR -8.80 to -1.80), and the median difference on the Epworth Sleepiness Scale for daytime sleepiness was 0 points (IQR -1.0 to 0.00). Methylxanthine derivatives versus inactive control Results were based on one study of theophylline versus placebo for CSA associated with heart failure (n = 15). We are uncertain whether methylxanthine derivatives compared to inactive control reduce cAHI (MD -20.00 events per hour, 95% CI -32.15 to -7.85; 15 participants; very low certainty) or AHI (MD -19.00 events per hour, 95% CI -30.27 to -7.73; 15 participants; very low certainty). Hypnotics versus inactive control Results were based on one trial of triazolam versus placebo for primary CSA (n = 5). Due to very serious methodological limitations and insufficient reporting of outcome measures, we were unable to draw any conclusions regarding the effects of this intervention.

There is insufficient evidence to support the use of pharmacological therapy in the treatment of CSA. Although small studies have reported positive effects of certain agents for CSA associated with heart failure in reducing the number of respiratory events during sleep, we were unable to assess whether this reduction may impact the quality of life of people with CSA, owing to scarce reporting of important clinical outcomes such as sleep quality or subjective impression of daytime sleepiness. Furthermore, the trials mostly had short-term follow-up. There is a need for high-quality trials that evaluate longer-term effects of pharmacological interventions.

Schizophrenia spectrum disorders (SSD) have heterogeneous outcomes. If we could predict individual outcome and identify predictors of outcome, we could personalize and optimize treatment and care. Recent research showed that recovery rates tend to stabilize early in the course of disease. Short- to medium- term treatment goals are most relevant for clinical practice.

We performed a systematic review and meta-analysis to identify predictors of outcome ≤1 year in prospective studies of patients with SSD. For our meta-analysis risk of bias was assessed with the QUIPS tool.

178 studies were included for analysis. Our systematic review and meta-analysis showed that the chance of symptomatic remission was lower in males, and in patients with longer duration of untreated psychosis, more symptoms, worse global functioning, more previous hospital admissions and worse treatment adherence. The chance of readmission was higher for patients with more previous admissions. The chance of functional improvement was lower in patients with worse functioning at baseline. For other proposed predictors of outcome, like age at onset and depressive symptoms, limited to no evidence was found.

This study illuminates predictors of outcome of SSD. Level of functioning at baseline was the best predictor of all investigated outcomes. Furthermore, we found no evidence for many predictors proposed in original research. Possible reasons for this include the lack of prospective research, between-study heterogeneity and incomplete reporting. We therefore recommend open access to datasets and analysis scripts, enabling other researchers to reanalyze and pool the data.

Borderline personality disorder (BPD) affects approximately 0.7% to 2.7% of adults in the US. The disorder is associated with considerable social and vocational impairments and greater use of medical services.

Borderline personality disorder is characterized by sudden shifts in identity, interpersonal relationships, and affect, as well as by impulsive behavior, periodic intense anger, feelings of emptiness, suicidal behavior, self-mutilation, transient, stress-related paranoid ideation, and severe dissociative symptoms (eg, experience of unreality of one’s self or surroundings). Borderline personality disorder is typically diagnosed by a mental health specialist using semistructured interviews. Most people with BPD have coexisting mental disorders such as mood disorders (ie, major depression or bipolar disorder) (83%), anxiety disorders (85%), or substance use disorders (78%). The etiology of BPD is related to both genetic factors and adverse childhood experiences, such as sexual and physical abuse. Psychotherapy is the treatment of choice for BPD. Psychotherapy such as dialectical behavior therapy and psychodynamic therapy reduce symptom severity more than usual care, with medium effect sizes (standardized mean difference) between -0.60 and -0.65. There is no evidence that any psychoactive medication consistently improves core symptoms of BPD. For discrete and severe comorbid mental disorders, eg, major depression, pharmacotherapy such as the selective serotonin reuptake inhibitors escitalopram, sertraline, or fluoxetine may be prescribed. For short-term treatment of acute crisis in BPD, consisting of suicidal behavior or ideation, extreme anxiety, psychotic episodes, or other extreme behavior likely to endanger a patient or others, crisis management is required, which may include prescription of low-potency antipsychotics (eg, quetiapine) or off-label use of sedative antihistamines (eg, promethazine). These drugs are preferred over benzodiazepines such as diazepam or lorazepam.

Borderline personality disorder affects approximately 0.7% to 2.7% of adults and is associated with functional impairment and greater use of medical services. Psychotherapy with dialectical behavior therapy and psychodynamic therapy are first-line therapies for BPD, while psychoactive medications do not improve the primary symptoms of BPD.

While individuals at clinical high-risk (CHR) for psychosis experience higher levels of discrimination than healthy controls, it is unclear how these experiences contribute to the etiology of attenuated positive symptoms. The present study examined the association of perceived discrimination with positive symptoms in a cohort from the North American Prodrome Longitudinal Study (NAPLS2). It predicted that CHR individuals will report higher levels of lifetime and past year perceived discrimination related to their race and ethnicity (ethnoracial discrimination) and that this form of discrimination will be significantly associated with baseline positive symptoms.

Participants included 686 CHR and 252 healthy controls. The present study examined data from the perceived discrimination (PD) scale, the Brief Core Schema Scale, and the Scale for the Psychosis-Risk Symptoms. Structural equation modeling was employed to examine whether negative schema of self and others mediated the relation of past year ethnoracial PD to baseline suspiciousness symptoms.

CHR individuals report higher levels of past year and lifetime PD compared to healthy controls. Lifetime ethnoracial PD was associated with suspiciousness and total positive symptoms. Negative schema of self and others scores partially mediated the relation of past year ethnoracial PD to suspiciousness, one of five positive symptom criteria for CHR.

For CHR individuals, past year ethnoracial discrimination was associated with negative beliefs about themselves and others, which was associated with suspiciousness. These findings contribute to an emerging literature characterizing the mechanisms by which discrimination contributes to the positive symptoms characterizing the CHR syndrome.

Trichotillomania and skin-picking disorder are underrecognized and often disabling conditions in which individuals repeatedly pull at their hair or pick at their skin, leading to noticeable hair loss or tissue damage. To date there is a severe paucity of evidence-based treatments for these conditions. In this study, the authors sought to determine whether memantine, a glutamate modulator, is more effective than placebo in reducing hair-pulling and skin-picking behavior.

One hundred adults with trichotillomania or skin-picking disorder (86 women; mean age, 31.4 years [SD=10.2]) were enrolled in a double-blind trial of memantine (dosing range, 10-20 mg/day) or placebo for 8 weeks. Participants were assessed with measures of pulling and picking severity. Outcomes were examined using a linear mixed-effects model. The prespecified primary outcome measure was treatment-related change on the NIMH Trichotillomania Symptom Severity Scale, modified to include skin picking.

Compared with placebo, memantine treatment was associated with significant improvements in scores on the NIMH scale, Sheehan Disability Scale, and Clinical Global Impressions severity scale in terms of treatment-by-time interactions. At study endpoint, 60.5% of participants in the memantine group were “much or very much improved,” compared with 8.3% in the placebo group (number needed to treat=1.9). Adverse events did not differ significantly between the treatment arms.

This study found that memantine treatment resulted in statistically significant reductions in hair pulling and skin-picking symptoms compared with placebo, with relatively high efficacy (based on number needed to treat), and was well tolerated. The glutamate system may prove to be a beneficial target in the treatment of compulsive behaviors.

Despite high antidepressant placebo response rates, the mechanisms underlying the persistence of antidepressant placebo effects are still poorly understood.

To investigate the neurobehavioral mechanisms underlying the evolution of antidepressant placebo effects using a reinforcement learning (RL) framework.

In this acute within-patient cross-sectional study of antidepressant placebos, patients aged 18 to 55 years not receiving medication for major depressive disorder (MDD) were recruited at the University of Pittsburgh between February 21, 2017, to March 1, 2021.

The antidepressant placebo functional magnetic resonance imaging task manipulates placebo-associated expectancies using visually cued fast-acting antidepressant infusions and controls their reinforcement with sham visual neurofeedback while assessing expected and experienced mood improvement.

The trial-by-trial evolution of expectancies and mood was examined using multilevel modeling and RL, relating model-predicted signals to spatiotemporal dynamics of blood oxygenation level-dependent (BOLD) response.

A bayesian RL model comparison in 60 individuals (mean [SE] age, 24.5 [0.8] years; 51 females [85%]) with MDD revealed that antidepressant placebo trial-wise expectancies were updated by composite learning signals multiplexing sensory evidence (neurofeedback) and trial-wise mood (bayesian omnibus risk <0.001; exceedance probability = 97%). Placebo expectancy, neurofeedback manipulations, and composite learning signals modulated the visual cortex and dorsal attention network (threshold-free cluster enhancement [TFCE] = 1 – P >.95). As participants anticipated antidepressant infusions, learned placebo expectancies modulated the salience network (SN, TFCE = 1 – P >.95), positively scaling with depression severity.

Results of this cross-sectional study suggest that on a timescale of minutes, antidepressant placebo effects were maintained by positive feedback loops between expectancies and mood improvement. During learning, representations of placebos and their perceived effects were enhanced in primary and secondary sensory cortices. Latent learned placebo expectancies were encoded in the SN.

Viral infections are increasingly recognized in the etiology of psychiatric disorders based on epidemiological and serological studies. Few studies have analyzed viruses directly within the brain and no comprehensive investigation of viral infection within diseased brains has been completed. This study aims to determine whether viral infection in brain tissues is a risk factor for 3 major psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder.

This study directly evaluated the presence of viral DNA or RNA in 1569 brains of patients and controls using whole-genome sequencing and RNA sequencing data with 4 independent cohorts. The PathSeq tool was used to identify known human viruses in the genome and transcriptome of patients and controls.

A variety of DNA and RNA viruses related to the central nervous system were detected in the brains of patients with major psychiatric disorders, including viruses belonging to Herpesviridae, Polyomaviridae, Retroviridae, Flaviviridae, Parvoviridae, and Adenoviridae. However, no consistent significant differences were found between patients and controls in terms of types and amount of virus detected at both DNA and RNA levels.

The findings of this study do not suggest an association between viral infection in postmortem brains and major psychiatric disorders.

We sought to evaluate the relationship between social determinants of health and physician-based mental healthcare utilization and virtual care use among children and adolescents in Ontario, Canada, during the COVID-19 pandemic.

This population-based repeated cross-sectional study of children and adolescents (3-17 years; N = 2.5 million) used linked health and demographic administrative data in Ontario, Canada (2017-2021). Multivariable Poisson regressions with generalized estimating equations compared rates of outpatient physician-based mental healthcare use during the first year of the COVID-19 pandemic with expected rates based on pre-COVID patterns. Analyses were conducted by socioeconomic status (material deprivation quintiles of the Ontario Marginalization index), urban/rural region of residence, and immigration status.

Overall, pediatric physician-based mental healthcare visits were 5% lower than expected (rate ratio [RR] = 0.95, 95% confidence interval [CI], 0.92 to 0.98) among those living in the most deprived areas in the first year of the pandemic, compared with the least deprived with 4% higher than expected rates (RR = 1.04, 95% CI, 1.02 to 1.06). There were no differences in overall observed and expected visit rates by region of residence. Immigrants had 14% to 26% higher visit rates compared with expected from July 2020 to February 2021, whereas refugees had similarly observed and expected rates. Virtual care use was approximately 65% among refugees, compared with 70% for all strata.

During the first year of the pandemic, pediatric physician-based mental healthcare utilization was higher among immigrants and lower than expected among those with lower socioeconomic status. Refugees had the lowest use of virtual care. Further work is needed to understand whether these differences reflect issues in access to care or the need to help inform ongoing pandemic recovery planning.

(1) To calculate the proportions of people who sought mental health and addiction (MHA) specialty services in Nova Scotia, overall and by sex and age. (2) To describe the health and psychosocial profiles of the MHA Intake clients. (3) To identify factors associated with acceptance for MHA services.

The data of the Nova Scotia MHA Intake clients aged 19 to 64 years old in 2020 (N = 10,178) and in 2021 (N = 12,322) were used. The proportions of unique clients in the general population were calculated based on 2021 census data. The percentages of primary presenting concerns, the presence and frequency of psychiatric symptoms in the past month, suicide risk levels, current or past provisional psychiatric diagnosis, medical problems, and psychosocial stressors were calculated. Logistic regression was conducted to identify factors associated with the acceptance of MHA services after the assessment.

It was found that 1.48% and 2.33% of Nova Scotians aged 19 to 64 contacted the MHA Intake in 2020 and 2021. Over 66% were self-referrals, followed by physician referrals (28.34%). Mood (28.3%), anxiety (25.17%), and substance use (19.81%) were the top three presenting concerns for the contact. Many clients had a current or past provisional psychiatric diagnosis (58.7% in 2020, 61.8% in 2021). Among the clients, 74.67% and 68.29% reported at least 1 psychosocial stressor in 2020 and 2021, respectively. The clients with a current or past psychiatric diagnosis, suicide risk, and 2 or more psychosocial stressors, those who lived outside of Central Zone, and who had employee assistance program benefits/private insurance, were more likely to be qualified and accepted for MHA services than others.

The Intake clients have complex health and psychosocial profiles. Future studies are needed to monitor the trajectories of the clients to reduce inequities in receiving MHA services and improve client outcomes.

One in three adults with major depressive disorder (MDD) do not experience clinically significant improvement after multiple sequential courses of antidepressants and have treatment-resistant depression (TRD). The presence of TRD contributes to the morbidity and excess mortality associated with MDD and has been linked to significantly increased health care expenses. In the absence of a consensus definition of TRD, this report takes a broad approach by considering inadequate response to one or more courses of antidepressants and focuses on atypical antipsychotics that are approved by the U.S. Food and Drug Administration for treatment of depression (aripiprazole, brexpiprazole, cariprazine, extended-release quetiapine, and olanzapine-fluoxetine combination). While multiple acute-phase studies have demonstrated the efficacy of these medications in improving depressive symptoms, clinically meaningful improvement (i.e., remission) remains limited, with significant concerns about side effects (including weight gain, metabolic dysfunction, extrapyramidal symptoms, and tardive dyskinesia), especially with long-term use. With the rapidly evolving landscape of antidepressant treatments over the past few years, which has witnessed approval of rapid-acting antidepressants (e.g., esketamine nasal spray and dextromethorphan-bupropion combination) and several more in the late-stage pipeline (e.g., zuranolone and psilocybin), it remains to be seen whether the use of atypical antipsychotics will go the way of the older and rarely prescribed antidepressants (such as tricyclics and monoamine oxidase inhibitors). Pragmatic clinical trials are needed to compare the effectiveness of atypical antipsychotics with TRD-specific pharmacotherapies and neuromodulation treatments and to identify the optimal sequencing of these varied approaches for patients with MDD. When using atypical antipsychotics, clinicians and patients are encouraged to use a shared decision-making approach by personalizing treatment selection based on anticipated side effects, tolerability, cost, and feasibility.

Repetitive transcranial magnetic stimulation (rTMS) protocols increasingly use subgenual anterior cingulate cortex (sgACC) functional connectivity to individualize treatment targets. However, the efficacy of this approach is unclear, with conflicting findings and varying effect sizes across studies. Here, the authors investigated the effect of the stimulation site’s functional connectivity with the sgACC (sgACC-StimFC) on treatment outcome to rTMS in 295 patients with major depression.

The reliability and accuracy of estimating sgACC functional connectivity were validated with data from individuals who underwent extensive functional MRI testing. Electric field modeling was used to analyze associations between sgACC-StimFC and clinical improvement using standardized assessments and to evaluate sources of heterogeneity.

An imputation-based method provided reliable and accurate sgACC functional connectivity estimates. Treatment responses weakly but robustly correlated with sgACC-StimFC (r=-0.16), but only when the stimulated cortex was identified using electric field modeling. Surprisingly, this association was driven by patients with strong global signal fluctuations stemming from a specific periodic respiratory pattern (r=-0.49).

Functional connectivity between the sgACC and the stimulated cortex was correlated with individual differences in treatment outcomes, but the association was weaker than those observed in previous studies and was accentuated in a subgroup of patients with distinct, respiration-related signal patterns in their scans. These findings indicate that in a large representative sample of patients with major depressive disorder, individual differences in sgACC-StimFC explained only ∼3% of the variance in outcomes, which may limit the utility of existing sgACC-based targeting protocols. However, these data also provide strong evidence for a true-albeit small-effect and highlight opportunities for incorporating additional functional connectivity measures to generate models of rTMS response with enhanced predictive power.

Previous meta-analyses of psychotherapies for children and adolescents with post-traumatic stress disorder (PTSD) did not investigate whether treatment efficacy is diminished when patients report multiple (versus single) traumas.

To examine whether efficacy of psychological interventions for paediatric PTSD is diminished when patients report multiple (versus single) traumas.

We systematically searched PsycInfo, MEDLINE, Web of Science and PTSDpubs on 21 April 2022 and included randomised controlled trials (RCTs) meeting the following criteria: (a) random allocation; (b) all participants presented with partial or full PTSD; (c) PTSD is the primary treatment focus; (d) sample mean age <19 years; (e) sample size n ≥ 20. Trauma frequency was analysed as a dichotomous (single versus ≥2 traumas) and continuous (mean number of exposures) potential moderator of efficacy.

Of the 57 eligible RCTs (n = 4295), 51 RCTs were included in quantitative analyses. Relative to passive control conditions, interventions were found effective for single-trauma-related PTSD (Hedges’ g = 1.09; 95% CI 0.70-1.48; k = 8 trials) and multiple-trauma-related PTSD (g = 1.11; 95% CI 0.74-1.47; k = 12). Psychotherapies were also more effective than active control conditions in reducing multiple-trauma-related PTSD. Comparison with active control conditions regarding single-event PTSD was not possible owing to scarcity (k = 1) of available trials. Efficacy did not differ with trauma exposure frequency irrespective of its operationalisation and subgroup analyses (e.g. trauma-focused cognitive-behavioural therapy only).

The current evidence base suggests that psychological interventions for paediatric PTSD can effectively treat PTSD in populations reporting single and multiple traumas. Future trials for PTSD following single-event trauma need to involve active control conditions.

Drug use is an increasing global public health concern. We reviewed the prevalence and patterns of drug use, drug use disorders, and the extent of treatment services in 21 countries and one territory in the Eastern Mediterranean region from 2010 to 2022. Online databases were systematically searched on April 17, 2022, along with other sources for grey literature. The extracted data were analysed and used for synthesis at the country, subregional, and regional levels. The prevalence of drug use is higher in the Eastern Mediterranean region than global estimates, with cannabis, opium, khat, and tramadol among the main drugs used in the region. Data on the prevalence of drug use disorders were scarce and heterogeneous. Treatment facilities for drug use disorders are available in most countries, but opioid agonist treatment exists in only seven countries. There is a need to expand evidence-based and cost-effective care. Limited data exist, especially regarding drug use disorders, treatment coverage, and drug use among women and young people.

For people with psychotic disorders, the negative outcomes associated with continuing cannabis use would suggest that discontinuing such use may be beneficial for their symptomatic and functional recovery. However, existing evidence that discontinuation is associated with better clinical outcomes is inconsistent and it remains unclear whether discontinuing use is associated with improvements in outcomes for people with an established psychotic disorder. In this 3-5-year longitudinal study we examined baseline and follow-up symptomatic and functional profiles of 371 people with an established psychotic disorder, comparing those who continued to use cannabis with those who discontinued use after baseline assessment. At follow-up, one third (33.3 %) of baseline cannabis users had discontinued use. Discontinuation was associated with significantly lower odds of past-year hallucinations and a mean improvement in level of functioning (Personal and Social Performance Scale) compared to a decline in functioning in continuing users. No significant differences in severity of negative symptoms were observed. With few longitudinal studies examining symptomatic and functional outcomes for people with established psychotic disorders who continue to use cannabis compared to those who discontinue use, our findings that discontinuing cannabis was associated with significant clinical improvements fill gaps in the evidence-base.

Antipsychotic-induced metabolic adverse effects are risk factors for cardiometabolic comorbidities. Whether dose lowering could mitigate such effects remains unclear. The present study aims to investigate the associations between clozapine doses and modifications of weight, blood pressure, blood glucose, and lipid levels.

Linear mixed-effects models of weight changes over 1 year and of variations of other metabolic parameters over 4 months were applied to a prospective cohort of 115 patients. Age- and sex-stratified analyses of weight changes were also performed.

Each 100 mg dose increment of clozapine was associated on average with a +0.48% weight increase (P = .004) over 1 year of treatment. Weight increase was greater for treatment duration ≤3 vs >3 months (+0.84% and +0.47% per month, respectively, P < .001), with a significant association with the dose for durations >3 months (+0.54%, P = .004) and a trend for durations ≤3 months (+0.33%, P = .075). Dose increments of 100 mg were also associated with weight increases of +0.71% among adults (P = .001), +1.91% among the elderly (P < .001) and +1.32% among men (P < .001) with no associations among women (P = .62). Among young adults, weight change was positively associated with doses ≤300 mg/day (+2.19% per 100 mg, P = .001), whereas no association was found with doses >300 mg/day (P = .60). No significant effect of clozapine dose on other metabolic parameters was found.

This study reports a modest effect of clozapine dose increases on weight gain over 1 year with differences among age categories and sexes and no dose effect on other metabolic parameters over 4 months.

Cognitive deficits in visuospatial learning (VSL) are highly associated with an increased risk of developing psychosis among populations with clinical high risk (CHR) for psychosis. Early interventions targeting VSL enhancement are warranted in CHR but remain rudimentary. We investigated whether personalized transcranial magnetic stimulation (TMS) over the left parieto-hippocampal network could improve VSL performance in CHR patients and if it could reduce the risk of psychosis conversion within 1 year.

Sixty-five CHR patients were randomized to receive active or sham TMS treatments using an accelerated TMS protocol, consisting of 10 sessions of 20 Hz TMS treatments within 2 days. TMS target was defined by individual parieto-hippocampal functional connectivity and precisely localized by individual structural magnetic resonance imaging. VSL performance was measured using Brief Visuospatial Memory Test-Revised included in measurement and treatment research to improve cognition in schizophrenia consensus cognitive battery (MCCB). Fifty-eight CHR patients completed the TMS treatments and MCCB assessments and were included in the data analysis.

We observed significant VSL improvements in the active TMS subgroup (Cohen’s d = 0.71, P < .001) but not in the sham TMS subgroup (Cohen’s d = 0.07, P = .70). In addition, active TMS improved the precision of VSL performance. At a 1-year follow-up, CHR patients who received active TMS showed a lower psychosis conversion rate than those who received sham TMS (6.7% vs 28.0%, χ2 = 4.45, P = .03).

Our findings demonstrate that personalized TMS in the left parieto-hippocampal network may be a promising preventive intervention that improves VSL in CHR patients and reduces the risk of psychosis conversion at follow-up.

There are communities in which hearing voices frequently is common and expected, and in which participants are not expected to have a need for care. This paper compares the ideas and practices of these communities. We observe that these communities utilize cultural models to identify and to explain voice-like events-and that there are some common features to these models across communities. All communities teach participants to “discern,” or identify accurately, the legitimate voice of the spirit or being who speaks. We also observe that there are roughly two methods taught to participants to enable them to experience spirits (or other invisible beings): trained attention to inner experience, and repeated speech to the invisible other. We also observe that all of these communities model a learning process in which the ability to hear spirit (or invisible others) becomes more skilled with practice, and in which what they hear becomes clearer over time. Practice-including the practice of discernment-is presumed to change experience. We also note that despite these shared cultural ideas and practices, there is considerable individual variation in experience-some of which may reflect psychotic process, and some perhaps not. We suggest that voice-like events in this context may be shaped by cognitive expectation and trained practice as well as an experiential pathway. We also suggest that researchers could explore these common features both as a way to help those struggling with psychosis, and to consider the possibility that expectations and practice may affect the voice-hearing experience.

The social deafferentation hypothesis (SDA) has been proposed as an explanatory mechanism of hallucinations, based on the theory that social withdrawal triggers the initial phase of schizophrenia. The current study tests the SDA by assessing how loneliness is associated with different types of hallucinations. Under the SDA, increased loneliness is hypothesized to affect the occurrence of hallucinations that carry social meaning, but not of nonsocial hallucinations.

As part of an online survey, 2038 adolescents and young adults from the general population (median age 21 years; 75% female) filled out the Questionnaire for Psychotic Experiences, and the shortened De Jong Gierveld Loneliness Scale. Binomial logistic regression was used to investigate the effects of loneliness severity on past month prevalence of hallucinations, and on the presence of social versus nonsocial hallucinations.

Loneliness increased the prevalence of hallucinations across modalities in the past month. Moreover, stronger degree of loneliness increased the likelihood of hearing voices or laughter, and of hallucinating being touched. Conversely, loneliness decreased the likelihood of experiencing the nonsocial hallucination of a tingling feeling. As expected, loneliness did not increase the prevalence of experiencing nonsocial hallucinations. Surprisingly, neither was loneliness associated with experiencing felt presence.

Our results are novel in showing that loneliness specifically increases the likelihood of hearing human sounds such as voices or laughter, or feeling a human touch. Hallucinations without social meaning were not more likely to be experienced with increasing loneliness. This forms a confirmation of the SDA.

Distress associated with auditory (AH) and visual (VH) hallucinations in the general population was found to be predictive of later need for mental healthcare. It is, therefore, important to understand factors relating to the distress individuals experience from their hallucinations. Hallucinations can easily occur under substance-induced states, but recreational drug use is also known as a self-medication strategy. The current study, therefore, investigated whether recreational drug use by individuals from the general population is associated with the degree of distress experienced from AH and/or VH.

Drug use and distress severity associated with AH (N = 3.041) and/or VH (N = 2.218) were assessed by means of an online survey in the general Dutch population (>14 years of age).

Multiple linear regression revealed that while past month consumption of alcohol was associated with less AH- and VH-related distress, past month cannabis use was associated with more AH- and VH-related distress. Furthermore, past month use of nitrous oxide was associated with more severe VH-related distress.

Recreational use of alcohol, cannabis, and nitrous oxide may play important differential roles in the degree of distress associated with AH and VH in individuals from the general population. The consumption of these substances could form a potential risk factor for the development of distressing hallucinations or function as a signal marker for their occurrence. Due to the cross-sectional design of the current study, the causal relation between recreational drug use and distressing hallucinations remains to be elucidated.

Patients with hearing impairment (HI) may experience hearing sounds without external sources, ranging from random meaningless noises (tinnitus) to music and other auditory hallucinations (AHs) with meaningful qualities. To ensure appropriate assessment and management, clinicians need to be aware of these phenomena. However, sensory impairment studies have shown that such clinical awareness is low.

An online survey was conducted investigating awareness of AHs among clinicians and their opinions about these hallucinations.

In total, 125 clinicians (68.8% audiologists; 18.4% Ear-Nose-Throat [ENT] specialists) across 10 countries participated in the survey. The majority (96.8%) was at least slightly aware of AHs in HI. About 69.6% of participants reported encountering patients with AHs less than once every 6 months in their clinic. Awareness was significantly associated with clinicians’ belief that patients feel anxious about their hallucinations (β = .018, t(118) = 2.47, P < .01), their belief that clinicians should be more aware of these hallucinations (β =.018, t(118) = 2.60, P < .01), and with confidence of clinicians in their skills to assess them (β = .017, t(118) = 2.63, P < .01). Clinicians felt underequipped to treat AHs (Median = 31; U = 1838; PFDRadj < .01).

Awareness of AHs among the surveyed clinicians was high. Yet, the low frequency of encounters with hallucinating patients and their belief in music as the most commonly perceived sound suggest unreported cases. Clinicians in this study expressed a lack of confidence regarding the assessment and treatment of AHs and welcome more information.

While literature indicates that culture modulates phenomenological characteristics of hallucinations in schizophrenia-spectrum disorders, little is known about the extent culture modulates these characteristics in nonclinical samples.

We compared lifetime prevalence, age of onset, and phenomenology of hallucinations as assessed with the Questionnaire for Psychotic Experiences between samples of nonclinical participants used from the Netherlands (N = 2999) and Qatar (N = 2999). While participant recruitment differed between the 2 countries, the samples were relatively equal in terms of demographic factors.

Our findings indicate that the lifetime prevalence of tactile and olfactory hallucinations are the same across countries. However, the prevalence of auditory hallucinations (AH) and visual hallucinations (VH) were twice as high in the Dutch sample. The reported age of onset for auditory and tactile hallucinations was younger for the Dutch sample. Findings from the measurement invariance supported cross-cultural comparisons with exception for duration, distress, and insight. Qatar’s and Dutch participants reported similar valence and extent of interaction with AH and VH. However, compared to those in the Netherlands, participants from Qatar reported significantly more impact on daily functioning and a higher prevalence of receiving commands from hallucinations in the past week.

While AH and VH were more often reported in the Dutch sample, participants in Qatar generally had higher mean factor scores for past week AH and VH than in the Netherlands. The phenomenology of hallucinations in the Qatar sample was of greater clinical relevance, with potentially important implications for early screening and prevention.

Approximately one-third of patients with a psychotic disorder experience visual hallucinations (VH). While new, more targeted treatment options are warranted, the pathophysiology of VH remains largely unknown. Previous studies hypothesized that VH result from impaired functioning of the vision-related networks and impaired interaction between those networks, including a possible functional disconnection between the primary visual cortex (V1) and higher-order visual processing regions. Testing these hypotheses requires sufficient data on brain activation during actual VH, but such data are extremely scarce.

We therefore recruited seven participants with a psychotic disorder who were scanned in a 3 T fMRI scanner while indicating the occurrence of VH by pressing a button. Following the scan session, we interviewed participants about the VH experienced during scanning. We then used the fMRI scans to identify regions with increased or decreased activity during VH periods versus baseline (no VH).

In six participants, V1 was not activated during VH, and in one participant V1 showed decreased activation. All participants reported complex VH such as human-like beings, objects and/or animals, during which higher-order visual areas and regions belonging to the vision-related networks on attention and memory were activated.

These results indicate that VH are associated with diffuse involvement of the vision-related networks, with the exception of V1. We therefore propose a model for the pathophysiology of psychotic VH in which a dissociation of higher-order visual processing areas from V1 biases conscious perception away from reality and towards internally generated percepts.

It has been theorized that hallucinations, a common symptom of schizophrenia, are caused by failures in reality monitoring. The paracingulate sulcus (PCS) has been implicated as a brain structure supporting reality monitoring with the absence or shorter length of PCS associated with an occurrence of hallucinations in schizophrenia. The absence or shorter length of PCS has been associated with an occurrence of hallucinations. There are inconsistent findings in the literature regarding the role of the asymmetry of this structure for hallucinations. Here, we investigated the length of the PCS and cortical thickness of surrounding structures in patients with a lifetime history of auditory verbal hallucinations (AVH).

Seventy-seven patients and twenty-eight healthy controls (HC) underwent an anatomical MRI scan. PCS length and cortical thickness were estimated using Mango brain visualization and FreeSurfer, respectively. Patients with AVH (n = 45) and patients without AVH were compared (n = 32) to the controls.

PCS length significantly differed between HC and patient groups (F(2,102) = 3.57, P = .032) in the left but not in the right sulcus. We found significantly longer PCS between HC and AVH group but no difference between patient groups. Similarly, we found significant thinning of cortical structures including structures surrounding anterior parts of PCS between HC and patients either in general or per group, but no significant differences were observed between patient groups.

PCS length in the left hemisphere is shorter in schizophrenia patients with hallucinations as compared to HC subjects. The patient group without hallucinations was in between those 2 groups. Cortical thickness of neighboring areas of PCS is diminished in patient groups relative to the healthy comparison subjects. The role of lateralization and functional involvement of the PCS region in processes underlying hallucinations, such as reality monitoring, needs further clarification.

Several hypotheses have been proposed to explain why individuals with psychosis consume more tobacco compared with the general population, but the reasons remain unclear. The phases predating the onset of psychosis could provide an interesting framework to clarify this association. The aim of this systematic review and meta-analysis is to provide an updated and comprehensive synthesis of the association between tobacco smoking and Clinical High Risk for Psychosis (CHRP) status. We performed a multistep systematic PRISMA/MOOSE-compliant electronic search for articles published from inception until October 1st, 2021. Web of Science was searched, complemented by a manual search of original articles reporting the outcome of tobacco consumption (defined as the number of individuals which were smoking tobacco at baseline) in a group of CHR-P patients versus healthy controls (HC). We employed quality assessment of the included studies with Newcastle Ottawa Scale (NOS). The effect size for the primary outcome was the odds ratio (OR) of smoking tobacco in CHR-P samples vs HC. We performed a random-effects model meta-analysis, assessment of heterogeneity with I index, sensitivity analyses excluding one study at a time for primary outcome, meta-regressions with four independent moderators (mean age, female ratio, sample size, NOS) and assessment of publication bias with funnel plot and Egger’s test. We included 21 independent articles, totalling 2018 CHR-P individuals (mean age of 21.35 ± 2.91 years and average female ratio of 41 ± 7 %) and 1160 HC (mean age of 22.42 ± 3.70 years and average female ratio of 45 ± 11 %). The NOS score was 6.52 ± 1.25 (range from 0 to 9). The OR of smoking status was 2.22 (95%CI 1.74-2.84, p < 0.01). Heterogeneity (I) was 24.09 (p = 0.16). Sensitivity analyses, removing one study at a time, revealed the robustness of our main finding. Meta-regressions did not reveal any significant association between the moderators and the main outcome. Visual inspection of the funnel plot and Egger’s test did not reveal evident publication bias. Our main finding of an increased OR of smokers in the CHR-P individuals compared to healthy controls corroborates the accumulation of unhealthy lifestyles in this vulnerable group. This does not demonstrate any causal association between tobacco smoking and incidence of psychosis, which should be investigated in future prospective cohorts. In conclusion, the window of opportunity represented by CHR-P status should involve more efficient physical health screening and better investigating the aetiological impact of smoking in the development of psychosis.

Psychiatry has increasingly adopted explanations for psychopathology that are based on neurobiological reductionism. With the recognition of health disparities and the realisation that someone’s postcode can be a better predictor of health outcomes than their genetic code, there are increasing efforts to ensure cultural and social-structural competence in psychiatric practice. Although neuroscientific and social-cultural approaches in psychiatry remain largely separate, they can be brought together in a multilevel explanatory framework to advance psychiatric theory, research, and practice. In this Personal View, we outline how a cultural-ecosocial systems approach to integrating neuroscience in psychiatry can promote social-contextual and systemic thinking for more clinically useful formulations and person-centred care.

Numerous studies have established the association of the common APOE ε2 and APOE ε4 alleles with Alzheimer disease (AD) risk across ancestries. Studies of the interaction of these alleles with other amino acid changes on APOE in non-European ancestries are lacking and may improve ancestry-specific risk prediction.

To determine whether APOE amino acid changes specific to individuals of African ancestry modulate AD risk.

Case-control study including 31 929 participants and using a sequenced discovery sample (Alzheimer Disease Sequencing Project; stage 1) followed by 2 microarray imputed data sets derived from the Alzheimer Disease Genetic Consortium (stage 2, internal replication) and the Million Veteran Program (stage 3, external validation). This study combined case-control, family-based, population-based, and longitudinal AD cohorts, which recruited participants (1991-2022) in primarily US-based studies with 1 US/Nigerian study. Across all stages, individuals included in this study were of African ancestry.

Two APOE missense variants (R145C and R150H) were assessed, stratified by APOE genotype.

The primary outcome was AD case-control status, and secondary outcomes included age at AD onset.

Stage 1 included 2888 cases (median age, 77 [IQR, 71-83] years; 31.3% male) and 4957 controls (median age, 77 [IQR, 71-83] years; 28.0% male). In stage 2, across multiple cohorts, 1201 cases (median age, 75 [IQR, 69-81] years; 30.8% male) and 2744 controls (median age, 80 [IQR, 75-84] years; 31.4% male) were included. In stage 3, 733 cases (median age, 79.4 [IQR, 73.8-86.5] years; 97.0% male) and 19 406 controls (median age, 71.9 [IQR, 68.4-75.8] years; 94.5% male) were included. In ε3/ε4-stratified analyses of stage 1, R145C was present in 52 individuals with AD (4.8%) and 19 controls (1.5%); R145C was associated with an increased risk of AD (odds ratio [OR], 3.01; 95% CI, 1.87-4.85; P = 6.0 × 10-6) and was associated with a reported younger age at AD onset (β, -5.87 years; 95% CI, -8.35 to -3.4 years; P = 3.4 × 10-6). Association with increased AD risk was replicated in stage 2 (R145C was present in 23 individuals with AD [4.7%] and 21 controls [2.7%]; OR, 2.20; 95% CI, 1.04-4.65; P = .04) and was concordant in stage 3 (R145C was present in 11 individuals with AD [3.8%] and 149 controls [2.7%]; OR, 1.90; 95% CI, 0.99-3.64; P = .051). Association with earlier AD onset was replicated in stage 2 (β, -5.23 years; 95% CI, -9.58 to -0.87 years; P = .02) and stage 3 (β, -10.15 years; 95% CI, -15.66 to -4.64 years; P = 4.0 × 10-4). No significant associations were observed in other APOE strata for R145C or in any APOE strata for R150H.

In this exploratory analysis, the APOE ε3[R145C] missense variant was associated with an increased risk of AD among individuals of African ancestry with the ε3/ε4 genotype. With additional external validation, these findings may inform AD genetic risk assessment in individuals of African ancestry.

Schizophrenia is a serious mental disorder, and existing antipsychotic drugs show limited efficacy and cause unwanted side effects. The development of glutamatergic drugs for schizophrenia is currently challenging. Most functions of histamine in the brain are mediated by the histamine H₁ receptor; however, the role of the H₂ receptor (H₂R) is not quite clear, especially in schizophrenia. Here, we found that expression of H₂R in glutamatergic neurons of the frontal cortex was decreased in schizophrenia patients. Selective knockout of the H₂R gene (Hrh2) in glutamatergic neurons (CaMKIIα-Cre; Hrh2 ) induced schizophrenia-like phenotypes including sensorimotor gating deficits, increased susceptibility to hyperactivity, social withdrawal, anhedonia, and impaired working memory, as well as decreased firing of glutamatergic neurons in the medial prefrontal cortex (mPFC) in in vivo electrophysiological tests. Selective knockdown of H₂R in glutamatergic neurons in the mPFC but not those in the hippocampus also mimicked these schizophrenia-like phenotypes. Furthermore, electrophysiology experiments established that H₂R deficiency decreased the firing of glutamatergic neurons by enhancing the current through hyperpolarization-activated cyclic nucleotide-gated channels. In addition, either H₂R overexpression in glutamatergic neurons or H₂R agonism in the mPFC counteracted schizophrenia-like phenotypes in an MK-801-induced mouse model of schizophrenia. Taken together, our results suggest that deficit of H₂R in mPFC glutamatergic neurons may be pivotal to the pathogenesis of schizophrenia and that H₂R agonists can be regarded as potentially efficacious medications for schizophrenia therapy. The findings also provide evidence for enriching the conventional glutamate hypothesis for the pathogenesis of schizophrenia and improve the understanding of the functional role of H₂R in the brain, especially in glutamatergic neurons.

NA RNA methylation controls synaptic protein synthesis and may play a role in cognitive decline associated with aging and AD.

We used event-related potentials (ERPs) to examine encoding and retrieval during episodic memory in people with schizophrenia (SZ) and biological relatives of SZ (SZr). To isolate contextual from item-specific aspects of memory, we employed the Relational and Item-Specific Encoding (RISE) task. Twenty two healthy controls (HCs), 22 SZ, and 19 SZr, encoded visual depictions of objects when displayed alone (item-specific) or in pairs (relational encoding), and were later tested on recognition of specific objects and whether pairs of objects had appeared together. An early posterior component (P2) during encoding predicted later recognition and was diminished in SZ. A late negative potential (LNP) over left frontal brain regions during recognition was larger for relationally encoded objects than new and item-specific encoded objects in HCs. This pattern was absent for SZ and SZr. Smaller P2 and LNP components were associated with greater self-reported cognitive-perceptual abnormalities. Early posterior brain responses likely relevant to perceptual functions supporting memory formation were diminished in schizophrenia. Late frontal electrophysiological responses associated with relational aspects of memory appear diminished in SZ and SZr, potentially reflecting the influence of genetic liability for schizophrenia on brain functions supporting episodic memory.

The “emotion paradox” of schizophrenia suggests people with schizophrenia demonstrate deficits when reporting anticipated and retrospective pleasure; yet, in-the-moment, consummatory pleasure is largely intact. It is uncertain how these findings extend to social situations. This meta-analysis aimed to (1) determine the mean difference in consummatory social pleasure between people with schizophrenia and healthy controls, and (2) examine moderators of this effect, including study design and clinical characteristics of participants.

A literature search using PsycINFO, Web of Science, Pubmed, and EMBASE databases was conducted. Studies measuring consummatory social pleasure using experience sampling methods and laboratory social simulations were included. Random effects meta-analyses were conducted using Hedge’s g.

Meta-analysis of 26 studies suggests people with schizophrenia exhibited a small, significant deficit in consummatory social pleasure (g = -0.38, 90% CI [-0.53, -0.22]). There was significant heterogeneity in effect sizes; magnitude was moderated by study design and type of measure used to assess social pleasure.

Overall, people with schizophrenia seem to exhibit less consummatory social pleasure than controls. However, this deficit is smaller than in studies of anticipated and retrospective pleasure. Thus, consummatory social pleasure may not be quite as impaired in people with schizophrenia as traditional anhedonia research suggests. Moreover, pleasure deficits observed in people with schizophrenia may result from differences in the quality of their daily social experiences rather than differences in their capacity for social pleasure. Results have important implications for clinical interventions that address barriers to social engagement, low-pleasure beliefs, and cognitive remediation to treat schizophrenia.

Numerous studies have investigated the impacts of common types of chronic pain (CP) on patients’ cognitive function and observed that CP was associated with later dementia. More recently, there is a growing recognition that CP conditions frequently coexist at multiple body sites and may bring more burdens on patients’ overall health. However, whether and how multisite CP (MCP) contributes to an increased risk of dementia, compared to single-site CP (SCP) and pain-free (PF), is largely unclear. In the current study, utilizing the UK Biobank cohort, we first investigated dementia risk in individuals (n = 354,943) with different numbers of coexisting CP sites using Cox proportional hazards regression models. We then applied generalized additive models to investigate whether MCP leads to excessive deterioration of participants’ (n = 19,116) cognition and brain structure. We found that individuals with MCP were associated with significantly higher dementia risk, broader and faster cognitive impairment, and greater hippocampal atrophy than both PF individuals and those with SCP. Moreover, the detrimental effects of MCP on dementia risk and hippocampal volume aggravated along with the number of coexisting CP sites. Mediation analyses further revealed that the decline of fluid intelligence in MCP individuals was partially mediated by hippocampal atrophy. Our results suggested that cognitive decline and hippocampal atrophy interact biologically and may underlie the increased risk of dementia associated with MCP.

We report emergency department and inpatient amphetamine-related trends focusing on co-occurring substance use and psychiatric diagnoses at the Centre for Addiction and Mental Health, the largest mental health teaching hospital in Canada.

We describe yearly trends in amphetamine-related Centre for Addiction and Mental Health emergency department visits and inpatient admissions out of all emergency department visits and inpatient admissions between 2014 and 2021, along with proportions of concurrent substance-related admissions and mental/psychotic disorders emergency department visits and inpatient admissions among amphetamine-related contacts; joinpoint regression analyses assessed changes in amphetamine-related emergency department visits and inpatient admissions.

Amphetamine-related emergency department visits rose from 1.5% in 2014 to 8.3% in 2021, with a peak of 9.9% in 2020. Amphetamine-related inpatient admissions rose from 2.0% to 8.8% in 2021, with a peak of 8.9% in 2020. Significant increasing trends in the percentage of amphetamine-related emergency department visits happened especially between the second and the fourth quarter of 2014 (quarterly percent change = + 71.4, P <0.01). Similarly, the percentage of amphetamine-related inpatient admissions increased mostly between the second quarter of 2014 and the third quarter of 2015 (quarterly percent change = + 32.6, P <0.01). The proportion of concurrent opioid-related contacts among amphetamine-related emergency department visits and inpatient admission increased markedly between 2014 and 2021; psychotic disorders in amphetamine-related inpatient admissions more than doubled from 2015 to 2021.

Prevalence of amphetamine use, mostly from methamphetamine, has been increasing in Toronto as have co-occurring psychiatric disorders and opioid use. Our findings highlight the need for increases in accessible efficacious treatments for complex populations with polysubstance use and co-occurring disorders.

The OPUS 20-year follow-up is the longest follow-up of a randomized clinical trial testing early intervention services (EIS) among individuals with first-episode schizophrenia spectrum disorder.

To report on long-term associations of EIS compared with treatment as usual (TAU) for first-episode schizophrenia spectrum disorder.

A total of 547 individuals were included in this Danish multicenter randomized clinical trial between January 1998 and December 2000 and allocated to early intervention program group (OPUS) or TAU. Raters who were blinded to the original treatment performed the 20-year follow-up. A population-based sample aged 18 to 45 years with first-episode schizophrenia spectrum disorder were included. Individuals were excluded if they were treated with antipsychotics (>12 weeks prior to randomization), had substance-induced psychosis, had mental disability, or had organic mental disorders. Analysis took place between December 2021 and August 2022.

EIS (OPUS) consisted of 2 years of assertive community treatment including social skill training, psychoeducation, and family involvement by a multidisciplinary team. TAU consisted of the available community mental health treatment.

Psychopathological and functional outcomes, mortality, days of psychiatric hospitalizations, number of psychiatric outpatient contacts, use of supported housing/homeless shelters, symptom remission, and clinical recovery.

Of 547 participants, 164 (30%) were interviewed at 20-year follow-up (mean [SD] age, 45.9 [5.6] years; 85 [51.8%] female). No significant differences were found between the OPUS group compared with the TAU group on global functional levels (estimated mean difference, -3.72 [95% CI, -7.67 to 0.22]; P = .06), psychotic symptom dimensions (estimated mean difference, 0.14 [95% CI, -0.25 to 0.52]; P = .48), and negative symptom dimensions (estimated mean difference, 0.13 [95% CI, -0.18 to 0.44]; P = .41). The mortality rate was 13.1% (n = 36) in the OPUS group and 15.1% (n = 41) in the TAU group. Likewise, no differences were found 10 to 20 years after randomization between the OPUS and TAU groups on days of psychiatric hospitalizations (incidence rate ratio, 1.20 [95% CI, 0.73-1.20]; P = .46) or number of outpatient contacts (incidence rate ratio, 1.20 [95% CI, 0.89-1.61]; P = .24). Of the entire sample, 53 participants (40%) were in symptom remission and 23 (18%) were in clinical recovery.

In this follow-up study of a randomized clinical trial, no differences between 2 years of EIS vs TAU among individuals with diagnosed schizophrenia spectrum disorders at 20 years were found. New initiatives are needed to maintain the positive outcomes achieved after 2 years of EIS and furthermore improve very long-term outcomes. While registry data was without attrition, interpretation of clinical assessments are limited by high attrition rate. However, this attrition bias most likely confirms the lack of an observed long-term association of OPUS with outcomes.

ClinicalTrials.gov Identifier: NCT00157313.

Frailty is associated with reduced physiological reserve, lack of independence, and depression and may be salient for identifying older adults at increased risk of suicide attempt.

To examine the association between frailty and risk of suicide attempt and how risk differs based on components of frailty.

This nationwide cohort study integrated databases from the US Department of Veterans Affairs (VA) inpatient and outpatient health care services, Centers for Medicare & Medicaid Services data, and national suicide data. Participants included all US veterans aged 65 years or older who received care at VA medical centers from October 1, 2011, to September 30, 2013. Data were analyzed from April 20, 2021, to May 31, 2022.

Frailty, defined based on a validated cumulative-deficit frailty index measured using electronic health data and categorized into 5 levels: nonfrailty, prefrailty, mild frailty, moderate frailty, and severe frailty.

The main outcome was suicide attempts through December 31, 2017, provided by the national Suicide Prevention Applications Network (nonfatal attempts) and Mortality Data Repository (fatal attempts). Frailty level and components of the frailty index (morbidity, function, sensory loss, cognition and mood, and other) were assessed as potential factors associated with suicide attempt.

The study population of 2 858 876 participants included 8955 (0.3%) who attempted suicide over 6 years. Among all participants, the mean (SD) age was 75.4 (8.1) years; 97.7% were men, 2.3% were women, 0.6% were Hispanic, 9.0% were non-Hispanic Black, 87.8% were non-Hispanic White, and 2.6% had other or unknown race and ethnicity. Compared with patients without frailty, risk of suicide attempt was uniformly higher among patients with prefrailty to severe frailty, with adjusted hazard ratios (aHRs) of 1.34 (95% CI, 1.27-1.42; P < .001) for prefrailty, 1.44 (95% CI, 1.35-1.54; P < .001) for mild frailty, 1.48 (95% CI, 1.36-1.60; P < .001) for moderate frailty, and 1.42 (95% CI, 1.29-1.56; P < .001) for severe frailty. Lower levels of frailty were associated with greater risk of lethal suicide attempt (aHR, 1.20 [95% CI, 1.12-1.28] for prefrail veterans). Bipolar disorder (aHR, 2.69; 95% CI, 2.54-2.86), depression (aHR, 1.78; 95% CI, 1.67-1.87), anxiety (aHR, 1.36; 95% CI, 1.28-1.45), chronic pain (aHR, 1.22; 95% CI, 1.15-1.29), use of durable medical equipment (aHR, 1.14; 95% CI, 1.03-1.25), and lung disease (aHR, 1.11; 95% CI, 1.06-1.17) were independently associated with increased risk of suicide attempt.

This cohort study found that among US veterans aged 65 years or older, frailty was associated with increased risk of suicide attempts and lower levels of frailty were associated with greater risk of suicide death. Screening and involvement of supportive services across the spectrum of frailty appear to be needed to help reduce risk of suicide attempts.

This systematic review focuses on personality traits according to both the Five Factor Model and Cloninger Psychobiological Model in relation to treatment related outcome variables across all stages of clinical psychotic illness. Search of Pubmed and Psychinfo databases led to final inclusion of 65 studies, which were ranked on quality and analyzed according to the associations between personality and outcome. Main findings are that higher levels of Harm Avoidance and Neuroticism are associated with higher symptom levels, tendency towards passive coping, greater self-stigma, lower quality of life, and Harm Avoidance to higher suicidality. Higher levels of Extraversion and higher levels of Self-Directedness are associated with more preference for active coping, more intrinsic motivation and higher self-esteem. Higher Novelty Seeking is related to more substance use and aggression, in men specifically. On outcome of trauma, care consumption and duration of untreated illness no consistent associations with personality traits were found. Combined evidence from both personality models however reveals a consistent pattern of personality traits related to clinical outcome in psychotic disorder, which is discussed in a dimensional manner.

Schizophrenia is a complex and heterogeneous disorder involving multiple regions and types of cells in the brain. Despite rapid progress made by genome-wide association studies (GWAS) of schizophrenia, the mechanisms of the illness underlying the GWAS significant loci remain less clear.

We investigated schizophrenia risk genes using summary-data-based Mendelian randomization based on single-cell sequencing data, and explored the types of brain cells involved in schizophrenia through the expression weighted cell-type enrichment analysis.

We identified 54 schizophrenia risk genes (two-thirds of these genes were not identified using sequencing data of bulk tissues) using single-cell RNA-sequencing data. Further cell type enrichment analysis showed that schizophrenia risk genes were highly expressed in excitatory neurons and caudal ganglionic eminence interneurons, suggesting putative roles of these cells in the pathogenesis of schizophrenia. We also found that these risk genes identified using single-cell sequencing results could form a large protein-protein interaction network with genes affected by disease-causing rare variants.

Through integrative analyses using expression data at single-cell levels, we identified 54 risk genes associated with schizophrenia. Notably, many of these genes were only identified using single-cell RNA-sequencing data, and their altered expression levels in particular types of cells, rather than in the bulk tissues, were related to the increased risk of schizophrenia. Our results provide novel insight into the biological mechanisms of schizophrenia, and future single-cell studies are necessary to further facilitate the understanding of the disorder.

The effect of lorazepam in the treatment of catatonia is outstanding and almost immediate. Clinicians are familiar with its effects: mute patients can speak again, akinetic patients can move again and patients with negativism can eat and drink again within usually a short duration of about 10 min to 1-2 h. Fear is often gone after lorazepam administration. While not always effective, the introduction of lorazepam into clinical practice represented a breakthrough and was often life-saving for many patients suffering from catatonia. It is rare to observe such rapid therapeutic effects in other domains of psychiatry. In this narrative review we will briefly look at the past, present and future of lorazepam in the treatment of catatonia. It is gratifying to reflect on the fact that clinicians using the age-old medical practice of observation and empirical treatment succeeded in advancing the management of catatonia 40 years ago. The present evidence shows that the clinical effect of lorazepam in catatonia treatment is excellent and more or less immediate although it remains to be explicitly tested against other substances such as diazepam, zolpidem, clozapine, quetiapine, amantadine, memantine, valproate and dantrolene in randomized clinical trials. In addition, future studies need to answer the question how long lorazepam should be given to patients with catatonia, months or even years? This narrative review promotes the rapid use of lorazepam in the treatment of acute catatonic patients and stipulates further scientific examination of its often impressive clinical effects.

Theories propose that visual impairment might increase the risk of psychosis, and vice versa. We aimed to investigate the relationship between visual impairment and psychosis in the UK Biobank cohort.

In a nested case control study of ~116,000 adults, we tested whether a Schizophrenia Spectrum Disorder (SSD) diagnosis as exposure was associated with visual impairment. We also tested longitudinally whether poorer visual acuity, and thinner retinal structures on Optical Coherence Tomography (OCT) scans in 2009 were associated with psychotic experiences in 2016. We adjusted for age, sex, depression and anxiety symptoms; and socioeconomic variables and vascular risk factors where appropriate. We compared complete case with multiple imputation models, designed to reduce bias potentially introduced by missing data.

People with visual impairment had greater odds of SSD than controls in multiply imputed data (Adjusted Odds Ratio [AOR] 1.42, 95 % Confidence Interval [CI] 1.05-1.93, p = 0.021). We also found evidence that poorer visual acuity was associated with psychotic experiences during follow-up (AOR per 0.1 point worse visual acuity score 1.06, 95 % CI 1.01-1.11, p = 0.020; and 1.04, 95 % CI 1.00-1.08, p = 0.037 in right and left eye respectively). In complete case data (15 % of this cohort) we found no clear association, although confidence intervals included the multiple imputation effect estimates. OCT measures were not associated with psychotic experiences.

Our findings highlight the importance of eye care for people with psychotic illnesses. We could not conclude whether visual impairment is a likely causal risk factor for psychosis.

Studies have suggested that fingolimod, a sphingosine-1-phosphate receptor modulator, exerts neuroprotective and anti-inflammatory effects. Although fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis, limited studies have investigated its effects in patients with schizophrenia. This study investigated the efficacy and safety of fingolimod adjuvant to risperidone in schizophrenia treatment.

This eight-week, randomized, double-blinded, placebo-controlled trial included 80 (clinical trials registry code: IRCT20090117001556N137) patients with chronic schizophrenia. Participants were assigned to two equal arms and received risperidone plus either fingolimod (0.5 mg/day) or a matched placebo. The positive and negative symptom scale (PANSS) was used to measure and compare the effectiveness of treatment strategies at baseline and weeks 2, 4, 6, and 8. Treatment side effects were also compared.

Seventy participants completed the trial (35 in each arm). The baseline characteristics of the groups were comparable (P-value > 0.05). There were significant time-treatment interaction effects on negative symptoms (P-value = 0.003), general symptoms (P-value = 0.037), and the PANSS total score (P-value = 0.035), suggesting greater improvement in symptoms following the fingolimod adjuvant therapy. In contrast, the longitudinal changes in positive and depressive symptoms were similar between the groups (P-values > 0.05). Regarding the safety of treatments, there were no differences in extrapyramidal symptoms [assessed by the extrapyramidal symptom rating scale (ESRS)] or frequency of other complications between the fingolimod and the placebo groups (P-values > 0.05).

This study indicated that fingolimod is a safe and effective adjuvant agent for schizophrenia treatment. However, further clinical trials are required to suggest extensive clinical application.

Understanding the evolution of negative symptoms in first-episode psychosis (FEP) requires long-term longitudinal study designs that capture the progression of this condition and the associated brain changes.

To explore the factors underlying negative symptoms and their association with long-term abnormal brain trajectories.

We followed up 357 people with FEP over a 10-year period. Factor analyses were conducted to explore negative symptom dimensionality. Latent growth mixture modelling (LGMM) was used to identify the latent classes. Analysis of variance (ANOVA) was conducted to investigate developmental trajectories of cortical thickness. Finally, the resulting ANOVA maps were correlated with a wide set of regional molecular profiles derived from public databases.

Three trajectories (stable, decreasing and increasing) were found in each of the three factors (expressivity, experiential and attention) identified by the factor analyses. Patients with an increasing trajectory in the expressivity factor showed cortical thinning in caudal middle frontal, pars triangularis, rostral middle frontal and superior frontal regions from the third to the tenth year after the onset of the psychotic disorder. The F-statistic map of cortical thickness expressivity differences was associated with a receptor density map derived from positron emission tomography data.

Stable and decreasing were the most common trajectories. Additionally, cortical thickness abnormalities found at relatively late stages of FEP onset could be exploited as a biomarker of poor symptom outcome in the expressivity dimension. Finally, the brain areas with less density of receptors spatially overlap areas that discriminate the trajectories of the expressivity dimension.

Recent functional imaging studies in schizophrenia consistently report a disruption of brain connectivity. However, most of these studies analyze the brain connectivity during resting state. Since psychological stress is a major factor for the emergence of psychotic symptoms, we sought to characterize the brain connectivity reconfiguration induced by stress in schizophrenia. We tested the hypothesis that an alteration of the brain’s integration-segregation dynamic could be the result of patients with schizophrenia facing psychological stress. To this end, we studied the modular organization and the reconfiguration of networks induced by a stress paradigm in forty subjects (twenty patients and twenty controls), thus analyzing the dynamics of the brain in terms of integration and segregation processes by using 3T-fMRI. Patients with schizophrenia did not show statistically significant differences during the control task compared with controls, but they showed an abnormal community structure during stress condition and an under-connected reconfiguration network with a reduction of hub nodes, suggesting a deficit of integration dynamic with a greater compromise of the right hemisphere. These results provide evidence that schizophrenia has a normal response to undemanding stimuli but shows a disruption of brain functional connectivity between key regions involved in stress response, potentially leading to altered functional brain dynamics by reducing integration capacity and showing deficits recruiting right hemisphere regions. This could in turn underlie the hyper-sensitivity to stress characteristic of schizophrenia.

Emerging evidence suggests that the duration of risk symptoms (DUR) may have an impact on clinical outcomes in clinical high-risk for psychosis (CHRP) participants. To explore this hypothesis, we performed a meta-analysis on studies that examined DUR in CHR-P individuals in relation to their clinical outcomes. This review was conducted in accordance with the PRISMA guidelines and the protocol was registered with PROSPERO on 16th April 2021 (ID no. CRD42021249443). Literature searches were conducted using PsycINFO and Web of Science in March and November 2021, for studies reporting on DUR in CHR-P populations, in relation to transition to psychosis or symptomatic, functional, or cognitive outcomes. The primary outcome was transition to psychosis, while the secondary outcomes were remission from CHR-P status and functioning at baseline. Thirteen independent studies relating to 2506 CHR-P individuals were included in the meta-analysis. The mean age was 19.88 years (SD = 1.61) and 1194 individuals (47.65 %) were females. The mean length of DUR was 23.61 months (SD = 13.18). There was no meta-analytic effect of DUR on transition to psychosis at 12-month follow-up (OR = 1.000, 95%CI = 0.999-1.000, k = 8, p = .98), while DUR was related to remission (Hedge’s g = 0.236, 95%CI = 0.014-0.458, k = 4, p = .037). DUR was not related to baseline GAF scores (beta = -0.004, 95%CI = -0.025-0.017, k = 3, p = .71). The current findings suggest that DUR is not associated with transition to psychosis at 12 months, but may impact remission. However, the database was small and further research in this area is required.

Suicide prevention is a major challenge in the treatment of first-episode affective psychoses. The literature reports that combinations of manic, depressive and paranoid symptoms, which may interact, are associated with an increased risk of suicide. The present study investigated whether interactions between manic, depressive and paranoid symptoms affected suicidality in first-episode affective psychoses.

We prospectively studied 380 first-episode psychosis patients enrolled in an early intervention programme and diagnosed with affective or non-affective psychoses. We compared intensity and presence of suicidal thoughts and occurrence of suicide attempts over a three-year follow-up period and investigated the impact of interactions between manic, depressive and paranoid symptoms on level of suicidality.

At 12 months follow-up, we observed a higher level of suicidal thoughts and higher occurrence of suicide attempts among the affective psychoses patients compared to non-affective psychoses patients. Combined presence of either depressive and paranoid symptoms, or manic and paranoid symptoms, was significantly associated with increased suicidal thoughts. However, the combination of depressive and manic symptoms showed a significant negative association with suicidal thoughts.

This study suggests that paranoid symptoms combined with either manic or depressive symptoms are associated with an increased risk of suicide in first-episode affective psychoses. Detailed assessment of these dimensions is therefore warranted in first-episode affective patients and integrated treatment should be adapted to increased suicidal risk, even if patients do not display full-blown depressive or manic syndromes.

Microglia play a critical role in the pathogenic process of neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Upon pathological stimulation, microglia are converted from a surveillant to an overactivated phenotype. However, the molecular characters of proliferating microglia and their contributions to the pathogenesis of neurodegeneration remain unclear. Here, we identify chondroitin sulfate proteoglycan 4 (Cspg4, also known as neural/glial antigen 2)-expressing microglia as a specific subset of microglia with proliferative capability during neurodegeneration. We found that the percentage of Cspg4 microglia are one of the origins of microgliosis during neurodegeneration and may open up a avenue for the treatment of neurodegenerative diseases.

Traditional substance use (SU) surveillance methods, such as surveys, incur substantial lags. Due to the continuously evolving trends in SU, insights obtained via such methods are often outdated. Social media-based sources have been proposed for obtaining timely insights, but methods leveraging such data cannot typically provide fine-grained statistics about subpopulations, unlike traditional approaches. We address this gap by developing methods for automatically characterizing a large Twitter nonmedical prescription medication use (NPMU) cohort (n = 288,562) in terms of age-group, race, and gender. Our natural language processing and machine learning methods for automated cohort characterization achieved 0.88 precision (95% CI:0.84 to 0.92) for age-group, 0.90 (95% CI: 0.85 to 0.95) for race, and 94% accuracy (95% CI: 92 to 97) for gender, when evaluated against manually annotated gold-standard data. We compared automatically derived statistics for NPMU of tranquilizers, stimulants, and opioids from Twitter with statistics reported in the National Survey on Drug Use and Health (NSDUH) and the National Emergency Department Sample (NEDS). Distributions automatically estimated from Twitter were mostly consistent with the NSDUH [Spearman r: race: 0.98 (P < 0.005); age-group: 0.67 (P < 0.005); gender: 0.66 (P = 0.27)] and NEDS, with 34/65 (52.3%) of the Twitter-based estimates lying within 95% CIs of estimates from the traditional sources. Explainable differences (e.g., overrepresentation of younger people) were found for age-group-related statistics. Our study demonstrates that accurate subpopulation-specific estimates about SU, particularly NPMU, may be automatically derived from Twitter to obtain earlier insights about targeted subpopulations compared to traditional surveillance approaches.

Root cause analysis (RCA), imported from high-reliability industries into health two decades ago, is the mandated methodology to investigate adverse events in most health systems. In this analysis, we argue that the validity of RCA in health and in psychiatry must be established, given the impact of these investigations on mental health policy and practice.

Microglial phagocytosis is an energetically demanding process that plays a critical role in the removal of toxic protein aggregates in Alzheimer’s disease (AD). Recent evidence indicates that a switch in energy production from mitochondrial respiration to glycolysis disrupts this important protective microglial function and may provide therapeutic targets for AD. Here, we demonstrate that the translocator protein (TSPO) and a member of its mitochondrial complex, hexokinase-2 (HK), play critical roles in microglial respiratory-glycolytic metabolism and phagocytosis. Pharmacological and genetic loss-of-function experiments showed that TSPO is critical for microglial respiratory metabolism and energy supply for phagocytosis, and its expression is enriched in phagocytic microglia of AD mice. Meanwhile, HK controlled glycolytic metabolism and phagocytosis via mitochondrial binding or displacement. In cultured microglia, TSPO deletion impaired mitochondrial respiration and increased mitochondrial recruitment of HK, inducing a switch to glycolysis and reducing phagocytosis. To determine the functional significance of mitochondrial HK recruitment, we developed an optogenetic tool for reversible control of HK localization. Displacement of mitochondrial HK inhibited glycolysis and improved phagocytosis in TSPO-knockout microglia. Mitochondrial HK recruitment also coordinated the inflammatory switch to glycolysis that occurs in response to lipopolysaccharide in normal microglia. Interestingly, cytosolic HK increased phagocytosis independent of its metabolic activity, indicating an immune signaling function. Alzheimer’s beta amyloid drastically stimulated mitochondrial HK recruitment in cultured microglia, which may contribute to microglial dysfunction in AD. Thus, targeting mitochondrial HK may offer an immunotherapeutic approach to promote phagocytic microglial function in AD.