Psychiatry.dev - All Abstracts TTS: Recent Episodes
Psychiatry.dev
https://psychiatry.dev/wp-content/uploads/speaker/post-12345.mp3?cb=1679354264.mp3 Playback speed: 0.8x
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J L Kingston et al.
Schizophrenia Bulletin.
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.
minority group; negative beliefs; paranoia; positive beliefs; social rank.
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https://psychiatry.dev/wp-content/uploads/speaker/post-12341.mp3?cb=1679332315.mp3 Playback speed: 0.8x
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Erica L Karp et al.
Schizophrenia Bulletin.
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.
CHR; cognition; gesture; prodrome; working memory.
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https://psychiatry.dev/wp-content/uploads/speaker/post-12337.mp3?cb=1679327338.mp3 Playback speed: 0.8x
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Jiyoen Kim et al.
Neuron.
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.
RNF130; RNF149; USP7; genetic screens; modifier; neurodegeneration; tau levels; ubiquitination.
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Hannah L Phillips et al.
Neuron.
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.
C9orf72; affiliative behavior; behavioral variant FTD; consolation; dorsomedial prefrontal cortex; empathy; frontotemporal dementia; hypoexcitability; observational fear.
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https://psychiatry.dev/wp-content/uploads/speaker/post-12329.mp3?cb=1679320021.mp3 Playback speed: 0.8x
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Review
Sriram Balusu et al.
Neuron.
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.
Alzheimer’s disease; Parkinson’s disease; neurodegeneration; single-cell sequencing.
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https://psychiatry.dev/wp-content/uploads/speaker/post-12325.mp3?cb=1679316255.mp3 Playback speed: 0.8x
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Review
Ben Fleming et al.
British Medical Journal.
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.
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Hyunjun Yang et al.
PNAS.
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.
conformational strain; fluorescent excitation/emission; machine learning; neurodegenerative diseases; proteins fold.
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https://psychiatry.dev/wp-content/uploads/speaker/post-12317.mp3?cb=1679310178.mp3 Playback speed: 0.8x
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Ghassen Soufi et al.
Canadian Journal of Psychiatry.
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.
emergency shelter; homeless persons; housing; mental disorders; mental health services; quality of life.; severe; urban health services.
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https://psychiatry.dev/wp-content/uploads/speaker/post-12311.mp3?cb=1679225220.mp3 Playback speed: 0.8x
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Joanne B Newbury et al.
Schizophrenia Bulletin.
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.
disadvantage; intelligence; mediation; neighborhood; psychosis; urban.
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https://psychiatry.dev/wp-content/uploads/speaker/post-12307.mp3?cb=1679217775.mp3 Playback speed: 0.8x
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Sarah I Pratt et al.
Schizophrenia Research.
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.
Fitness; Healthy lifestyle; Incentives; Schizophrenia; Weight management.
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Jonathan Rabinowitz et al.
Schizophrenia Research.
Roluperidone has antagonist properties for 5-HT2A, sigma2, α1A– and α1B-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.
Negative symptoms; Schizophrenia; Treatment.
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https://psychiatry.dev/wp-content/uploads/speaker/post-12299.mp3?cb=1679210211.mp3 Playback speed: 0.8x
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Julia-Katharina Pfarr et al.
Schizophrenia Research.
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.
Factor analysis; Prodrome; Psychosis; Schizophrenia; Schizotypy.
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Tomas Mastellari et al.
Schizophrenia Research.
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.
Catatonia; Cosinor model; Season of birth; Seasonality; Seasonality of presentation.
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Matthew F Dobbs et al.
Schizophrenia Research.
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.
Clinical high-risk; Natural language processing; Part-of-speech tagging; Psychosis; Semantic similarity; Suicidal ideation.
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Manel Monsonet et al.
Schizophrenia Research.
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.
Experience sampling; Loneliness; Paranoia; Schizotypy; Self-esteem; Social connectedness.
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Alexander C R Burnett et al.
The British Journal of Psychiatry.
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.
Suicide; gender; intentional self-harm; occupation; skill level.
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Stephanie Santarriaga et al.
Schizophrenia Research.
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.
Cognitive deficits; Schizophrenia; Synaptic plasticity; iPSCs.
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Ryo Endo et al.
PNAS.
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 GABAA 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.
TTC3; UFMylation; cognitive disorders; ribosome stalling; ribosome-associated quality control.
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M Cecchi et al.
Schizophrenia Research.
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.
Automated data analysis; ERP Biomarker Qualification Consortium; Event related potentials; Quantitative EEG; Schizophrenia; Test-retest reliability.
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Wladimir Tantchik et al.
Schizophrenia Research.
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.
Mentalizing; Social cognition; fMRI; mPFC.
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Faye McKenna et al.
Schizophrenia Bulletin.
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.
diffusion MRI; free water; gray matter; inflammation; magnetic resonance spectroscopy imaging; memory; perfusion; white matter.
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Takuya Ishida et al.
Schizophrenia Bulletin.
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.
bipolar disorder; dynamic causal modeling; major depressive disorder; schizophrenia.
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Review
Matteo Cella et al.
The British Journal of Psychiatry.
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.
Psychosis; negative symptoms; psychosocial; review; schizophrenia.
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Isabel Morales-Muñoz et al.
The British Journal of Psychiatry.
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.
Anxiety; adverse outcome; comorbidity; depression; longitudinal cohort.
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Manne Sjöstrand et al.
The British Journal of Psychiatry.
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.
Ethics; philosophy; risk assessment; stigma and discrimination; suicide.
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Subash Raj Susai et al.
Schizophrenia Bulletin.
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.
Schizophrenia; antipsychotic agents; biomarkers; complement system proteins; immune markers; psychotic disorder.
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Louise Isham et al.
Schizophrenia Bulletin.
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.
grandiosity; immersion behaviors; repetitive thinking.
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Lyn Ellett et al.
Schizophrenia Bulletin.
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.
competition; distrust; paranoia; persecutory delusions; prisoner’s dilemma game; schizophrenia.
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Myungwoon Lee et al.
PNAS.
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.
Alzheimer’s disease; amyloid structure; cryogenic electron microscopy; molecular dynamics; solid-state NMR.
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Jason Smucny et al.
Schizophrenia Bulletin.
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.
caudate; dorsolateral prefrontal cortex; drift rate; psychosis; putamen; striatum.
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Sheri Madigan et al.
Lancet Psychiatry.
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.
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Nancy Murillo-García et al.
Schizophrenia Research.
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.
Intelligence; Longitudinal; Neurocognition; Schizophrenia spectrum disorders.
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Rebecca L D Kan et al.
Lancet Psychiatry.
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.
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Ann-Catherine Lemonde et al.
Schizophrenia Bulletin.
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.
delusions; first episode psychosis; geo-cultural context; symptomatology.
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Meta-Analysis
Ying Sun et al.
British Medical Journal.
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.
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James A G Crispo et al.
Canadian Journal of Psychiatry.
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.
Ontario; amphetamines; emergency department; marginalization.
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Laura Brandt et al.
American Journal of Psychiatry.
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.
Addiction Psychiatry; Medication-Assisted Treatment; Opioids; Substance-Related and Addictive Disorders.
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L Felice Reddy et al.
American Journal of Psychiatry.
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.
Behavioral; Psychotherapy; Schizophrenia Spectrum and Other Psychotic Disorders.
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Review
Cemal Demirlek et al.
Schizophrenia Research.
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.
Cognition; Memory; Memory consolidation; Schizophrenia; Sleep.
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Sugai Liang et al.
Schizophrenia Research.
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.
Anterior cingulate cortex; Bipolar disorder; First-episode schizophrenia; Resting-state functional connectivity; Transdiagnostic signature.
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Alexandra Roddy Mitchell et al.
JAMA Psychiatry.
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.
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Philip R Corlett et al.
JAMA Psychiatry.
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.
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Yue Gao et al.
Cell.
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.
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Adeyinka Adejumo et al.
Gastroenterology.
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.
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Pan Zhang et al.
PNAS.
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.
ASD; neuron-specific; transcriptome.
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Afraa Delvi et al.
Schizophrenia Research.
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.
Catatonia; Electroconvulsive therapy; Perinatal; Peripartum; Postnatal; Postpartum.
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Til Wykes et al.
Schizophrenia Bulletin.
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.
cognitive training; early intervention; functioning; goal achievement; therapist support.
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John R Purcell et al.
Schizophrenia Bulletin.
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.
Psychosis; cingulate; decision-making; fMRI; nucleus accumbens; risk-taking; schizoaffective disorder.
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Jeggan Tiego et al.
Schizophrenia Bulletin.
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.
general intellectual functioning; negative symptoms; polygenic risk; positive symptoms; schizophrenia; schizotypy.
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Lot D de Witte et al.
Schizophrenia Bulletin.
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.
doxycycline; observational study; schizophrenia; tetracycline antibiotics.
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Samuel J Abplanalp et al.
Schizophrenia Bulletin.
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.
DAG; facial affect; negative symptoms; processing speed; psychosis.
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Navona Calarco et al.
Schizophrenia Bulletin.
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.
Research Domain Criteria; diffusion imaging; neurocognition; schizophrenia spectrum disorders; social cognition; white matter.
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Nikitas C Koussis et al.
Schizophrenia Bulletin.
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.
Neural gain; bipolar disorder; cognitive control; prediction errors; schizophrenia.
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Review
Aline Rocha et al.
Cochrane Database of Systematic Reviews.
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.
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Review
Violet van Dee et al.
Schizophrenia Research.
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.
Outcome; Predictor; Psychosis; Recovery; Remission; Schizophrenia.
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Review
Falk Leichsenring et al.
Journal of the American Medical Association.
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.
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Timothy I Michaels et al.
Schizophrenia Research.
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.
Clinical high-risk; Paranoia; Perceived discrimination; Psychosis; Racism; Suspiciousness.
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Jon E Grant et al.
American Journal of Psychiatry.
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.
Obsessive-Compulsive Disorder (OCD); Pharmacotherapy; Psychopharmacology.
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Marta Peciña et al.
JAMA Psychiatry.
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.
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Shishi Min et al.
Schizophrenia Bulletin.
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.
RNA sequencing; brain tissue; major psychiatric disorders; viral infection; whole-genome sequencing.
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Alene Toulany et al.
Canadian Journal of Psychiatry.
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.
COVID-19; digital; equity; immigrant; mental health; pandemic; telemedicine; virtual care.
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JianLi Wang et al.
Canadian Journal of Psychiatry.
(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.
central intake/triage; mental health and addiction; mental health needs; mental health services; service planning.; specialty services.
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Review
Manish K Jha et al.
American Journal of Psychiatry.
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.
Antidepressants; Atypical Antipsychotics; Depressive Disorders; Esketamine; Ketamine; Psychedelics; Treatment-Resistant Depression (TRD).
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Immanuel G Elbau et al.
American Journal of Psychiatry.
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.
Functional connectivity; Major depressive disorder; Neuroimaging; Neurostimulation; Subgenual anterior cingulate cortex; Transcranial magnetic stimulation.
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Review
Thole H Hoppen et al.
The British Journal of Psychiatry.
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.
PTSD; efficacy; meta-analysis; multiple trauma; psychological intervention.
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Review
Yasna Rostam-Abadi et al.
Lancet Psychiatry.
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.
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A Waterreus et al.
Schizophrenia Research.
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.
Clinical outcomes; Longitudinal study.
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Marianna Piras et al.
Schizophrenia Bulletin.
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.
dose dependency; metabolic adverse effects; psychotropic drugs.
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Yingying Tang et al.
Schizophrenia Bulletin.
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.
Brief Visuospatial Memory Test-Revised; MATRICS Consensus Cognitive Battery; accelerated TMS protocol; clinical high risk for psychosis; risk of developing psychosis.
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Tanya M Luhrmann et al.
Schizophrenia Bulletin.
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.
discernment; hallucination; learning; psychosis; religion; voices.
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Sanne G Brederoo et al.
Schizophrenia Bulletin.
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.
loneliness/hallucinations/adolescents/young adults; social deafferentation.
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Monique van der Weijden-Germann et al.
Schizophrenia Bulletin.
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.
alcohol; cannabis; hallucinatory distress; nitrous oxide; recreational drug use; schizophrenia.
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Theresa M Marschall et al.
Schizophrenia Bulletin.
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.
auditory hallucinations; deafferentation; hearing-impairment; online survey; awareness.
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Salma M Khaled et al.
Schizophrenia Bulletin.
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.
Netherlands; Qatar; Questionnaire of Psychotic Experiences; measurement invariance; phenomenology; prevalence.
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Marouska M van Ommen et al.
Schizophrenia Bulletin.
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.
functional magnetic resonance imaging; schizophrenia; visual hallucinations.
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Branislava Ćurčić-Blake et al.
Schizophrenia Bulletin.
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.
auditory verbal hallucinations; paracingulate sulcus; schizophrenia.
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Review
Andrea De Micheli et al.
Schizophrenia Research.
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.
CHR-P; Psychosis; Smoking; Tobacco.
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Review
Ana Gómez-Carrillo et al.
Lancet Psychiatry.
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.
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Yann Le Guen et al.
Journal of the American Medical Association.
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.
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Qianyi Ma et al.
PNAS.
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.
HCN channel; glutamatergic neuron; histamine H2 receptor; medial prefrontal cortex; schizophrenia.
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Ricardo Castro-Hernández et al.
PNAS.
NA RNA methylation controls synaptic protein synthesis and may play a role in cognitive decline associated with aging and AD.
Alzheimer’s disease; RNA-methylation; epi-transcriptomics; epigenetics; neuro-epigenetics.
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Kara L Stevens et al.
Schizophrenia Research.
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.
Encoding; Episodic memory; Event-related potential; Genetic liability; Schizophrenia.
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Danielle B Abel et al.
Schizophrenia Bulletin.
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.
emotion paradox of schizophrenia; experience sampling methods; psychotic disorders; social anhedonia; social functioning.
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Wenhui Zhao et al.
PNAS.
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.
UK Biobank; cognitive function; dementia; hippocampus; multisite chronic pain.
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Vitor S Tardelli et al.
Canadian Journal of Psychiatry.
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.
comorbidity; hospitals; longitudinal studies; methamphetamine.
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Helene Gjervig Hansen et al.
JAMA Psychiatry.
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.
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Randall L Kuffel et al.
JAMA Psychiatry.
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.
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Review
Anne Neeltje Scholte-Stalenhoef et al.
Schizophrenia Research.
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.
Character; Cloninger psychobiological model; Five factor model; Personality; Psychosis; Temperament.
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Yong Wu et al.
Schizophrenia Bulletin.
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.
cell types; eQTL; risk genes; scRNA-seq; schizophrenia.
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Dusan Hirjak et al.
Schizophrenia Research.
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.
Catatonia; History; Lorazepam; Treatment.
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Natalie Shoham et al.
Schizophrenia Research.
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.
OCT; Psychosis; Schizophrenia; UK Biobank; Visual impairment.
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Monire Karbalaee et al.
Schizophrenia Research.
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.
Antipsychotic agents; Clinical trial; Fingolimod; Schizophrenia; White matter.
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Manuel Canal-Rivero et al.
The British Journal of Psychiatry.
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.
MRI; Negative symptoms; cortical thickness; factor analysis; first episode psychosis.
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Mariana N Castro et al.
Schizophrenia Research.
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.
Functional brain connectivity; Graph theory; Modularity; Networks brain dynamics; Psychological stress; Schizophrenia.
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Review
Saskia M Cooper et al.
Schizophrenia Research.
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.
Clinical high-risk for psychosis; Duration of risk symptoms; Functioning; Psychosis; Remission; Transition.
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Julie Ramain et al.
Schizophrenia Research.
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.
Early intervention; First-episode; Mood; Paranoid symptom; Psychosis; Suicide.
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Ya-Jing Liu et al.
PNAS.
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.
Alzheimer’s disease; Cspg4; Parkinson’s disease; microglia; neurodegenerative diseases.
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Yuan-Chi Yang et al.
PNAS.
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.
Twitter; machine learning; natural language processing; substance use; toxicovigilance.
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Mayura Deshpande et al.
The British Journal of Psychiatry.
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.
RCA; Root cause analysis; adverse events; investigation; validity.
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Lauren H Fairley et al.
PNAS.
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.
Alzheimer’s disease; hexokinase; immunometabolism; mitochondria; translocator protein.
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Lyna Z Schieber et al.
JAMA Psychiatry.
During the COVID-19 pandemic, US emergency department (ED) visits for psychiatric disorders (PDs) and drug overdoses increased. Psychiatric disorders and substance use disorders (SUDs) independently increased the risk of COVID-19 hospitalization, yet their effect together is unknown. To assess how comorbid PD and SUD are associated with the probability of hospitalization among ED patients with COVID-19.
This retrospective cross-sectional study analyzed discharge data for adults (age ≥18 years) with a COVID-19 diagnosis treated in 970 EDs and inpatient hospitals in the United States from April 2020 to August 2021.
Any past diagnosis of (1) SUD from opioids, stimulants, alcohol, cannabis, cocaine, sedatives, or other substances and/or (2) PD, including attention-deficit/hyperactivity disorder (ADHD), anxiety, bipolar disorder, major depression, other mood disorder, posttraumatic stress disorder (PTSD), or schizophrenia.
The main outcome was any hospitalization. Differences in probability of hospitalization were calculated to assess its association with both PD and SUD compared with PD alone, SUD alone, or neither condition.
Of 1 274 219 ED patients with COVID-19 (mean [SD] age, 54.6 [19.1] years; 667 638 women [52.4%]), 18.6% had a PD (mean age, 59.0 years; 37.7% men), 4.6% had a SUD (mean age, 50.1 years; 61.7% men), and 2.3% had both (mean age, 50.4 years; 53.1% men). The most common PDs were anxiety (12.9%), major depression (9.8%), poly (≥2) PDs (6.4%), and schizophrenia (1.4%). The most common SUDs involved alcohol (2.1%), cannabis (1.3%), opioids (1.0%), and poly (≥2) SUDs (0.9%). Prevalence of SUD among patients with PTSD, schizophrenia, other mood disorder, or ADHD each exceeded 21%. Based on significant specific PD-SUD pairs (Q < .05), probability of hospitalization of those with both PD and SUD was higher than those with (1) neither condition by a weighted mean of 20 percentage points (range, 6 to 36; IQR, 16 to 25); (2) PD alone by 12 percentage points (range, -4 to 31; IQR, 8 to 16); and (3) SUD alone by 4 percentage points (range, -7 to 15; IQR, -2 to 7). Associations varied by types of PD and SUD. Substance use disorder was a stronger predictor of hospitalization than PD.
This study found that patients with both PD and SUD had a greater probability of hospitalization, compared with those with either disorder alone or neither disorder. Substance use disorders appear to have a greater association than PDs with the probability of hospitalization. Overlooking possible coexisting PD and SUD in ED patients with COVID-19 can underestimate the likelihood of hospitalization. Screening and assessment of both conditions are needed.
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Gary S Sachs et al.
American Journal of Psychiatry.
The purpose of this study was to investigate the efficacy of cariprazine, a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist, as adjunctive therapy for patients with major depressive disorder and nonresponse to at least one antidepressant monotherapy. In this double-blind placebo-controlled study, adults with major depressive disorder and inadequate response to antidepressants alone were randomized in a 1:1:1 ratio to placebo, cariprazine at 1.5 mg/day, or cariprazine at 3.0 mg/day. The primary outcome was change from baseline to week 6 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS). Least-squares mean differences were estimated in the modified intent-to-treat (mITT) population using a mixed-effects model for repeated measures with adjustment for multiple comparisons.
The mITT population comprised 751 patients (placebo: N=249; cariprazine 1.5 mg/day: N=250; cariprazine 3.0 mg/day: N=252). At week 6, the mean reduction from baseline in MADRS total score was significantly greater with cariprazine 1.5 mg/day than with placebo (-14.1 vs. -11.5) but not with cariprazine 3.0 mg/day (-13.1). Significant differences between the cariprazine 1.5 mg/day and placebo groups were also observed at weeks 2 and 4. Meeting the MADRS response criteria was significantly more likely among patients receiving cariprazine 1.5 mg/day than placebo (44.0% vs. 34.9%); remission rates were not significantly different among groups. Common treatment-emergent adverse events (≥5% in either cariprazine group and twice the placebo rate) were akathisia and nausea.
Adjunctive cariprazine at 1.5 mg/day demonstrated efficacy in reducing depressive symptoms in adults with major depressive disorder and inadequate response to antidepressants alone. Cariprazine was generally well tolerated, with a safety profile that was consistent with previous findings.
Adjunctive treatment; cariprazine; clinical drug studies; major depressive disorder; randomized controlled trial.
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Kate L Harkness et al.
Canadian Journal of Psychiatry.
Childhood maltreatment is a potent enviromarker of risk for poor response to antidepressant medication (ADM). However, childhood maltreatment is a heterogeneous construct that includes distinct exposures that have distinct neurobiological and psychological correlates. The purpose of the current study is to examine the differential associations of emotional, physical, and sexual maltreatment to ADM outcome and to examine the unique role of anhedonia in driving poor response in patients with specific maltreatment histories. In a multicentre clinical trial of major depression, 164 individuals were assessed for childhood emotional, physical, and sexual maltreatment with a contextual interview with independent, standardized ratings. All individuals received 8 weeks of escitalopram, with nonresponders subsequently also receiving augmentation with aripiprazole, with outcomes measured with depression rating scales and an anhedonia scale.
Greater severity of emotional maltreatment perpetrated by the mother was a significant and direct predictor of lower odds of week 16 remission (odds ratio [OR] = 1.68, P = 0.02). In contrast, the relations of paternal-perpetrated emotional maltreatment and physical maltreatment to week 16 remission were indirect, mediated through greater severity of anhedonia at week 8.
We identify emotional maltreatment as a specific early exposure that places patients at the greatest risk for nonremission following pharmacological treatment. Further, we suggest that anhedonia is a key symptom domain driving nonremission in patients with particular maltreatment histories.
anhedonia; antidepressant treatment; childhood maltreatment; major depression.
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David Branford et al.
The British Journal of Psychiatry.
Antiseizure medications (ASMs) are the second most widely prescribed psychotropic for people with intellectual disabilities in England. Multiple psychotropic prescribing is prevalent in almost half of people with intellectual disabilities on ASMs. This analysis identifies limited evidence of ASM benefit in challenging behaviour management and suggests improvements needed to inform clinical practice.
Epilepsy; challenging behaviour; learning disabilities; neurodevelopmental; psychiatric conditions.
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Review
Juliane Rf Sanner et al.
Cochrane Database of Systematic Reviews.
‘Neurodisability’ refers to a group of conditions that result primarily from a neurological problem (e.g. cerebral palsy), neuromuscular problem (e.g. a muscular dystrophy) or developmental problems (e.g. developmental impairment, Down syndrome). Children and young people with these conditions may have similar problems with mobility, feeding and airway clearance. Chest and breathing problems (including pulmonary infections) are commonly experienced by children and young people with neurodisabilities and are often a cause for them requiring hospital care. For those who are unable to completely clear their airway of secretions, or have frequent infections, pulmonary infections may not be able to be completely eradicated and therefore become chronic. It is unclear what treatment is best for children and young people in this position. To assess the effectiveness and adverse effects of antibiotic treatment for chronic pulmonary infection in children and young people living with a neurodisability, including quality-of-life measures, effects on hospitalisation and healthcare contacts.
We searched the Cochrane Airways Trials Register, Cochrane Acute Respiratory Infections Group Register of Trials (CARIGRT), Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), OpenGrey (www.opengrey.eu) and three trials registries up to 8 February 2022. Additionally, we identified related systematic reviews through Epistemonikos.org (8 February 2022) and searched reference lists of these.
All randomised controlled trials of antibiotic therapy for chronic pulmonary infection in children and young people up to the age of 18 living with a neurodisability were eligible.
Two independent review authors screened results of the searches against predetermined inclusion criteria, resolving any discrepancies by discussion.
We identified a total of 1968 independent records through our searches, of which we assessed six full-text articles for eligibility. We identified one ongoing study as well as one related substudy but did not identify any completed studies eligible for inclusion in this systematic review.
The findings of this systematic review highlight a lack of evidence in the antibiotic treatment of chronic pulmonary infection in children and young people up to the age of 18 living with a neurodisability. Further research examining this topic is therefore required.
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Jonatan M Panula et al.
Schizophrenia Research.
Multiple different cognitive biases, among them the liberal acceptance (LA) bias, have been suggested to contribute to reality distortion in psychotic disorders. Earlier studies have been cross-sectional and considered a limited set of cognitive correlates of psychosis, thus the relationship between LA bias and psychosis remains poorly known. We studied a similar bias (acceptance of the implausible (AOI)) in 62 first-episode psychosis (FEP) patients and 62 control subjects, who watched movie scenes with varying degrees of realism and were asked to evaluate the probability of these events occurring in real life. We assessed theory of mind (ToM) performance using the Hinting task and delusion severity using Brief Psychiatric Rating Scale item 11. We correlated the magnitude of AOI with the severity of delusions and performance in the ToM task. Furthermore, we used 1-year follow-up data from 40 FEP patients and 40 control subjects to disentangle state vs trait-like characteristics of AOI. At baseline FEP patients expressed more AOI than control subjects, and the magnitude of AOI correlated positively with the severity of delusions and negatively with ToM performance. At the one-year follow-up, when most patients were in remission, patients still displayed increased AOI, which no longer correlated with delusions. These findings support the notion that the AOI bias could represent a trait rather than a state feature and support further studies to test the hypothesis that it could be one of the causal factors of psychotic disorders, possibly associated with ToM.
Cognitive bias; Schizophrenia; Social cognition; Theory of mind.
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Daniel Y Rubinstein et al.
Schizophrenia Bulletin.
We used the uniquely high combined spatial and temporal resolution of magnetoencephalography to characterize working memory (WM)-related modulation of beta band activity in neuroleptic-free patients with schizophrenia in comparison to a large sample of performance-matched healthy controls. We also tested for effects of antipsychotic medication on identified differences in these same patients. Inpatients with schizophrenia (n = 21) or psychotic disorder not otherwise specified (n = 4) completed N-back and control tasks during magnetoencephalography while on placebo and during antipsychotic medication treatment, in a blinded, randomized, counterbalanced manner. Healthy, performance-matched controls (N = 100) completed the same tasks. WM-related neural activation was estimated as beta band (14-30 Hz) desynchronization throughout the brain in successive 400 ms time windows. Voxel-wise statistical comparisons were performed between controls and patients while off-medication at each time window. Significant clusters resulting from this between-groups analysis were then used as regions-of-interest, the activations of which were compared between on- and off-medication conditions in patients.
Controls showed beta-band desynchronization (activation) of a fronto-parietal network immediately preceding correct button press responses-the time associated with WM updating and task execution. Altered activation in medication-free patients occurred largely during this time, in prefrontal, parietal, and visual cortices. Medication altered patients’ neural responses such that the activation time courses in these regions-of-interest more closely resembled those of controls.
These findings demonstrate that WM-related beta band alterations in schizophrenia are time-specific and associated with neural systems targeted by antipsychotic medications. Future studies may investigate this association by examining its potential neurochemical basis.
cognition; prefrontal cortex; psychosis.
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Scott Veldhuizen et al.
Canadian Journal of Psychiatry.
People with schizophrenia are much more likely than others to smoke tobacco, raising risks of disease and premature mortality. These individuals are also less likely to quit successfully after treatment, but the few existing clinical and observational studies have been limited by small sample sizes, and have generally considered specialized treatment approaches. In this analysis, we examine outcomes, service use, and potential explanatory variables in a large sample of people with schizophrenia treated in a general-population cessation program. Our sample comprised 3,011 people with schizophrenia and 77,790 controls receiving free nicotine replacement therapy through 400 clinics and health centres. We analysed self-reported 7-day abstinence or reduction at 6-month follow-up, as well as the number of visits attended and self-reported difficulties in quitting. We adjusted for demographic, socioeconomic, and health variables, and used multiple imputation to address missing data.
Abstinence was achieved by 16.2% (95% confidence interval [CI], 14.5% to 17.8%) of people with schizophrenia and 26.4% (95% CI, 26.0% to 26.7%) of others (absolute difference = 10.2%; 95% CI, 8.5% to 11.9%; P < 0.001). After adjustment, this difference was reduced to 7.3% (95% CI, 5.4% to 9.3%; P < 0.001). Reduction in use was reported by 11.8% (95% CI, 10.3% to 13.3%) and 12.5% (95% CI, 12.2% to 12.8%), respectively; this difference was nonsignificant after adjustment. People with schizophrenia attended more clinic visits (internal rate of return [IRR] = 1.15, 95% CI = 1.12% to 1.18%, P < 0.001) and reported more difficulties related to “being around other smokers” (odds ratio [OR] = 1.28; 95% CI, 1.11% to 1.47%; P = 0.001).
There is abundant demand for tobacco cessation treatment in this population. Outcomes were substantially poorer for people with schizophrenia, and this difference was not explained by covariates. Cessation remained much better than for unaided quit attempts, however, and engagement was high, demonstrating that people with schizophrenia benefit from nonspecialized pharmacological treatment programs.
nicotine replacement therapy; tobacco; treatment engagement.
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Garima Sharma et al.
Journal of the American College of Cardiology.
Mental illness among physicians is an increasingly recognized concern. Global data on mental health conditions (MHCs) among cardiologists are limited. The purpose of this study was to investigate the global prevalence of MHCs among cardiologists and its relationships to professional life.
The American College of Cardiology conducted an online survey with 5,931 cardiologists globally in 2019. Data on demographics, practice, MHC, and association with professional activities were analyzed. The P values were calculated using the chi-square, Fischer exact, and Mann-Whitney U tests. Univariate and multivariate logistic regression analysis determined the association of characteristics with MHC.
Globally, 1 in 4 cardiologists experience any self-reported MHC, including psychological distress, or major or other psychiatric disorder. There is significant geographic variation in MHCs, with highest and lowest prevalences in South America (39.3%) and Asia (20.1%) (P < 0.001). Predictors of MHCs included experiencing emotional harassment (OR: 2.81; 95% CI: 2.46-3.20), discrimination (OR: 1.85; 95% CI: 1.61-2.12), being divorced (OR: 1.85; 95% CI: 1.27-2.36), and age <55 years (OR: 1.43; 95% CI: 1.24-1.66). Women were more likely to consider suicide within the past 12 months (3.8% vs 2.3%), but were also more likely to seek help (42.3% vs 31.1%) as compared with men (all P < 0.001). Nearly one-half of cardiologists reporting MHCs (44%) felt dissatisfied on at least one professional metric including feeling valued, treated fairly, and adequate compensation.
More than 1 in 4 cardiologists experience self-reported MHCs globally, and the association with adverse experiences in professional life is substantial. Dedicated efforts toward prevention and treatment are needed to maximize the contributions of affected cardiologists.
burnout; cardiologist; mental health; mental health condition; mental illness; physician; well-being.
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Brooke C Schneider et al.
Schizophrenia Research.
Reduction of positive symptoms is often the focus of psychiatric treatment for patients with psychosis; however, it is becoming increasingly clear that some patients experience ambivalence towards positive symptoms or may even experience them as pleasant. The present study extends upon work from online studies of patients without verified diagnoses. The first aim was to examine the frequency with which patients report negative, neutral or even positive appraisals of positive symptoms. A second aim was to identify whether these appraisals were associated with medication adherence. One-hundred twelve treatment-seeking patients with current symptoms of psychosis completed the Subjective Perception of Positive Symptoms-Revised (SUPPOSY-R), a scale assessing appraisals of positive symptoms (e.g., gain from illness, impact on daily life), as well as questions regarding medication adherence.
Although most patients reported experiencing positive symptoms as predominantly unpleasant, appraisals differed between symptom clusters and up to 54.4 % reported that they would miss at least some aspects of positive symptoms should they disappear. Patients particularly welcomed the disappearance of auditory hallucinations (71.2 %). Symptom appraisal was not significantly associated with medication compliance (p > .17); however, more patients with low medication adherence reported they would feel at least some regret if their symptoms were to completely disappear (48.9 %, n = 23) versus patients with high adherence (41.7 %, n = 20).
Ambivalent or positive appraisals of positive symptoms are lower among treatment-seeking patients compared to patients recruited for online studies, who may not be actively seeking treatment. Auditory hallucinations may cause most distress among treatment-seeking patients. A collaborative approach including assessment of possible positive appraisals of symptoms is important when identifying treatment goals.
Medication adherence; Patient preferences; Positive symptoms; Psychosis.
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Jayashri Kulkarni et al.
Schizophrenia Research.
There is limited knowledge about the effects of antipsychotic exposure on the development of gestational diabetes mellitus (GDM) in women with mental illness. Studies have demonstrated an association between antipsychotic medications and metabolic problems such as weight gain and diabetes mellitus in non-pregnant patients with psychiatric disorders. GDM increases the risk of adverse maternal outcomes, including pregnancy-induced hypertension, antepartum and postpartum haemorrhage, and caesarean delivery. The National Register of Antipsychotic Medication in Pregnancy (NRAMP) is a prospective Australian cohort study that observed women who took antipsychotics during pregnancy. Data from 205 women were extracted for the final analysis and included women who took first or second-generation antipsychotics (FGA,SGA) during the first trimester of pregnancy (at minimum) and had a diagnosis of a psychotic disorder (n = 180). The comparison (non-exposed) group (n = 25) were women with psychosis who chose not to take any antipsychotic during the first trimester (at minimum). The comparison groups were not matched, although groups were homogenous in terms of sex, age range, diagnosis and perinatal status. The results of logistic regression analysis revealed that women who were exposed to FGAs, SGAs were seven and five times, respectively, more likely to develop GDM compared to non-exposed groups. When adjusted for confounding variables such as BMI and family history of diabetes, the potential of developing GDM decreased for women taking SGAs. In conclusion, the risk of developing GDM is lower in women taking SGAs compared with women taking FDAs. In addition, family history of diabetes and BMI adds to the risk.
Antipsychotics; Gestational diabetes mellitus (GDM); Pregnancy; Psychosis.
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Gregory Fricchione.
Schizophrenia Research.
Back in 2004, in a chapter titled “Brain Evolution and the Meaning of Catatonia”, a case was made that the syndrome’s core meaning is embedded in millions of years of vertebrate brain evolution. (Fricchione, 2004) In this update, advances over the last almost 20 years, in catatonia theory and research in particular, and pertinent neuropsychiatry in general, will be applied to this question of meaning. The approach will rely heavily on a number of thought leaders, including Nicos Tinbergen, Paul MacLean, John Bowlby, M. Marsel Mesulam, Bruce McEwen and Karl Friston. Their guidance will be supplemented with a selected survey of 21 century neuropsychiatry, neurophysiology, molecular biology, neuroimaging and neurotherapeutics as applied to the catatonic syndrome. In an attempt to address the question of the meaning of the catatonic syndrome in human life, we will employ two conceptual networks representing the intersubjectivity of the quantitative conceptual network of physical terms and the subjectivity of the qualitative conceptual network of mental and spiritual terms. In the process, a common referent providing extensional identity may emerge (Goodman, 1991). The goal of this exercise is to enhance our attunement with the experience of patients suffering with catatonia. A deeper understanding of catatonia’s origins in brain evolution and of the challenges of individual epigenetic development in the setting of environmental events coupled with appreciation of what has been described as the most painful mammalian condition, that of separation, has the potential to foster greater efforts on the part of clinicians to diagnose and treat patients who present with catatonia. In addition, in this ancient and extreme tactic, evolved to provide safety from extreme survival threat, one can speculate what is at the core of human fear and the challenge it presents to all of us. And when the biology, psychology and sociology of catatonia are examined, the nature of solutions to the challenge may emerge.
Attachment; Catatonia; Meaning; Neuro-evolution; Separation; Stress.
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Sarah I Tarbox-Berry et al.
Schizophrenia Bulletin.
Attenuated Psychosis Syndrome (APS) impacts functioning and predicts increased risk of psychosis. Risk for developing APS itself has received minimal attention. Knowledge of familial and environmental contributions to APS symptoms would advance understanding of APS and risk for psychosis. As an initial step, this report presents the first data on APS symptoms in family members of APS patients. This study utilized a discordant sibling-pair family study design. The Structured Interview for Psychosis-risk Syndromes (SIPS) was administered to 17 APS probands and 26 non-APS biological siblings. Probands and siblings were compared on positive, negative, disorganized, and general SIPS symptom scales and factors derived from those scales.
There was significantly greater symptom severity in probands compared to siblings on nine of 19 SIPS scales. Negative/anxiety, functioning, and positive symptom factors were identified. Probands showed significantly greater severity than siblings on the negative/anxiety and positive factors. Elevated pathology on the negative/anxiety factor best differentiated between probands and siblings, over and above the contribution of the positive factor. No difference was found for the functioning factor.
Results support the importance of non-familial effects on risk for APS and suggest differences in familial contribution to APS symptoms. Understanding the relative contribution of familial and environmental effects on APS symptoms may reveal important differences among APS patients, with implications for risk characterization, symptom course, and treatment selection.
APS; CHR; family study; prodrome; psychosis.
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Eric A Nelson et al.
Schizophrenia Bulletin.
Converging lines of evidence point to hippocampal dysfunction in psychosis spectrum disorders, including altered functional connectivity. Evidence also suggests that antipsychotic medications can modulate hippocampal dysfunction. The goal of this project was to identify patterns of hippocampal connectivity predictive of response to antipsychotic treatment in 2 cohorts of patients with a psychosis spectrum disorder, one medication-naïve and the other one unmedicated. We hypothesized that we would identify reliable patterns of hippocampal connectivity in the 2 cohorts that were predictive of treatment response and that medications would modulate abnormal hippocampal connectivity after 6 weeks of treatment.
We used a prospective design to collect resting-state fMRI scans prior to antipsychotic treatment and after 6 weeks of treatment with risperidone, a commonly used antipsychotic medication, in both cohorts. We enrolled 44 medication-naïve first-episode psychosis patients (FEP) and 39 unmedicated patients with schizophrenia (SZ).
In both patient cohorts, we observed a similar pattern where greater hippocampal connectivity to regions of the occipital cortex was predictive of treatment response. Lower hippocampal connectivity of the frontal pole, orbitofrontal cortex, subcallosal area, and medial prefrontal cortex was predictive of treatment response in unmedicated SZ, but not in the medication-naïve cohort. Furthermore, greater reduction in hippocampal connectivity to the visual cortex with treatment was associated with better clinical response.
Our results suggest that greater connectivity between the hippocampus and occipital cortex is not only predictive of better treatment response, but that antipsychotic medications have a modulatory effect by reducing hyperconnectivity.
antipsychotic; first-episode; hippocampus; psychosis; resting-state functional connectivity.
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Kristin Köhler-Forsberg et al.
JAMA Psychiatry.
The cerebral serotonin 4 (5-HT4) receptor is a promising novel target for treatment of major depressive disorder (MDD), and pharmacological stimulation of the 5-HT4 receptor has been associated with improved learning and memory in healthy individuals. To map the neurobiological signatures of patients with untreated MDD compared with healthy controls and to examine the association between cerebral 5-HT4 receptor binding and cognitive functions in the depressed state.
This case-control study used baseline data from the NeuroPharm clinical depression trial in Denmark. Adult participants included antidepressant-free outpatients with a current moderate to severe depressive episode and healthy controls. All participants completed positron emission tomography (PET) scanning with [11C]SB207145 for quantification of brain 5-HT4 receptor binding, but only the patients underwent cognitive testing. Data analyses were performed from January 21, 2020, to April 22, 2022.
The main study outcome was the group difference in cerebral 5-HT4 receptor binding between patients with MDD and healthy controls. In addition, the association between 5-HT4 receptor binding and verbal memory performance in the patient group was tested. Other cognitive domains (working memory, reaction time, emotion recognition bias, and negative social emotions) were assessed as secondary outcomes.
A total of 90 patients with untreated MDD (mean [SD] age, 27.1 [8.2] years; 64 women [71.1%]) and 91 healthy controls (mean [SD] age, 27.1 [8.0] years; 55 women [60.4%]) were included in the analysis. Patients with current MDD had significantly lower cerebral 5-HT4 receptor binding than healthy controls (-7.0%; 95% CI, -11.2 to -2.7; P = .002). In patients with MDD, there was a correlation between cerebral 5-HT4 receptor binding and verbal memory (r = 0.29; P = .02).
Results of this study show that cerebral 5-HT4 receptor binding was lower in patients with MDD than in healthy controls and that the memory dysfunction in patients with MDD was associated with lower cerebral 5-HT4 receptor binding. The cerebral 5-HT4 receptor is a promising treatment target for memory dysfunction in patients with MDD.
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Frederikke Hørdam Gronemann et al.
JAMA Psychiatry.
Major depression (MD) aggregates within families, but how family history of MD confers risk of MD over the life course is unclear. Such knowledge is important to identify and prevent possible depressogenic effects of family environment. To examine the association between family MD history and risk of MD including association with age, sex, type of kinship, and age of the affected family member.
This cohort study included all Danish citizens born from 1960 to 2003 with known parental identity followed up from their 15th birthday until time of MD, censoring, or December 31, 2018. Analysis took place between April 2022 and December 2022.
Family members with first-time MD using International Classification of Diseases, Eighth Revision codes 296.09, 296.29, 298.09, and 300.49 or 10th Revision codes F32.0-F33.9, family members’ age at MD onset, and individuals’ age at exposure to family MD.
Multivariable Poisson regression was applied to estimate the incidence rate ratio (IRR) with 95% CI of first-time MD.
Of 2 903 430 individuals (1 486 574 [51.2%] men), 37 970 men (2.6%) and 70 223 women (5.0%) developed MD during follow-up. For men, exposure to maternal, paternal, or full sibling MD were associated with a 2-times higher risk of MD (IRR, 2.10 [95% CI, 2.02-2.19]; IRR, 2.04 [95% CI, 1.94-2.14]; IRR, 2.08 [95% CI, 1.97-2.19]) and the associated risk increased with number of affected family members. This pattern was similar for women. For men, family members’ age at MD onset was not associated with MD. For women, maternal MD onset at 69 years or younger was associated with higher IRRs of MD (age <40 years: IRR, 1.64 [95% CI, 1.28-2.10]; age 40-49 years: IRR, 1.62 [95% CI, 1.27-2.07]; age 50-59 years: IRR, 1.56 [95% CI, 1.22-2.00]; and age 60-69 years: IRR, 1.67 [95% CI, 1.28-2.16]) compared with women with maternal MD onset at 70 years or older. For men, exposure to maternal MD younger than 30 years (age <1 year: IRR, 1.95 [95% CI, 1.70-2.25]; age 1 to <12 years: IRR, 2.31 [95% CI, 2.16-2.47]; age 12 to <19 years: IRR, 2.18 [95% CI, 2.03-2.35]; age 19 to <30 years: IRR, 1.42 [95% CI, 1.32-1.53]) was associated with increased IRRs, while exposure to maternal MD at 30 years or older was associated with a lower IRR (0.77 [95% CI, 0.70-0.85]). The findings were similar across type of kinships and for women.
In this study, risk of MD was associated with increased numbers of affected family members but did not vary by gender or type of kinship. Exposure to family MD during childhood and adolescence was associated with increased risk.
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Manu S Goyal et al.
PNAS.
The distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta (Aβ) deposition in individuals with symptomatic and preclinical Alzheimer disease (AD). Brain AG decreases with age, but the functional significance of this decrease with regard to the development of AD symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption, and glucose utilization-from which we derive AG-we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher than that seen in cognitively unimpaired, amyloid negative adults. Similar findings were not seen for blood flow nor oxygen consumption. Finally, in cognitively unimpaired adults, white matter hyperintensity burden was found to be specifically associated with decreased youthful brain AG. Our results suggest that AG may have a role in the resilience and/or response to early stages of amyloid pathology and that age-related white matter disease may impair this process.
Alzheimer’s disease; aerobic glycolysis; aging; resilience; white matter hyperintensities.
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Alfredo L Sklar et al.
Schizophrenia Bulletin.
There is growing appreciation for the contribution of sensory disruptions to disease morbidity in psychosis. The present study examined auditory cortex (AC) dynamic range: the scaling of neurophysiological responses to stimulus intensity, among individuals with a schizophrenia spectrum illness (FESz) and its relationship to clinical outcomes at disease onset. Magnetoencephalography (MEG) was recorded from 35 FESz and 40 healthy controls (HC) during binaural presentation of tones at three intensities (75 dB, 80 dB, and 85 dB). MRIs were obtained to enhance cortical localization of MEG sensor-level activity. All participants completed the MATRICS cognitive battery (MCCB) and Global Functioning: Role and Social scales (GFR/GFS). Patients were administered the Positive and Negative Syndrome Scale (PANSS).
FESz exhibited reduced AC response relative to HC. Enhancement of AC activity to tones of increasing intensity was blunted in FESz relative to HC. Reduced dynamic range (85-75 dB AC response) was associated with lower GFS (r = .58) and GFR (r = .45) scores, worse MCCB performance (r = .45), and increased PANSS Negative symptom subscale scores (r = -.55) among FESz, relationships not observed with AC responses to individual tones.
Beyond an impaired AC response to pure tones, FESz exhibit reduced dynamic range relative to HC. This impairment was correlated with markers of disease morbidity including poorer community functioning as well as cognitive and negative symptoms. The relationship with impaired social functioning may reflect the role of AC dynamic range in decoding the emotional content of language and highlights its importance to future therapeutic sensory remediation protocols.
auditory processing; first episode psychosis; magnetoencephalography; psychometric function; social functioning; sound intensity.
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Yongsheng Zhu et al.
Cell.
Dysregulation of the immune system is a cardinal feature of opioid addiction. Here, we characterize the landscape of peripheral immune cells from patients with opioid use disorder and from healthy controls. Opioid-associated blood exhibited an abnormal distribution of immune cells characterized by a significant expansion of fragile-like regulatory T cells (Tregs), which was positively correlated with the withdrawal score. Analogously, opioid-treated mice also showed enhanced Treg-derived interferon-γ (IFN-γ) expression. IFN-γ signaling reshaped synaptic morphology in nucleus accumbens (NAc) neurons, modulating subsequent withdrawal symptoms. We demonstrate that opioids increase the expression of neuron-derived C-C motif chemokine ligand 2 (Ccl2) and disrupted blood-brain barrier (BBB) integrity through the downregulation of astrocyte-derived fatty-acid-binding protein 7 (Fabp7), which both triggered peripheral Treg infiltration into NAc. Our study demonstrates that opioids drive the expansion of fragile-like Tregs and favor peripheral Treg diapedesis across the BBB, which leads to IFN-γ-mediated synaptic instability and subsequent withdrawal symptoms.
interferon-γ; opioid; regulatory T cell; synaptic plasticity; withdrawal symptom.
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Samuel Tromans et al.
The British Journal of Psychiatry.
The draft Mental Health Bill, which amends the Mental Health Act 1983 for England and Wales, proposes protections for people with intellectual disability and/or autism (ID/A) to prevent detention in hospital in the absence of mental illness. This editorial critically appraises the positive impact and unintended consequences of the proposed reforms for people with ID/A.
Mental Health Act; autism; equality; intellectual disability; mental health law.
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Katie L Andrews et al.
Canadian Journal of Psychiatry.
Royal Canadian Mounted Police (RCMP) report extremely frequent and varied exposures to potentially psychologically traumatic events (PPTEs). While occupational exposures to PPTEs may be one explanation for the symptoms of mental disorders prevalent among serving RCMP, exposures occurring prior to service may also play a role. The objective of the current study was to provide estimates of lifetime PPTE exposures among RCMP cadets in training and assess for associations with mental disorders or sociodemographic variables. RCMP cadets (n = 772; 72.0% male) beginning the Cadet Training Program (CTP) completed a survey assessing self-reported PPTE exposures as measured by the Life Events Checklist for the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition-Extended. Binomial tests were conducted to compare the current results to previously collected data from the general population, a diverse sample of public safety personnel (PSP) and serving RCMP.
Cadets reported statistically significantly fewer PPTE exposures for all PPTE types than serving RCMP (all p’s < 0.001) and PSP (all p’s < 0.001) but more PPTE exposures for all PPTE types than the general population (all p’s < 0.001). Cadets also endorsed fewer PPTE types (6.00 ± 4.47) than serving RCMP (11.64 ± 3.40; p < 0.001) and other PSP (11.08 ± 3.23) but more types than the general population (2.31 ± 2.33; p < 0.001). Participants who reported being exposed to any PPTE type reported the exposures occurred 1-5 times (29.1% of participants), 6-10 times (18.3%) or 10 + times (43.1%) before starting the CTP. Several PPTE types were associated with positive screens for one or more mental disorders. There were associations between PPTE types and increased odds of screening positive for post-traumatic stress disorder (PTSD), major depressive disorder (MDD), generalized anxiety disorder (GAD) and social anxiety disorder (SAD) (all p’s < 0.05). Serious transport accident (11.1%), physical assault (9.5%) and sudden accidental death (8.4%) were the PPTEs most identified as the worst event, and all were associated with positive screens for one or more mental disorders.
The current results provide the first information describing PPTE histories of cadets, evidencing exposure frequencies and types much higher than the general population. PPTE exposures may have contributed to the cadet’s vocational choices. The current results support the growing evidence that PPTEs can be associated with diverse mental disorders; however, the results also suggest cadets may be uncommonly resilient, based on how few screened positive for mental disorders, despite reporting higher frequencies of PPTE exposures prior to CTP than the general population.
critical incident; mental disorders; police; post-traumatic stress injury (PTSI); public safety personnel.
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Sheng Chen et al.
Canadian Journal of Psychiatry.
This study aimed to provide a general overview of mental health randomized controlled trials (RCTs) and summarize the temporal trends in terms of the number of studies, median sample sizes, and median effect sizes using data collected from the Cochrane Database of Systematic Reviews (CDSR). Using data collected from the CDSR, the temporal trends are compared in terms of the number of studies, median sample sizes, and median effect sizes between two broad categories of interventions: pharmacological RCT (ph-RCT) and non-pharmacological RCT (nph-RCT), and in conjunction with major mental disorder categories.
Chronologically, the number of mental health RCTs reported in publications has increased exponentially from 1955 to 2020. While ph-RCT comprised a majority of mental health RCTs in the earlier years, the proportion of nph-RCTs increased more quickly over time and markedly exceeded ph-RCT after 2010. The median sample size for all 6,652 mental health RCTs was 61, with 61 for ph-RCT and 60 for nph-RCT. Over time, the median fluctuated but an increasing trend was observed over the past 60+ years. The median of the effect size, measured by Pearson’s r, for overall RCTs was 0.18, and nph-RCT (0.19) had a larger median effect size compared to ph-RCT (0.16). Over the years, the nph-RCT had a larger median effect size than the ph-RCT. Differences in the median effect sizes among the categories of mental disorders were also noted. Schizophrenia had the most RCTs, with a median Pearson’s r value of 0.17. Mood disorder had the second largest number of RCTs and a median Pearson’s r value of 0.15. Neurotic/stress-related mental disorder had the third largest number of RCTs with the highest median Pearson’s r being 0.23.
This study provides meaningful information and filled the knowledge gap in mental health RCTs.
effect size; mental health; non-pharmacological interventions; pharmacological interventions; randomized controlled trial.
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Srividya N Iyer et al.
Canadian Journal of Psychiatry.
Most cross-cultural psychosis research has focused on a limited number of outcomes (generally symptom-related) and perspectives (often clinician-/observer-rated). It is unknown if the purported superior outcomes for psychosis in some low- and middle-income countries extend to patient-reported measures of social, recreational, and independent functioning. Addressing this gap, this study aimed to compare these outcomes in first-episode psychosis at a high-income site and a lower middle-income site. Patients receiving similarly designed early intervention for psychosis in Chennai, India (N = 164) and Montreal, Canada (N = 140) completed the self-reported Social Functioning Scale-Early Intervention, which measures prosocial, recreation, and independence-performance functioning. Their case managers rated expected independence-performance functioning. Both sets of assessments were done at entry and Months 6, 18, and 24. Linear mixed model analyses of differences between sites and over time were conducted, accounting for other pertinent variables, especially negative symptoms.
Linear mixed models showed that prosocial, recreation, and independence-performance functioning scores were significantly higher in Montreal than Chennai and did not change over time. Expected independence-performance was also higher in Montreal and increased over time. Negative symptoms and education independently predicted prosocial, recreation, and expected independence-performance functioning. When added to the model, expected independence-performance predicted actual independence-performance and site was no longer significant. At both sites, prosocial and recreation scores were consistently lower (<40%) than independence-performance (40-65%).
This is the first cross-cultural investigation of prosocial, recreation, and independent functioning in early psychosis. It demonstrates that these outcomes differ by socio-cultural context. Differing levels of expectations about patients, themselves shaped by cultural, illness, and social determinants, may contribute to cross-cultural variations in functional outcomes. At both sites, social, recreational, and independent functioning were in the low-to-moderate range and there was no improvement over time, underscoring the need for effective interventions specifically designed to impact these outcomes.
LMICs; cross-cultural; early intervention; first-episode psychosis; functioning; leisure; recreation; social.
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Yiguo Qiu et al.
PNAS.
Alzheimer’s disease (AD) is the most common form of incurable dementia and represents a critical public health issue as the world’s population ages. Although microglial dysregulation is a cardinal feature of AD, the extensive heterogeneity of these immunological cells in the brain has impeded our understanding of their contribution to this disease. Here, we identify a pathogenic microglial subset which expresses the CD11c surface marker as the sole producer of Osteopontin (OPN) in the 5XFAD mouse model of AD. OPN production divides Disease-Associated Microglia (DAM) into two functionally distinct subsets, i.e., a protective CD11c microglia correlate strongly with the degree of cognitive deficit and AD neuropathology. These findings define an OPN-dependent pathway to disease driven by a distinct microglial subset, and identify OPN as a novel therapeutic target for potentially effective immunotherapy to treat AD.
Alzheimer’s disease; Osteopontin; integrins; microglia; neuroinflammation.
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Manuel Canal-Rivero et al.
Schizophrenia Research.
A high Coronavirus Disease 19 (COVID-19) morbidity and mortality have been reported among users and workers of long-term care facilities. The main objective of this work was to explore the prevalence and temporal pattern of COVID-19 in comprehensive network of long-term mental health facilities in Spain. Secondly, we aimed to estimate the effect of having a severe mental health diagnosis on prevalence and COVID-19 outcomes. A cohort of 2552 participants were followed-up over a one-year. Sociodemographic and clinical data related to COVID-19 were recollected using a proforma. Frequency analyses were used to determine the prevalence of COVID-19 disease. Multivariable binary regression models sequentially adjusted by gender and age were employed to explore the potential role of severe mental health diagnosis on COVID-19 outcomes.
Workers had higher risk of testing positive than mental health users (odds ratio [OR] 1.57 [95 % CI 1.01-2.43; p < 0.05] who presented an equivalent risk of testing positive after accounting for age and gender (OR 1.62 [95 % CI 0.98-2.66; p = 0.06].
The significant lower prevalence of COVID-19 among mental health users could be explained by the measures implemented to prevent COVID-19 as well as by the possible role that antipsychotic treatment could play in the prevention of SARS-CoV-2 infection.
COVID-19; Mental health; Mental health long-term facilities; SARS-CoV-2.
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Jolan Nisbet et al.
Canadian Journal of Psychiatry.
Royal Canadian Mounted Police (RCMP) report diverse occupational stressors and repeated exposures to potentially psychologically traumatic events, which may increase the odds of screening positive for a mental disorder, and increase the risk of death by suicide. The current study was designed to provide prevalence information regarding suicidal behaviours (i.e., ideation, planning, attempts) and assess for sociodemographic differences among cadets at the start of the RCMP Cadet Training Program (CTP). Cadets (n = 736, 74.0% male) were administered the structured Mini International Neuropsychiatric Interview by a mental health clinician or a supervised clinical psychologist trainee. The interview includes an assessment of past month suicidal ideation, planning, attempts and lifetime suicide attempts.
Within 1 month of starting the CTP, a small percentage of cadets reported past month suicidal ideation (1.6%) and no cadets reported any suicidal planning (0%) or attempts (0%). Lifetime suicide attempts were reported by (1.5%) of cadets.
The current results provide the first information describing the prevalence of suicidal ideation, planning, and attempts among RCMP cadets starting the CTP. The estimates of suicidal behaviours appear lower than the general population and lower than reports from serving RCMP. Higher prevalence estimates of suicidal behaviours reported by serving RCMP, relative to lower estimates among cadets starting the CTP in the current study, may be related to age, cumulative experiences or protracted exposures to operational and organizational stressors, rather than insufficient screening of recruits.
RCMP; mental health; police cadets; public safety personnel; suicide.
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J M M Bayer et al.
Schizophrenia Research.
Psychotic symptoms are typically measured using clinical ratings, but more objective and sensitive metrics are needed. Hence, we will assess thought disorder using the Research Domain Criteria (RDoC) heuristic for language production, and its recommended paradigm of “linguistic corpus-based analyses of language output”. Positive thought disorder (e.g., tangentiality and derailment) can be assessed using word-embedding approaches that assess semantic coherence, whereas negative thought disorder (e.g., concreteness, poverty of speech) can be assessed using part-of-speech (POS) tagging to assess syntactic complexity. We aim to establish convergent validity of automated linguistic metrics with clinical ratings, assess normative demographic variance, determine cognitive and functional correlates, and replicate their predictive power for psychosis transition among at-risk youths. This study will assess language production in 450 English-speaking individuals in Australia and Canada, who have recent onset psychosis, are at clinical high risk (CHR) for psychosis, or who are healthy volunteers, all well-characterized for cognition, function and symptoms. Speech will be elicited using open-ended interviews. Audio files will be transcribed and preprocessed for automated natural language processing (NLP) analyses of coherence and complexity. Data analyses include canonical correlation, multivariate linear regression with regularization, and machine-learning classification of group status and psychosis outcome.
This prospective study aims to characterize language disturbance across stages of psychosis using computational approaches, including psychometric properties, normative variance and clinical correlates, important for biomarker development. SPEAK will create a large archive of language data available to other investigators, a rich resource for the field.
Latent semantic analysis; Natural language processing; Part-of-speech-tagging; Psychosis; Thought disorder; Ultra/clinical high risk.
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Richard Morriss et al.
Lancet Psychiatry.
Randomised sham-controlled trials of cranial electrostimulation with the Alpha-Stim Anxiety Insomnia and Depression (AID) device have reported improved anxiety and depression symptoms; however, no adequately powered sham-controlled trials in major depression are available. We investigated whether active Alpha-Stim AID is superior to sham Alpha-Stim AID in terms of clinical effectiveness for depression symptoms in major depression. The Alpha-Stim-D trial was a multicentre, parallel group, double-blind, randomised controlled trial, recruiting participants from 25 primary care centres in two regions in England, UK. Eligible participants were aged 16 years or older with a current diagnosis of primary major depression, a score of 10-19 on the nine-item Patient Health Questionnaire, and had been offered or prescribed and reported taking antidepressant medication for at least 6 weeks in the previous 3 months. Main exclusion criteria were contraindications to Alpha-Stim AID device use, having persistent suicidal ideation or self-harm, neurological conditions, a substance use disorder or dependence, an eating disorder, bipolar disorder, or non-affective psychosis, or receiving psychological treatment in the past 3 months. Eligible participants were randomly assigned (1:1, minimised by region, anxiety disorder, and antidepressant use) to 1 h daily use of active (100 μA) or sham Alpha-Stim AID treatment for 8 weeks. Randomisation was via an independent web-based system, with participants, outcome assessors, and data analyst masked to treatment assignment. The primary outcome was change from baseline in score on the 17-item Hamilton Depression Rating Scale (HDRS-17, GRID version) at 16 weeks after randomisation, with participants analysed by intention to treat (ITT; all randomly assigned participants). Safety was assessed in all randomly assigned participants. The trial is registered with the ISRCTN registry (ISRCTN11853110); status completed.
Between Sept 8, 2020, and Jan 14, 2022, 236 eligible participants were randomly assigned to active or sham Alpha-Stim AID (n=118 each). 156 (66%) participants were women, 77 (33%) were men, and three (1%) self-reported as other gender; 200 (85%) were White British or Irish; and the mean age was 38·0 years (SD 15·3; range 16-83). 102 (86%) participants in the active Alpha-Stim AID group and 98 (83%) in the sham group were followed up 16 weeks after randomisation. In the ITT population, mean change in GRID-HDRS-17 at 16 weeks was -5·9 (95% CI -7·1 to -4·8) in the active Alpha-Stim AID group and -6·5 (-7·7 to -5·4) in the sham group (mean change difference -0·6 [95% CI -1·0 to 2·2], p=0·46). Among the 236 participants, 17 adverse events were reported in 17 (7%) participants (nine [8%] participants in the active Alpha-Stim AID group; and eight [7%] participants in the sham group). One serious adverse event of suicidal ideation leading to hospitalisation was reported in the sham group, which was judged to be unrelated to the device.
Active Alpha-Stim AID was safe and acceptable, but no more clinically effective than sham Alpha-Stim AID in major depression.
National Institute for Health Research Applied Research Collaboration East Midlands and Electromedical Products International.
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Nousayhah Amdanee et al.
Schizophrenia Bulletin.
Antipsychotics (APs), the cornerstone of schizophrenia treatment, confer a relatively high risk of constipation. However, the mechanisms underpinning AP-induced constipation are poorly understood. Thus, we hypothesized that (1) schizophrenia patients with AP-induced constipation have distinct metabolic patterns; (2) there is more than one mechanism at play in producing this adverse drug effect; and (3) AP-associated changes in the gut microbiome are related to the altered metabolic profiles. Eighty-eight schizophrenia patients, including 44 with constipation (C) and 44 matched patients without constipation (NC), were enrolled in this study. Constipation was diagnosed by Rome IV criteria for constipation and colonic transit time using radiopaque markers (ROMs) while severity was evaluated with the Bristol Stool Form Scale (BSS) and Constipation Assessment Scale (CAS). Fasting blood samples were drawn from all participants and were subjected to non-targeted liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis.
Eleven metabolites were significantly altered in AP-induced constipation which primarily disturbed sphingolipid metabolism, choline metabolism, and sphingolipid signaling pathway (P value < .05, FDR < 0.05). In the C group, changes in the gut bacteria showed a certain degree of correlation with 2 of the significantly altered serum metabolites and were associated with alterations in choline metabolism.
Our findings indicated that there were disturbances in distinct metabolic pathways that were associated with AP-induced constipation. In addition, this study presents evidence of a link between alterations in the gut microbiome and host metabolism which provides additional mechanistic insights on AP-induced constipation.
antipsychotics; constipation; gastrointestinal hypomotility; mechanism; metabolomics; schizophrenia.
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Josef Isung et al.
JAMA Psychiatry.
Maternal immune activation (MIA) leading to altered neurodevelopment in utero is a hypothesized risk factor for psychiatric outcomes in offspring. Primary antibody immunodeficiencies (PIDs) constitute a unique natural experiment to test the MIA hypothesis of mental disorders. To assess the association of maternal and paternal PIDs with psychiatric disorders and suicidal behavior in offspring.
Cohort study of 4 294 169 offspring of parents with and without PIDs living in Sweden at any time between 1973 and 2013. Data were extracted from Swedish nationwide health and administrative registers and were analyzed from May 5 to September 30, 2022. All individuals with diagnoses of PIDs identified between 1973 and 2013 from the National Patient Register were included. Offspring were included if born before 2003. Parent-offspring pairs in which both parents had a history of PIDs were excluded.
Lifetime records of parental PIDs according to the International Classification of Diseases, Eighth Revision (ICD-8); International Classification of Diseases, Ninth Revision (ICD-9); and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes.
Lifetime records of 10 psychiatric disorders and suicidal behavior identified using ICD-8, ICD-9, and ICD-10 diagnostic codes, including suicide attempts and death by suicide, among offspring. Covariates included sex, birth year, parental psychopathology, suicide attempts, and autoimmune diseases. Additional analyses excluded offspring with their own PIDs and autoimmune diseases. Poisson regression models were fitted separately for mothers and fathers to estimate incidence rate ratios (IRRs) and 95% CIs for the risk of psychiatric and suicidal behavior outcomes in the offspring of PID-exposed vs PID-unexposed mothers or fathers.
The cohort included 4 294 169 offspring (2 207 651 males [51.4%]) and 3 954 937 parents (1 987 972 females [50.3%]). A total of 7270 offspring (0.17%) had parents with PIDs, and 4 286 899 offspring had parents without PIDs. In fully adjusted models, offspring of mothers with PIDs had an increased risk of any psychiatric disorder, while no such risks were observed in offspring of fathers with PIDs (IRR, 1.17; 95% CI, 1.10-1.25 vs IRR, 1.03; 95% CI, 0.94-1.14; P < .001). Likewise, an increased risk of suicidal behavior was observed among offspring of mothers with PIDs but not offspring of fathers with PIDs (IRR, 1.20; 95% CI, 1.06-1.36 vs IRR, 1.10; 95% CI, 0.91-1.34; P = .01). For the offspring of mothers with PIDs, the risk of developing any psychiatric disorder was significantly higher for those with mothers with 6 of 10 individual disorders, with IRRs ranging from 1.15 (95% CI, 1.04-1.26) for anxiety and stress-related disorders and 1.15 (95% CI, 1.03-1.30) for substance use disorders to 1.71 (95% CI, 1.37-2.14) for bipolar disorders. Offspring of mothers with both PIDs and autoimmune diseases had the highest risk for any psychiatric disorder (IRR, 1.24; 95% CI, 1.11-1.38) and suicidal behavior (IRR, 1.44; 95% CI, 1.17-1.78).
Findings of this cohort study suggest that maternal, but not paternal, PIDs were associated with a statistically significant increased risk of psychiatric disorders and suicidal behavior in the offspring, particularly when PIDs co-occur with autoimmune diseases. These findings align with the MIA hypothesis of mental disorders, but the precise mechanisms remain to be elucidated.
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Teng Yang et al.
JAMA Psychiatry.
Air pollution is increasingly recognized as an important environmental risk factor for mental health. However, epidemiologic evidence on long-term exposure to low levels of air pollutants with incident depression and anxiety is still very limited. To investigate the association of long-term joint exposure to multiple air pollutants with incident depression and anxiety.
This prospective, population-based cohort study used data from the UK Biobank. The participants were recruited between March 13, 2006, and October 1, 2010, and included individuals who had never been diagnosed with depression or anxiety at baseline and had full information on exposure and covariates. Data were analyzed from May 1 to October 10, 2022.
Annual mean air pollution concentrations of particulate matter (PM) with aerodynamic diameter of 2.5 μm or less (PM2.5) and PM with aerodynamic diameter between 2.5 μm and 10 μm (PM2.5-10). Nitrogen dioxide (NO2) and nitric oxide (NO) were estimated for each participant’s residential address using the land use regression model, and joint exposure to air pollution reflected by air pollution score was calculated by principal components analysis.
Incidence of diagnosed depression (F32-F33) and anxiety (F40-F48) were ascertained with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes.
During a median (IQR) follow-up of 10.9 (10.1-11.6) years, among 389 185 participants (mean [SD] age, 56.7 [8.1] years, 205 855 female individuals [52.9%]), a total of 13 131 and 15 835 patients were diagnosed with depression and anxiety, respectively. The median (IQR) concentration of pollutants was as follows: PM2.5, 9.9 (9.3-10.6) μg/m3; PM2.5-10, 6.1 (5.8-6.6) μg/m3; NO2, 26.0 (21.3-31.1) μg/m3; and NO, 15.9 (11.6-20.6) μg/m3. Long-term estimated exposure to multiple air pollutants was associated with increased risk of depression and anxiety, and the exposure-response curves were nonlinear, with steeper slopes at lower concentrations and plateauing trends at higher exposure. The hazard ratios (HRs) and 95% CIs for depression and anxiety were 1.16 (95% CI, 1.09-1.23; P < .001) and 1.11 (95% CI, 1.05-1.17; P < .001) in the highest quartile compared with the lowest quartile of air pollution score, respectively. Similar trends were shown for PM2.5, NO2, and NO. Subgroup analysis showed the association between PM2.5 and anxiety tended to be higher in male individuals than in female individuals (quartile 4: male individuals, 1.18; 95% CI, 1.08-1.29; female individuals, 1.07; 95% CI, 1.00-1.14; P = .009).
Study results suggest that estimates of long-term exposure to multiple air pollutants was associated with increased risk of depression and anxiety. The nonlinear associations may have important implications for policy making in air pollution control. Reductions in joint exposure to multiple air pollutants may alleviate the disease burden of depression and anxiety.
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Kenneth S Kendler et al.
JAMA Psychiatry.
We know little about the transmission of obsessive-compulsive disorder (OCD) across generations. To evaluate the sources of parent-offspring transmission of OCD and familial cross-generational association with more typical anxiety disorders.
This Swedish population register-based study analyzed data for offspring born in Sweden from 1960 to 1995 from the following 4 family types: intact, not-lived-with biological father, lived-with stepfather, and adoptive. Follow-up occurred on December 31, 2018, and data were analyzed from April 6, 2022, to September 26, 2022.
Three sources of parent-offspring resemblance: genes plus rearing, genes only, and rearing only.
Diagnoses of OCD, all anxiety disorders, generalized anxiety disorder (GAD), social phobia, and panic disorder were obtained from national inpatient, outpatient, and primary care medical registers. Parent-child resemblance was assessed by tetrachoric correlation (r).
The offspring population consisted of 2 413 128 individuals; mean (SD) age at follow-up was 40.2 (10.7) years, 1 258 670 individuals (52.2%) were male, and 1 154 458 individuals (47.8%) were female. For each type of parent-child relationship, the best-estimate correlation for OCD for genes plus rearing was 0.19 (95% CI, 0.17 to 0.20); genes only, 0.18 (95% CI, 0.11 to 0.24); and rearing only, 0.04 (95% CI, -0.10 to 0.19). From bivariate adoption analyses, the cross-generational genetic correlations between OCD with anxiety disorder diagnostic categories were estimated as follows: for all anxiety disorders, 0.62 (95% CI, 0.46 to 0.77); GAD, 0.87 (95% CI, 0.53 to 1.00); social phobia, 0.70 (95% CI, 0.31 to 1.00); and panic disorder, 0.47 (95% CI, 0.20 to 0.73).
This Swedish population register-based study found that OCD was transmitted from parents to children largely through a genetic relationship, with rearing playing a minor role. Viewed cross-generationally, OCD and anxiety disorders were moderately genetically correlated, with the genetic correlations strongest between OCD and GAD, intermediate for OCD and social phobia, and weakest between OCD and panic disorder. These genetic correlations were modestly attenuated when diagnostic hierarchies were imposed before analysis.
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Lisa Dinkler et al.
JAMA Psychiatry.
Avoidant restrictive food intake disorder (ARFID) is characterized by an extremely limited range and/or amount of food eaten, resulting in the persistent failure to meet nutritional and/or energy needs. Its etiology is poorly understood, and knowledge of genetic and environmental contributions to ARFID is needed to guide future research. To estimate the extent to which genetic and environmental factors contribute to the liability to the broad ARFID phenotype.
This nationwide Swedish twin study includes 16 951 twin pairs born between 1992 and 2010 whose parents participated in the Child and Adolescent Twin Study in Sweden (CATSS) at twin age 9 or 12 years. CATSS was linked to the National Patient Register (NPR) and the Prescribed Drug Register (PDR). Data were collected from July 2004 to April 2020, and data were analyzed from October 2021 to October 2022.
From CATSS, NPR, and PDR, all parent reports, diagnoses, procedures, and prescribed drugs that were relevant to the DSM-5 ARFID criteria were extracted when twin pairs were aged 6 to 12 years and integrated into a composite measure for the ARFID phenotype (ie, avoidant/restrictive eating with clinically significant impact, such as low weight or nutritional deficiency, and with fear of weight gain as an exclusion). In sensitivity analyses, autism and medical conditions that could account for the eating disturbance were controlled for. Univariate liability threshold models were fitted to estimate the relative contribution of genetic and environmental variation to the liability to the ARFID phenotype.
Of 33 902 included children, 17 151 (50.6%) were male. A total of 682 children (2.0%) with the ARFID phenotype were identified. The heritability of ARFID was 0.79 (95% CI, 0.70-0.85), with significant contributions from nonshared environmental factors (0.21; 95% CI, 0.15-0.30). Heritability was very similar when excluding children with autism (0.77; 95% CI, 0.67-0.84) or medical illnesses that could account for the eating disturbance (0.79; 95% CI, 0.70-0.86).
Prevalence and sex distribution of the broad ARFID phenotype were similar to previous studies, supporting the use of existing epidemiological data to identify children with ARFID. This study of the estimated genetic and environmental etiology of ARFID suggests that ARFID is highly heritable, encouraging future twin and molecular genetic studies.
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Rongguang Wang et al.
PNAS.
Despite the great promise that machine learning has offered in many fields of medicine, it has also raised concerns about potential biases and poor generalization across genders, age distributions, races and ethnicities, hospitals, and data acquisition equipment and protocols. In the current study, and in the context of three brain diseases, we provide evidence which suggests that when properly trained, machine learning models can generalize well across diverse conditions and do not necessarily suffer from bias. Specifically, by using multistudy magnetic resonance imaging consortia for diagnosing Alzheimer’s disease, schizophrenia, and autism spectrum disorder, we find that well-trained models have a high area-under-the-curve (AUC) on subjects across different subgroups pertaining to attributes such as gender, age, racial groups and different clinical studies and are unbiased under multiple fairness metrics such as demographic parity difference, equalized odds difference, equal opportunity difference, etc. We find that models that incorporate multisource data from demographic, clinical, genetic factors, and cognitive scores are also unbiased. These models have a better predictive AUC across subgroups than those trained only with imaging features, but there are also situations when these additional features do not help.
MRI; algorithmic bias; heterogeneity; machine learning; neuroscience.
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Nathalie M Dumornay et al.
American Journal of Psychiatry.
Black Americans in the United States are disproportionately exposed to childhood adversity compared with White Americans. Such disparities may contribute to race-related differences in brain structures involved in regulating the emotional response to stress, such as the amygdala, hippocampus, and prefrontal cortex (PFC). The authors investigated neuroanatomical consequences of racial disparities in adversity. The sample included 7,350 White American and 1,786 Black American children (ages 9-10) from the Adolescent Brain Cognitive Development Study (public data release 2.0). Structural MRI data, parent and child self-reports of adversity-related measures, and U.S. Census neighborhood data were used to investigate the relationship between racial disparities in adversity exposure and race-related differences in brain structure.
Black children experienced more traumatic events, family conflict, and material hardship on average compared with White children, and their parents or caregivers had lower educational attainment, lower income, and more unemployment compared with those of White children. Black children showed lower amygdala, hippocampus, and PFC gray matter volumes compared with White children. The volumes of the PFC and amygdala, but not the hippocampus, also varied with metrics of childhood adversity, with income being the most common predictor of brain volume differences. Accounting for differences in childhood adversity attenuated the magnitude of some race-related differences in gray matter volume.
The results suggest that disparities in childhood adversity contribute to race-related differences in gray matter volume in key brain regions associated with threat-related processes. Structural alterations of these regions are linked to cognitive-affective dysfunction observed in disorders such as posttraumatic stress disorder. More granular assessments of structural inequities across racial/ethnic identities are needed for a thorough understanding of their impact on the brain. Together, the present findings may provide insight into potential systemic contributors to disparate rates of psychiatric disease among Black and White individuals in the United States.
Adversity; Brain Structure; MRI; Neuroimaging; Race Disparities; Racism; Sociopolitical Issues; Stress.
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Alison C Leslie et al.
Schizophrenia Bulletin.
Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia with an estimated prevalence of 1/10,000. Schizophrenia and Autism spectrum disorder (ASD) have shared phenotypic features and shared genetic etiology. There is growing research surrounding the co-occurrence of psychomotor syndromes like catatonia with neurodevelopmental disorders like ASD or psychiatric disorders like schizophrenia. In 2013, Shorter and Wachtel described a phenomenon of the ‘Iron Triangle’ where COS, ASD, and catatonia often co-occur. The Iron Triangle theory is based on observation of historical case literature, which showed that all three diagnoses in the Iron Triangle were routinely assigned to children and adolescents. The pattern of this “Iron Triangle” suggests there may be a single underlying pathology resulting in a unique mixed form of catatonia, autism, and psychosis. We describe the case of a boy with sequential development of COS, ASD, and catatonia who also has syndromic facial and musculoskeletal features. This case highlights overlapping diagnostic features of these three disorders and can help us better understand how “hidden” features of catatonia may occur in patients with COS or ASD but go unrecognized, because they are grouped as features under autism/schizophrenia rather than a distinct diagnosis of catatonia. Further study is warranted to elucidate if this phenotypic pattern constitutes a new single diagnosis that is not well understood, an endophenotype of schizophrenia, or if this is the result of phenomenological overlap between catatonia, ASD, and COS.
Autism spectrum disorder (ASD); catatonia/schizophrenia; childhood-onset schizophrenia (COS).
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Review
Judith A Paice et al.
Journal of Clinical Oncology.
To provide guidance on the use of opioids to manage pain from cancer or cancer treatment in adults. A systematic review of the literature identified systematic reviews and randomized controlled trials of the efficacy and safety of opioid analgesics in people with cancer, approaches to opioid initiation and titration, and the prevention and management of opioid adverse events. PubMed and the Cochrane Library were searched from January 1, 2010, to February 17, 2022. American Society of Clinical Oncology convened an Expert Panel to review the evidence and formulate recommendations.
The evidence base consisted of 31 systematic reviews and 16 randomized controlled trials. Opioids have primarily been evaluated in patients with moderate-to-severe cancer pain, and they effectively reduce pain in this population, with well-characterized adverse effects. Evidence was limited for several of the questions of interest, and the Expert Panel relied on consensus for these recommendations or noted that no recommendation could be made at this time.
Opioids should be offered to patients with moderate-to-severe pain related to cancer or active cancer treatment unless contraindicated. Opioids should be initiated PRN (as needed) at the lowest possible dose to achieve acceptable analgesia and patient goals, with early assessment and frequent titration. For patients with a substance use disorder, clinicians should collaborate with a palliative care, pain, and/or substance use disorder specialist to determine the optimal approach to pain management. Opioid adverse effects should be monitored, and strategies are provided for prevention and management.Additional information is available at www.asco.org/supportive-care-guidelines.
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Inge Winter-van Rossum et al.
Lancet Psychiatry.
Schizophrenia is a severe psychiatric disorder with periods of remission and relapse. As discontinuation of antipsychotic medication is the most important reason for relapse, long-term maintenance treatment is key. Whether intramuscular long-acting (depot) antipsychotics are more efficacious than oral medication in preventing medication discontinuation is still unresolved. We aimed to compare time to all-cause discontinuation in patients randomly allocated to long-acting injectable (LAI) versus oral medication. EULAST was a pragmatic, randomised, open-label trial conducted at 50 general hospitals and psychiatric specialty clinics in 15 European countries and Israel. Patients aged 18 years and older, with DSM-IV schizophrenia (as confirmed by the Mini International Neuropsychiatric Interview 5 plus) and having experienced their first psychotic episode from 6 months to 7 years before screening, were randomly allocated (1:1:1:1) using block randomisation to LAI paliperidone, LAI aripiprazole, or the respective oral formulations of these antipsychotics. Randomisation was stratified by country and duration of illness (6 months up to 3 years vs 4 to 7 years). Patients were followed up for up to 19 months. The primary endpoint was discontinuation, regardless of the reason, during 19 months of treatment. We used survival analysis to assess the time until all-cause discontinuation in the intention-to-treat (ITT) group, and per protocol analyses were also done. This trial is registered with ClinicalTrials.gov, NCT02146547, and is complete.
Between Feb 24, 2015, and Dec 15, 2018, 533 individuals were recruited and assessed for eligibility. The ITT population included 511 participants, with 171 (33%) women and 340 (67%) men, and a mean age of 30·5 (SD 9·6) years. 410 (80%) of 511 participants were White, 35 (7%) were Black, 20 (4%) were Asian, and 46 (9%) were other ethnicity. In the combined oral antipsychotics treatment group of 247 patients, 72 (29%) patients completed the study and 175 (71%) met all-cause discontinuation criteria. In the combined LAI treatment arm of 264 patients, 95 (36%) completed the study and 169 (64%) met the all-cause discontinuation criteria. Cox regression analyses showed that treatment discontinuation for any cause did not differ between the two combined treatment groups (hazard ration [HR] 1·16, 95% CI 0·94-1·43, p=0·18). No significant difference was found in the time to all-cause discontinuation between the combined oral and combined LAI treatment groups (log rank test χ=1·87 [df 1]; p=0·17). During the study, 121 psychiatric hospitalisations occurred in 103 patients, and one patient from each of the LAI groups died; the death of the patient assigned to paliperidone was assessed to be unrelated to the medication, but the cause of other patient’s death was not shared with the study team. 86 (25%) of 350 participants with available data met akathisia criteria and 70 (20%) met parkinsonism criteria at some point during the study.
We found no substantial advantage for LAI antipsychotic treatment over oral treatment regarding time to discontinuation in patients with early-phase schizophrenia, indicating that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice.
Lundbeck and Otsuka.
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Review
Manas K Mandal et al.
Schizophrenia Research.
Impaired ability to recognize emotion in other’s face (decoding) or to express emotion through the face (encoding) are considered critical in schizophrenia. The topic of research draws considerable attention since clinicians rely heavily on the patient’s facial expressions for diagnosis and on the patient’s ability to understand the clinician’s communicative intent. While most researchers argue in favor of a generalized emotion deficit, others indicate an emotion-specific deficit in schizophrenia. An early review (Mandal et al., 1998) indicated a possible breakdown in perception-expression-experience link of emotion; later reviews (Kohler et al., 2010; Chan et al., 2010) pointed to a generalized emotion processing deficit due to perceptual deficits in schizophrenia. The present review (2010-2022) revisits this controversy with 47 published studies (37 decoding, 10 encoding) conducted on 2364 patients in 20 countries. Schizophrenia is characterized by reduced emotion processing ability, especially with negative symptoms and at an acute state of illness. It is however still unclear whether this dysfunction is independent of a generalized face perception deficit or of subjective experience of emotion in schizophrenia.
Decoding; Encoding; Face; Facial emotion; Generality; Specificity.
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Review
Olivia Wootton et al.
Schizophrenia Research.
Schizophrenia is a neurodevelopmental disorder and a leading cause of disability worldwide. Deficits in cognitive function are characteristic of schizophrenia and are predictors of functional outcomes in the disorder. Within-individual variability (WIV) in cognitive performance is elevated in schizophrenia and has been suggested to provide additional insight into cognitive function over and above mean performance measures. Despite growing interest in WIV in schizophrenia, research on the clinical significance and neural correlates of WIV in the disorder remains sparse. The present narrative review summarizes the key literature linking WIV in schizophrenia to clinical, neural, and genetic correlates. Here, we aim to highlight key knowledge gaps and provide directions for future research into WIV in schizophrenia.
Cognition; Genetic predisposition to disease; Neuroimaging; Reaction time; Schizophrenia; Within-individual variability.
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Review
Aaron J Hauptman et al.
Lancet Psychiatry.
Despite the inclusion of catatonia as a specifier of autism spectrum disorder in DSM-5, we-a team of child and adolescent neuropsychiatrists who specialise in paediatric catatonia and neurodevelopmental disorders-have identified a number of issues with the diagnosis and clinical management of catatonia in our patients. In this Personal View, we summarise the literature regarding catatonia in people with neurodevelopmental disorders, including autism spectrum disorder, describe our concerns, and offer a novel approach to addressing important issues with current diagnostic and treatment paradigms. We emphasise the need for a measure to diagnose and monitor people with catatonia and their history of neurodevelopmental disorders. This measure should consider previous complex and underlying motor, medical, functional, and neurobehavioural symptoms. We propose two concepts for understanding catatonia that relate to the baseline status of an individual: the personalised score at baseline, an estimate of premorbid neurobehavioral and motor symptoms, and the catatonic deterioration from baseline, an estimate of current features that are due to catatonia rather than an underlying neurodevelopmental disorder. We hope this measure will provide a practical tool for clinicians and researchers working with this underserved and high-risk population.
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Nikolai Albert et al.
Schizophrenia Research.
The association between duration of untreated psychosis (DUP) and later outcome is not fully understood. Jonas et al. in their 20-year follow-up found that the association could be explained by lead-time bias. In this study we aimed to analyze the relationship between DUP, time since onset of psychosis and functional outcome using a similar statistical approach as the Jonas study. Using data from 496 participants with first-episode schizophrenia, DUP was assessed using the IRAOS and functioning at the baseline assessment and the subsequent follow-ups (1, 2, 5 and 10 years) was assessed using the GAF-F. For premorbid functioning, the Premorbid Assessment of Functioning Scale was used and rescaled to correspond to the GAF.
The model with the best fit of data included both a slope and a level change. This model of level of function over time had the inflection point at the time of first treatment. This model indicated a slow decline per year until first treatment, at which point there was a sharp decrease in functioning, and after which functioning gradually improved again. Both in this model and in models accounting for potential lead-time bias, however, longer DUP was associated with a decrease in function for each additional week of DUP. This is in contrast with the Jonas et al. study.
In this study, we did not find evidence of a lead-time bias, but rather found that onset of treatment occurs at the time when participants level of functioning was most impaired, and consequently was not at random.
Duration of untreated psychosis; Lead time bias; Outcome; Psychosis; Schizophrenia.
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Yusuke Okada et al.
Schizophrenia Research.
To compare the effectiveness of different long-acting injectable antipsychotics (LAIs) (aripiprazole, paliperidone, risperidone, and fluphenazine/haloperidol) in patients with schizophrenia in Japan. We conducted a retrospective cohort study using two administrative claims databases. The study population consisted of outpatients with schizophrenia who initiated LAIs between May 1, 2015, and November 30, 2019. We directly compared the risk of psychiatric hospitalization and LAI discontinuation among the LAIs based on hazard ratios (HRs) using Cox proportional hazards regression models.
The numbers of eligible patients who initiated aripiprazole, paliperidone, risperidone, and fluphenazine/haloperidol were 303, 124, 73, and 123, respectively. Regarding psychiatric hospitalization, aripiprazole and paliperidone were associated with significantly lower risk compared to fluphenazine/haloperidol (HR of aripiprazole: 0.47, 95 % CI: 0.28-0.78, HR of paliperidone: 0.50, 95 % CI: 0.28-0.89); HR of risperidone showed the same trend as the aripiprazole and paliperidone. Regarding LAI discontinuation, aripiprazole and paliperidone were associated with significantly lower risk of LAI discontinuation compared to fluphenazine/haloperidol (HR of aripiprazole: 0.53, 95 % CI: 95 % CI: 0.35-0.80, HR of paliperidone: 0.57, 95 % CI: 0.35-0.92). Aripiprazole was also associated with a significantly lower risk compared to risperidone (HR: 0.56, 95 % CI: 0.32-0.98).
Our study suggests that aripiprazole and paliperidone are superior to fluphenazine/haloperidol in the risk of psychiatric hospitalization and LAI discontinuation. Aripiprazole is superior to risperidone in the risk of LAI discontinuation.
Administrative claims databases; Discontinuation; Hospitalization; Long-acting injectable antipsychotics; Schizophrenia.
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Dongfang Wang et al.
Schizophrenia Research.
Although plenty of evidence has shown the huge negative impact of COVID-19 on individuals’ mental health conditions, little is known about its impact on the psychotic-like experiences (PLEs) in the general population. We aim to explore the prevalence of PLEs and relevant influential factors among adolescents during COVID-19 lockdown. A total of 3234 students completed one online survey between April to May 2020. PLEs were assessed using the 15-item Positive Subscale of the Community Assessment of Psychic Experiences (CAPE-P15). Resilience, social support, childhood trauma, and a series of socio-demographic factors were also evaluated.
In this sample, 51.4 % adolescents reported having at least one PLE, while 11.6 % experienced PLEs frequently during COVID-19 lockdown. Senior high school students showed more frequent PLEs than college students (p < 0.001). Female gender (OR = 1.77), history of mental disorders (OR = 3.07) or chronic physical illness (OR = 2.04), having relatives or friends being infected with COVID-19 (OR = 3.12), longer daily exposure to media coverage of the COVID-19 (OR = 1.60), and more childhood trauma (OR = 1.54-3.49) were correlated with more frequent PLEs, while higher resilience (OR = 0.35-0.54) and more perceived social support (OR = 0.63-0.72) were associated with decreased odds for frequent PLEs. Additionally, there were several differences among the influential factors between senior high school and college students.
PLEs were relatively common among Chinese adolescents, with higher prevalence among senior high school students during COVID-19 lockdown. Adolescents with specific characteristics should receive more attention in the development of intervention measures in mental health during pandemic lockdown.
Adolescents; COVID-19; Lockdown; Psychotic-like experiences.
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Henrik Myhre Ihler et al.
Schizophrenia Research.
To investigate the trajectories of diminished expression and apathy over 10 years. Further, to explore the effects of baseline- and persistent cannabis use on the development of diminished expression and apathy during follow-up, while controlling other potential sources and predictors of secondary negative symptoms. 351 participants with a first episode of non-affective psychosis were examined at baseline and invited to follow-up at one year and 10 years. The trajectories of diminished expression and apathy were investigated using linear mixed models. Subsequently, cannabis use and other potential predictors and sources of secondary negative symptoms were added to the model to investigate the respective impact on their trajectories.
The severity of both diminished expression and apathy decreased during the follow-up period after the first episode of psychosis, with the most improvement observed from baseline to 1-year follow-up. Cannabis use at baseline was associated with a long-lasting higher symptom load for diminished expression, but not apathy. Introducing persistent cannabis use to the model further strengthened the association with diminished expression.
Both cannabis use at baseline and persistent cannabis use after a first episode of psychosis were associated with more severe symptoms of diminished expression. Our results imply a causal relationship between cannabis use and diminished expression and suggest that measures to reduce cannabis use both before and after psychosis onset may reduce expressive negative symptoms.
Apathy; Cannabis; Diminished expression; Negative symptoms; Psychosis; Schizophrenia.
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Jianping Jia et al.
British Medical Journal.
To identify an optimal lifestyle profile to protect against memory loss in older individuals. Population based, prospective cohort study.
Participants from areas representative of the north, south, and west of China.
Individuals aged 60 years or older who had normal cognition and underwent apolipoprotein E (APOE) genotyping at baseline in 2009.
Participants were followed up until death, discontinuation, or 26 December 2019. Six healthy lifestyle factors were assessed: a healthy diet (adherence to the recommended intake of at least 7 of 12 eligible food items), regular physical exercise (≥150 min of moderate intensity or ≥75 min of vigorous intensity, per week), active social contact (≥twice per week), active cognitive activity (≥twice per week), never or previously smoked, and never drinking alcohol. Participants were categorised into the favourable group if they had four to six healthy lifestyle factors, into the average group for two to three factors, and into the unfavourable group for zero to one factor. Memory function was assessed using the World Health Organization/University of California-Los Angeles Auditory Verbal Learning Test, and global cognition was assessed via the Mini-Mental State Examination. Linear mixed models were used to explore the impact of lifestyle factors on memory in the study sample.
29 072 participants were included (mean age of 72.23 years; 48.54% (n=14 113) were women; and 20.43% (n=5939) were APOE ε4 carriers). Over the 10 year follow-up period (2009-19), participants in the favourable group had slower memory decline than those in the unfavourable group (by 0.028 points/year, 95% confidence interval 0.023 to 0.032, P<0.001). APOE ε4 carriers with favourable (0.027, 95% confidence interval 0.023 to 0.031) and average (0.014, 0.010 to 0.019) lifestyles exhibited a slower memory decline than those with unfavourable lifestyles. Among people who were not carriers of APOE ε4, similar results were observed among participants in the favourable (0.029 points/year, 95% confidence interval 0.019 to 0.039) and average (0.019, 0.011 to 0.027) groups compared with those in the unfavourable group. APOE ε4 status and lifestyle profiles did not show a significant interaction effect on memory decline (P=0.52).
A healthy lifestyle is associated with slower memory decline, even in the presence of the APOE ε4 allele. This study might offer important information to protect older adults against memory decline.
ClinicalTrials.gov NCT03653156.
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Sarah Baumeister et al.
The British Journal of Psychiatry.
Reward processing has been proposed to underpin the atypical social feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social reward processing in ASD. Utilising a large sample, we aimed to assess reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD.
Functional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6-30.6 years of age) and 181 typically developing participants (7.6-30.8 years of age).
Across social and monetary reward anticipation, whole-brain analyses showed hypoactivation of the right ventral striatum in participants with ASD compared with typically developing participants. Further, region of interest analysis across both reward types yielded ASD-related hypoactivation in both the left and right ventral striatum. Across delivery of social and monetary reward, hyperactivation of the ventral striatum in individuals with ASD did not survive correction for multiple comparisons. Dimensional analyses of autism and attention-deficit hyperactivity disorder (ADHD) scores were not significant. In categorical analyses, post hoc comparisons showed that ASD effects were most pronounced in participants with ASD without co-occurring ADHD.
Our results do not support current theories linking atypical social interaction in ASD to specific alterations in social reward processing. Instead, they point towards a generalised hypoactivity of ventral striatum in ASD during anticipation of both social and monetary rewards. We suggest this indicates attenuated reward seeking in ASD independent of social content and that elevated ADHD symptoms may attenuate altered reward seeking in ASD.
ADHD symptoms; Autism spectrum disorder; autism traits; fMRI; multisite; reward processing.
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Protsenko Maria et al.
Schizophrenia Research.
Type 2 diabetes and dyslipidemias co-occur frequently with severe mental illnesses (SMI). However, less is known about serum insulin and lipid levels and prevalence of Insulin Resistance (IR) in offspring with familial risk for SMI. The Northern Finland Birth Cohort 1966 consists of 12,068 mothers, 11,068 fathers, and 12,231 children from the two northernmost provinces in Finland. At age 46 they participated in clinical examination including measurements of glucose, lipids, and IR and answered a questionnaire including information about their nutrition and physical activity. The information on parental SMI was obtained from the Hospital Discharge Register. Parents with SMI were those who had been treated in hospital for any psychiatric disorder during 1969-1982 (ICD-8 codes 290-315). The final study group included 334 (7.3 %) offspring who had a parent with SMI and 4249 (92.7 %) offspring in the comparison group.
We did not find increased risk for disturbances in lipid levels, insulin levels, or IR levels between the study group (offspring of either parent with SMI) compared with the comparison group. All offspring, especially female offspring of either parent with SMI, had an increased risk for higher glucose levels and waist circumference. The results remained the same after excluding offspring with SMI.
Our findings suggest that offspring of parents with SMI, especially female offspring, have partly increased risk for disturbances in cardiometabolic risk factors. Disturbances in glucose metabolism may have an effect via familial risk of severe mental illness.
Birth cohort; Insulin resistance; Insulin sensitivity; Mental illness.
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Review
Laura Richmond et al.
Lancet Psychiatry.
The importance of patient and public involvement (PPI) in mental health research is increasingly acknowledged by funders, researchers, and patients. However, the impact of PPI on those who bring their own lived experiences to research environments is underexplored. A retrospective reflective approach was undertaken collaboratively by four people bringing lived experiences of mental health difficulties to a study adapting a social network intervention for mental health services. Authors considered their experiences of involvement and how these affected them personally. We identified six characteristics of involvement that benefit not only research quality, but also people participating in PPI activities: reframing painful memories, recognising value, practising reciprocity, bridging gaps, countering stigma, and challenging established narratives. When designing and conducting research, it is important to engage empathetically with how involvement is experienced by different people. Values should be translated collaboratively into action so that unintended harms might be avoided. This Personal View offers reflections and recommendations to support this process.
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Anna Tkachev et al.
JAMA Psychiatry.
No clinically applicable diagnostic test exists for severe mental disorders. Lipids harbor potential as disease markers. To define a reproducible profile of lipid alterations in the blood plasma of patients with schizophrenia (SCZ) independent of demographic and environmental variables and to investigate its specificity in association with other psychiatric disorders, ie, major depressive disorder (MDD) and bipolar disorder (BPD).
This was a multicohort case-control diagnostic analysis involving plasma samples from psychiatric patients and control individuals collected between July 17, 2009, and May 18, 2018. Study participants were recruited as consecutive and volunteer samples at multiple inpatient and outpatient mental health hospitals in Western Europe (Germany and Austria [DE-AT]), China (CN), and Russia (RU). Individuals with DSM-IV or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses of SCZ, MDD, BPD, or a first psychotic episode, as well as age- and sex-matched healthy controls without a mental health-related diagnosis were included in the study. Samples and data were analyzed from January 2018 to September 2020.
Plasma lipidome composition was assessed using liquid chromatography coupled with untargeted mass spectrometry.
Blood lipid levels were assessed in 980 individuals (mean [SD] age, 36 [13] years; 510 male individuals [52%]) diagnosed with SCZ, BPD, MDD, or those with a first psychotic episode and in 572 controls (mean [SD] age, 34 [13] years; 323 male individuals [56%]). A total of 77 lipids were found to be significantly altered between those with SCZ (n = 436) and controls (n = 478) in all 3 sample cohorts. Alterations were consistent between cohorts (CN and RU: [Pearson correlation] r = 0.75; DE-AT and CN: r = 0.78; DE-AT and RU: r = 0.82; P < 10-38). A lipid-based predictive model separated patients with SCZ from controls with high diagnostic ability (area under the receiver operating characteristic curve = 0.86-0.95). Lipidome alterations in BPD and MDD, assessed in 184 and 256 individuals, respectively, were found to be similar to those of SCZ (BPD: r = 0.89; MDD: r = 0.92; P < 10-79). Assessment of detected alterations in individuals with a first psychotic episode, as well as patients with SCZ not receiving medication, demonstrated only limited association with medication restricted to particular lipids.
In this study, SCZ was accompanied by a reproducible profile of plasma lipidome alterations, not associated with symptom severity, medication, and demographic and environmental variables, and largely shared with BPD and MDD. This lipid alteration signature may represent a trait marker of severe psychiatric disorders, indicating its potential to be transformed into a clinically applicable testing procedure.
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Hao Luo et al.
JAMA Psychiatry.
Concerns have been raised that the use of antipsychotic medication for people living with dementia might have increased during the COVID-19 pandemic. To examine multinational trends in antipsychotic drug prescribing for people living with dementia before and during the COVID-19 pandemic.
This multinational network cohort study used electronic health records and claims data from 8 databases in 6 countries (France, Germany, Italy, South Korea, the UK, and the US) for individuals aged 65 years or older between January 1, 2016, and November 30, 2021. Two databases each were included for South Korea and the US.
The introduction of population-wide COVID-19 restrictions from April 2020 to the latest available date of each database.
The main outcomes were yearly and monthly incidence of dementia diagnosis and prevalence of people living with dementia who were prescribed antipsychotic drugs in each database. Interrupted time series analyses were used to quantify changes in prescribing rates before and after the introduction of population-wide COVID-19 restrictions.
A total of 857 238 people with dementia aged 65 years or older (58.0% female) were identified in 2016. Reductions in the incidence of dementia were observed in 7 databases in the early phase of the pandemic (April, May, and June 2020), with the most pronounced reduction observed in 1 of the 2 US databases (rate ratio [RR], 0.30; 95% CI, 0.27-0.32); reductions were also observed in the total number of people with dementia prescribed antipsychotic drugs in France, Italy, South Korea, the UK, and the US. Rates of antipsychotic drug prescribing for people with dementia increased in 6 databases representing all countries. Compared with the corresponding month in 2019, the most pronounced increase in 2020 was observed in May in South Korea (Kangwon National University database) (RR, 2.11; 95% CI, 1.47-3.02) and June in the UK (RR, 1.96; 95% CI, 1.24-3.09). The rates of antipsychotic drug prescribing in these 6 databases remained high in 2021. Interrupted time series analyses revealed immediate increases in the prescribing rate in Italy (RR, 1.31; 95% CI, 1.08-1.58) and in the US Medicare database (RR, 1.43; 95% CI, 1.20-1.71) after the introduction of COVID-19 restrictions.
This cohort study found converging evidence that the rate of antipsychotic drug prescribing to people with dementia increased in the initial months of the COVID-19 pandemic in the 6 countries studied and did not decrease to prepandemic levels after the acute phase of the pandemic had ended. These findings suggest that the pandemic disrupted the care of people living with dementia and that the development of intervention strategies is needed to ensure the quality of care.
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Muhammad Ummear Raza et al.
Schizophrenia Bulletin.
Neural synchrony at gamma frequency (~40 Hz) is important for information processing and is disrupted in schizophrenia. From a drug development perspective, molecules that can improve local gamma synchrony are promising candidates for therapeutic development. Given their differentiated clinical profile, clozapine, and haloperidol may have distinct effects on local gamma synchrony engendered by 40 Hz click trains, the so-called auditory steady-state response (ASSR).
Clozapine and haloperidol at doses known to mimic clinically relevant D2 receptor occupancy were evaluated using the ASSR in separate cohorts of female SD rats.
Clozapine (2.5-10 mg/kg, sc) robustly increased intertrial phase coherence (ITC), across all doses. Evoked response increased but less consistently. Background gamma activity, unrelated to the stimulus, showed a reduction at all doses. Closer scrutiny of the data indicated that clozapine accelerated gamma phase resetting. Thus, clozapine augmented auditory information processing in the gamma frequency range by reducing the background gamma, accelerating the gamma phase resetting and improving phase precision and signal power. Modest improvements in ITC were seen with Haloperidol (0.08 and 0.24 mg/kg, sc) without accelerating phase resetting. Evoked power was unaffected while background gamma was reduced at high doses only, which also caused catalepsy.
Using click-train evoked gamma synchrony as an index of local neural network function, we provide a plausible neurophysiological basis for the superior and differentiated profile of clozapine. These observations may provide a neurophysiological template for identifying new drug candidates with a therapeutic potential for treatment-resistant schizophrenia.
ASSR; CNS biomarker; EEG; drug development; event-related potentials; gamma oscillations.
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Maud Gratuze et al.
Neuron.
In addition to tau and Aβ pathologies, inflammation plays an important role in Alzheimer’s disease (AD). Variants in APOE and TREM2 increase AD risk. ApoE4 exacerbates tau-linked neurodegeneration and inflammation in P301S tau mice and removal of microglia blocks tau-dependent neurodegeneration. Microglia adopt a heterogeneous population of transcriptomic states in response to pathology, at least some of which are dependent on TREM2. Previously, we reported that knockout (KO) of TREM2 attenuated neurodegeneration in P301S mice that express mouse Apoe. Because of the possible common pathway of ApoE and TREM2 in AD, we tested whether TREM2 KO (T2KO) would block neurodegeneration in P301S Tau mice expressing ApoE4 (TE4), similar to that observed with microglial depletion. Surprisingly, we observed exacerbated neurodegeneration and tau pathology in TE4-T2KO versus TE4 mice, despite decreased TREM2-dependent microgliosis. Our results suggest that tau pathology-dependent microgliosis, that is, TREM2-independent microgliosis, facilitates tau-mediated neurodegeneration in the presence of ApoE4.
Alzheimer’s disease; ApoE4; TREM2; microgliosis; tau pathology; tau-mediated neurodegeneration.
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Ho Namkung et al.
Neuron.
Schizophrenia (SZ) and bipolar disorder (BP) are highly heritable major psychiatric disorders that share a substantial portion of genetic risk as well as their clinical manifestations. This raises a fundamental question of whether, and how, common neurobiological pathways translate their shared polygenic risks into shared clinical manifestations. This study shows the miR-124-3p-AMPAR pathway as a key common neurobiological mediator that connects polygenic risks with behavioral changes shared between these two psychotic disorders. We discovered the upregulation of miR-124-3p in neuronal cells and the postmortem prefrontal cortex from both SZ and BP patients. Intriguingly, the upregulation is associated with the polygenic risks shared between these two disorders. Seeking mechanistic dissection, we generated a mouse model that upregulates miR-124-3p in the medial prefrontal cortex. We demonstrated that the upregulation of miR-124-3p increases GRIA2-lacking calcium-permeable AMPARs and perturbs AMPAR-mediated excitatory synaptic transmission, leading to deficits in the behavioral dimensions shared between SZ and BP.
AMPAR; bipolar disorder; miR-124; polygenic risk; schizophrenia.
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Rachel Babij et al.
Neuron.
Dysfunction of gamma-aminobutyric acid (GABA)ergic circuits is strongly associated with neurodevelopmental disorders. However, it is unclear how genetic predispositions impact circuit assembly. Using in vivo two-photon and widefield calcium imaging in developing mice, we show that Gabrb3, a gene strongly associated with autism spectrum disorder (ASD) and Angelman syndrome (AS), is enriched in contralaterally projecting pyramidal neurons and is required for inhibitory function. We report that Gabrb3 ablation leads to a developmental decrease in GABAergic synapses, increased local network synchrony, and long-lasting enhancement in functional connectivity of contralateral-but not ipsilateral-pyramidal neuron subtypes. In addition, Gabrb3 deletion leads to increased cortical response to tactile stimulation at neonatal stages. Using human transcriptomics and neuroimaging datasets from ASD subjects, we show that the spatial distribution of GABRB3 expression correlates with atypical connectivity in these subjects. Our studies reveal a requirement for Gabrb3 during the emergence of interhemispheric circuits for sensory processing.
Angelman; GABA; GABRB3; callosal projections; corpus callosum; interhemispheric connectivity; network synchrony; projection neurons; pyramidal neurons.
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Review
M E A Barendse et al.
Schizophrenia Research.
Sex is a significant source of heterogeneity in schizophrenia, with more negative symptoms in males and more affective symptoms and internalizing comorbidity in females. In this narrative review, we argue that there are likely sex differences in the pathophysiological mechanisms of schizophrenia-spectrum disorders (SZ) that originate during puberty and relate to the sex-specific impacts of pubertal maturation on brain development. Pubertal maturation might also trigger underlying (genetic or other) vulnerabilities in at-risk individuals, influencing brain development trajectories that contribute to the emergence of SZ. This review is the first to integrate links between pubertal development and neural development with cognitive neuroscience research in SZ to form and evaluate these hypotheses, with a focus on the frontal-striatal and frontal-limbic networks and their hypothesized contribution to negative and mood symptoms respectively. To test these hypotheses, longitudinal research with human adolescents is needed that examines the role of sex and pubertal development using large cohorts or high risk samples. We provide recommendations for such studies, which will integrate the fields of psychiatry, developmental cognitive neuroscience, and developmental endocrinology towards a more nuanced understanding of the role of pubertal factors in the hypothesized sex-specific pathophysiological mechanisms of schizophrenia.
Hormones; MRI; Pathophysiology; Psychosis; Sex-specific.
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Samantha M Coury et al.
Schizophrenia Research.
Winter birth has been hypothesized to be associated with increased schizophrenia risk for nearly a century. Major hypotheses regarding the potential etiological risk factors for schizophrenia such as vitamin D deficiency and virus exposure in utero are predicated based on the observation that risk of schizophrenia is higher in children born in winter months. We conducted a systematic review and meta-analysis to examine the association between season and month of birth and risk of schizophrenia. We further investigated this relationship stratified by hemisphere.
Forty-three studies spanning 30 countries and territories and 440,039 individuals with schizophrenia were included in this meta-analysis. Winter births were associated with a small but statistically significant increased risk of schizophrenia (OR 1.05, 95 % CI 1.03-1.07, p < 0.0001) and summer births were associated with a small but statistically significant decreased risk of schizophrenia (OR 0.96, 95 % CI 0.94-0.98, p = 0.0001). Stratified subgroup analysis demonstrated no significant difference between hemispheres in the risk of schizophrenia for either winter or summer births.
Analysis using birth month data demonstrated a clear seasonal trend towards increased risk of schizophrenia being associated with winter birth months and decreased risk of schizophrenia in summer-to-fall months in the Northern but not Southern Hemisphere. These data suggest a small-but-substantial increased risk of schizophrenia in winter birth month. Further research needs to examine potential etiologic causes for this association.
Birth month; Meta-analysis; Schizophrenia; Season of birth; Seasonality; Systematic review.
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Huaiqiang Sun et al.
Schizophrenia Research.
Numerous studies have used machine learning with neuroimaging data for identifying individuals with a schizophrenia diagnosis. However, inconsistent results have limited the ability of the psychiatric community to objectively judge and accept the value of this approach. One factor that has contributed to the inconsistency, but has long been ignored, is randomness in the practice of machine learning. This is manifest when executing the same machine learning pipeline multiple times on the same dataset but getting different results. In the current study, a dataset of anatomical MRI scans from 158 patients with first-episode medication-naïve schizophrenia and 166 matched controls was used to investigate the effect of randomness on classifier performance estimates under different algorithm complexity and data splitting ratios. The maximum discriminatory accuracy that could be reached was 62.6 % ± 4.7 % (43.5 %-79.3 %) obtained when using extra-trees classifiers without feature normalization. Regions contributing to discrimination were located at bilateral temporal lobes and right frontal lobe. The results show that randomness has a significant impact on the precision of model performance estimates, especially when the size of test set is small. Current neuroimaging feature engineering combined with machine learning still falls short of being able to make diagnoses in the clinical context, but has value in revealing patterns of regional brain alteration associated with the illness. The current results indicate that effects of randomness on model performance should be reported and considered in interpreting model utility and it is necessary to evaluate models on large test sets to obtain valid estimates of model performance.
Machine learning; Performance; Psychoradiology; Randomness; Schizophrenia.
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Melanie E Bennett et al.
Schizophrenia Research.
People living with schizophrenia often face challenges engaging in social and community activities. A critical barrier is negative symptoms that reflect diminished feelings and thoughts that support social interaction. Several years ago, we began a process of specifying an intervention for individuals with schizophrenia and clinically meaningful negative symptoms that could be delivered in an integrated fashion with mental health services offered in VA medical centers with the primary focus of improving social and community engagement. In the present study, we examined the impact of a multi-component intervention to improve social and community participation in a group of Veterans living with schizophrenia and negative symptoms. We compared an intervention called Engaging in Community Roles and Experiences (EnCoRE) – a 12-week program of individual and group meetings that support learning and implementing skills with the goal of helping participants increase engagement in personally-relevant social and community activities – to an active wellness education control condition. Participants in both conditions attended on average of at least half of the groups that were offered, indicating that many individuals living with negative symptoms are willing to participate in an intervention to improve social and community participation. Although there were no significant differences on the two primary outcomes, those in EnCoRE showed better social and general functioning at post treatment and improved social motivational negative symptoms and decreases in perceived limitations at a 3-month follow-up. EnCoRE may be especially beneficial for participants who endorsed more dysfunctional attitudes about their abilities.
Negative symptoms; Psychosocial interventions; Schizophrenia.
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M J Cuesta et al.
Schizophrenia Research.
The validation of nosological diagnoses in psychiatry remains a conundrum. Leonhard’s (1979) nosology seems to be one of the few acceptable alternative categorical models to current DSM/ICD systems. We aimed to empirically validate Leonhard’s four classes of psychoses: systematic schizophrenia (SSch), unsystematic (USch), cycloid psychosis (Cyclo), and manic-depressive illness (MDI) using a comprehensive set of explanatory validators. 243 patients with first-episode psychosis were followed between 10 and 31 years. A wide-ranging assessment was carried out by collecting data on antecedent, illness-related, concurrent, response to treatment, neuromotor abnormalities, and cognitive impairment variables. Compared with USch, Cyclo, and MDI, SSch displayed a pattern of impairments significantly larger across the seven blocks of explanatory variables. There were no significant differences between Cyclo and MDI in explanatory variables. Except for the majority of illness-onset features, USch displayed more substantial abnormalities in the explanatory variables than Cyclo and MDI. SSch and MDI showed higher percentages of correctly classified patients than USch and Cyclo in linear discriminant analyses. Partial validation of Leonhard’s classification was found. SSch showed differences in explanatory variables with respect to Cyclo and MDI. USch showed also significant differences in explanatory variables regarding Cyclo and MDI, although with a lower strength than SSch. There was strong empirical evidence of the separation between both Leonhard’s schizophrenia subtypes; however, the distinction between the Cyclo and MDI groups was not empirically supported. A mild to moderate discriminative ability between Leonhard’s subtypes on the basis of explanatory blocks of variables was observed.
Cycloid; First-episode psychosis; Follow-up; Leonhard; Nosology; Schizophrenia.
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Tiffany P Gutteridge et al.
Schizophrenia Research.
Among children with psychotic-like experiences (PLEs), the presence of co-occurring psychopathology may distinguish children’s self-report of clinically significant experiences (i.e., PLEs that are distressing and/or impairing of daily functioning) from reports of more benign experiences. The aim of this study was to examine whether the likelihood of distressing or impairing PLEs differed according to type of co-occurring psychopathology symptoms. A community sample of 5268 children aged 9-12 years were recruited from Greater London, UK. Participants completed the Psychotic-Like Experiences Questionnaire for Children, and the Strengths and Difficulties Questionnaire to measure internalising and externalising problems. Multinomial logistic regressions were used to determine the likelihood of PLEs being distressing and/or impairing (vs. not) among children with different co-occurring symptom profiles (PLEs only; PLEs with internalising problems only – PLE-I; PLEs with externalising problems only – PLE-E; and PLEs with both internalising and externalising problems – PLE-IE). Children with co-occurring internalising and/or externalising problems had greater odds of distressing and/or impairing PLEs compared to children without co-occurring psychopathology (PLEs only). These associations were moderate for PLE-E and strong for PLE-I and PLE-IE, with the greatest odds of distressing and impairing PLEs evident in the presence of internalising plus externalising comorbidities (odds ratios [with 99 % confidence intervals] for PLE-IE relative to PLE-I = 2.00 [1.34-2.99]; PLE-IE relative to PLE-E = 5.46 [3.78-7.90]). These results affirm the importance of screening for the presence and type of co-occurring psychopathology among children with PLEs to demarcate potentially different treatment needs.
Community screening; Developmental psychopathology; Early intervention; Middle childhood; Psychosis symptoms.
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Brian J Miller et al.
Schizophrenia Research.
Insomnia commonly occurs in schizophrenia, and insomnia is associated with suicide risk. Clozapine has anti-suicidal properties and beneficial effects on sleep. We performed a meta-analysis of insomnia in randomized controlled trials (RCTs) of patients with schizophrenia treated with clozapine. We hypothesized that compared to clozapine there is an increased odds of insomnia in patients treated with other antipsychotics. We systematically searched , PsycINFO, and Web of Science databases. We included RCTs, in English, with data on insomnia in patients with schizophrenia treated with clozapine versus other antipsychotics. Data were pooled using a random effects model.
Eight RCTs (1952 patients: 922 on clozapine and 1030 on other antipsychotics) met inclusion criteria. Patients treated with other antipsychotics versus clozapine had a significant increased odds of insomnia (22.3 % versus 12.4 %, OR = 2.20, 95 % CI = 1.64-2.94, p < 0.01). Olanzapine, quetiapine, risperidone, and ziprasidone were each associated with significant increased odds of insomnia compared to clozapine. In meta-regression analyses, clozapine dose, publication year, sex, trial duration, and study quality score were unrelated to the association; however, there was a significant association with age. The observed ORs for insomnia from RCTs were almost perfectly correlated with reported ORs from pharmacovigilance data.
Clozapine is associated with significantly less insomnia compared to other antipsychotics. Findings provide additional evidence for improvement in sleep as a potential pathway underlying clozapine’s anti-suicidal properties. A greater mechanistic understanding of this association is needed.
Antipsychotics; Clozapine; Insomnia; Meta-analysis.
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Carmen Miralles et al.
Schizophrenia Research.
The relationship between maladaptive personality traits and psychotic disorders in the early stages of disease has not been thoroughly investigated, even though it is essential for developing prevention and early intervention strategies. The five domains and the 25 facets of the Personality Inventory for DSM-5 (PID-5) were compared between 102 patients with recent-onset psychosis (ROP) and 116 community subjects (C) with a general linear model including age and sex in the analyses. In addition, multiple linear regression models were used to identify which factors associated with the PID-5 domains in ROP, and correlation analyses were used to explore the relationship between personality traits.
Patients with ROP, compared to C, exhibited higher scores in four out of the five domains with medium effect sizes (Cohen’s f ≥ 0.15) in two of them: negative affect (NA, p = 0.013, f = 0.04), detachment (DET, p < 0.001, f = 0.15), disinhibition (DIS, p < 0.001, f = 0.14) and psychoticism (PSY, p < 0.001, f = 0.16). Significant group differences were observed in 15 of the 25 facets and the largest effects were observed in the facets of withdrawal (p ≤ 0.001, f = 0.20), irresponsibility (p < 0.001, f = 0.23) and unusual beliefs (p = 0.001, f = 0.22). Interestingly, being on antidepressants and high scores on the positive subscale of the Positive and Negative Syndrome Scale (PANSS) were associated with high scores of NA, antagonism (ANT) and PSY.
Maladaptive personality traits were prominent in persons with ROP. These findings suggest that personality traits might play a role in vulnerability to psychosis and highlight the importance of evaluating personality in the early stages of psychosis.
Antidepressants; PANSS; PID-5; Personality; Recent-onset psychosis.
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Anne Mette G Jensen et al.
PNAS.
SORL1, the gene encoding the large multidomain SORLA protein, has emerged as only the fourth gene that when mutated can by itself cause Alzheimer’s disease (AD), and as a gene reliably linked to both the early- and late-onset forms of the disease. SORLA is known to interact with the endosomal trafficking regulatory complex called retromer in regulating the recycling of endosomal cargo, including the amyloid precursor protein (APP) and the glutamate receptor GluA1. Nevertheless, SORLA’s precise structural-functional relationship in endosomal recycling tubules remains unknown. Here, we address these outstanding questions by relying on crystallographic and artificial-intelligence evidence to generate a structural model for how SORLA folds and fits into retromer-positive endosomal tubules, where it is found to dimerize via both SORLA’s fibronectin-type-III (3Fn)- and VPS10p-domains. Moreover, we identify a SORLA fragment comprising the 3Fn-, transmembrane, and cytoplasmic domains that has the capacity to form a dimer, and to enhance retromer-dependent recycling of APP by decreasing its amyloidogenic processing. Collectively, these observations generate a model for how SORLA dimer (and possibly polymer) formation can function in stabilizing and enhancing retromer function at endosome tubules. These findings can inform investigation of the many AD-associated SORL1 variants for evidence of pathogenicity and can guide discovery of novel drugs for the disease.
Alzheimer’s disease; SORL1; dimerization; minigene; pathogenicity.
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Sherry Kit Wa Chan et al.
Schizophrenia Research.
This study explores the longitudinal changes and trajectories of cognitive functions in patients with adult-onset first-episode schizophrenia (FES) over four years and their relationships with the baseline subdomains of negative symptoms. A total of 177 patients of age 25-55 with FES were recruited. Baseline demographics, clinical, social and cognitive functions were assessed. Diminished expression and diminished motivation of negative symptoms were assessed with Scale for the Assessment of Negative Symptoms (SANS). Patients had yearly follow-up of cognitive function assessments over four years. Latent class growth analysis (LCGA) and mixed linear regression model were used to explore the longitudinal changes of cognitive functions and the effect of baseline negative symptoms on the longitudinal cognitive function changes. Relationships of baseline negative symptoms subdomains and cognitive functions were also explored.
Two trajectories of cognitive functions were identified. Longitudinal improvements were found in most cognitive functions apart from the logical memory. One trajectory of patients had significant deterioration of logical memory while the other group had significant improvement. Baseline diminished expression was associated with baseline and longitudinal changes of processing speed and verbal fluency while diminished motivation was associated with baseline and longitudinal changes of processing speed.
Adult-onset FES patients had a homogeneous longitudinal improvement in most cognitive functions but not for logical memory suggesting the unique nature of verbal memory. The distinct relationship between baseline subdomains of negative symptoms with baseline and longitudinal cognitive functions suggesting the presence of differential overlapping etiology between negative symptom subdomains and cognitive functions.
Adult-onset; Cognitive functions; Diminished expression; First episode schizophrenia; Longitudinal trajectories; Negative symptoms.
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Enrico Patrono et al.
Schizophrenia Research.
Schizophrenia research has increased in recent decades and focused more on its neural basis. Decision-making and cognitive flexibility are the main cognitive functions that are impaired and considered schizophrenia endophenotypes. Cognitive impairment was recently connected with altered functions of N-methyl-d-aspartate (NMDAR) glutamatergic receptors, which increased cortical activity. Selective NMDAR antagonists, such as MK-801, have been used to model cognitive inflexibility in schizophrenia. Decreased GABAergic inhibitory activity has been shown elsewhere with enhanced cortical activity. This imbalance in the excitatory/inhibitory may reduce the entrainment of prefrontal gamma and hippocampal theta rhythms and result in gamma/theta band de-synchronization. The current study established an acute MK-801 administration model of schizophrenia-like cognitive inflexibility in rats and used the attentional set-shifting task in which rats learned to switch/reverse the relevant rule. During the task, we used in vivo optogenetic stimulations of parvalbumin-positive interneurons at specific light pulses in the prefrontal cortex and ventral hippocampus. The first experiments showed that acute dizocilpine in rats produced schizophrenia-like cognitive inflexibility. The second set of experiments demonstrated that specific optogenetic stimulation at specific frequencies of parvalbumin-positive interneurons in the prefrontal cortex and ventral hippocampus rescued the cognitive flexibility rats that received acute MK-801. These findings advance our knowledge of the pivotal role of parvalbumin interneurons in schizophrenia-like cognitive impairment and may guide further research on this severe psychiatric disorder.
Attentional set-shifting task; Excitatory/inhibitory ratio; Gamma waves; MK-801; theta waves.
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Review
Shaynna N Herrera et al.
Schizophrenia Research.
Psychoeducation is recommended in the treatment of patients with schizophrenia and has been shown to improve satisfaction with mental health service and treatment adherence, reduce relapse and hospital readmission rates, and enhance functioning and quality of life. Youth at clinical high risk for psychosis (CHR) may also benefit from receiving psychoeducation as part of their treatment. The goal of this study was to conduct a scoping review to map out the existing literature on psychoeducation for CHR individuals, including content, utilization, and benefits, in order to identify areas for future research and clinical care. Following PRISMA guidelines, we conducted a systematic search of electronic databases (MEDLINE, Embase, PsycINFO, Scopus, and Web of Science Core Collection) to identify literature through 02/25/2022 that provided data or significant commentary about the provision of psychoeducation to CHR individuals. After screening titles and abstracts, four co-authors assessed full-text articles for eligibility. Thirty-three studies were included in the review. Psychoeducation is recommended in the treatment of CHR individuals, is a preferred treatment option among CHR individuals, and many CHR programs report offering psychoeducation. However, details about the psychoeducational content and method of delivery are notably absent from recommendations and reports on the provision of CHR psychoeducation in real-world settings. We identified two brief and structured CHR psychoeducation interventions and one longer-term psychoeducational multifamily group model for CHR that show feasibility and promise, though they have not yet undergone randomized trials to evaluate effectiveness of the psychoeducation. We also identified several comprehensive CHR interventions that included an explicit psychoeducation module, though the unique role of the psychoeducational component is unknown. Despite being recommended as a critical component of treatment for CHR individuals and preferred by CHR individuals, the ways in which psychoeducation are being delivered to CHR individuals in real-world practice is still largely ambiguous. Rigorous evaluations of psychoeducation treatment models are needed, as well as investment from clinical programs to facilitate the implementation and dissemination of standardized psychoeducation for CHR individuals.
Communication; Early intervention; Feedback; Mental health literacy; Patient-centered care.
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Friederike S David et al.
Schizophrenia Research.
Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorders (SZ) exhibit considerable phenotypic and genetic overlap. However, the contribution of genetic factors to their shared psychopathological symptom dimensions remains unclear. The present exploratory study investigated genetic contributions to the symptom dimensions “Depression”, “Negative syndrome”, “Positive formal thought disorder”, “Paranoid-hallucinatory syndrome”, and “Increased appetite” in a transdiagnostic subset of the German FOR2107 cohort (n = 1042 patients with MDD, BD, or SZ). As replication cohort, a subset of the German/Austrian PsyCourse study (n = 816 patients with MDD, BD, or SZ) was employed. First, the relationship between symptom dimensions and common variants associated with MDD, BD, and SZ was investigated via polygenic risk score (PRS) association analyses, with disorder-specific PRS as predictors and symptom dimensions as outcomes. In the FOR2107 study sample, PRS for BD and SZ were positively associated with “Positive formal thought disorder”, the PRS for SZ was positively associated with “Paranoid-hallucinatory syndrome”, and the PRS for BD was negatively associated with “Depression”. The effects of PRS for SZ were replicated in PsyCourse. No significant associations were observed for the MDD PRS. Second, genome-wide association studies (GWAS) were performed for the five symptom dimensions. No genome-wide significant associations and no replicable suggestive associations (p < 1e-6 in the GWAS) were identified. In summary, our results suggest that, similar to diagnostic categories, transdiagnostic psychiatric symptom dimensions are attributable to polygenic contributions with small effect sizes. Further studies in larger thoroughly phenotyped psychiatric cohorts are required to elucidate the genetic factors that shape psychopathological symptom dimensions.
Affective disorders; Factor model; GWAS; Polygenic risk scores; Psychosis.
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Aina Sastre-Buades et al.
Schizophrenia Research.
Suicidal behavior (SB) is common in first-episode psychosis (FEP), and cognitive impairment has also been described in psychosis. Despite well-established risk factors for SB in psychosis, the role of cognition and insight remains unclear. This study aimed to explore the relationship between history of SB and cognition in recent-onset FEP, distinguishing between neurocognition, social cognition, and metacognition, and including cognitive insight (CI) as a metacognitive variable. The sample consisted of 190 participants with recent-onset FEP recruited from two multicentric studies. Two groups were formed based on presence/absence of a history of SB. Demographic, clinical, and cognitive data were compared by group, including significance level adjustments and size effect calculation. No differences were found regarding demographic, clinical, neurocognitive, social cognition, and metacognitive variables except for CI (18.18 ± 4.87; t = -3.16; p = 0.0020; d = -0.635), which showed a medium effect size. Small to medium effect size were found for attributional style (externalizing bias) (1.15 ± 3.94; t = 2.07; d = 0.482), theory of mind (ToM) (1.73 ± 0.22; t = 2.04; d = -0.403), jumping to conclusions bias (JTC) (23.3 %; X = 0.94; V = 0.178). In recent-onset psychosis, neurocognitive functioning was not related to the history of SB. As novelty, individuals with previous SB showed higher CI. Also, regarding social cognition and metacognition, individuals with prior SB tended to present extremely low externalizing bias, better ToM, and presence of JTC.
Metacognition; Neurocognition; Recent-onset psychosis; Social cognition; Suicidal behavior.
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Sofie Hasseris et al.
American Journal of Psychiatry.
The authors investigated associations between polygenic liabilities for bipolar disorder, major depression, and schizophrenia and episode polarity among individuals with bipolar disorder. The sample consisted of 2,705 individuals diagnosed with bipolar disorder at Danish psychiatric hospitals between January 1995 and March 2017. DNA was obtained from dried blood spots collected at birth as part of routine screening. Polygenic risk scores (PRSs) for bipolar disorder, major depression, and schizophrenia were generated using a meta-PRS method combining internally and externally trained components. Associations between PRS and polarity at first episode, polarity at any episode, and number of episodes with a given polarity were evaluated for each disorder-specific PRS using logistic and negative binominal regressions adjusted for the other two PRSs, age, sex, genotype platform, and five ancestral principal components.
PRS for bipolar disorder was positively associated with any manic episodes (odds ratio=1.23, 95% CI=1.09-1.38). PRS for depression was positively associated with any depressive (odds ratio=1.11, 95% CI=1.01-1.23) and mixed (odds ratio=1.15, 95% CI=1.03-1.28) episodes and negatively associated with any manic episodes (odds ratio=0.76, 95% CI=0.69-0.84). PRS for schizophrenia was positively associated with any manic episodes (odds ratio=1.13, 95% CI=1.01-1.27), but only when psychotic symptoms were present (odds ratio for psychotic mania: 1.27, 95% CI=1.05-1.54; odds ratio for nonpsychotic mania: 1.06, 95% CI=0.93-1.20). These patterns were similar for first-episode polarity and for the number of episodes within each pole.
PRSs for bipolar disorder, major depression, and schizophrenia are associated with episode polarity and psychotic symptoms in a congruent manner among individuals with bipolar disorder.
Bipolar and Related Disorders; Genetics/Genomics; Polygenic Risk.
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Boadie W Dunlop et al.
American Journal of Psychiatry.
The authors sought to determine the shared and unique changes in brain resting-state functional connectivity (rsFC) between patients with major depressive disorder who achieved remission with cognitive-behavioral therapy (CBT) or with antidepressant medication. The Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) trial randomized adults with treatment-naive major depressive disorder to 12 weeks of treatment with CBT (16 1-hour sessions) or medication (duloxetine 30-60 mg/day or escitalopram 10-20 mg/day). Resting-state functional MRI scans were performed at baseline and at week 12. The primary outcome was change in the whole-brain rsFC of four seeded brain networks among participants who achieved remission.
Of the 131 completers with usable MRI data (74 female; mean age, 39.8 years), remission was achieved by 19 of 40 CBT-treated and 45 of 91 medication-treated patients. Three patterns of connectivity changes were observed. First, those who remitted with either treatment shared a pattern of reduction in rsFC between the subcallosal cingulate cortex and the motor cortex. Second, reciprocal rsFC changes were observed across multiple networks, primarily increases in CBT remitters and decreases in medication remitters. And third, in CBT remitters only, rsFC increased within the executive control network and between the executive control network and parietal attention regions.
Remission from major depression via treatment with CBT or medication is associated with changes in rsFC that are mostly specific to the treatment modality, providing biological support for the clinical practice of switching between or combining these treatment approaches. Medication is associated with broadly inhibitory effects. In CBT remitters, the increase in rsFC strength between networks involved in cognitive control and attention provides biological support for the theorized mechanism of CBT. Reducing affective network connectivity with motor systems is a shared process important for remission with both CBT and medication.
Antidepressants; Biological Markers; Cognitive-Behavioral Therapy; Depressive Disorders; Major Depressive Disorder; Psychotherapy.
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Emily Peckham et al.
The British Journal of Psychiatry.
People with severe mental ill health (SMI) experience some of the largest health inequalities of any sector within society. For these inequalities to be reduced, an understanding of the behavioural determinants of health in this population is needed. Utilising data from the Closing the Gap Health Study, we aimed to assess the extent to which people with SMI report health-risk factors and behaviours, their interest in modifying them, and the factors associated with being motivated to modify these behaviours.
Adult (≥18 years old) participants were recruited via primary and secondary care in the English National Health Service. To be eligible, participants needed to have a documented diagnosis of schizophrenia, psychotic disorders or bipolar disorder. Data were collected by survey on demographics, general physical health, diet, physical activity, alcohol, smoking and body mass index.
Between April 2016 and March 2020, n = 9914 participants were recruited. Among people with SMI, high rates of obesity (37.5%), infrequent physical activity (62.0%), not meeting current guidelines (≥5) for the consumption of fruit and vegetables (85.0%) and smoking (42.2%) were observed. However, most participants were motivated to reduce health-risk behaviours. Perceiving the importance of health-promoting behaviours, being of poorer general health and being female were significantly associated with being motivated to modify health-risk behaviours.
Despite experiencing poor physical and mental health outcomes compared with the general population, and contrary to popular misconceptions, people with SMI perceive health as important and are motivated to make behavioural changes to improve health.
Severe mental ill health; bipolar disorder; health risk behaviours; psychosis; schizophrenia.
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Review
Steven Marwaha et al.
Lancet.
Depression is common, costly, debilitating, and associated with increased risk of suicide. It is one of the leading global public health problems. Although existing available pharmacological treatments can be effective, their onset of action can take up to 6 weeks, side-effects are common, and recovery can require treatment with multiple different agents. Although psychosocial interventions might also be recommended, more effective treatments than those currently available are needed for people with moderate or severe depression. In the past 10 years, treatment trials have developed and tested many new targeted interventions. In this Review, we assess novel and emerging biological treatments for major depressive disorder, evaluate their putative brain and body mechanisms, and highlight how close each might be to clinical use.
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Anna Alkelai et al.
Schizophrenia Research.
Childhood-onset schizophrenia (COS) is a rare form of schizophrenia with an onset prior to 13 years of age. Although genetic factors play a role in COS etiology, only a few causal variants have been reported to date. This study presents a diagnostic exome sequencing (ES) in 37 Israeli Jewish families with a proband diagnosed with COS. By implementing a trio/duo ES approach and applying a well-established diagnostic pipeline, we detected clinically significant variants in 7 probands (19 %). These single nucleotide variants and indels were mostly inherited. The implicated genes were ANKRD11, GRIA2, CHD2, CLCN3, CLTC, IGF1R and MICU1. In a secondary analysis that compared COS patients to 4721 healthy controls, we observed that patients had a significant enrichment of rare loss of function (LoF) variants in LoF intolerant genes associated with developmental diseases. Taken together, ES could be considered as a valuable tool in the genetic workup for COS patients.
Childhood onset schizophrenia; Diagnostic yield; Whole exome sequencing.
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Emma C Palmer-Cooper et al.
Schizophrenia Research.
Metacognition refers to appraising one’s thoughts and behaviours. Deficits in metacognition are associated with psychosis-spectrum experiences, such as hallucinations and delusions, in both clinical and non-clinical populations. Assessments of metacognitive function and abilities in clinical populations often vary in administration duration, and subjectivity of scores. This study investigates associations between different measures of metacognition and their prediction of psychosis spectrum experiences using objective and self-report measures in a cross-sectional study of psychosis-spectrum disorder (PSD) participants and controls. Twenty-three individuals with PSD and forty-four controls were recruited online and completed in-the-moment objective ratings of metacognitive accuracy (meta-Dots Task), and retrospective self-report of metacognitive self-reflection (Beck Cognitive Insight Scale) and abilities (Metacognition Self-Assessment Scale).
There were group differences in self-reported metacognition, with PSD participants having lower scores of metacognitive ability, but no differences in self-reflectiveness or objective metacognitive accuracy. In the PSD group, only self-reported metacognitive ability was associated with and predicted distress about, and conviction in, delusional thoughts.
The findings demonstrate group differences in some self-reported, but not objective, measures of metacognition, and highlight that prediction of PSD experiences depends on the metacognitive construct being measured, and the type of measurement used.
Cognitive insight; Delusions; Hallucinations; Metacognition; Psychosis.
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Kamiyu Ogyu et al.
Schizophrenia Research.
Thirty percent of patients with schizophrenia do not respond to non-clozapine antipsychotics and are termed treatment-resistant schizophrenia (TRS). The 40-Hz auditory steady-state response (ASSR) is a well-known to be reduced in patients with schizophrenia compared to healthy controls (HCs), suggesting impaired gamma oscillation in schizophrenia. Given no ASSR study on TRS, we aimed to examine the neurophysiological basis of TRS employing 40-Hz ASSR paradigm. We compared ASSR measures among HCs, patients with non-TRS, and patients with TRS. TRS criteria were defined by a score of 4 or higher on two items of the Positive and Negative Syndrome Scale (PANSS) positive symptoms despite standard antipsychotic treatment. Participants were examined for ASSR with 40-Hz click-train stimulus, and then time-frequency analysis was performed to calculate evoked power and phase-locking factor (PLF) of 40-Hz ASSR.
A total of 79 participants were included: 27 patients with TRS (PANSS = 92.6 ± 15.8); 27 patients with non-TRS (PANSS = 63.3 ± 14.7); and 25 HCs. Evoked power in 40-Hz ASSR was lower in the TRS group than in the HC group (F2,79 = 8.37, p = 0.015; TRS vs. HCs: p = 0.012, d = 1.1) while no differences in PLF were found between the groups.
These results suggest that glutamatergic and GABAergic neurophysiological dysfunctions are involved in the pathophysiology of TRS. Our findings warrant more comprehensive and longitudinal studies for deep phenotyping of TRS.
Auditory steady-state response; Evoked power; Gamma oscillation; Phase-locking factor; Treatment-resistant schizophrenia.
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Timo Holttinen et al.
Schizophrenia Research.
This study explored the incidence and stability of schizophrenia in a large national register data of all adolescents first admitted to psychiatric inpatient care at ages 13-17 in Finland 1980-2010. The study population (N 17,112) comprised all Finnish citizens aged 13-17 receiving their first ever psychiatric inpatient treatment between 1980 and 2010 in Finland. To explore incidence and stability of schizophrenia, the diagnostic information on inpatient care or disability pension was obtained from the appropriate registers.
The incidence of schizophrenia disorders (F20 + F25) during adolescence was higher in the study population for those admitted to psychiatric inpatient care 1980-1989 than in other decades examined. Overall, psychiatric inpatient care during adolescence was a risk factor for subsequent schizophrenia, especially if a diagnosis of F20-29 was set although a considerable share of those with psychotic disorders other than schizophrenia diagnosis did not subsequently convert to schizophrenia. The stability of adolescent onset schizophrenia diagnosis was high.
Adolescents requiring psychiatric inpatient care have a higher later rate of schizophrenia diagnosis than prevalence at community level. Whereas adolescent onset schizophrenia diagnosis is a fairly stable diagnosis, there are other adolescent psychotic disorders which are more transient in nature.
Adolescent; Inpatient; Longitudal study; Mental health disorders; Register study; Schizophrenia.
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Sharon Florentin et al.
Schizophrenia Research.
Schizoaffective disorder (SAD) remains a controversial diagnosis in terms of necessity and reliability. We assessed diagnostic patterns of SAD and schizophrenia (SZ) among hospitalized psychiatric patients over a fifty-year period.
Data from the Israeli National Psychiatric Registry on 16,341 adults diagnosed with SZ or SAD, hospitalized at least twice in 1963-2017, were analyzed. Stability between most-frequent, first and last diagnosis, and diagnostic-constancy (the same diagnosis in >75 % of a person’s hospitalizations) were calculated. Three groups were compared: People with both SAD and SZ diagnoses over the years (SZ-SAD), and people with only one of these diagnoses (SZ-only; SAD-only). The incidence of SAD and SZ before and after DSM-5 publication was compared.
Reliability between last and first diagnosis was 60 % for SAD and 94 % for SZ. Agreement between first and most-frequent diagnosis was 86 % for SAD and 92 % for SZ. Diagnostic shifts differ between persons with SAD and with SZ. Diagnostic-constancy was observed for 50 % of SAD-only patients. In the SZ-SAD group, 9 % had a constant SAD diagnosis. Compared to the other groups, the SZ-SAD group exhibited a higher substance use prevalence, younger age at first-hospitalization, and more hospitalizations/person (p < 0.0001). The incidence of a first-hospitalization SAD diagnosis increased by 2.2 % in the 4-years after vs. prior to DSM-5.
A SAD diagnosis is less stable than SZ. The incidence of a SAD diagnosis increased after DSM-5, despite stricter diagnostic criteria. The SZ-SAD group exhibited the poorest outcomes. SAD may evolve over time necessitating periodic re-evaluation.
DSM-5; Diagnostic stability; Reliability; Schizoaffective disorder; Schizophrenia.
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Jihye Oh et al.
Schizophrenia Research.
Negative symptoms are closely related to the poor prognosis of schizophrenia, for which there is no effective treatment to date. Behavioral activation (BA), which is an effective treatment for depression, is a behavioral approach that targets low levels of response-contingent positive reinforcement. This study aimed to explore BA as an effective intervention for relieving the negative symptoms of schizophrenia. This was a randomized single-blind controlled trial. Eighty-four patients with schizophrenia were enrolled in community mental health settings. Excluding 14 patients who opted out of the study, 70 were randomly assigned to receive BA in addition to treatment-as-usual (BA + TAU) or treatment-as-usual (TAU) only. Negative symptoms were assessed using the Clinical Assessment Interview for Negative Symptoms (CAINS) and Brief Negative Symptom Scale (BNSS) at baseline, post-treatment, and 6-months follow-up.
Significant differences between the BA + TAU and TAU only groups were observed in the measures of negative symptoms post-treatment. The total score of CAINS was significantly decreased after BA treatment (η = 0.13). The tendency of the BA + TAU treatment effect was also observed for the BNSS total score and PANSS negative symptom subscale (η = 0.10 and η = 0.11, respectively). However, the difference between the two groups was not sustained at the six-month follow-up.
Our findings suggest that BA could be a promising time-limited and structured psychosocial intervention for schizophrenia-associated negative symptoms with the merit of easy dissemination. Further studies are needed to examine the factors involved in sustaining improvement.
Behavioral activation; Negative symptoms of schizophrenia; Psychosocial interventions for negative symptoms.
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Justine de With et al.
Schizophrenia Research.
In patients with psychotic disorders, insecure attachment styles and impaired social functioning are highly prevalent. Our aim was to explore the multi-cross-sectional and longitudinal associations between attachment style and social functioning. This study was performed in a subsample of 119 patients with non-affective psychotic disorders, 128 unaffected siblings and 66 healthy controls within the Genetic Risk and Outcome of Psychosis (GROUP) Study. Attachment style (using the Psychosis Attachment Measure) and three social functioning domains, namely withdrawal, interpersonal behaviour and pro-social activities as measured with the Social Functioning Scale (SFS) were assessed on two moments in time. Generalized linear mixed models and linear regression models were used. Bonferroni correction for multiple testing was applied.
In the patient group, a significant negative association was found between avoidant attachment and pro-social functioning. In the sibling and control group, we found significant negative associations between avoidant attachment and the social functioning domains withdrawal and interpersonal behaviour. We also found a significant negative association between anxious attachment and the social functioning domain withdrawal in siblings. Higher levels of insecure anxious attachment at baseline predicted a reduction of the social functioning domain interpersonal behaviour in siblings over a period of three years on a trend level.
Findings indicate that levels of insecure attachment are elevated in patients with psychotic disorders and have a negative association with social functioning in both patients, siblings and controls. These findings warrant specific attention for attachment style in the treatment of patients with psychotic disorders and individuals with an increased vulnerability for developing psychosis.
Attachment; Psychosis; Schizophrenia; Social functioning.
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Maja R Radojčić et al.
Lancet Psychiatry.
The prescription of antipsychotics to children and adolescents has been increasing worldwide. We described up-to-date trends in antipsychotic prescribing and identified likely indications in a contemporary English cohort. We used a large primary care database, the Clinical Practice Research Datalink (CPRD) Aurum database, and we included all children and adolescents aged 3-18 years in the database and registered in England between Jan 1, 2000, and Dec 31, 2019, excluding those whose gender was recorded as indeterminate. Participants were followed up until the earliest of Dec 31, 2019, June 30 of the year they turned 18 years, their death, when they transferred from the primary care practice, or when the practice left the database. Data were not collected on ethnicity. We recorded antipsychotic prescriptions using the date a prescription was issued. As CPRD prescriptions are not linked to indications, we developed an algorithm to ascertain the most likely indication associated with participants’ first antipsychotic prescription using clinical codes. We reported prescribing trends as annual period prevalence and the rate of first antipsychotic prescription, and we used joinpoint regression analysis to identify changes in the outcome trend. We stratified prevalence estimates by age group, gender, and Index of Multiple Deprivation quintiles, we reported frequencies of likely indications associated with incident prescriptions, and we explored clinical preference for typical versus atypical antipsychotics within deprivation quintiles.
Between Jan 1, 2000, and Dec 31, 2019, we included 7 216 791 children and adolescents, of whom 3 480 730 (48·2%) were girls and 3 736 061 (51·8%) were boys, with a mean age at the start of follow-up of 7·3 years (SD 4·9; range 3-18). Median follow-up was 4·1 years (IQR 1·5-8·5). 19 496 (0·3%) individuals received 243 529 antipsychotic prescriptions over follow-up, including 225 710 (92·7%) atypical and 17 819 (7·3%) typical antipsychotic prescriptions. The annual period prevalence of antipsychotic prescriptions rose from 0·057% (95% CI 0·052-0·063%) in 2000 to 0·105% (0·100-0·111%) in 2019. From joinpoint analyses, the period prevalence of all antipsychotic prescriptions increased by an average of 3·3% per year (2·2-4·9%) and the rate of first prescriptions increased by 2·2% per year (1·7-2·7%). The most likely indications of the first identified antipsychotic prescriptions were for autism spectrum disorder (2477 [12·7%]), non-affective psychosis (1669 [8·6%]), anxiety disorders (1466 [7·5%]), ADHD (1391 [7·1%]), depression (1256 [6·4%]), and conduct disorders (1181 [6·1%]).
The observed increase in antipsychotic prescriptions over 20 years results from the accumulation of repeated prescriptions to the same individuals combined with an increase in new prescriptions. These findings highlight the need for continued monitoring of trends in antipsychotic use and, although this was not examined in this paper, the findings highlights the need for better information about long-term antipsychotic safety.
None.
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Daniel Kapustin et al.
Canadian Journal of Psychiatry.
Neuropsychiatric symptoms (NPS) are prevalent in neurodegenerative disorders, however, their frequency and impact on function across different disorders is not well understood. We compared the frequency and severity of NPS across Alzheimer’s disease (AD) (either with mild cognitive impairment or dementia), Cerebrovascular disease (CVD), Parkinson’s disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and explored the association between NPS burden and function. We obtained data from Ontario Neurodegenerative Disease Research Initiative (ONDRI) that included following cohorts: AD (N = 111), CVD (N = 148), PD (N = 136), FTD (N = 50) and ALS (N = 36). We compared the frequency and severity of individual NPS (assessed by the neuropsychiatric inventory questionnaire) across cohorts using generalized estimating equations and analysis of variance. Second, we assessed the relationship of NPS burden with instrumental (iADLs) and basic (ADLs) activities of living across cohorts using multivariate linear regression while adjusting for relevant demographic and clinical covariates.
Frequency of NPS varied across cohorts (χ(4) = 34.4, p < .001), with post-hoc tests showing that FTD had the greatest frequency as compared to all other cohorts. The FTD cohort also had the greatest severity of NPS (H(4) = 34.5, p < .001). Further, there were differences among cohorts in terms of the association between NPS burden and ADLs (F(4,461) = 3.1, p = 0.02). Post-hoc comparisons suggested that this finding was driven by the FTD group, however, the differences did not remain significant following Bonferroni correction. There were no differences among cohorts in terms of the association between NPS burden and IADLs.
NPS frequency and severity are markedly greater in FTD as compared to other neurodegenerative diseases. Further, NPS burden appears to be associated differently with function across neurodegenerative disorders, highlighting the need for individualized clinical interventions.
Alzheimer’s disease; aging; aging and memory; cohort study; geriatric psychiatry.
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Jessica Emily Green et al.
Canadian Journal of Psychiatry.
Perturbations of the intestinal microbiota have been associated with mental health disorders, including major depressive disorder (MDD). Therefore, faecal microbiota transplantation (FMT) holds promise as a microbiota-modulating treatment for MDD. Yet, to date, there are no published controlled studies evaluating the use of FMT for MDD. This study aimed to address this gap by evaluating the feasibility, acceptability, and safety of FMT for MDD. The study was an 8-week, double-blind, 2:1 parallel group, randomized controlled pilot trial (n = 15) of enema-delivered FMT (n = 10) compared with a placebo enema (n = 5) in adults with moderate-to-severe MDD.
Recruitment was completed within 2 months, with 0% attrition and 100% attendance at key study appointments. There were no major protocol deviations. The placebo and blinding strategies were considered successful; nurses and participants correctly guessing their treatment allocation at a rate similar to that anticipated by chance. No serious or severe adverse events were reported in either group, and there were no significant differences in mild-to-moderate adverse events between groups (median of 2 adverse events per participant reported in both groups). Furthermore, the 12/15 participants who completed the Week 2 participant satisfaction survey agreed or strongly agreed that the enema delivery was tolerable and that they would have the treatment again if required. Whilst the study was not designed to measure clinical outcomes, exploratory data also suggested that the active FMT treatment may lead to improvements in gastrointestinal symptoms and quality of life in this population, noting that irritable bowel syndrome is commonly comorbid with MDD.
All feasibility targets were met or exceeded. This study found that enema-delivered FMT is feasible, acceptable, well-tolerated, and safe in patients with MDD. The findings of this study support further research to evaluate clinical efficacy, and the use of this protocol is supported.
FMT; MDD; depression; faecal microbiota transplantation; major depressive disorder; mental disorder; mental health; microbiome; mood disorders; psychiatry.
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Annette Erlangsen et al.
The British Journal of Psychiatry.
Case studies have linked SARS-CoV-2 infection to suicidal behaviour. However, conclusive evidence is lacking. To examine whether a history of SARS-CoV-2 infection or SARS-CoV-2-related hospital admission was associated with self-harm in the general population and in high-risk groups.
A cohort design was applied to nationwide data on all people aged ≥15 years and living in Denmark between 27 February 2020 and 15 October 2021. Exposure was identified as having had a positive SARS-CoV-2 PCR test, and further assessed as SARS-CoV-2-related hospital admission. Rates of probable self-harm were examined using adjusted incidence rate ratios (aIRRs). The following subgroups were identified: (a) lower educational level, (b) chronic medical conditions, (c) disability pension, (d) mental disorders, (e) substance use disorders, and history of (f) homelessness and (g) imprisonment.
Among 4 412 248 included individuals, 260 663 (5.9%) had tested positive for SARS-CoV-2. Out of 5453 individuals presenting with self-harm, 131 (2.4%) had been infected. Individuals with a history of a positive SARS-CoV-2 test result had an aIRR for self-harm of 0.86 (95% CI 0.72-1.03) compared with those without. High rates were found after a SARS-CoV-2-related hospital admission (aIRR = 7.68; 95% CI 5.61-10.51) or a non-SARS-CoV-2-related admission (aIRR = 10.27; 95% CI 9.65-10.93) versus non-infected and not admitted. In sensitivity analyses with a more restrictive definition of self-harm, a positive PCR test was associated with lower rates of self-harm.
Individuals with a PCR-confirmed SARS-CoV-2 infection did not have higher rates of self-harm than those without. Hospital admission in general, rather than being SARS-CoV-2 positive. seemed to be linked to elevated rates of self-harm.
COVID-19; SARS-CoV-2; Suicide attempt; epidemiology; self-harm.
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Shiori Honda et al.
Schizophrenia Research.
Accumulating evidence indicates that pathophysiology of schizophrenia involves abnormalities in the dopamine and glutamatergic neuronal systems. Antipsychotic medications are currently used to normalize dopaminergic function for schizophrenia. However, approximately 30 % of the patients have no response to antipsychotic medications, which is classified as treatment-resistant schizophrenia (TRS). Furthermore, dopamine and glutamate levels in the neural basis have been reported to differ between TRS and non-TRS. In this study, we assumed that these differences may affect music rhythm perception and production abilities between the two groups. We examined fifty-seven schizophrenia (26 TRS, 31 non-TRS) and thirty-one healthy controls (HCs) by using the Harvard Beat Assessment Test (H-BAT). As a result, we found that rhythm production was worse in patients with TRS compared to patients with non-TRS and HCs, while no difference was observed between patients with non-TRS and HCs. In addition, rhythm perception and production abilities were impaired in the whole patient group compared with HCs. Furthermore, in the patient group, the deficits were correlated with cognitive impairments. Collectively, these results suggest that patients with schizophrenia may have rhythm processing deficits, with particular a rhythm production problem in the TRS group.
H-BAT; Music rhythm perception; Music rhythm production; Schizophrenia; Treatment response.
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Gunnhild E Hoprekstad et al.
Schizophrenia Research.
Depression occurs frequently in all phases of schizophrenia spectrum disorders. Altered activity in the immune system is seen in both depression and schizophrenia. We aimed to uncover depressive trajectories in a sample of 144 adult individuals with schizophrenia spectrum disorders followed for one year, in order to identify possible cytokine profile differences. Patients were assessed longitudinally with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS), where a score above 6 predicts depression. The serum cytokine concentrations for tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p70 and IL-17A were measured using immunoassays. Latent growth curve models, multilevel models and latent class growth analysis (LCGA) were applied. The LCGA model supported three latent classes (trajectories) with differing CDSS profiles during the one-year follow-up: a high CDSS group (40.8 % of participants), a moderate CDSS group (43.9 %) and a low CDSS group (15.3 %). Five single PANSS items predicted affiliation to depressive trajectory: hallucinations, difficulty in abstract thinking, anxiety, guilt feelings and tension. In the high CDSS group, despite diminishing psychotic symptoms, depressive symptoms persisted throughout one year. The pro-inflammatory cytokines IFN-γ, IL-1β and TNF-α were differentially distributed between the depressive trajectories, although levels remained remarkably stable throughout 12 months. Significant changes were found for the anti-inflammatory cytokine IL-10 at baseline with an accompanying difference in change over time. More research is required to optimize future treatment stratification and investigate the contribution of inflammation in depressed patients with schizophrenia spectrum disorders.
CRP; Depression; Inflammation; Interleukin; Psychosis; Trajectory.
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Brian J Miller et al.
Schizophrenia Research.
The clinical course of schizophrenia is often characterized by recurrent relapses. Blood inflammatory markers are altered in acute psychosis, and may be state markers for illness relapse in schizophrenia. Few studies have investigated longitudinal, intra-individual changes in inflammatory markers as a predictor of relapse. In the present study, we explored this association in a relapse prevention trial in patients with schizophrenia. We analyzed blood inflammatory markers in 200 subjects, with a mean 11 samples per subject, during the 30 month Preventing Relapse in schizophrenia: Oral Antipsychotics Compared to Injectable: eValuating Efficacy (PROACTIVE) trial. Associations between longitudinal changes in inflammatory markers and relapse were analyzed using a within-subjects design.
70 (35 %) of subjects relapsed during the study period. There were no significant differences in mean inflammatory marker levels based on relapse status (yes/no). Baseline levels of inflammatory markers did not predict incident relapse. Among subjects who relapsed, there was a significant decrease in mean blood IL-6 (n = 38, p = 0.019) and IFN-γ (n = 44, p = 0.012) levels from the visit before the relapse to the visit after relapse.
Although there was some evidence for inflammation as a potential state marker for acute psychosis, we did not find significant evidence for its utility as a relapse-predictive marker.
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Diana D van Bergen et al.
Canadian Journal of Psychiatry.
To examine whether sexual and gender minority (SGM) emerging adults perceived their SGM status was linked to suicidal ideation, and to explore if their responses fell within tenets of the minority stress framework. Open text (survey) responses of Dutch and Flemish SGM emerging adults (n = 187) were thematically analysed using the constant comparative comparison method for qualitative analysis.
We identified 8 themes in our qualitative analysis. Two themes fell within the scope of the minority stress framework that has received little attention: (1) concerns about relationships and family planning and (2) feeling different (internal stressor). Two additional themes emerged largely beyond the scope of existing minority stress framework studies on suicidality: (3) SGM-related questioning; (4) negativity in LGBT communities. Four established minority stress framework themes emerged: (5) gender identity stress; (6) victimization; (7) coming-out stress; (8) psychological difficulties linked to SGM status.
Suicide prevention needs to focus on supporting SGM emerging adults who worry about feeling “different”, or who have concerns over their romantic and family life, on reducing gender minority stress, as well as on caring for those who are victimized due to their sexual or gender identity.
emerging adults; minority stress; sexual/gender minorities; suicidal ideation.
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Review
Tomoya Hirota et al.
Journal of the American Medical Association.
Autism spectrum disorder (ASD), characterized by deficits in social communication and the presence of restricted, repetitive behaviors or interests, is a neurodevelopmental disorder affecting approximately 2.3% children aged 8 years in the US and approximately 2.2% of adults. This review summarizes evidence on the diagnosis and treatment of ASD. The estimated prevalence of ASD has been increasing in the US, from 1.1% in 2008 to 2.3% in 2018, which is likely associated with changes in diagnostic criteria, improved performance of screening and diagnostic tools, and increased public awareness. No biomarkers specific to the diagnosis of ASD have been identified. Common early signs and symptoms of ASD in a child’s first 2 years of life include no response to name when called, no or limited use of gestures in communication, and lack of imaginative play. The criterion standard for the diagnosis of ASD is a comprehensive evaluation with a multidisciplinary team of clinicians and is based on semistructured direct observation of the child’s behavior and semistructured caregiver interview focused on the individual’s development and behaviors using standardized measures, such as the Autism Diagnostic Observation Schedule-Second Edition and the Autism Diagnostic Interview. These diagnostic measures have sensitivity of 91% and 80% and specificity of 76% and 72%, respectively. Compared with people without ASD, individuals with ASD have higher rates of depression (20% vs 7%), anxiety (11% vs 5%), sleep difficulties (13% vs 5%), and epilepsy (21% with co-occurring intellectual disability vs 0.8%). Intensive behavioral interventions, such as the Early Start Denver Model, are beneficial in children 5 years or younger for improvement in language, play, and social communication (small to medium effect size based on standardized mean difference). Pharmacotherapy is indicated for co-occurring psychiatric conditions, such as emotion dysregulation or attention-deficit/hyperactivity disorder. Risperidone and aripiprazole can improve irritability and aggression (standardized mean difference of 1.1, consistent with a large effect size) compared with placebo. Psychostimulants are effective for attention-deficit/hyperactivity disorder (standardized mean difference of 0.6, consistent with a moderate effect size) compared with placebo. These medications are associated with adverse effects including, most commonly, changes in appetite, weight, and sleep.
ASD affects approximately 2.3% of children aged 8 years and approximately 2.2% of adults in the US. First-line therapy consists of behavioral interventions, while co-occurring psychiatric conditions, such as anxiety or aggression, may be treated with specific behavioral therapy or medication.
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Ian Kelleher.
The British Journal of Psychiatry.
Existing approaches to psychosis prediction capture only a small minority of future cases. Recent research shows that specialist child and adolescent mental health services (CAMHS) offer a (previously unrecognised) high-risk and high-capacity approach for psychosis early identification, prediction and, ultimately, prevention.
Psychotic disorders; epidemiology; in-patient treatment; out-patient treatment; schizophrenia.
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Evan Lester et al.
PNAS.
Tau aggregates are a hallmark of multiple neurodegenerative diseases and can contain RNAs and RNA-binding proteins, including serine/arginine repetitive matrix protein 2 (SRRM2) and pinin (PNN). However, how these nuclear proteins mislocalize and their influence on the prion-like propagation of tau aggregates is unknown. We demonstrate that polyserine repeats in SRRM2 and PNN are necessary and sufficient for recruitment to tau aggregates. Moreover, we show tau aggregates preferentially grow in association with endogenous cytoplasmic assemblies-mitotic interchromatin granules and cytoplasmic speckles (CSs)-which contain SRRM2 and PNN. Polyserine overexpression in cells nucleates assemblies that are sites of tau aggregate growth. Further, modulating the levels of polyserine-containing proteins results in a corresponding change in tau aggregation. These findings define a specific protein motif, and cellular condensates, that promote tau aggregate propagation. As CSs form in induced pluripotent stem cell (iPSC) derived neurons under inflammatory or hyperosmolar stress, they may affect tau aggregate propagation in neurodegenerative disease.
Alzheimer’s disease; RNA-binding proteins; SRRM2; frontotemporal dementia; tau.
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Toby Pillinger et al.
Lancet Psychiatry.
Cardiovascular disease is a major cause of excess mortality in people with schizophrenia. Several factors are responsible, including lifestyle and metabolic effects of antipsychotics. However, variations in cardiac structure and function are seen in people with schizophrenia in the absence of cardiovascular disease risk factors and after accounting for lifestyle and medication. Therefore, we aimed to explore whether shared genetic causes contribute to these cardiac variations. For this observational study, we used data from the UK Biobank and included White British or Irish individuals without diagnosed schizophrenia with variable polygenic risk scores for the condition. To test the association between polygenic risk score for schizophrenia and cardiac phenotype, we used principal component analysis and regression. Robust regression was then used to explore the association between the polygenic risk score for schizophrenia and individual cardiac phenotypes. We repeated analyses with fibro-inflammatory pathway-specific polygenic risk scores for schizophrenia. Last, we investigated genome-wide sharing of common variants between schizophrenia and cardiac phenotypes using linkage disequilibrium score regression. The primary outcome was principal component regression.
Of 33 353 individuals recruited, 32 279 participants had complete cardiac MRI data and were included in the analysis, of whom 16 625 (51·5%) were female and 15 654 (48·5%) were male. 1074 participants were excluded on the basis of incomplete cardiac MRI data (for all phenotypes). A model regressing polygenic risk scores for schizophrenia onto the first five cardiac principal components of the principal components analysis was significant (F=5·09; p=0·00012). Principal component 1 captured a pattern of increased cardiac volumes, increased absolute peak diastolic strain rates, and reduced ejection fractions; polygenic risk scores for schizophrenia and principal component 1 were negatively associated (β=-0·01 [SE 0·003]; p=0·017). Similar to the principal component analysis results, for individual cardiac phenotypes, we observed negative associations between polygenic risk scores for schizophrenia and indexed right ventricular end-systolic volume (β=-0·14 [0·04]; p=0·0013, pFDR=0·015), indexed right ventricular end-diastolic volume (β=-0·17 [0·08]); p=0·025; pFDR=0·082), and absolute longitudinal peak diastolic strain rates (β=-0·01 [0·003]; p=0·0024, pFDR=0·015), and a positive association between polygenic risk scores for schizophrenia and right ventricular ejection fraction (β=0·09 [0·03]; p=0·0041, pFDR=0·015). Models examining the transforming growth factor-β (TGF-β)-specific and acute inflammation-specific polygenic risk scores for schizophrenia found significant associations with the first five principal components (F=2·62, p=0·022; F=2·54, p=0·026). Using linkage disequilibrium score regression, we observed genetic overlap with schizophrenia for right ventricular end-systolic volume and right ventricular ejection fraction (p=0·0090, p=0·0077).
High polygenic risk scores for schizophrenia are associated with decreased cardiac volumes, increased ejection fractions, and decreased absolute peak diastolic strain rates. TGF-β and inflammatory pathways might be implicated, and there is evidence of genetic overlap for some cardiac phenotypes. Reduced absolute peak diastolic strain rates indicate increased myocardial stiffness and diastolic dysfunction, which increases risk of cardiac disease. Thus, genetic risk for schizophrenia is associated with cardiac structural changes that can worsen cardiac outcomes. Further work is required to determine whether these associations are specific to schizophrenia or are also seen in other psychiatric conditions.
National Institute for Health Research, Maudsley Charity, Wellcome Trust, Medical Research Council, Academy of Medical Sciences, Edmond J Safra Foundation, British Heart Foundation.
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Laura D Straus et al.
JAMA Psychiatry.
Adverse posttraumatic neuropsychiatric sequelae after traumatic stress exposure are common and have higher incidence among socioeconomically disadvantaged populations. Pain, depression, avoidance of trauma reminders, reexperiencing trauma, anxiety, hyperarousal, sleep disruption, and nightmares have been reported. Wrist-wearable devices with accelerometers capable of assessing 24-hour rest-activity characteristics are prevalent and may have utility in measuring these outcomes. To evaluate whether wrist-wearable devices can provide useful biomarkers for recovery after traumatic stress exposure.
Data were analyzed from a diverse cohort of individuals seen in the emergency department after experiencing a traumatic stress exposure, as part of the Advancing Understanding of Recovery After Trauma (AURORA) study. Participants recruited from 27 emergency departments wore wrist-wearable devices for 8 weeks, beginning in the emergency department, and completed serial assessments of neuropsychiatric symptoms. A total of 19 019 patients were screened. Of these, 3040 patients met study criteria, provided informed consent, and completed baseline assessments. A total of 2021 provided data from wrist-wearable devices, completed the 8-week assessment, and were included in this analysis. The data were randomly divided into 2 equal parts (n = 1010) for biomarker identification and validation. Data were collected from September 2017 to January 2020, and data were analyzed from May 2020 to November 2022.
Participants were recruited for the study after experiencing a traumatic stress exposure (most commonly motor vehicle collision).
Rest-activity characteristics were derived and validated from wrist-wearable devices associated with specific self-reported symptom domains at a point in time and changes in symptom severity over time.
Of 2021 included patients, 1257 (62.2%) were female, and the mean (SD) age was 35.8 (13.0) years. Eight wrist-wearable device biomarkers for symptoms of adverse posttraumatic neuropsychiatric sequelae exceeded significance thresholds in the derivation cohort. One of these, reduced 24-hour activity variance, was associated with greater pain severity (r = -0.14; 95% CI, -0.20 to -0.07). Changes in 6 rest-activity measures were associated with changes in pain over time, and changes in the number of transitions between sleep and wake over time were associated with changes in pain, sleep, and anxiety. Simple cutoffs for these biomarkers identified individuals with good recovery for pain (positive predictive value [PPV], 0.85; 95% CI, 0.82-0.88), sleep (PPV, 0.63; 95% CI, 0.59-0.67, and anxiety (PPV, 0.76; 95% CI, 0.72-0.80) with high predictive value.
These findings suggest that wrist-wearable device biomarkers may have utility as screening tools for pain, sleep, and anxiety symptom outcomes after trauma exposure in high-risk populations.
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Jessie R Baldwin et al.
American Journal of Psychiatry.
Childhood maltreatment is associated with mental health problems, but the extent to which this relationship is causal remains unclear. To strengthen causal inference, the authors conducted a systematic review and meta-analysis of quasi-experimental studies examining the relationship between childhood maltreatment and mental health problems. A search of , PsycINFO, and Embase was conducted for peer-reviewed, English-language articles from database inception until January 1, 2022. Studies were included if they examined the association between childhood maltreatment and mental health problems using a quasi-experimental method (e.g., twin/sibling differences design, children of twins design, adoption design, fixed-effects design, random-intercept cross-lagged panel model, natural experiment, propensity score matching, or inverse probability weighting).
Thirty-four quasi-experimental studies were identified, comprising 54,646 independent participants. Before quasi-experimental adjustment for confounding, childhood maltreatment was moderately associated with mental health problems (Cohen’s d=0.56, 95% CI=0.41, 0.71). After quasi-experimental adjustment, a small association between childhood maltreatment and mental health problems remained (Cohen’s d=0.31, 95% CI=0.24, 0.37). This adjusted association between childhood maltreatment and mental health was consistent across different quasi-experimental methods, and generalized across different psychiatric disorders.
These findings are consistent with a small, causal contribution of childhood maltreatment to mental health problems. Furthermore, the findings suggest that part of the overall risk of mental health problems in individuals exposed to maltreatment is due to wider genetic and environmental risk factors. Therefore, preventing childhood maltreatment and addressing wider psychiatric risk factors in individuals exposed to maltreatment could help to prevent psychopathology.
Child/Adolescent Psychiatry; Environmental Risk Factors; Genetics/Genomics; Violence/Aggression.
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Ziv Ben-Zion et al.
American Journal of Psychiatry.
The weak link between subjective symptom-based diagnostic methods for posttraumatic psychopathology and objectively measured neurobiological indices forms a barrier to the development of effective personalized treatments. To overcome this problem, recent studies have aimed to stratify psychiatric disorders by identifying consistent subgroups based on objective neural markers. Along these lines, a promising 2021 study by Stevens et al. identified distinct brain-based biotypes associated with different longitudinal patterns of posttraumatic symptoms. Here, the authors conducted a conceptual nonexact replication of that study using a comparable data set from a multimodal longitudinal study of recent trauma survivors. A total of 130 participants (mean age, 33.61 years, SD=11.21; 48% women) admitted to a general hospital emergency department following trauma exposure underwent demographic, clinical, and neuroimaging assessments 1, 6, and 14 months after trauma. All analyses followed the pipeline outlined in the original study and were conducted in collaboration with its authors.
Task-based functional MRI conducted 1 month posttrauma was used to identify four clusters of individuals based on profiles of neural activity reflecting threat and reward reactivity. These clusters were not identical to the previously identified brain-based biotypes and were not associated with prospective symptoms of posttraumatic psychopathology.
Overall, these findings suggest that the original brain-based biotypes of trauma resilience and psychopathology may not generalize to other populations. Thus, caution is warranted when attempting to define subtypes of psychiatric vulnerability using neural indices before treatment implications can be fully realized. Additional replication studies are needed to identify more stable and generalizable neuroimaging-based biotypes of posttraumatic psychopathology.
Biological Markers; Neuroimaging; Neuroscience; Posttraumatic Stress Disorder (PTSD); Replication Study; Stress.
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Jennifer L Cleary et al.
American Journal of Psychiatry.
Despite substantial progress in identifying genomic variation associated with major depression, the mechanisms by which genomic and environmental factors jointly influence depression risk remain unclear. Genomically conferred sensitivity to the social environment may be one mechanism linking genomic variation and depressive symptoms. The authors assessed whether social support affects the likelihood of depression development differently across the spectrum of genomic risk in two samples that experienced substantial life stress: 1,011 first-year training physicians (interns) in the Intern Health Study (IHS) and 435 recently widowed Health and Retirement Study (HRS) participants. Participants’ depressive symptoms and social support were assessed with questionnaires that were administered before and after the life stressor. Polygenic risk scores (PRSs) for major depressive disorder were calculated for both samples.
Depressive symptom scores increased by 126% after the start of internship in the IHS sample and by 34% after widowing in the HRS sample. There was an interaction between depression PRS and change in social support in the prediction of depressive symptoms in both the IHS sample (incidence rate ratio [IRR]=0.96, 95% CI=0.93, 0.98) and the HRS sample (IRR=0.78, 95% CI=0.66, 0.92), with higher depression PRS associated with greater sensitivity to changes in social support. Johnson-Neyman intervals indicated a crossover effect, with losses and gains in social support moderating the effect of PRS on depressive symptoms. (Johnson-Neyman interval in the IHS sample, -0.02, 0.71; in the HRS sample, -0.49, 1.92).
The study findings suggest that individuals with high genomic risk for developing increased depressive symptoms under adverse social conditions also benefit more from nurturing social environments.
Depressive Disorders; Development; Genetics/Genomics; Major Depressive Disorder; Stress.
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Soo Yun Choi et al.
Schizophrenia Research.
Negative symptoms in schizophrenia include cognitive and affective dysfunction, such as diminished expression and amotivation. Although the cerebellar posterior hemisphere and vermis are involved in cognitive and affective functioning, previous studies on the neural mechanism of negative symptoms have mostly been confined to the cerebral cortex. This study aimed to investigate whether resting-state cerebellar-cerebral functional connectivity (FC) is altered in first-episode psychosis (FEP) patients and whether this connectivity is related to negative symptoms. Resting-state functional magnetic resonance images were obtained from 38 FEP patients and 100 healthy controls (HCs). Using the posterior hemisphere and vermis of the cerebellum as seeds, whole-brain FC was compared between FEP patients and HCs. As cerebellar-parietal cortex connectivity is associated with negative symptoms and sociocognitive dysfunctions in schizophrenia patients, its correlation with negative symptoms was explored in FEP patients.
FEP patients showed hyperconnectivity between the cerebellum and bilateral frontal pole (FP), occipital pole, fusiform gyrus, right lingual gyrus, central opercular cortex, anterior middle temporal gyrus, precuneus, and subcallosal cortex. Hypoconnectivity was found between the cerebellum and left FP, right anterior supramarginal gyrus (aSMG), and cerebellum crus I. FC between the left crus II and right aSMG was negatively correlated with the severity of negative symptoms and diminished expression.
Altered FC between the cerebellum and cerebral regions related to cognitive, affective, and sensory processing was found in FEP patients and was connected to negative symptoms. These results suggest that the cerebellum plays a role in the pathophysiology of negative symptoms in schizophrenia.
Cerebellum; First-episode psychosis; Functional connectivity; Negative symptoms; Schizophrenia.
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Michael R Das et al.
PNAS.
CAG trinucleotide repeat expansions cause several neurodegenerative diseases, including Huntington’s disease and spinocerebellar ataxia. RNAs with expanded CAG repeats contribute to disease in two unusual ways. First, these repeat-containing RNAs may agglomerate in the nucleus as foci that sequester several RNA-binding proteins. Second, these RNAs may undergo aberrant repeat-associated non-AUG (RAN) translation in multiple frames and produce aggregation-prone proteins. The relationship between RAN translation and RNA foci, and their relative contributions to cellular dysfunction, are unclear. Here, we show that CAG repeat-containing RNAs that undergo RAN translation first accumulate at nuclear foci and, over time, are exported to the cytoplasm. In the cytoplasm, these RNAs are initially dispersed but, upon RAN translation, aggregate with the RAN translation products. These RNA-RAN protein agglomerates sequester various RNA-binding proteins and are associated with the disruption of nucleocytoplasmic transport and cell death. In contrast, RNA accumulation at nuclear foci alone does not produce discernable defects in nucleocytoplasmic transport or cell viability. Inhibition of RAN translation prevents cytoplasmic RNA aggregation and alleviates cell toxicity. Our findings demonstrate that RAN translation-induced RNA-protein aggregation correlates with the key pathological hallmarks observed in disease and suggest that cytoplasmic RNA aggregation may be an underappreciated phenomenon in CAG trinucleotide repeat expansion disorders.
RAN translation; RNA aggregation; RNA localization; Repeat expansion diseases.
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Brittany M Gouse et al.
Schizophrenia Research.
Many patients with schizophrenia spectrum disorders disengage from treatment, with negative impacts on prognosis and recovery. This commentary provides an overview of common reasons underlying treatment dropout and strategies for overcoming obstacles and enhancing patient engagement. Basic clinical skills such as open-ended questions and reflective listening can be powerful tools in unmasking structural and attitudinal barriers to psychosis care.
Clozapine; Dropout; Engagement; Motivational interviewing; Psychotherapy; Treatment.
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Noham Wolpe et al.
The British Journal of Psychiatry.
Negative symptoms of schizophrenia manifest as reduced motivation and pleasure (MAP) and impaired emotional expressivity (EXP). These can occur as primary phenomena, but have also been suggested to occur secondary to other clinical factors, including antipsychotic-induced sedation. However, this relationship has not been established formally. Here, we examined the effect of antipsychotic-induced sedation (assessed via the proxy of total daily sleep duration) on MAP and EXP in a cohort of 187 clozapine-treated patients with schizophrenia followed for over 2 years on average, using multilevel regression and mediation models. MAP, but not EXP, was adversely influenced by sedation, independently of the severity of psychosis or depression. Moreover, clozapine impaired MAP indirectly by worsening sedation, but after accounting for clozapine-induced sedation, clozapine improved MAP. Our results highlight the importance of addressing sedative side-effects of antipsychotics to improve clinical outcomes.
antipsychotic; apathy; motivation; negative symptoms; psychopharmacology.
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Abigail C Wright et al.
Schizophrenia Research.
Hallucinations have been linked to failures in metacognitive reflection suggesting an association between hallucinations and overestimation of performance, although the cross-sectional findings are inconsistent. This inconsistency may relate to the fluctuating hallucinatory experiences that are not captured in cross-sectional studies. Ecological Momentary Assessment (EMA) captures in-the-moment experiences over time so can identify causal relationships between variables such as the associations between metacognition and hallucinatory experience in daily life and overcome problems in cross-sectional designs. Participants (N = 41) experiencing daily hallucinations completed baseline questionnaires and smartphone surveys 7 times per day for 14 days. They were prompted to identify a task they would complete in the next 4 h and to make metacognitive predictions around the likelihood of completing the task, the difficulty of the task, and how well they would complete it (standard of completion).
76 % finished the 14-days of assessment with an average of 42.2 % survey completion. Less accurate metacognition was associated with more hallucinations, but less accurate likelihood and standard of completion was associated with fewer hallucinations. Using a cross-lagged analysis, metacognitive predictions around the likelihood of completion (p < .001) and standard of completion (p = .01) predicted hallucination intensity at the following timepoint, and metacognitive predictions regarding likelihood of completion (p = .02) predicted hallucination control at the following timepoint.
Interventions that aim to improve metacognitive ability in-the-moment may serve to reduce the intensity and increase the control of hallucinations.
Cognitive-affective processing; EMA; ESM; Hallucinations; Metacognition; Mobile health; Psychosis.
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Paul Roux et al.
Schizophrenia Research.
Social metacognition is still poorly understood in schizophrenia, particularly its neuropsychological basis and its impact on insight and medication adherence. We therefore quantified social metacognition as the agreement between objective and subjective mentalization and assessed its correlates in a sample of individuals with schizophrenia spectrum disorders. Participants consisted of 143 patients with schizophrenia or schizoaffective disorders who underwent a metacognitive version of a mentalization task, an extensive neuropsychological battery, and a clinical evaluation to assess their insight into illness and medication adherence. We studied potential interactions between confidence judgments and several neuropsychological and clinical variables on mentalization accuracy with mixed-effects multiple logistic regressions.
Confidence judgments were closely associated with mentalization accuracy, indicative of good social metacognition in this task. Working memory, visual memory, and reasoning and problem-solving were the three neuropsychological dimensions positively associated with metacognition. By contrast, the two measures of medication adherence were associated with poorer metacognition, whereas no association was found between metacognition and clinical insight. The multiple regression model showed a significant positive impact of better working memory, older age at onset, longer duration of hospitalization, and worse medication adherence on social metacognition.
We discuss possible mechanisms underlying the apparent association between social metacognition and working memory. Adherence should be monitored when remediating social metacognition, and psychoeducation should be given to patients with a high level of awareness of their capacity to mentalize.
Insight; Medication adherence; Mentalization; Metacognition; Neuropsychological assessment; Schizophrenia; Social cognition.
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Randomized Controlled Trial
Carmen Tse et al.
Gastroenterology.
We investigated sleep disturbances, bowel movement (BM) kinetics, and travel experience with different bowel preparation regimens in a substudy of patients enrolled in a randomized multicenter Canadian clinical trial. Patients scheduled to have a colonoscopy between 7:30 am and 10:30 am (early morning) were randomized to (i) 4-L single-dose polyethylene glycol (PEG) given in the evening before, (ii) 2-L split-dose PEG (+bisacodyl 15 mg), or (iii) 4-L split-dose PEG. Patients scheduled to undergo a colonoscopy between 10:30 am and 4:30 pm (afternoon) were randomized to (iv) 2-L single-dose PEG (+bisacodyl 15 mg) in the morning, (v) 2-L split-dose PEG (+bisacodyl 15 mg), or (vi) 4-L split-dose PEG. Patients were asked to record information on BM kinetics, sleep, and travel to the endoscopy unit. Continuous and categorical variables were compared between groups using a Kruskal-Wallis test or χ 2 test, respectively. Intention-to-treat analyses were performed.
Overall, 641 patients were included in this substudy. Patients undergoing early morning colonoscopies reported the most awakenings in the night when assigned to 4-L single-dose day-before PEG and the highest reduction in sleep hours when assigned to 4-L split-dose PEG. There were no significant between-group differences in urgent BMs, fecal incontinence episodes, or travel interruptions. Overall, 17% of those traveling for more than an hour had to stop for a BM during travel, with no significant difference between groups.
Day-before and split-dose high-volume PEG regimens for colonoscopies scheduled before 10:30 am lead to the greatest sleep disturbance.
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Gustavo J Gil-Berrozpe et al.
Schizophrenia Research.
First-episode psychosis is a critical period for early interventions to reduce the risk of poor outcomes and relapse as much as possible. However, uncertainties about the long-term outcomes of symptomatology remain to be ascertained. The aim of the present study was to use network analysis to investigate first-episode and long-term stages of psychosis at three levels of analysis: micro, meso and macro. The sample was a cohort of 510 patients with first-episode psychoses from the SEGPEP study, who were reassessed at the long-term follow-up (n = 243). We used the Comprehensive Assessment of Symptoms and History for their assessments and lifetime outcome variables of clinical relevance.
Our results showed a similar pattern of clustering between first episodes and long-term follow-up in seven psychopathological dimensions at the micro level, 3 and 4 dimensions at the meso level, and one at the macro level. They also revealed significant differences between first-episode and long-term network structure and centrality measures at the three levels, showing that disorganization symptoms have more influence in long-term stabilized patients.
Our findings suggest a relative clustering invariance at all levels, with the presence of two domains of disorganization as the most notorious difference over time at micro level. The severity of disorganization at the follow-up was associated with a more severe course of the psychosis. Moreover, a relative stability in global strength of the interconnections was found, even though the network structure varied significantly in the long-term follow-up. The macro level was helpful in the integration of all dimensions into a common psychopathology factor, and in unveiling the strong relationships of psychopathological dimensions with lifetime outcomes, such as negative with poor functioning, disorganization with high antipsychotic dose-years, and delusions with poor adherence to treatment. These results add evidence to the hierarchical, dimensional and longitudinal structure of psychopathological symptoms and their clinical relevance in first-episode psychoses.
First-episode psychosis; Follow-up; Long-term; Network analysis; Psychopathology.
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Jin Hu et al.
Neuron.
The pathology of Alzheimer’s disease (AD) is featured with extracellular amyloid-β (Aβ) plaques, whose impact on the mechanical properties of the surrounding brain tissues is unclear. Microglia sense and integrate biochemical cues of the microenvironment. However, whether the microglial mechanosensing pathways influence AD pathogenesis is unknown. Here, we surveyed the elevated stiffness of Aβ-plaque-associated tissues and observed the selective upregulation of the mechanosensitive ion channel Piezo1 in Aβ-plaque-associated microglia. Piezo1 sensed the stiffness stimuli of Aβ fibrils and subsequently induced Ca influx for microglial clustering, phagocytosis, and compacting of Aβ plaques. Microglia lacking Piezo1 led to the exacerbation of Aβ pathology and cognitive decline, whereas pharmacological activation of microglial Piezo1 ameliorated brain Aβ burden and cognitive impairment in 5 × FAD mice. Together, our results reveal that Piezo1, a mechanosensor of Aβ fibril stiffness in microglia, represents a potential therapeutic target for AD.
Alzheimer’s disease; Aβ plaque; Piezo1; microglial mechanosensor.
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Rose Jeppesen et al.
Schizophrenia Research.
Antineuronal antibodies can cause psychotic symptoms, particularly NMDAR antibodies; however, studies on the prevalence of antineuronal antibodies in cerebrospinal fluid (CSF) and serum of patients with psychotic disorders compared to matched healthy controls are sparse. We included 104 patients with a first-time diagnosis of a psychotic disorder within one year prior to inclusion (50 % outpatients) and 104 individually matched healthy controls, all without any known immunological conditions. CSF and serum were tested for IgG antibodies (Abs) against NMDAR NR1-subunit, GAD65, LGI1, CASPR2, AMPAR1, AMPAR2 and GABAb-receptor B1/B2 using commercial fixed cell-based assays (CBAs) (Euroimmun). Positive samples were retested with CBA twice, and tested with tissue-based assays (TBA). Primary outcomes were the presence of any of the seven anti-neuronal antibodies in CSF or serum. Secondarily, we analyzed the prevalence of each autoantibody.
No antineuronal IgG antibodies were consistently found in any CSF sample and NMDAR-antibodies were not consistently present in any of the 208 participants, neither in CSF nor serum. CASPR2-Abs were consistently found in the serum of one patient and one control, and one healthy control, without diabetes, was seropositive for GAD65-Abs. CASPR2 borderline seropositivity was additionally found in one patient and two controls. All samples positive on CBA were negative on TBA.
We found no significant differences between patients and controls. Antineuronal IgG antibodies are very rare when screening a broad group of individuals with recent-onset psychotic disorders without other indications of autoimmune encephalitis. Thus, much larger studies are needed to conclude on potential contrasts in prevalence compared to healthy controls.
Antibodies; Autoimmune encephalitis; CSF; Psychosis; Schizophrenia.
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Nina Dalkner et al.
Schizophrenia Research.
Mood states have been reported to manifest a cross-sectional correlation with self-assessment accuracy across functional domains and psychiatric conditions. Ecological momentary assessment (EMA) provides a strategy to examine the momentary course and correlates of mood states. This study tested the association of moods assessed longitudinally with accuracy of immediate self-assessments of cognitive test performance in participants with schizophrenia and bipolar disorder. 240 well-diagnosed participants with schizophrenia and bipolar disorder completed a subset of tests from the MATRICS Consensus Cognitive Battery and an immediate self-assessment of cognitive performance. Differences between actual and self-reported performance were used to index the accuracy of self-assessment. Daily smartphone EMA, 3× per day for 30 days, sampled participants´ momentary moods (sad, happy, relaxed, anxious), aggregated into positive affect and negative affect (NA).
Bipolar participants had better cognitive performance, but both samples had equivalent mis-estimation. Repeated-measures analyses found that NA did not manifest significant variability over time either between or within participants in the two diagnostic groups. Within-group analyses found that higher average NA was associated with greater mis-estimation and poorer cognitive performance in participants with bipolar disorder, but not in those with schizophrenia.
Negative moods had a significant association with impairments in self-assessment of cognitive performance in participants with bipolar disorder. Our study did not confirm previous cross-sectional findings of more accurate self-assessment associated with greater NA in schizophrenia. These findings suggest that cross-sectional assessments, particularly self-reports, may lead to different results than aggregated data from longitudinal evaluations.
Bipolar disorder; Cognitive functioning; Ecological momentary assessment; Introspective accuracy; Negative affect; Schizophrenia.
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Review
Ana Luísa Lamounier Costa et al.
Schizophrenia Research.
Visual illusions have long been used as tools to investigate sensory-perceptual deficits in schizophrenia. Recent conflicting accounts have called into question the assumption of abnormal illusion perception in patients and, therefore, the validity of this approach. Here, we present a systematic review of the current evidence regarding visual illusion perception abnormalities in patients with schizophrenia. Relevant publications were identified by a systematic search of , Literatura LILACS, PsycINFO, Embase, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), IBECS, BIOSIS, and Web of Science. Forty-five studies were selected which included illusions classified as ‘Motion illusions’, ‘Geometric-optical illusions’, ‘Illusory contours’, ‘Depth inversion illusion’, and ‘Non-specific’. There is concordant evidence of abnormal processing of illusions in patients for most categories, especially in facial Depth Inversion and Müller-Lyer illusions. There were significant methodological disparities and shortcomings, but risk of bias was overall low for individual studies. The usefulness of visual illusions as tools in clinical settings as well as in basic research may be contingent on significant methodological refinements.
Schizophrenia; Systematic review; Visual illusions; Visual perception.
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Paola Bucci et al.
Schizophrenia Research.
Gender differences in clinical and psychosocial aspects of schizophrenia have been widely reported. Findings have not always been consistent, and some of them need further research. In a large sample of community dwelling persons with schizophrenia, we investigated gender differences in clinical, cognitive and functional indices, as well as their changes over a 4-year follow-up and their impact on real-life functioning. Gender differences in personal resources, cognitive and functional indices were explored also in a sample of healthy controls. Men with respect to women had an earlier age of illness onset, a worse premorbid adjustment in the academic domain, more severe avolition, expressive deficit and positive symptoms, lower prevalence of comorbidity for affective disorders, less frequent use of two coping strategies (‘religion’ and ‘use of emotional support’) and more frequent positive history of substance and alcohol abuse. In addition, men were more impaired in verbal learning, while women in reasoning/problem solving. Some patterns of gender differences observed in healthy controls were not confirmed in patients. Men’s disadvantages in the clinical picture did not translate into a worse outcome. This finding may be related to the complex interplay of several factors acting as predictors or mediators of outcome.
Cognition; Functional remission; Gender differences; Personal resources; Schizophrenia; Symptomatic remission.
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Birgitte Klee Burton et al.
Lancet Psychiatry.
Motor abnormalities have clinical relevance as a component of psychotic illness; they are not only a proxy of altered neurodevelopment, but also intimately related to psychotic risk. We aimed to assess motor development and its association with psychotic experiences in children with familial high risk (FHR) of schizophrenia or bipolar disorder compared with controls. The Danish High Risk and Resilience Study is a prospective longitudinal cohort study, for which participants were extracted from Danish registers. Children born in Denmark between Sept 1, 2004, and Aug 31, 2009, with no, one, or two parents born in Denmark with schizophrenia or bipolar disorder, could be included in the study. No ethnicity data were collected. Children with no biological parent diagnosed with schizophrenia spectrum disorder or bipolar disorder were matched to children with FHR of schizophrenia (one or two parents with schizophrenia spectrum disorder) on the basis of sex, age, and municipality. Children with FHR of bipolar disorder (one or two parents with bipolar disorder) were included as a non-matched group. We assessed motor function in children with FHR of schizophrenia, children with FHR of bipolar disorder, and children in the control group at approximately age 8 years (baseline; 2013-16) and age 12 years (follow-up; 2017-20) using the Movement Assessment Battery for Children-Second Edition (Movement ABC-2). Psychotic experiences were assessed using the psychosis section of the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Raters were masked regarding familial risk status. Motor development from baseline to follow-up in the different groups was assessed using a linear mixed model. Logistic regression examined the relationship between definite motor problems (≤5th percentile on Movement ABC-2) and psychotic experiences.
Between March 1, 2017, and June 30, 2020, we studied 437 children (234 [54%] boys, 203 [46%] girls; mean age 11·99 years [SD 0·26, range 11·08-12·86]). Children with FHR of schizophrenia showed stable motor developmental deficits in manual dexterity (difference in intercept -1·62 [95% CI -2·39 to -0·85], p<0·0001; difference in slope 0·17 [-0·48 to 0·81], p=0·61) and balance (difference in intercept -1·58 [-2·34 to -0·82], p<0·0001; difference in slope 0·32 [-0·34 to 0·99], p=0·34), and a developmental lag in aiming and catching (difference in slope -1·07 [-1·72 to -0·41], p=0·0015; difference in intercept -0·59 [-1·35 to 0·17], p=0·13) compared with controls. Children with FHR of bipolar disorder showed no motor developmental differences on a group basis. Compared with controls, children with FHR of schizophrenia were more likely to have definite motor problems (odds ratio [OR] 2·86 [95% CI 1·60 to 5·11], p=0·0004), as were children with FHR of bipolar disorder (OR 2·45 [1·28 to 4·70], p=0·0068). Children with definite motor problems across all groups were more likely (OR 1·90 [1·12 to 3·21, p=0·017] to have had psychotic experiences than children with no definite motor problems.
Clinicians should be aware that motor impairment in childhood can reflect neurodevelopmental vulnerability to psychosis. Our findings contribute to the identification of early risk markers for severe mental illness, both for use by clinicians and for establishing a basis for future primary preventive intervention studies in the premorbid phase.
The Independent Research Fund Denmark, the Mental Health Services of the Capital Region of Denmark, the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, the Beatrice Surovell Haskell Fund, the Tryg Foundation, and the Innovation Fund Denmark.
For the Danish translation of the abstract see Supplementary Materials section.
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Dusan Hirjak et al.
Schizophrenia Research.
A comprehensive assessment of catatonic symptoms is decisive for diagnosis, neuronal correlates, and evaluation of treatment response and prognosis of catatonia. Studies conducted so far used different cut-off criteria and clinical rating scales to assess catatonia. Therefore, the main aim of this study was to examine the frequency and distribution of diagnostic criteria and clinical rating scales for assessing catatonia that were used in scientific studies so far. We conducted a systematic review using searching for articles using catatonia rating scales/criteria published from January 1st 1952 (introduction of catatonic schizophrenia to first edition of the Diagnostic and Statistical Manual of Mental Disorders [DSM]) up to December 5th, 2022.
1928 articles were considered for analysis. 1762 (91,39 %) studies used one and 166 (8,61 %) used ≥2 definitions of catatonia. However, 979 (50,7 %) articles did not report any systematic assessment of catatonia. As for clinical criteria, DSM criteria were used by the majority of studies (n = 290; 14.0 %), followed by International Classification of Diseases (ICD) criteria (n = 61; 2.9 %). The Bush-Francis Catatonia Rating Scale (BFCRS) was found to be by far the most frequently utilized scale (n = 464; 22.4 % in the respective years), followed by Northoff Catatonia Rating Scale (NCRS) (n = 31; 1.5 % in the respective years).
DSM and ICD criteria as well as BFCRS and NCRS were most frequently utilized and can therefore be recommended as valid instruments for the assessment of catatonia symptomatology.
Catatonia; Clinical rating scale; Frequency; Review.
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Randomized Controlled Trial
Christopher H van Dyck et al.
The New England Journal of Medicine.
The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer’s disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer’s disease. We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer’s disease (mild cognitive impairment or mild dementia due to Alzheimer’s disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer’s Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).
A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.
Lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).
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Kathleen J O’Brien et al.
The British Journal of Psychiatry.
Evidence suggests that both childhood trauma and perceived stress are risk factors for the development of psychosis, as well as negative symptoms such as anhedonia. Previous findings link increases in perceived stress to anhedonia in individuals at clinical high risk for psychosis (CHR) and depression; however, the role of childhood trauma in this relationship has not yet been explored, despite consistent evidence that it is associated with sensitisation to later stress. To examine whether perceived stress mediates the relationship between childhood trauma and anhedonia in a group of youth at CHR as well as in controls (groups with depression and with no diagnosed mental health concerns).
The study used multigroup mediation to examine the indirect effects of childhood trauma on anhedonia via perceived stress in CHR (n = 117) and depression groups (n = 284) and non-psychiatric controls (n = 124).
Perceived stress mediated the relationship between childhood trauma and consummatory anhedonia regardless of group status. Perceived stress mediated the relationship between childhood trauma and anticipatory anhedonia for the CHR and depression groups, but not for non-psychiatric controls. Further, groups differed in the magnitude of this relationship, with the effects trending towards stronger for those in the CHR group.
Our findings suggest a potential transdiagnostic pathway through which childhood trauma contributes to anhedonia across severe mental illness.
Trauma; childhood experience; comorbidity; depressive disorders; psychotic disorders.
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Chenzhong Yin et al.
PNAS.
The gap between chronological age (CA) and biological brain age, as estimated from magnetic resonance images (MRIs), reflects how individual patterns of neuroanatomic aging deviate from their typical trajectories. MRI-derived brain age (BA) estimates are often obtained using deep learning models that may perform relatively poorly on new data or that lack neuroanatomic interpretability. This study introduces a convolutional neural network (CNN) to estimate BA after training on the MRIs of 4,681 cognitively normal (CN) participants and testing on 1,170 CN participants from an independent sample. BA estimation errors are notably lower than those of previous studies. At both individual and cohort levels, the CNN provides detailed anatomic maps of brain aging patterns that reveal sex dimorphisms and neurocognitive trajectories in adults with mild cognitive impairment (MCI, N = 351) and Alzheimer’s disease (AD, N = 359). In individuals with MCI (54% of whom were diagnosed with dementia within 10.9 y from MRI acquisition), BA is significantly better than CA in capturing dementia symptom severity, functional disability, and executive function. Profiles of sex dimorphism and lateralization in brain aging also map onto patterns of neuroanatomic change that reflect cognitive decline. Significant associations between BA and neurocognitive measures suggest that the proposed framework can map, systematically, the relationship between aging-related neuroanatomy changes in CN individuals and in participants with MCI or AD. Early identification of such neuroanatomy changes can help to screen individuals according to their AD risk.
Alzheimer’s disease; brain age; cognitive impairment; deep learning.
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Review
Kristin L Szuhany et al.
Journal of the American Medical Association.
Anxiety disorders have a lifetime prevalence of approximately 34% in the US, are often chronic, and significantly impair quality of life and functioning. Anxiety disorders are characterized by symptoms that include worry, social and performance fears, unexpected and/or triggered panic attacks, anticipatory anxiety, and avoidance behaviors. Generalized anxiety disorder (6.2% lifetime prevalence), social anxiety disorder (13% lifetime prevalence), and panic disorder (5.2% lifetime prevalence) with or without agoraphobia are common anxiety disorders seen in primary care. Anxiety disorders are associated with physical symptoms, such as palpitations, shortness of breath, and dizziness. Brief screening measures applied in primary care, such as the Generalized Anxiety Disorder-7, can aid in diagnosis of anxiety disorders (sensitivity, 57.6% to 93.9%; specificity, 61% to 97%). Providing information about symptoms, diagnosis, and evidence-based treatments is a first step in helping patients with anxiety. First-line treatments include pharmacotherapy and psychotherapy. Selective serotonin reuptake inhibitors (SSRIs, eg, sertraline) and serotonin-norepinephrine reuptake inhibitors (SNRIs, eg, venlafaxine extended release) remain first-line pharmacotherapy for generalized anxiety disorder, social anxiety disorder, and panic disorder. Meta-analyses suggest that SSRIs and SNRIs are associated with small to medium effect sizes compared with placebo (eg, generalized anxiety disorder: standardized mean difference [SMD], -0.55 [95% CI, -0.64 to -0.46]; social anxiety disorder: SMD, -0.67 [95% CI, -0.76 to -0.58]; panic disorder: SMD, -0.30 [95% CI, -0.37 to -0.23]). Cognitive behavioral therapy is the psychotherapy with the most evidence of efficacy for anxiety disorders compared with psychological or pill placebo (eg, generalized anxiety disorder: Hedges g = 1.01 [large effect size] [95% CI, 0.44 to 1.57]; social anxiety disorder: Hedges g = 0.41 [small to medium effect] [95% CI, 0.25 to 0.57]; panic disorder: Hedges g = 0.39 [small to medium effect[ [95% CI, 0.12 to 0.65]), including in primary care. When selecting treatment, clinicians should consider patient preference, current and prior treatments, medical and psychiatric comorbid illnesses, age, sex, and reproductive planning, as well as cost and access to care.
Anxiety disorders affect approximately 34% of adults during their lifetime in the US and are associated with significant distress and impairment. First-line treatments for anxiety disorders include cognitive behavioral therapy, SSRIs such as sertraline, and SNRIs such as venlafaxine extended release.
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Tara A Niendam et al.
JAMA Psychiatry.
Reducing the duration of untreated psychosis (DUP) is essential to improving outcomes for people with first-episode psychosis (FEP). Current US approaches are insufficient to reduce DUP to international standards of less than 90 days. To determine whether population-based electronic screening in addition to standard targeted clinician education increases early detection of psychosis and decreases DUP, compared with clinician education alone.
This cluster randomized clinical trial included individuals aged 12 to 30 years presenting for services between March 2015 and September 2017 at participating sites that included community mental health clinics and school support and special education services. Eligible participants were referred to the Early Diagnosis and Preventative Treatment (EDAPT) Clinic. Data analyses were performed in September and October 2019 for the primary and secondary analyses, with the exploratory subgroup analyses completed in May 2021.
All sites in both groups received targeted education about early psychosis for health care professionals. In the active screening group, clients also completed the Prodromal Questionnaire-Brief using tablets at intake; referrals were based on those scores and clinical judgment. In the group receiving treatment as usual (TAU), referrals were based on clinical judgment alone.
Primary outcomes included DUP, defined as the period from full psychosis onset to the date of the EDAPT diagnostic telephone interview, and the number of individuals identified with FEP or a psychosis spectrum disorder. Exploratory analyses examined differences by site type, completion rates between conditions, and days from service entry to telephone interview.
Twenty-four sites agreed to participate, and 12 sites were randomized to either the active screening or TAU group. However, only 10 community clinics and 4 school sites were able to fully implement population screening and were included in the final analysis. The total potentially eligible population size within each study group was similar, with 2432 individuals entering at active screening group sites and 2455 at TAU group sites. A total of 303 diagnostic telephone interviews were completed (178 [58.7%] female individuals; mean [SD] age, 17.09 years [4.57]). Active screening sites reported a significantly higher detection rate of psychosis spectrum disorders (136 cases [5.6%], relative to 65 [2.6%]; P < .001) and referred a higher proportion of individuals with FEP and DUP less than 90 days (13 cases, relative to 4; odds ratio, 0.30; 95% CI, 0.10-0.93; P = .03). There was no difference in mean (SD) DUP between groups (active screening group, 239.0 days [207.4]; TAU group 262.3 days [170.2]).
In this cluster trial, population-based technology-enhanced screening across community settings detected more than twice as many individuals with psychosis spectrum disorders compared with clinical judgment alone but did not reduce DUP. Screening could identify people undetected in US mental health services. Significant DUP reduction may require interventions to reduce time to the first mental health contact.
ClinicalTrials.gov Identifier: NCT02841956.
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Review
Denise Wilfling et al.
Cochrane Database of Systematic Reviews.
Sleep disturbances occur frequently in people with dementia with a reported prevalence of up to 40%. Common problems are increased number and duration of awakenings and increased percentage of light sleep. Sleep disturbances are associated with a number of problems for people with dementia, their relatives, and carers. In people with dementia, they may lead to worsening of cognitive symptoms, challenging behaviours such as restlessness or wandering, and further harms, such as accidental falls. Sleep disturbances are also associated with significant carer distress and have been reported as a factor contributing to institutionalisation of people with dementia. As pharmacological approaches have shown unsatisfactory results, there is a need to synthesise the research evidence on non-pharmacological strategies to improve sleep in people with dementia. As interventions are often complex, consisting of more than one active component, and implemented in complex contexts, it may not be easy to identify effective intervention components. To evaluate the benefits and harms of non-pharmacological interventions on sleep disturbances in people with dementia compared to usual care, no treatment, any other non-pharmacological intervention, or any drug treatment intended to improve sleep, and to describe the components and processes of any complex intervention included.
We used standard, extensive Cochrane search methods. The latest search was 13 January 2022.
We included individually or cluster-randomised controlled trials in people with dementia comparing non-pharmacological interventions to improve sleep compared to usual care or to other interventions of any type. Eligible studies had to have a sleep-related primary outcome. We included people with a diagnosis of dementia and sleep problems at baseline irrespective of age, type of dementia, severity of cognitive impairment, or setting. Studies reporting results on a mixed sample (e.g. in a nursing home) were only considered for inclusion if at least 80% of participants had dementia.
We used standard Cochrane methods. Our primary outcomes were 1. objective sleep-related outcomes (e.g. total nocturnal sleep time, consolidated sleep time at night, sleep efficiency, total wake time at night (or time spent awake after sleep onset), number of nocturnal awakenings, sleep onset latency, daytime/night-time sleep ratio, night-time/total sleep ratio over 24 hours) and 2.
Our secondary outcomes were 3. subjective sleep-related outcomes, 4. behavioural and psychological symptoms of dementia, 5. quality of life, 6. functional status, 7. institutionalisation, 8. compliance with the intervention, and 9. attrition rates. We used GRADE to assess the certainty of evidence and chose key outcomes to be included in summary of findings tables.
We included 19 randomised controlled trials with 1335 participants allocated to treatment or control groups. Fourteen studies were conducted in nursing homes, three included community residents, one included ‘inpatients’, one included people from a mental health centre, and one included people from district community centres for older people. Fourteen studies were conducted in the US. We also identified nine ongoing studies. All studies applied one or more non-pharmacological intervention aiming to improve physiological sleep in people with dementia and sleep problems. The most frequently examined single intervention was some form of light therapy (six studies), five studies included physical or social activities, three carer interventions, one daytime sleep restriction, one slow-stroke back massage, and one transcranial electrostimulation. Seven studies examined multimodal complex interventions. Risk of bias of included studies was frequently unclear due to incomplete reporting. Therefore, we rated no study at low risk of bias. We are uncertain whether light therapy has any effect on sleep-related outcomes (very low-certainty evidence). Physical activities may slightly increase the total nocturnal sleep time and sleep efficiency, and may reduce the total time awake at night and slightly reduce the number of awakenings at night (low-certainty evidence). Social activities may slightly increase total nocturnal sleep time and sleep efficiency (low-certainty evidence). Carer interventions may modestly increase total nocturnal sleep time, may slightly increase sleep efficiency, and may modestly decrease the total awake time during the night (low-certainty evidence from one study). Multimodal interventions may modestly increase total nocturnal sleep time and may modestly reduce the total wake time at night, but may result in little to no difference in number of awakenings (low-certainty evidence). We are uncertain about the effects of multimodal interventions on sleep efficiency (very low-certainty evidence). We found low-certainty evidence that daytime sleep restrictions, slow-stroke back massage, and transcranial electrostimulation may result in little to no difference in sleep-related outcomes. Only two studies reported information about adverse events, detecting only few such events in the intervention groups.
Despite the inclusion of 19 randomised controlled trials, there is a lack of conclusive evidence concerning non-pharmacological interventions for sleep problems in people with dementia. Although neither single nor multimodal interventions consistently improved sleep with sufficient certainty, we found some positive effects on physical and social activities as well as carer interventions. Future studies should use rigorous methods to develop and evaluate the effectiveness of multimodal interventions using current guidelines on the development and evaluation of complex interventions. At present, no single or multimodal intervention can be clearly identified as suitable for widespread implementation.
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Natalie Bareis et al.
Schizophrenia Research.
Adults with schizophrenia have increased risk of suicide with highest risk among younger adults. We investigated whether means of suicide among these adults were different from the general population. This retrospective longitudinal analysis used the National Death Index to characterize means of suicide among 4 cohorts of Medicare patients with schizophrenia (2007-2016) by age: 18 to 34, 35 to 44, 45 to 54, and aged 55+ years. Means of suicide were categorized by age at death and sex. Adjusted hazard ratios were calculated for common means. Mortality rates per 100,000 person-years were estimated by age group stratified by sex, and standardized to the general population by age, sex, and race-ethnicity using standardized mortality ratios.
668,836 adults were included with 2218 suicide decedents: 1444 men and 774 women. The most common means of suicide was poisoning (36.8 %), with a significant sex difference by means: 55.9 % of women died by poisoning, 13.8 % by firearms, 11.0 % by hanging and 9.4 % by jumping, while among men suicide by poisoning (26.6 %), firearms (25.5 %), and hanging (24.2 %) were similar, followed by jumping (12.0 %). Suicide by poisoning among the schizophrenia cohort was 10 times that of the general population, while suicide by firearm was twice that of the general population.
Means of suicide differed for patients with schizophrenia compared to the general population: poisoning was the most common means among men and women with schizophrenia, while firearms accounted for over half of all suicides in the general U.S.
Psychiatric epidemiology; Schizophrenia; Suicide.
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Gordon Shymko et al.
Schizophrenia Research.
Weight gain remains a major problem in young people with psychosis treated with antipsychotic medication. Aripiprazole is now available in monthly long-acting injection (LAI) and daily oral tablet formulation, but information is lacking about differences in weight gain between the two formulations. We monitored for up to 24 months the weight changes associated with oral or LAI-administered aripiprazole and in a group who not prescribed any antipsychotic medication. Participants included 109 young people with early psychosis (n = 30 Oral, 41 LAI, 38 Nil antipsychotic) with a treatment completion median time of 15 months. Weight (kilogram) and body mass index (BMI) were recorded at 3 monthly intervals. Multilevel modelling analyses assessed the contribution of time and group on weight change.
Participants taking nil antipsychotics did not gain weight over time, while the two aripiprazole groups gained a combined average of 7.1 kg (SD = 5.0) or 1.9 BMI (SD = 0.4). An examination of formulation effects showed a significantly greater rate of change over time in the Oral group with a weight increase of approximately 11.0 kg (SD = 8.2) or 3.5 BMI (SD = 0.7, compared to the LAI group with a gain of 3.7 kg (SD = 2.1) or 0.8 BMI (SD = 0.1) in the LAI group. These differences could not be explained by demographic or clinical characteristics, medication dosage, or baseline weight.
While aripiprazole is generally considered relatively benign in terms of weight, it still poses a significant risk especially for people with early psychosis. However the current study suggests that the risk may be lower in those treated with LAI than with Oral formulation, consolidating the clinical utility of LAI.
Antipsychotic; LAI; Monthly injections; Oral tablets; Risk; Safety; Schizophrenia; Side effects.
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Rosanna May Maletta et al.
Schizophrenia Research.
There have been increasing calls for schizophrenia to be renamed to reduce negative associations with the diagnosis. ‘Psychosis’ is one proposed alternative, yet some research suggests this has greater negative connotations. This study compared the use of both terms within UK newspapers longitudinally to assess which is more negatively portrayed in the media. Using LexisLibrary News, six UK newspaper archives were searched for the terms ‘schizophrenia’ and ‘psychosis’ in articles published between 2000 and 2019; the included article total was n = 9802. Articles were analysed using Linguistic Inquiry and Word Count software.
A two-level multilevel model was created of newspaper articles nested within newspapers. Adding predictors revealed that diagnostic term was a significant predictor of the emotional tone of articles (β = -2.30, SE = 0.51, p < .001, 95 % CI -3.30 to -1.30), with ‘psychosis’ having a more negative tone than ‘schizophrenia.’ Tabloids were shown to have a significantly more negative tone than broadsheets (β = -9.32, SE = 1.04, p < .001, 95 % CI -11.36 to -7.28), and emotional tone of writing had become more negative over time (β = -0.26, SE = 0.04, p < .001, 95 % CI -0.34 to -0.18).
These findings suggest ‘psychosis’ is associated with greater negativity than ‘schizophrenia’ within UK newspapers, and may be a poor substitute term to reduce stigma. As article tone worsened for both diagnoses over time, increased stigma reduction campaigns are required to target negativity within the media.
Diagnostic labels; Media; Mental health; Stereotyping.
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Randomized Controlled Trial
Nina C Andersen-Ranberg et al.
The New England Journal of Medicine.
Haloperidol is frequently used to treat delirium in patients in the intensive care unit (ICU), but evidence of its effect is limited. In this multicenter, blinded, placebo-controlled trial, we randomly assigned adult patients with delirium who had been admitted to the ICU for an acute condition to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or placebo. Haloperidol or placebo was administered in the ICU for as long as delirium continued and as needed for recurrences. The primary outcome was the number of days alive and out of the hospital at 90 days after randomization.
A total of 1000 patients underwent randomization; 510 were assigned to the haloperidol group and 490 to the placebo group. Among these patients, 987 (98.7%) were included in the final analyses (501 in the haloperidol group and 486 in the placebo group). Primary outcome data were available for 963 patients (97.6%). At 90 days, the mean number of days alive and out of the hospital was 35.8 (95% confidence interval [CI], 32.9 to 38.6) in the haloperidol group and 32.9 (95% CI, 29.9 to 35.8) in the placebo group, with an adjusted mean difference of 2.9 days (95% CI, -1.2 to 7.0) (P = 0.22). Mortality at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group (adjusted absolute difference, -6.9 percentage points [95% CI, -13.0 to -0.6]). Serious adverse reactions occurred in 11 patients in the haloperidol group and in 9 patients in the placebo group.
Among patients in the ICU with delirium, treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days than placebo. (Funded by Innovation Fund Denmark and others; AID-ICU ClinicalTrials.gov number, NCT03392376; EudraCT number, 2017-003829-15.).
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Liuhua Shi et al.
PNAS.
Growing evidence suggests that fine particulate matter (PM2.5) likely increases the risks of dementia, yet little is known about the relative contributions of different constituents. Here, we conducted a nationwide population-based cohort study (2000 to 2017) by integrating the Medicare Chronic Conditions Warehouse database and two independently sourced datasets of high-resolution PM2.5 major chemical composition, including black carbon (BC), organic matter (OM), nitrate (NO3, BC, and OM related to traffic and fossil fuel combustion might drive the observed associations.
Alzheimer’s disease; PM2.5 constituents; air pollution; dementia; epidemiology.
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Randall J Eck et al.
PNAS.
The pathological accumulation of the microtubule binding protein tau drives age-related neurodegeneration in a variety of disorders, collectively called tauopathies. In the most common tauopathy, Alzheimer’s disease (AD), the accumulation of pathological tau strongly correlates with cognitive decline. The underlying molecular mechanisms that drive neurodegeneration in tauopathies remain incompletely understood and no effective disease modifying pharmacological interventions currently exist. Here, we show that tau toxicity depends on the highly conserved nuclear E3 ubiquitin ligase adaptor protein SPOP in a Caenorhabditis elegans model of tauopathy. Loss of function mutations in the C. elegans spop-1 gene significantly improves behavioral deficits in tau transgenic animals, while neuronal overexpression of SPOP-1 protein significantly worsens behavioral deficits. In addition, loss of spop-1 rescues a variety of tau-related phenotypes including the accumulation of total and phosphorylated tau protein, neurodegeneration, and shortened lifespan. Knockdown of SPOP-1’s E3 ubiquitin ligase cul-3/Cullin3 does not improve tauopathy suggesting a non-degradative mechanism of action for SPOP-1. Suppression of disease-related phenotypes occurs independently of the nuclear speckle resident poly(A)-binding protein SUT-2/MSUT2. MSUT2 modifies tauopathy in mammalian neurons and in AD. Our work identifies SPOP as a novel modifier of tauopathy and a conceptual pathway for therapeutic intervention.
Alzheimer’s disease; C. elegans; neurodegeneration; tau; tauopathy.
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Dong Wang et al.
Schizophrenia Research.
Recent findings have supported an association between deviations in gut microbiome composition and schizophrenia. However, the extent to which the gut microbiota contributes to schizophrenia remains unclear. Moreover, studies have yet to explore variations in ecological associations among bacterial types in subjects with schizophrenia, which can reveal differences in community interactions and gut stability. We examined the dataset collected by Nguyen et al. (2021) to investigate the similarities and differences in gut microbial constituents between 48 subjects with schizophrenia and 48 matched non-psychiatric comparison cases. We re-analyzed alpha- and beta-diversity differences and completed modified differential abundance analyses and confirmed the findings of Nguyen et al. (2021) that there was little variation in alpha-diversity but significant differences in beta-diversity between individuals with schizophrenia and non-psychiatric subjects. We also conducted mediation analysis, developed a machine learning (ML) model to predict schizophrenia, and completed network analysis to examine community-level interactions among bacterial taxa. Our study offers new insights, suggesting that the gut microbiome mediates the effects between schizophrenia and smoking status, BMI, anxiety score, and depression score. Our differential abundance and network analysis findings suggest that the differential abundance of Lachnospiraceae and Ruminococcaceae taxa fosters a decrease in stabilizing competitive interactions in the gut microbiome of subjects with schizophrenia. Loss of this competition may promote ecological instability and dysbiosis, altering gut-brain axis interactions in these subjects.
Machine learning; Microbiome; Network analysis; Schizophrenia.
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Thanh P Le et al.
Schizophrenia Research.
Systematic cognitive training and aerobic exercise programs have emerged as promising interventions to improve cognitive deficits in first-episode schizophrenia, with successful outcomes closely linked with greater treatment engagement (e.g., higher attendance and homework completion rates). Unfortunately, treatment disengagement from these services remains a persistent issue. Intrinsic motivation, or the willingness to exert effort because a task is inherently interesting or meaningful, has emerged as a promising malleable personal factor to enhance treatment engagement. This study investigated whether early task-specific intrinsic motivation and its domains (e.g., interest, perceived competence, and value) predicted treatment engagement within the context of intensive cognitive training and aerobic exercise interventions over a 6-month period. Thirty-nine participants with first-episode schizophrenia were administered baseline measures of task-specific intrinsic motivation inventories, one for cognitive training and one for exercise, and completed a 6-month randomized clinical trial comparing a neuroplasticity-based cognitive training plus aerobic exercise program against the same cognitive training alone. Results indicated that higher baseline scores of intrinsic motivation for cognitive training, specifically early perceptions of task interest and value, were predictive of greater cognitive training and exercise group attendance. Scores for exercise-specific intrinsic motivation were generally unrelated to indices of exercise participation, with the exception that the gain over time in perceived choice for exercise was linked with greater exercise homework completion and a similar directional tendency for greater in-clinic exercise attendance. This study provides support for monitoring and enhancing motivation early during service delivery to maximize engagement and the likelihood of successful treatment outcomes.
Cognitive remediation; Exercise intervention; First episode psychosis; Motivation; Treatment adherence; Treatment dropout.
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Shiral S Gangadin et al.
Schizophrenia Research.
Various lines of research suggest immune dysregulation as a potential therapeutic target for negative and cognitive symptoms in schizophrenia spectrum disorders (SSD). Immune dysregulation would lead to higher extracellular free-water (EFW) in cerebral white matter (WM), which may partially underlie the frequently reported lower fractional anisotropy (FA) in SSD. We aim to investigate differences in EFW concentrations – a presumed proxy for neuro-inflammation – between early-phase SSD patients (n = 55) and healthy controls (HC; n = 37), and to explore immunological and cognitive correlates. To increase specificity for EFW, we study several complementary magnetic resonance imaging contrasts that are sensitive to EFW. FA, mean diffusivity (MD), magnetization transfer ratio (MTR), myelin water fraction (MWF) and quantitative T1 and T2 were calculated from diffusion-weighted imaging (DWI), magnetization transfer imaging (MTI) and multicomponent driven equilibrium single-pulse observation of T1/T2 (mcDESPOT). For each measure, WM skeletons were constructed with tract-based spatial statistics. Multivariate SSD-HC comparisons with WM skeletons and their average values (i.e. global WM) were not statistically significant. In voxel-wise analyses, FA was significantly lower in SSD in the genu of the corpus callosum and in the left superior longitudinal fasciculus (p < 0.04). Global WM measures did not correlate with immunological markers (i.e. IL1-RA, IL-6, IL-8, IL-10 and CRP) or cognition in HC and SSD after corrections for multiple comparisons. We confirmed lower FA in early-phase SSD patients. However, nonFA measures did not provide additional evidence for immune dysregulation or for higher EFW as the primary mechanism underlying the reported lower FA values in SSD.
Free water; Inflammation; Magnetic resonance imaging; Psychotic disorders; Schizophrenia; White matter.
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Jonathan Zandberg et al.
JAMA Psychiatry.
Many states in the United States enforce restrictions to reproductive care, with access to abortion remaining a highly divisive issue. Denial of abortion is linked with heightened stress and anxiety among reproductive-aged women. However, no studies have tested whether access to reproductive care is linked to suicide. To evaluate whether state-level restrictions in access to reproductive care in the United States were associated with suicide rates among reproductive-aged women from 1974 to 2016.
A longitudinal ecologic study with a difference-in-differences analysis assessed whether annual changes in the enforcement of state-level restrictions to reproductive care were related to annual state-level suicide rates vs rates of death due to motor vehicle crashes. Duration of follow-up varied between different states (range, 4-40 years), contingent on the first year that restrictions were implemented. Models controlled for year and state fixed effects and other relevant demographic and economic factors. Analyses were conducted between December 2021 and January 2022.
Targeted Regulation of Abortion Providers (TRAP) laws index measuring state-year-level restrictions to reproductive care.
Annual state-level suicide rates and motor vehicle crash death rates among reproductive-aged women (ages 20-34 years; target group) vs women of postreproductive age (ages 45-64 years; control group).
Twenty-one US states enforced at least 1 TRAP law between 1974 and 2016. Annual rates of death by suicide ranged from 1.4 to 25.6 per 100 000 women of reproductive age to 2.7 to 33.2 per 100 000 women of postreproductive age during the study period (1974-2016). Annual motor vehicle crash death rates among women of reproductive age ranged from 2.4 to 42.9 per 100 000. Enforcement of TRAP laws was associated with higher suicide rates among reproductive-aged women (β = 0.17; 95% CI, 0.03 to 0.32; P = .02) but not women of postreproductive age (β = 0.06; 95% CI, -0.11 to 0.24; P = .47) nor to deaths due to motor vehicle crashes (β = 0.03, 95% CI, -0.04 to 0.11; P = .36). Among reproductive-aged women, the weighted average annual-state level suicide death rate when no TRAP laws were enforced was 5.5 per 100 000. Enforcement of a TRAP law was associated with a 5.81% higher annual rate of suicide than in pre-enforcement years. Findings remained significant when using alternative, broader indices of reproductive care access and different age categorizations.
In this study with a difference-in-differences analysis of US women, restrictions on access to reproductive care from 1974 to 2016 were associated with suicide rates among reproductive-aged women. Given the limitations of the ecologic design of this study, further research is needed to assess whether current factors affecting access to reproductive care services are related to suicide risk among women of reproductive age and to inform suicide prevention strategies.
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Amanda Kiemes et al.
Schizophrenia Bulletin.
Converging lines of evidence suggest that dysfunction of cortical GABAergic inhibitory interneurons is a core feature of psychosis. This dysfunction is thought to underlie neuroimaging abnormalities commonly found in patients with psychosis, particularly in the hippocampus. These include increases in resting cerebral blood flow (CBF) and glutamatergic metabolite levels, and decreases in ligand binding to GABAA α5 receptors and to the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between inhibitory interneuron dysfunction and these neuroimaging readouts are yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal inhibitory interneurons leads to synaptic defects, and behavioral and cognitive phenotypes relevant to psychosis in mice. Here, we investigated how this inhibitory interneuron disruption affects hippocampal in vivo neuroimaging readouts. Adult Erbb4 conditional mutant mice (Lhx6-Cre;Erbb4F/F, n = 12) and their wild-type littermates (Erbb4F/F, n = 12) were scanned in a 9.4T magnetic resonance scanner to quantify CBF and glutamatergic metabolite levels (glutamine, glutamate, GABA). Subsequently, we assessed GABAA receptors and SV2A density using quantitative autoradiography.
Erbb4 mutant mice showed significantly elevated ventral hippccampus CBF and glutamine levels, and decreased SV2A density across hippocampus sub-regions compared to wild-type littermates. No significant GABAA receptor density differences were identified.
These findings demonstrate that specific disruption of cortical inhibitory interneurons in mice recapitulate some of the key neuroimaging findings in patients with psychosis, and link inhibitory interneuron deficits to non-invasive measures of brain function and neurochemistry that can be used across species.
Erbb4; hippocampus; inhibitory interneurons; mice; neuroimaging; psychosis.
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Natalie Piehl et al.
Cell.
Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 T cells. Clonal CD8 T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific T cell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.
Alzheimer’s disease; T cells; adaptive immunity; aging; cerebrospinal fluid; cognitive impairment.
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Harsharan Singh Bhatia et al.
Cell.
Spatial molecular profiling of complex tissues is essential to investigate cellular function in physiological and pathological states. However, methods for molecular analysis of large biological specimens imaged in 3D are lacking. Here, we present DISCO-MS, a technology that combines whole-organ/whole-organism clearing and imaging, deep-learning-based image analysis, robotic tissue extraction, and ultra-high-sensitivity mass spectrometry. DISCO-MS yielded proteome data indistinguishable from uncleared samples in both rodent and human tissues. We used DISCO-MS to investigate microglia activation along axonal tracts after brain injury and characterized early- and late-stage individual amyloid-beta plaques in a mouse model of Alzheimer’s disease. DISCO-bot robotic sample extraction enabled us to study the regional heterogeneity of immune cells in intact mouse bodies and aortic plaques in a complete human heart. DISCO-MS enables unbiased proteome analysis of preclinical and clinical tissues after unbiased imaging of entire specimens in 3D, identifying diagnostic and therapeutic opportunities for complex diseases. VIDEO ABSTRACT.
AI; Alzheimer’s; TBI; deep learning; human heart; mass spectrometry; proteomics; robotics; spatial-omics; tissue clearing.
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Einat Liebenthal et al.
Schizophrenia Research.
Disorganization, presenting as impairment in thought, language and goal-directed behavior, is a core multidimensional syndrome of psychotic disorders. This study examined whether scalable computational measures of spoken language, and smartphone usage pattern, could serve as digital biomarkers of clinical disorganization symptoms. We examined in a longitudinal cohort of adults with a psychotic disorder, the associations between clinical measures of disorganization and computational measures of 1) spoken language derived from monthly, semi-structured, recorded clinical interviews; and 2) smartphone usage pattern derived via passive sensing technologies over the month prior to the interview. The language features included speech quantity, rate, fluency, and semantic regularity. The smartphone features included data missingness and phone usage during sleep time. The clinical measures consisted of the Positive and Negative Symptom Scale (PANSS) conceptual disorganization, difficulty in abstract thinking, and poor attention, items. Mixed linear regression analyses were used to estimate both fixed and random effects.
Greater severity of clinical symptoms of conceptual disorganization was associated with greater verbosity and more disfluent speech. Greater severity of conceptual disorganization was also associated with greater missingness of smartphone data, and greater smartphone usage during sleep time. While the observed associations were significant across the group, there was also significant variation between individuals.
The findings suggest that digital measures of speech disfluency may serve as scalable markers of conceptual disorganization. The findings warrant further investigation into the use of recorded interviews and passive sensing technologies to assist in the characterization and tracking of psychotic illness.
Conceptual disorganization; Digital phenotyping; Psychosis; Smartphone-based passive sensing; Speech disfluency; Spoken language.
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Meta-Analysis
Ruth Peters et al.
European Heart Journal.
Observational studies indicate U-shaped associations of blood pressure (BP) and incident dementia in older age, but randomized controlled trials of BP-lowering treatment show mixed results on this outcome in hypertensive patients. A pooled individual participant data analysis of five seminal randomized double-blind placebo-controlled trials was undertaken to better define the effects of BP-lowering treatment for the prevention of dementia. Multilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, and presence of prior stroke. Mediation analysis was used to quantify the contribution of trial medication and changes in systolic and diastolic BP on risk of dementia. The total sample included 28 008 individuals recruited from 20 countries. After a median follow-up of 4.3 years, there were 861 cases of incident dementia. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval: 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4 mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age or sex. Mediation analysis confirmed the greater fall in BP in the actively treated group was associated with a greater reduction in dementia risk.
The first single-stage individual patient data meta-analysis from randomized double-blind placebo-controlled clinical trials provides evidence to support benefits of antihypertensive treatment in late-mid and later life to lower the risk of dementia. Questions remain as to the potential for additional BP lowering in those with already well-controlled hypertension and of antihypertensive treatment commenced earlier in the life-course to reduce the long-term risk of dementia.
Class I evidence in favour of antihypertensive treatment reducing risk of incident dementia compared with placebo.
Blood: Journal of the American Society of Hematology pressure; Clinical trials; Cognition; Dementia; Hypertension; Meta-analysis.
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Peter Ueda et al.
British Medical Journal.
To assess whether male elite football players are at increased risk of alcohol related disorders compared with men from the general population, and whether such an increased risk would vary on the basis of calendar year of the first playing season in the top tier of competition, age, career length, and goal scoring abilities. Nationwide cohort study.
Sweden, 1924-2020.
6007 male football players who had played in the Swedish top division, Allsvenskan, from 1924 to 2019 and 56 168 men from the general population matched to players based on age and region of residence.
Primary outcome was alcohol related disorders (diagnoses recorded in death certificates, during hospital admissions and outpatient visits, or use of prescription drugs for alcohol addiction); secondary outcome was disorders related to misuse of other drugs.
During follow-up up to 31 December 2020, 257 (4.3%) football players and 3528 (6.3%) men from the general population received diagnoses of alcohol related disorders. In analyses accounting for age, region of residence, and calendar time, risk of alcohol related disorders was lower among football players than among men from the general population (hazard ratio 0.71, 95% confidence interval 0.62 to 0.81). A reduced risk of alcohol related disorders was observed for football players who played their first season in the top tier in the early 1960s and later, while no significant difference versus men from the general population was seen in the risk for football players from earlier eras. The hazard ratio was lowest at around age 35 years, and then increased with age; at around age 75 years, football players had a higher risk of alcohol related disorders than men from the general population. No significant association was seen between goal scoring, number of games, and seasons played in the top tier and the risk of alcohol related disorders. Risk of disorders related to other drug misuse was significantly lower among football players than the general population (hazard ratio 0.22, 95% confidence interval 0.15 to 0.34).
In this nationwide cohort study, male football players who had played in the Swedish top tier of competition had a significantly lower risk of alcohol related disorders than men from the general population.
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Review
R Cunill et al.
Schizophrenia Research.
Schizophrenia patients often show obsessive-compulsive symptoms (OCS) and obsessive-compulsive disorder (OCD) and their presence has been associated with poorer prognosis. However, the impact of OCS/OCD on psychotic severity remains unclear. The aim of this study is twofold: 1) to investigate the effect of OCS/OCD on the severity of positive, negative, and global psychotic symptoms of schizophrenia patients and 2) to analyze the effect of patient and study-related covariates on moderating this relationship. A systematic review and meta-analysis (SRMA) of studies comparing the severity of psychotic symptoms among schizophrenia patients with and without OCS/OCD was performed. Standardized mean difference (SMD) was calculated for positive, negative, and global psychotic symptoms. The difference of SMD (Diff SMD) was calculated to analyze the effect of covariates on study outcomes using meta-regression.
Sixty-seven studies involving 7740 patients were included. Patients with schizophrenia and OCS/OCD showed a slightly higher severity of positive (SMD = 0.17, p value = 0.0089) and global psychotic symptoms (SMD = 0.24, p value = 0.0104) than patients without OCS/OCD but no differences in negative symptoms were found between groups (SMD = 0.11, p value = 0.0367). Only one covariate “proportion of patients without antipsychotics (AP)” was found to modify the effect on psychotic severity (Diff SMD = -0.008, p value = 0.002).
Comorbid OCS/OCD in schizophrenia has, at most, a minor impact on psychotic severity. Variability in this effect was considerable and was poorly explained by the covariates analyzed.
Meta-analysis; OCD; OCS; Schizo-obsessive; Systematic review.
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Christina Bruun Knudsen et al.
Schizophrenia Bulletin.
Familial high-risk (FHR) studies examining longitudinal associations between neurocognition and psychotic experiences are currently lacking. We hypothesized neurocognitive impairments at age 7 to be associated with increased risk of psychotic experiences from age 7 to 11 in children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) and population-based controls (PBC), and further, impaired functioning in some neurocognitive functions to be associated with greater risk of psychotic experiences in children at FHR-SZ or FHR-BP relative to PBC. Neurocognition was assessed at age 7 (early childhood) and psychotic experiences from age 7 to 11 (middle childhood) in 449 children from the Danish High Risk and Resilience Study. The neurocognitive assessment covered intelligence, processing speed, attention, visuospatial and verbal memory, working memory, and set-shifting. Psychotic experiences were assessed through face-to-face interviews with the primary caregiver and the child.
Set-shifting impairments at age 7 were associated with greater risk of psychotic experiences from age 7 to 11 in children at FHR-SZ. Children at FHR-BP and PBC showed no differential associations. Working memory and visuospatial memory impairments were related to increased risk of psychotic experiences across the cohort. However, adjusting for concurrent psychopathology attenuated these findings.
Early childhood neurocognitive impairments are risk markers of middle childhood psychotic experiences, of which impaired set-shifting appears to further increase the risk of psychotic experiences in children at FHR-SZ. More research is needed to examine longitudinal associations between neurocognitive impairments and psychotic experiences in FHR samples.
cognitive functions; preadolescence; psychosis; severe mental illness.
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Koen Bolhuis et al.
Schizophrenia Bulletin.
Previous studies have shown a robust relationship between childhood adversity and subsequent psychotic symptoms. However, the role of familial risk factors underlying this relationship remains largely unclear. Here, we tested whether offspring childhood adversity and postnatal maternal psychopathology mediated the relationship between maternal childhood adversity and offspring psychotic experiences. N = 3068 mother-offspring dyads were included. Maternal history of childhood adversity was retrospectively assessed using the Childhood Trauma Questionnaire during pregnancy. Maternal psychopathology was assessed during and after pregnancy. Twenty-four offspring childhood adversities were assessed by maternal interview when the child was 10 years old. Offspring psychotic experiences were examined using self-report at 14 years. Structural equation mediation models were conducted to explore whether maternal postnatal psychopathology and offspring childhood adversities sequentially mediated the relationship between maternal childhood adversity and offspring psychotic experiences. Analyses were adjusted for sociodemographic confounders.
Maternal history of childhood adversity was associated with offspring childhood adversities (β = 0.12, 95% CI: 0.09 to 0.16). Offspring childhood adversity mediated the association of maternal childhood adversity with offspring hallucinations (βindirect effect = 0.008, 95% CI: 0.002 to 0.014, proportion mediated = 16.3%) and delusions (βindirect effect = 0.006, 95% CI: 0.000 to 0.012, proportion mediated = 13.1%).
Intergenerational transmission of childhood adversity can be considered of relevance in the etiology of psychosis vulnerability and can potentially serve as a modifiable risk factor.
Generation R; child psychiatry; development; maltreatment; mediation analysis; schizophrenia.
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Emma C Johnson et al.
Schizophrenia Bulletin.
Risk for cannabis use and schizophrenia is influenced in part by genetic factors, and there is evidence that genetic risk for schizophrenia is associated with subclinical psychotic-like experiences (PLEs). Few studies to date have examined whether genetic risk for schizophrenia is associated with cannabis-related PLEs. We tested whether measures of cannabis involvement and polygenic risk scores (PRS) for schizophrenia were associated with self-reported cannabis-related experiences in a sample ascertained for alcohol use disorders (AUDs), the Collaborative Study on the Genetics of Alcoholism (COGA). We analyzed 4832 subjects (3128 of European ancestry and 1704 of African ancestry; 42% female; 74% meeting lifetime criteria for an AUD).
Cannabis use disorder (CUD) was prevalent in this analytic sample (70%), with 40% classified as mild, 25% as moderate, and 35% as severe. Polygenic risk for schizophrenia was positively associated with cannabis-related paranoia, feeling depressed or anhedonia, social withdrawal, and cognitive difficulties, even when controlling for duration of daily cannabis use, CUD, and age at first cannabis use. The schizophrenia PRS was most robustly associated with cannabis-related cognitive difficulties (β = 0.22, SE = 0.04, P = 5.2e-7). In an independent replication sample (N = 1446), associations between the schizophrenia PRS and cannabis-related experiences were in the expected direction and not statistically different in magnitude from those in the COGA sample.
Among individuals who regularly use cannabis, genetic liability for schizophrenia-even in those without clinical features-may increase the likelihood of reporting unusual experiences related to cannabis use.
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Evan H Goulding et al.
JAMA Psychiatry.
Bipolar disorder-specific psychotherapy combined with pharmacotherapy improves relapse risk, symptom burden, and quality of life, but psychotherapy is not easily accessible. To determine if a smartphone-based self-management intervention (LiveWell) can assist individuals with bipolar disorder to maintain wellness.
An assessor-blind randomized clinical trial enrolled participants from March 20, 2017, to April 25, 2019, with 48-week follow-up ending on April 10, 2020. Participants were randomly assigned to usual care or usual care plus the smartphone intervention stratified by relapse risk based on initial clinical status (low risk: asymptomatic recovery; high risk: continued symptomatic, prodromal, recovering, symptomatic recovery). Participants with bipolar disorder I were recruited from clinics in the Chicago and Minneapolis-Saint Paul areas. Data were analyzed from June 19, 2020, to May 25, 2022.
The smartphone-based self-management intervention consisted of an application (app), coach, and website. Over 16 weeks, participants had a coach visit followed by 6 phone calls, and they completed daily and weekly app check-ins. The app provided adaptive feedback and information for developing a personalized wellness plan, the coach provided support, and the website provided summary data and alerts.
The primary outcome was time to relapse. Secondary outcomes were percentage-time symptomatic, symptom severity, and quality of life.
Of the 205 randomized participants (mean [SD] age, 42 [12] years; 125 female individuals [61%]; 5 Asian [2%], 21 Black [10%], 13 Hispanic or Latino [6%], 7 multiracial [3%], 170 White [83%], 2 unknown race [1%]), 81 (40%) were randomly assigned to usual care, and 124 (60%) were randomly assigned to usual care plus the smartphone intervention. This clinical trial did not detect a reduction in relapse risk for the smartphone intervention (hazard ratio [HR], 0.65; 95% CI, 0.39-1.09; log-rank P = .08). However, decreased relapse was observed for low-risk individuals (HR, 0.32; 95% CI, 0.12-0.88; log-rank P = .02) but not high-risk individuals (HR, 0.86; 95% CI, 0.47-1.57; log-rank P = .62). Reduced manic symptom severity was observed for low-risk individuals (mean [SE] difference, -1.4 [0.4]; P = .001) but not for high-risk individuals (mean [SE] difference, 0 [0.3]; P = .95). The smartphone-based self-management intervention decreased depressive symptom severity (mean [SE] difference, -0.80 [0.34]; P = .02) and improved relational quality of life (mean [SE] difference, 1.03 [0.45]; P = .02) but did not decrease percentage-time symptomatic (mean [SE] difference, -5.6 [4.3]; P = .20).
This randomized clinical trial of a smartphone-based self-management intervention did not detect a significant improvement in the primary outcome of time to relapse. However, a significant decrease in relapse risk was observed for individuals in asymptomatic recovery. In addition, the intervention decreased depressive symptom severity and improved relational quality of life. These findings warrant further work to optimize the smartphone intervention and confirm that the intervention decreases relapse risk for individuals in asymptomatic recovery.
ClinicalTrials.gov Identifier: NCT03088462.
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Yukiko Matsumoto et al.
Schizophrenia Bulletin.
Schizophrenia is a mental illness that presents with thought disorders including delusions and disorganized speech. Thought disorders have been regarded as a consequence of the loosening of associations between semantic concepts since the term “schizophrenia” was first coined by Bleuler. However, a mechanistic account of this cardinal disturbance in terms of functional dysconnection has been lacking. To evaluate how aberrant semantic connections are expressed through brain activity, we characterized large-scale network structures of concept representations using functional magnetic resonance imaging (fMRI). We quantified various concept representations in patients’ brains from fMRI activity evoked by movie scenes using encoding modeling. We then constructed semantic brain networks by evaluating the similarity of these semantic representations and conducted graph theory-based network analyses.
Neurotypical networks had small-world properties similar to those of natural languages, suggesting small-worldness as a universal property in semantic knowledge networks. Conversely, small-worldness was significantly reduced in networks of schizophrenia patients and was correlated with psychological measures of delusions. Patients’ semantic networks were partitioned into more distinct categories and had more random within-category structures than those of controls.
The differences in conceptual representations manifest altered semantic clustering and associative intrusions that underlie thought disorders. This is the first study to provide pathophysiological evidence for the loosening of associations as reflected in randomization of semantic networks in schizophrenia. Our method provides a promising approach for understanding the neural basis of altered or creative inner experiences of individuals with mental illness or exceptional abilities, respectively.
Thought disorder; semantic network; small-worldness; voxelwise encoding modeling.
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Kimberly D Belfry et al.
Canadian Journal of Psychiatry.
Acquired brain injury (ABI) is a serious problem that disproportionately affects individuals in correctional services, but relatively little is known about ABI risks and correlates in forensic psychiatric services. We conducted a retrospective chart review of all admissions to a high secure forensic hospital in Ontario, Canada from January 2009 to December 2012 (n = 637) and collected data on ABI, psychiatric diagnoses, developmental disadvantage, criminal offending, and in-hospital aggression. A k-means cluster analysis was employed to assess risk factors by which men with ABI could be identified and multivariate general linear models were used to identify ABI-related differences in offending history and in-hospital aggression.
One-fifth of the men had a documented ABI indicator. Based on our cluster analysis, ABI was more likely to be identified by greater adverse childhood experiences (ACEs), more health problems from pregnancy to childhood, and lower socioeconomic status, suggesting that ABI within the forensic context is associated with greater developmental disadvantage. Men with ABI had more serious pre-admission offences, but not more serious admission offences or in-hospital aggression. Men with ABI were more likely than those without to have higher scores on the Violence Risk Appraisal Guide or to be diagnosed with mood and personality disorders, and less likely to have a schizophrenia diagnosis, suggesting an association between ABI and general mental health pathologies but not with psychotic illness.
The disadvantage of ABI among men in forensic psychiatric hospitals is most likely evinced in antisocial behaviour rather than serious mental illness. Given that ACEs are likely to precede or co-occur with ABI, strategies that mitigate ACEs hold promise for ABI prevention.
acquired brain injury; adverse childhood experiences; aggression; forensic psychiatric care; offending.
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Marie-Louise H Rasmussen et al.
The British Journal of Psychiatry.
Previous research has suggested that some women are at increased risk of postpartum depression (PPD) because of an extra sensitivity to fluctuating hormones before and after parturition. This may particularly apply to women with endocrine disease, characterised by a less than optimal capability to self-regulate the hormonal feedback system. To investigate if women with endocrine disease history are at increased risk of developing PPD.
Based on information from Danish national registers, this nationwide cohort study included 888 989 deliveries (1995-2018). Endocrine disease history was defined as thyroid disease, pre-pregnancy diabetes, polycystic ovary syndrome and/or previous gestational diabetes within 10 years before pregnancy start. PPD was defined as use of antidepressants and/or hospital contact for depression within 6 months after childbirth.
Among 888 989 deliveries, 4.1% had a history of endocrine disease and 0.5% had a PPD episode. Overall, women with an endocrine disease history had a 42% (risk ratio 1.42, 95% CI 1.24-1.62) higher risk of PPD when compared with women with no endocrine disease. However, we also found the reverse association, whereby women with a PPD history had a 50% (hazard ratio 1.5, 95% CI 1.4-1.6) higher risk of endocrine disease when compared with women with no PPD history.
Women with endocrine disease history had a 40% higher risk of PPD compared with women with no endocrine disease. More attention should be given to pregnant women with endocrine disease history to increase awareness of early signs of PPD. The bi-directionality of the association points to a common underlying factor.
Depressive disorders; antidepressants; epidemiology; neuroendocrinology; perinatal psychiatry.
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Jordan DeVylder et al.
Schizophrenia Research.
There is a well-documented epidemiological association between auditory hallucinations and self-harm in the general population. However, there has been limited research examining specific characteristics of auditory hallucinations (e.g., type, source, or context of voices) as correlates of self-harm. We used prospective data from the Tokyo Teen Cohort to explore whether characteristics of voices reported at age 14 were differentially associated with self-harm behaviors at ages 14 and 16. Among respondents with auditory hallucinations, respondents who experienced voices that “said something bad” about them or commented on their thoughts and actions were most likely to report concurrent self-harm, whereas positive or praising voices were protective. Negative voices continued to predict self-harm two years later, at age 16, even with adjustment for self-harm at age 14. The age of the voices, source of the voices, and context (e.g., falling asleep or while sick) was not associated with likelihood of reporting concurrent or subsequent self-harm behaviors. Assessing for negative voices in particular, rather than auditory hallucinations or psychotic experiences more broadly, may provide a more specific indicator of risk for self-harm among adolescents. The real-world utility of these epidemiological findings should be further examined in clinical settings.
Non-suicidal self-injury; Psychosis; Psychotic experiences; Self-harm; Suicide; Voices.
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Luana G Mororó et al.
Schizophrenia Research.
Digital cognitive training can remediate cognitive deficits present in schizophrenia. However, limited motivation and engagement may impact adherence to training. Therefore, identifying factors that may enhance (facilitators) or decrease (barriers) engagement in digital cognitive training and possibly modulate its effects are of great clinical relevance. We measured cognition, symptom severity, motivation (semi-structured interview), and engagement (adapted Utrecht Work Engagement Scale – UWES) of 27 patients with schizophrenia after a 40-h digital cognitive training. The interview transcript quotes were coded and categorized into facilitators and barriers. Thereafter, we tested the association of motivation and engagement with changes in cognition and symptoms after training.
The facilitator ‘good performance’ and the barrier ‘difficult exercise’ were associated with larger gains in attention (p = 0.03) and reasoning and problem solving (p = 0.02), respectively. ‘Poor performance’ was associated with smaller gains in global cognition (p < 0.01), attention (p = 0.03), and working memory (p = 0.02). The facilitator ‘welcoming setting’ was associated with larger reductions in the negative (p = 0.01) and total (p = 0.01) symptoms measured by the Positive and Negative Syndrome Scale. The UWES engagement scale was associated with different facilitators and barriers that emerged from the interview, an indication of consistency among both qualitative and quantitative assessments.
Using a mixed quantitative and qualitative research design, we showed associations between motivation and engagement and the response to digital cognitive training in schizophrenia. Facilitators and barriers were associated with engagement, gains in cognition, and reduced symptoms after the intervention, providing insights on how to increase engagement in the digital cognitive training delivered to subjects with schizophrenia.
Digital cognitive training; Engagement; Motivation; Schizophrenia.
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S C McEwen et al.
Schizophrenia Research.
Schizophrenia (SZ) is characterized by neurobiological and associated cognitive and functional deficits, including pronounced cortical thinning, that lead to acute and long-term functional impairment. Research with older adults supports the role of non-pharmacological interventions, such as exercise (E) and cognitive training (CT), for cognitive impairments. This literature influenced the development of combined CT&E treatments for individuals with SZ. However, the impact of longer combined treatment duration (6 months) on neuroanatomy has yet to be explored in patients in the early course of the illness. The impact of adding exercise to cognitive training for key brain regions associated with higher-order cognition was examined here using magnetic resonance imaging (MRI) in first-episode psychosis (FEP) patients. UCLA Aftercare Research Program patients with a recent first episode of schizophrenia were randomly assigned to either combined cognitive and exercise training (CT&E) (N = 20) or cognitive training alone (CT) (N = 17) intervention. Cortical thickness was measured longitudinally and analyzed for two regions of interest using FreeSurfer.
Compared to patients in the CT group, those in the CT&E group demonstrated an increase in cortical thickness within the left anterior cingulate cortex over the six-month treatment period (ACC: F(1, 35) = 4.666, P < .04). Directional tendencies were similar in the left dorsolateral prefrontal cortex (DLPFC: F(1,35) = 4.132, P < .05).
These findings suggest that exercise and cognitive training may synergistically increase fronto-cingulate cortical thickness to mitigate progressive neural atrophy in the early course of SZ. This combined intervention appears to be a valuable adjunct to standard pharmacologic treatment in FEP patients.
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Aaron K Jenkins et al.
Schizophrenia Research.
Cognitive disturbances in schizophrenia have been linked to a lower density of dendritic spines on pyramidal neurons in the prefrontal cortex (PFC). Complement component C4, which has previously been found at higher levels in schizophrenia, marks synapses for phagocytosis by microglia. Thus, elevated consumption of dendritic spines by microglia mediated through excessive complement activity may play a role in lower spine density in schizophrenia. However, it is unclear if microglia themselves have the molecular capacity for enhanced phagocytosis of spines in schizophrenia. Transcript levels for complement components and microglia-specific phagocytic markers were quantified using quantitative PCR in the PFC of 62 matched pairs of schizophrenia and unaffected comparison subjects and in antipsychotic-exposed monkeys.
Relative to comparison subjects, schizophrenia subjects had higher mRNA levels for C4 (+154 %); C1q (+69 %), which initiates the classical complement pathway that includes C4; and for microglia-specific markers that enable phagocytic activity including TAM receptor tyrosine kinases Axl (+27 %) and MerTK (+27 %) and lysosome-associated glycoprotein CD68 (+27 %) (all p ≤ .042). Transcript levels for microglial phagocytic markers were correlated with C4 mRNA levels in schizophrenia subjects (all r ≥ 0.31, p ≤ .015). We also found further evidence consistent with microglial activation in schizophrenia, including higher mRNA levels for THIK1 (TWIK-related halothane-inhibited potassium channel: +30 %) and lower mRNA levels for the purinergic receptor P2Y12 (-27 %) (all p ≤ .016). Transcript levels were unchanged in antipsychotic-exposed monkeys.
These results are consistent with the presence of increased complement activity and an elevated molecular capacity of microglia for phagocytosis in the same schizophrenia subjects.
Complement; Dendritic spines; Immune activation; Inflammation; Postmortem; Prefrontal cortex.
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Review
Xiaoying Chen et al.
Immunity.
Alzheimer’s disease (AD) is the most common neurodegenerative disease, with characteristic extracellular amyloid-β (Aβ) deposition and intracellular accumulation of hyperphosphorylated, aggregated tau. Several key regulators of innate immune pathways are genetic risk factors for AD. While these genetic risk factors as well as in vivo data point to key roles for microglia, emerging evidence also points to a role of the adaptive immune response in disease pathogenesis. We review the roles of innate and adaptive immunity, their niches, their communication, and their contributions to AD development and progression. We also summarize the cellular compositions and physiological functions of immune cells in the parenchyma, together with those in the brain border structures that form a dynamic disease-related immune niche. We propose that both innate and adaptive immune responses in brain parenchyma and border structures could serve as important therapeutic targets for treating both the pre-symptomatic and the symptomatic stages of AD.
Alzheimer’s disease; adaptive immunity; immune niche; innate immunity.
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James Knoll 4th et al.
JAMA Psychiatry.
Psychiatry has struggled to clarify the types of mental turmoil that are associated with mass violence. While the problem is complex, it may present an opportunity to improve research, as well as inform public dialogue about what types of mental illness are actually associated with such mass tragedies. Assuring the diagnostic accuracy of those who commit mass violence is challenging due to the retrospective nature of the analysis and lack of reliable psychiatric data. Psychiatric research has begun to use a dimensional approach that may be well suited to the study of mental illness in perpetrators of mass violence. This approach aggregates psychiatric symptoms into 3 domains of psychopathology: (1) internalizing, (2) externalizing, and (3) psychotic experience. This approach has practical clinical use and research support. A dimensional approach may help clear up misconceptions about the rate of psychosis in mass violence perpetrators, as well as reveal the most common dimensions of mental functioning associated with perpetrators.
Improved research methods are needed to clarify and prevent mass violence. More precisely identifying the symptoms and mental turmoil of perpetrators may be associated with improved early identification and prevention. Because adolescence is a critical and formative period in which internalizing and externalizing problems arise, early interventions may have the best chance of reducing future mass violence.
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Mette Bliddal et al.
JAMA Psychiatry.
The direct and indirect implications of the COVID-19 pandemic have been associated with the mental health of children and adolescents, but it is uncertain whether these implications have been associated with changes in prescribing and diagnosis patterns. To examine psychotropic medication use and rates of psychiatric disorders in Danish children, adolescents, and young adults during the COVID-19 pandemic.
This population-based, descriptive register-based cohort study included all Danish individuals aged 5 to 24 years from January 1, 2017, until June 30, 2022.
Rates of filled prescriptions of psychotropic medications, including antipsychotics, anxiolytics, hypnotics, sedatives, antidepressants, and psychostimulants, and all inpatient and outpatient contacts with mental and behavioral disorders. Rates of new (incident) and total (prevalent) psychotropic medication use and psychiatric diagnoses were estimated. Rate ratios (RRs) were assessed between observed and expected numbers of incident psychotropic medication use or psychiatric diagnoses from March 2020 to June 30, 2022, comparing observed numbers with expected numbers predicted from the modeled prepandemic trend.
The study identified 108 840 (58 856 female individuals [54%]; median [IQR] age, 18 [14-22] years) incident psychotropic medication users. From March 2020 (first national lockdown) to June 2022, the rate of incident users of any psychotropic medication showed a relative increase of 18% (RR, 1.18; CI, 1.17-1.20) compared with expected numbers, which was primarily associated with an increase among those aged 12 to 17 years of 37% (RR, 1.37; 95% CI, 1.34-1.41). Similarly, there was an overall relative increase of incident psychiatric disorders of 5% (incidence rate, 1.05; CI, 1.04-1.07) (incident cases, 114 048 [58 708 female individuals (51%)]), which was associated with an increase in hyperkinetic disorders (RR, 1.13; CI, 1.09-1.18) and anxiety disorders (RR, 1.04; CI, 1.02-1.06). Prevalence patterns showed similar trends of an overall increase in psychotropic medication use and psychiatric disorders. One of 3 new users of an individual drug group had filled a prescription for a drug from another psychotropic medication group within the prior 6 months.
The results of this cohort study suggest that Danish youths experienced an increase in rates of psychotropic treatment and psychiatric disorder diagnoses during the COVID-19 pandemic, which was most pronounced among those aged 12 to 17 years. The increase was observed for children and adolescents with and without a psychiatric history within the last 5 years.
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Nathan A Kimbrel et al.
JAMA Psychiatry.
Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown. To identify novel, replicable genomic risk loci for SITB.
This genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022.
SITB.
A total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P < 5 × 10-8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry-specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r > 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry.
The findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.
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Johan Lundberg et al.
JAMA Psychiatry.
The totality of the societal and individual impact of treatment-resistant depression (TRD) is unknown, as is the potential to prognosticate TRD. The generalizability of many observational studies on TRD is limited. To estimate the burden of TRD in a large population-wide cohort in an area with universal health care by including data from both health care types (psychiatric and nonpsychiatric) and, further, to develop a prognostic model for clinical use.
This cohort study, a population-based observational study, assessed data from the Stockholm MDD Cohort for episodes of major depressive disorder (MDD) between 2010 and 2017 that fulfilled predefined criteria for TRD (≥3 consecutive antidepressant treatments). Data analysis was performed from August 2020 to May 2022.
Outcomes were psychiatric and nonpsychiatric comorbid conditions, antidepressant treatments, health care resource utilization, lost workdays, all-cause mortality, and intentional self-harm and, in the prognostic model, TRD.
A total of 158 169 unipolar MDD episodes (in 145 577 patients) were identified between January 1, 2012, and December 31, 2017 (64.7% women; median [IQR] age, 42 years [30-56]). Of these, 12 793 episodes (11%) fulfilled criteria for TRD. The median (IQR) time from the start of MDD episode to TRD was 552 days (294-932). Selective serotonin reuptake inhibitor was the most common class of antidepressant treatment in all treatment steps, and 5907 patients (46.2%) received psychotherapy at some point before initiation of the third pharmacological antidepressant treatment. Compared with matched non-TRD episodes, TRD episodes had more inpatient bed-days (mean, 3.9 days; 95% CI, 3.6-4.1, vs 1.3 days; 95% CI, 1.2-1.4) and more lost workdays (mean, 132.3 days; 95% CI, 129.5-135.1, vs 58.7 days; 95% CI, 56.8-60.6) 12 months after the index date. Anxiety, stress, sleep disorder, and substance use disorder were all more common comorbid conditions in TRD episodes. Intentional self-harm was more than 4 times more common in TRD episodes. The all-cause mortality rate for patients with MDD with TRD episodes was 10.7/1000 person-years at risk, compared with 8.7/1000 person-years at risk for patients with MDD without TRD episodes (hazard ratio, 1.23; 95% CI, 1.07-1.41). Median time from start of the first antidepressant treatment to start of the second, and from start of the second antidepressant treatment to start of the third, was 165 and 197 days, respectively. The severity of MDD, defined using the self-rating Montgomery-Åsberg Depression Rating Scale (MADRS-S) at time of MDD diagnosis, was found to be the most important prognostic factor for TRD (C index = 0.69).
In this cohort study, TRD was a common variant of MDD when including patients from both health care types, which is associated with a high disease burden for both patients and society. The median time between initiation of new antidepressant treatments was longer than recommended in current treatment guidelines, suggesting room for more structured and timely depression care.
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Emily J Hird et al.
Schizophrenia Bulletin.
Around 20% of people at clinical high risk (CHR) for psychosis later develop a psychotic disorder, but it is difficult to predict who this will be. We assessed the incidence of hearing speech (termed speech illusions [SIs]) in noise in CHR participants and examined whether this was associated with adverse clinical outcomes. At baseline, 344 CHR participants and 67 healthy controls were presented with a computerized white noise task and asked whether they heard speech, and whether speech was neutral, affective, or whether they were uncertain about its valence. After 2 years, we assessed whether participants transitioned to psychosis, or remitted from the CHR state, and their functioning.
CHR participants had a lower sensitivity to the task. Logistic regression revealed that a bias towards hearing targets in stimuli was associated with remission status (OR = 0.21, P = 042). Conversely, hearing SIs with uncertain valence at baseline was associated with reduced likelihood of remission (OR = 7.72. P = .007). When we assessed only participants who did not take antipsychotic medication at baseline, the association between hearing SIs with uncertain valence at baseline and remission likelihood remained (OR = 7.61, P = .043) and this variable was additionally associated with a greater likelihood of transition to psychosis (OR = 5.34, P = .029).
In CHR individuals, a tendency to hear speech in noise, and uncertainty about the affective valence of this speech, is associated with adverse outcomes. This task could be used in a battery of cognitive markers to stratify CHR participants according to subsequent outcomes.
remission; signal-detection; transition; uncertainty; white noise task.
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Michael Lebenbaum et al.
Canadian Journal of Psychiatry.
There is mixed evidence on the link between mental health and addiction (MHA) history and recidivism. Few studies have examined post-release MHA care. Our objective was to examine the association between prior (pre-incarceration) MHA service use and post-release recidivism and service use. We conducted a population-based cohort study linking individuals held in provincial correctional institutions in 2010 to health administrative databases. Prior MHA service use was assigned hierarchically in order of hospitalization, emergency department visit and outpatient visit. We followed up individuals post-release for up to 5 years for the first occurrence of recidivism and MHA hospitalization, emergency department visit and outpatient visit. We use Cox-proportional hazards models to examine the association between prior MHA service use and each outcome adjusting for prior correctional involvement and demographic characteristics.
Among a sample consisting of 45,890 individuals, we found that prior MHA service use was moderately associated with recidivism (hazard ratio (HR): 1.20-1.50, all P < 0.001), with secondary analyses finding larger associations for addiction service use (HR range: 1.34-1.54, all P < 0.001) than for mental health service use (HR range: 1.09-1.18, all P < 0.001). We found high levels of post-release MHA hospitalization and low levels of outpatient MHA care relative to need even among individuals with prior MHA hospitalization.
Despite a high risk of recidivism and acute MHA utilization post-release, we found low access to MHA outpatient care, highlighting the necessity for greater efforts to facilitate access to care and care integration for individuals with mental health needs in correctional facilities.
mental health and addictions; population-based study; post-release care; recidivism.
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Gabriel Bastien et al.
Canadian Journal of Psychiatry.
This study aimed to evaluate the effectiveness of flexible take-home dosing of buprenorphine/naloxone (BUP/NX) and methadone standard model of care in reducing depressive symptoms in people with prescription-type opioid use disorder (POUD). This trial also evaluated whether improvements in depressive symptoms were mediated by opioid use. Analyzed data came from the OPTIMA study (clinicaltrials.gov identifier: NCT03033732), a pragmatic randomised controlled trial comparing flexible take-home dosing of BUP/NX and methadone standard model of care for reducing opioid use in people with POUD. A total of 272 participants were recruited in four Canadian provinces. Participants were randomised 1:1 to BUP/NX or methadone. After treatment induction, past two-week opioid use was measured using the Timeline Followback every two weeks for a total of 24 weeks. Depressive symptoms were measured with the Beck Depression Inventory at baseline, weeks 12 and 24.
Both BUP/NX and methadone significantly reduced depressive symptoms at week 12 (aβ ± SE = -3.167 ± 1.233; P < 0.001) and week 24 (aβ ± SE = -7.280 ± 1.285; P < 0.001), with no interaction between type of treatment and time (P = 0.284). Improvements in depressive symptoms were only partially mediated by a reduction in opioid use (proportion mediated = 36.8%; 95% confidence interval = -1.158 to -0.070; P = 0.015).
BUP/NX and methadone showed similar effectiveness in decreasing comorbid depressive symptoms in people with POUD. This effect was partially explained by a reduction in opioid use. As both treatments seem equally effective, clinicians are encouraged to tailor the selection of OAT to patients’ needs and characteristics.
comorbidity; depressive disorders; dual diagnosis; major depressive disorder; randomised controlled trial; substance use disorders.
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Soojin Kim et al.
PNAS.
The selenium-binding protein 1 (SELENBP1) has been reported to be up-regulated in the prefrontal cortex (PFC) of schizophrenia patients in postmortem reports. However, no causative link between SELENBP1 and schizophrenia has yet been established. Here, we provide evidence linking the upregulation of SELENBP1 in the PFC of mice with the negative symptoms of schizophrenia. We verified the levels of SELENBP1 transcripts in postmortem PFC brain tissues from patients with schizophrenia and matched healthy controls. We also generated transgenic mice expressing human SELENBP1 (hSELENBP1 Tg) and examined their neuropathological features, intrinsic firing properties of PFC 2/3-layer pyramidal neurons, and frontal cortex (FC) electroencephalographic (EEG) responses to auditory stimuli. Schizophrenia-like behaviors in hSELENBP1 Tg mice and mice expressing Selenbp1 in the FC were assessed. SELENBP1 transcript levels were higher in the brains of patients with schizophrenia than in those of matched healthy controls. The hSELENBP1 Tg mice displayed negative endophenotype behaviors, including heterotopias- and ectopias-like anatomical deformities in upper-layer cortical neurons and social withdrawal, deficits in nesting, and anhedonia-like behavior. Additionally, hSELENBP1 Tg mice exhibited reduced excitabilities of PFC 2/3-layer pyramidal neurons and abnormalities in EEG biomarkers observed in schizophrenia. Furthermore, mice overexpressing Selenbp1 in FC showed deficits in sociability. These results suggest that upregulation of SELENBP1 in the PFC causes asociality, a negative symptom of schizophrenia.
Brodmann area 9; SELENBP1; frontal cortex; schizophrenia; social behavior.
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James E Clark et al.
The British Journal of Psychiatry.
Recent developments in computational psychiatry have led to the hypothesis that mood represents an expectation (prior belief) on the likely interoceptive consequences of action (i.e. emotion). This stems from ideas about how the brain navigates its external world by minimising an upper bound on surprisal (free energy) of sensory information and echoes developments in other perceptual domains. In this paper we aim to present a simple partial observable Markov decision process that models mood updating in response to stressful or non-stressful environmental fluctuations while seeking to minimise surprisal in relation to prior beliefs about the likely interoceptive signals experienced with specific actions (attenuating or amplifying stress and pleasure signals).
We examine how, by altering these prior beliefs we can model mood updating in depression, mania and anxiety.
We discuss how these models provide a computational account of mood and its related psychopathology and relate it to previous research in reward processing.
Models such as this can provide hypotheses for experimental work and also open up the potential modelling of predicted disease trajectories in individual patients.
Bipolar affective disorders; aetiology; anxiety disorders; cognitive neuroscience; depressive disorders.
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Dylan Shea et al.
PNAS.
The formation of toxic Amyloid β-peptide (Aβ) oligomers is one of the earliest events in the molecular pathology of Alzheimer’s Disease (AD). These oligomers lead to a variety of downstream effects, including impaired neuronal signaling, neuroinflammation, tau phosphorylation, and neurodegeneration, and it is estimated that these events begin 10 to 20 y before the presentation of symptoms. Toxic Aβ oligomers contain a nonstandard protein structure, termed α-sheet, and designed α-sheet peptides target this main-chain structure in toxic oligomers independent of sequence. Here we show that a designed α-sheet peptide inhibits the deleterious effects on neuronal signaling and also serves as a capture agent in our soluble oligomer binding assay (SOBA). Pre-incubated synthetic α-sheet-containing Aβ oligomers produce strong SOBA signals, while monomeric and β-sheet protofibrillar Aβ do not. α-sheet containing oligomers were also present in cerebrospinal fluid (CSF) from an AD patient versus a noncognitively impaired control. For the detection of toxic oligomers in plasma, we developed a plate coating to increase the density of the capture peptide. The proof of concept was achieved by testing 379 banked human plasma samples. SOBA detected Aβ oligomers in patients on the AD continuum, including controls who later progressed to mild cognitive impairment. In addition, SOBA discriminated AD from other forms of dementia, yielding sensitivity and specificity of 99% relative to clinical and neuropathological diagnoses. To explore the broader potential of SOBA, we adapted the assay for a-synuclein oligomers and confirmed their presence in CSF from patients with Parkinson’s disease and Lewy body dementia.
Alzheimer’s disease; SOBA; alpha-sheet; detection; toxic oligomer.
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Review
Matthew Prebeg et al.
Lancet Psychiatry.
The value of involving people with lived experience in the research process (ie, patient engagement) is increasingly being recognised within youth mental health research. The wide-reaching benefits of patient engagement have been documented in the literature, including the empowerment of patients, improvement of research outcomes, and increased relevance of research findings. Although various models exist to guide patient engagement, there are key concepts that deserve exploration to ensure the authentic implementation of these models and development of patient roles. Our Personal View aims to: identify and discuss barriers to in-patient engagement roles in the context of youth mental health research; consider how key concepts of relational empowerment, fluidity, and flexibility can address some of these barriers; and provide tangible recommendations for implementing authentic patient engagement throughout the research process.
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Hannah R Scott et al.
Lancet Psychiatry.
Previous studies on the impact of the COVID-19 pandemic on the mental health of health-care workers have relied on self-reported screening measures to estimate the point prevalence of common mental disorders. Screening measures, which are designed to be sensitive, have low positive predictive value and often overestimate prevalence. We aimed to estimate prevalence of common mental disorders and post-traumatic stress disorder (PTSD) among health-care workers in England using diagnostic interviews. We did a two-phase, cross-sectional study comprising diagnostic interviews within a larger multisite longitudinal cohort of health-care workers (National Health Service [NHS] CHECK; n=23 462) during the COVID-19 pandemic. In the first phase, health-care workers across 18 NHS England Trusts were recruited. Baseline assessments were done using online surveys between April 24, 2020, and Jan 15, 2021. In the second phase, we selected a proportion of participants who had responded to the surveys and conducted diagnostic interviews to establish the prevalence of mental disorders. The recruitment period for the diagnostic interviews was between March 1, 2021 and Aug 27, 2021. Participants were screened with the 12-item General Health Questionnaire (GHQ-12) and assessed with the Clinical Interview Schedule-Revised (CIS-R) for common mental disorders or were screened with the 6-item Post-Traumatic Stress Disorder Checklist (PCL-6) and assessed with the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) for PTSD.
The screening sample contained 23 462 participants: 2079 participants were excluded due to missing values on the GHQ-12 and 11 147 participants due to missing values on the PCL-6. 243 individuals participated in diagnostic interviews for common mental disorders (CIS-R; mean age 42 years [range 21-70]; 185 [76%] women and 58 [24%] men) and 94 individuals participated in diagnostic interviews for PTSD (CAPS-5; mean age 44 years [23-62]; 79 [84%] women and 15 [16%] men). 202 (83%) of 243 individuals in the common mental disorders sample and 83 (88%) of 94 individuals in the PTSD sample were White. GHQ-12 screening caseness for common mental disorders was 52·8% (95% CI 51·7-53·8). Using CIS-R diagnostic interviews, the estimated population prevalence of generalised anxiety disorder was 14·3% (10·4-19·2), population prevalence of depression was 13·7% (10·1-18·3), and combined population prevalence of generalised anxiety disorder and depression was 21·5% (16·9-26·8). PCL-6 screening caseness for PTSD was 25·4% (24·3-26·5). Using CAPS-5 diagnostic interviews, the estimated population prevalence of PTSD was 7·9% (4·0-15·1).
The prevalence estimates of common mental disorders and PTSD in health-care workers were considerably lower when assessed using diagnostic interviews compared with screening tools. 21·5% of health-care workers met the threshold for diagnosable mental disorders, and thus might benefit from clinical intervention.
UK Medical Research Council; UCL/Wellcome; Rosetrees Trust; NHS England and Improvement; Economic and Social Research Council; National Institute for Health and Care Research (NIHR) Biomedical Research Centre at the Maudsley and King’s College London (KCL); NIHR Protection Research Unit in Emergency Preparedness and Response at KCL.
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Mahdis Kamali et al.
Canadian Journal of Psychiatry.
To examine differences in mental health-related service contacts between immigrant, refugee, racial and ethnic minoritized children and youth, and the extent to which social, and economic characteristics account for group differences. The sample for analyses includes 10,441 children and youth aged 4-17 years participating in the 2014 Ontario Child Health Study. The primary caregiver completed assessments of their child’s mental health symptoms, perceptions of need for professional help, mental health-related service contacts, experiences of discrimination and sociodemographic and economic characteristics.
Adjusting for mental health symptoms and perceptions of need for professional help, children and youth from immigrant, refugee and racial and ethnic minoritized backgrounds were less likely to have mental health-related service contacts (adjusted odds ratios ranged from 0.54 to 0.79), compared to their non-immigrant peers and those who identified as White. Group differences generally remained the same or widened after adjusting for social and economic characteristics. Large differences in levels of perceived need were evident across non-migrant and migrant children and youth.
Lower estimates of mental health-related service contacts among immigrant, refugee and racial and ethnic minoritized children and youth underscore the importance and urgency of addressing barriers to recognition and treatment of mental ill-health among children and youth from minoritized backgrounds.
children and youth; immigrant health; mental health disparities; mental healthcare need; service utilization.
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Mohammad Ahangari et al.
The British Journal of Psychiatry.
Psychotic disorders and schizotypal traits aggregate in the relatives of probands with schizophrenia. It is currently unclear how variability in symptom dimensions in schizophrenia probands and their relatives is associated with polygenic liability to psychiatric disorders. To investigate whether polygenic risk scores (PRSs) can predict symptom dimensions in members of multiplex families with schizophrenia.
The largest genome-wide data-sets for schizophrenia, bipolar disorder and major depressive disorder were used to construct PRSs in 861 participants from the Irish Study of High-Density Multiplex Schizophrenia Families. Symptom dimensions were derived using the Operational Criteria Checklist for Psychotic Disorders in participants with a history of a psychotic episode, and the Structured Interview for Schizotypy in participants without a history of a psychotic episode. Mixed-effects linear regression models were used to assess the relationship between PRS and symptom dimensions across the psychosis spectrum.
Schizophrenia PRS is significantly associated with the negative/disorganised symptom dimension in participants with a history of a psychotic episode (P = 2.31 × 10) and negative dimension in participants without a history of a psychotic episode (P = 1.42 × 10). Bipolar disorder PRS is significantly associated with the manic symptom dimension in participants with a history of a psychotic episode (P = 3.70 × 10). No association with major depressive disorder PRS was observed.
Polygenic liability to schizophrenia is associated with higher negative/disorganised symptoms in participants with a history of a psychotic episode and negative symptoms in participants without a history of a psychotic episode in multiplex families with schizophrenia. These results provide genetic evidence in support of the spectrum model of schizophrenia, and support the view that negative and disorganised symptoms may have greater genetic basis than positive symptoms, making them better indices of familial liability to schizophrenia.
Schizophrenia; genetics; negative symptoms; psychotic disorders; schizotypy.
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Mona Buhusi et al.
Schizophrenia Bulletin.
Latent inhibition (LI) is a measure of selective attention and learning relevant to Schizophrenia (SZ), with 2 abnormality poles: Disrupted LI in acute SZ, thought to underlie positive symptoms, and persistent LI (PLI) in schizotypy and chronic SZ under conditions where normal participants fail to show LI. We hypothesized that Brain-Derived Neurotrophic Factor (BDNF)-Met genotype shifts LI toward the PLI pole. We investigated the role of BDNF-Val66Met polymorphism and neural activation in regions involved in LI in mice, and the interaction between the BDNF and CHL1, a gene associated with SZ.
No LI differences occurred between BDNF-wild-type (WT) (Val/Val) and knock-in (KI) (Met/Met) mice after weak conditioning. Chronic stress or stronger conditioning disrupted LI in WT but not KI mice. Behavior correlated with activation in infralimbic and orbitofrontal cortices, and nucleus accumbens. Examination of LI in CHL1-KO mice revealed no LI with no Met alleles (BDNF-WTs), PLI in CHL1-WT mice with 1 Met allele (BDNF-HETs), and PLI in both CHL1-WTs and CHL1-KOs with 2 Met alleles (BDNF-KIs), suggesting a shift to LI persistence with the number of BDNF-Met alleles in the CHL1 model of acute SZ.
Results support a role for BDNF polymorphisms in gene-gene and gene-environment interactions relevant to SZ. BDNF-Met allele may reduce expression of some acute SZ symptoms, and may increase expression of negative symptoms in individuals with chronic SZ. Evaluation of (screening for) SZ phenotypes associated with mutations at a particular locus (eg, CHL1), may be masked by strong effects at different loci (eg, BDNF).
Brain-Derived Neurotrophic Factor; CHL1; Schizophrenia; c-Fos; chronic unpredictable stress; latent inhibition.
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Oleguer Plana-Ripoll et al.
Lancet Psychiatry.
Mental disorders can affect workforce participation via a range of mechanisms. In this study, we aimed to estimate the association between different types of mental disorders and working years lost, defined as the number of years not actively working or enrolled in an educational programme. In this population-based cohort study, we included all people aged 18-65 years (mean 38·0 [SD 13·9]) in the Danish Civil Registration System from Jan 1, 1995 to Dec 31, 2016. Information on mental disorders was obtained from the Danish Psychiatric Central Research Register and information on labour market characteristics was obtained from administrative registers. Follow-up started at age 18 years, immigration to Denmark, or on Jan 1, 1995, whichever came later; and it ended at age 65 years, death, emigration from Denmark, disability pension, voluntary early retirement, or Dec 31, 2016 (whichever came earlier). As the main outcome, we estimated working years lost for those diagnosed with any mental disorder and 24 types of mental disorders, as well as for the general population of same age and sex. We decomposed total working years lost into periods of unemployment or sick leave, disability pension, voluntary early retirement, or death. Data on ethnicity were not available through administrative registers.
A total of 5 163 321 individuals, 2 642 383 men and 2 520 938 women, were followed up for 65·4 million person-years. Overall, 488 775 (9·47%) individuals were diagnosed with a mental disorder. On average, individuals with mental disorders lost an additional 10·52 (95% CI 10·48-10·57) years of working life compared with the general Danish population. Receiving a disability pension (7·54 [7·49-7·59] years) and longer periods of unemployment (2·24 [2·21-2·27] years) accounted for most of this difference.
Our findings foreground the substantial impact of mental disorders on workforce participation. There is a need to invest in programmes that reduce the burden of working years lost and assist people with mental disorders in returning to the workforce.
Lundbeck Foundation and Danish National Research Foundation.
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Rosa Lundbye Allesøe et al.
JAMA Psychiatry.
Diagnoses and treatment of mental disorders are hampered by the current lack of objective markers needed to provide a more precise diagnosis and treatment strategy. To develop deep learning models to predict mental disorder diagnosis and severity spanning multiple diagnoses using nationwide register data, family and patient-specific diagnostic history, birth-related measurement, and genetics.
This study was conducted from May 1, 1981, to December 31, 2016. For the analysis, which used a Danish population-based case-cohort sample of individuals born between 1981 and 2005, genotype data and matched longitudinal health register data were taken from the longitudinal Danish population-based Integrative Psychiatric Research Consortium 2012 case-cohort study. Included were individuals with mental disorders (attention-deficit/hyperactivity disorder [ADHD]), autism spectrum disorder (ASD), major depressive disorder (MDD), bipolar disorder (BD), schizophrenia spectrum disorders (SCZ), and population controls. Data were analyzed from February 1, 2021, to January 24, 2022.
At least 1 hospital contact with diagnosis of ADHD, ASD, MDD, BD, or SCZ.
The predictability of (1) mental disorder diagnosis and (2) severity trajectories (measured by future outpatient hospital contacts, admissions, and suicide attempts) were investigated using both a cross-diagnostic and single-disorder setup. Predictive power was measured by AUC, accuracy, and Matthews correlation coefficient (MCC), including an estimate of feature importance.
A total of 63 535 individuals (mean [SD] age, 23 [7] years; 34 944 male [55%]; 28 591 female [45%]) were included in the model. Based on data prior to diagnosis, the specific diagnosis was predicted in a multidiagnostic prediction model including the background population with an overall area under the curve (AUC) of 0.81 and MCC of 0.28, whereas the single-disorder models gave AUCs/MCCs of 0.84/0.54 for SCZ, 0.79/0.41 for BD, 0.77/0.39 for ASD, 0.74/0.38, for ADHD, and 0.74/0.38 for MDD. The most important data sets for multidiagnostic prediction were previous mental disorders and age (11%-23% reduction in prediction accuracy when removed) followed by family diagnoses, birth-related measurements, and genetic data (3%-5% reduction in prediction accuracy when removed). Furthermore, when predicting subsequent disease trajectories of the disorder, the most severe cases were the most easily predictable, with an AUC of 0.72.
Results of this diagnostic study suggest the possibility of combining genetics and registry data to predict both mental disorder diagnosis and disorder progression in a clinically relevant, cross-diagnostic setting prior to clinical assessment.
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Joshua S Siegel et al.
JAMA Psychiatry.
Psychedelic drugs are becoming accessible in the US through a patchwork of state legislative reforms. This shift necessitates consensus on treatment models, education and guidance for health care professionals, and planning for implementation and regulation. To assess trends in psychedelics legislative reform and legalization in the US to provide guidance to health care professionals, policy makers, and the public.
Data were compiled from legislative databases (BillTrack50, LexisNexis, and Ballotpedia) from January 1, 2019, to September 28, 2022. Legislation was identified by searching for terms related to psychedelics (eg, psilocybin, MDMA, peyote, mescaline, ibogaine, LSD, ayahuasca, and DMT). Bills were coded by an attorney along 2 axes: which psychedelic drugs would be affected and in what ways (eg, decriminalization, funding for medical research, and right to try). To explore drivers and rates of legislative reform, data were compared with other state indices including 2020 presidential voting margins and marijuana legislative reform.
Twenty-five states have considered 74 bills (69 legislative initiatives, 5 ballot measures); 10 bills were enacted, and 32 were still active. The number of psychedelic reform bills introduced during each calendar year increased steadily from 5 in 2019 to 6 in 2020, 27 in 2021, and 36 in 2022. Nearly all bills specified psilocybin (67 [90%]), and many also included MDMA (3,4-methylenedioxy-methamphetamine; 27 [36%]). While bills varied in their framework, most (43 [58%]) proposed decriminalization, of which few delineated medical oversight (10 of 43 [23%]) or training and/or licensure requirements (15 of 43 [35%]). In general, bills contained less regulatory guidance than the enacted Oregon Measure 109. While early legislative efforts occurred in liberal states, the margin between liberal and conservative states has decreased over time (although the difference was not significant), suggesting that psychedelic drug reform is becoming a bipartisan issue. In addition, an analytic model based on marijuana legalization projected that a majority of states will legalize psychedelics by 2034 to 2037.
Legislative reform for psychedelic drugs has been proceeding in a rapid, patchwork fashion in the US. Further consideration should be given to key health care issues such as establishing (1) standards for drugs procured outside the medical establishment, (2) licensure criteria for prescribers and therapists, (3) clinical and billing infrastructure, (4) potential contraindications, and (5) use in special populations like youths, older adults, and pregnant individuals.
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Krista F Huybrechts et al.
JAMA Psychiatry.
Psychiatric disorders are common among female individuals of reproductive age. While antipsychotic medication use is increasing, the safety of such medications in pregnancy is an area with large evidence gaps. To evaluate the risk of first-trimester antipsychotic exposure with respect to congenital malformations, focusing on individual drugs and specific malformation subtypes.
This cohort study used data from nationwide health registers from the 5 Nordic countries and the US and spanned 1996 to 2018. The Nordic cohort included all pregnancies resulting in singleton live-born infants, and the US cohort consisted of publicly insured mothers linked to their live-born infants nested in the nationwide Medicaid Analytic eXtract. Data were analyzed from November 2020 to April 2022.
One or more first-trimester dispensing of any atypical, any typical, and individual antipsychotic drugs.
Any major congenital malformation and specific malformation subtypes previously suggested to be associated with antipsychotic exposure in utero: cardiovascular malformations, oral clefts, neural tube defects, hip dysplasia, limb reduction defects, anorectal atresia/stenosis, gastroschisis, hydrocephalus, other specific brain anomalies, and esophageal disorders. Propensity score stratification was used to control for potential confounders. Pooled adjusted estimates were calculated using indirect standardization.
A total of 6 455 324 unexposed mothers (mean maternal age range across countries: 24-31 years), 21 751 mothers exposed to atypical antipsychotic drugs (mean age range, 26-31 years), and 6371 mothers exposed to typical antipsychotic drugs (mean age range, 27-32 years) were included in the study cohort. Prevalence of any major malformation was 2.7% (95% CI, 2.7%-2.8%) in unexposed infants, 4.3% (95% CI, 4.1%-4.6%) in infants with atypical antipsychotic drug exposure, and 3.1% (95% CI, 2.7%-3.5%) in infants with typical antipsychotic drug exposure in utero. Among the most prevalent exposure-outcome combinations, adjusted relative risks (aRR) were generally close to the null. One exception was olanzapine exposure and oral cleft (aRR, 2.1 [95% CI, 1.1-4.3]); however, estimates varied across sensitivity analyses. Among moderately prevalent combinations, increased risks were observed for gastroschisis and other specific brain anomalies after atypical antipsychotic exposure (aRR, 1.5 [95% CI, 0.8-2.6] and 1.9 [95% CI, 1.1-3.0]) and for cardiac malformations after chlorprothixene exposure (aRR, 1.6 [95% CI, 1.0-2.7]). While the association direction was consistent across sensitivity analyses, confidence intervals were wide, prohibiting firm conclusions.
In this study, considering the evidence from primary and sensitivity analyses and inevitable statistical noise for very rare exposure-outcome combinations, in utero antipsychotic exposure generally was not meaningfully associated with an increased risk of malformations. The observed increased risks of oral clefts associated with olanzapine, gastroschisis, and other specific brain anomalies with atypical antipsychotics and cardiac malformations with chlorprothixene requires confirmation as evidence continues to accumulate.
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Laura B Jones et al.
Canadian Journal of Psychiatry.
Examine time trends in suicidal ideation in post-secondary students over the first three waves of the COVID-19 pandemic in Canada and identify subpopulations of students with increased risk. We analysed 14 months of data collected through repeated cross-sectional deployment of the World Health Organization (WHO) World Mental Health-International College Student (WMH-ICS) survey at the University of British Columbia. Estimated log odds weekly trends of 30-day suicidal ideation (yes/no) were plotted against time with adjustments for demographics using binary logistic generalized additive model (GAM). Risk factors for 30-day suicidal ideation frequency (four categories) were examined using the ordered logistic GAM, with a cubic smoothing spline for modelling time trend in obervation weeks and accounting for demographics.
Nearly one-fifth (18.9%) of students experienced suicidal ideation in the previous 30 days. While the estimated log odds suggested that binary suicidal ideation was relatively stable across the course of the pandemic, an initial drop followed by an increasing trend was observed. Risk factors for suicidal ideation frequency during the pandemic included identifying as Chinese or as another non-Indigenous ethnic minority; experiencing current symptoms of depression or anxiety; having a history of suicidal planning or attempts; and feeling overwhelmed but unable to get help as a result of COVID-19. Older age was identified as a protective factor.
The general university student population in our study was relatively resilient with respect to suicidal ideation during the first three waves of the pandemic, but trends indicate the possibility of delayed impact. Specific sub-populations were found to be at increased risk and should be considered for targeted support. Further analyses should be undertaken to continue monitoring suicidality trends throughout the remainder of the pandemic and beyond.
COVID-19; mental health; pandemic; student; suicidal ideation.
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Denise A Hien et al.
American Journal of Psychiatry.
Treatment efficacy for co-occurring posttraumatic stress disorder (PTSD) and substance use disorders is well established, yet direct evidence for comparative effectiveness across treatments is lacking. The present study compared the effectiveness of several behavioral and pharmacological therapies for adults with co-occurring PTSD and alcohol or other drug use disorders. A systematic search of PsycINFO, MEDLINE, and ClinicalTrials.gov was conducted through December 2020 for trials targeting PTSD, alcohol or other drug use disorders, or both disorders (36 studies, N=4,046). Primary outcomes were severity scores for PTSD, alcohol use, and drug use, estimated via moderated nonlinear factor analysis. Propensity score weight-adjusted multilevel models were used. Model-predicted effect sizes were estimated for each treatment, and comparative effect sizes for each active arm against treatment as usual, at end of treatment and at 12-month follow-up.
Compared with treatment as usual, combining trauma-focused therapy and pharmacotherapy for substance use disorders showed the largest comparative effect sizes for PTSD severity (d=-0.92, 95% CI=-1.57, -0.30) and alcohol use severity (d=-1.10, 95% CI=-1.54, -0.68) at end of treatment. Other treatments with large comparative effect sizes included pharmacotherapies for alcohol or other drug use disorders, trauma-focused integrated therapies, and trauma-focused nonintegrated therapies. Reductions in outcomes for PTSD symptoms and alcohol use were observed for nearly all treatments.
The findings provide support for treating comorbid PTSD and substance use disorders using a variety of approaches, with alcohol-targeted pharmacotherapies and trauma-focused behavioral therapies as a combination of treatments that lead to early and sustained improvements in PTSD and alcohol use severity. Further treatment development is indicated for combining behavioral and pharmacological treatments for synergized impact and understanding the mechanisms of action and conditions under which each treatment type is optimized.
Drug/Psychotherapy Combination; Pharmacotherapy; Posttraumatic Stress Disorder (PTSD); Psychotherapy; Substance-Related and Addictive Disorders.
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Stefanie Russman Block et al.
American Journal of Psychiatry.
Cortical-subcortical hyperconnectivity related to affective-behavioral integration and cortical network hypoconnectivity related to cognitive control have been demonstrated in obsessive-compulsive disorder (OCD); the study objective was to examine whether these connectivity patterns predict treatment response. Adolescents (ages 12-17) and adults (ages 24-45) were randomly assigned to 12 sessions of exposure and response prevention (ERP) or stress management therapy (SMT), an active control. Before treatment, resting-state connectivity of ventromedial prefrontal cortical (vmPFC), cingulo-opercular, frontoparietal, and subcortical regions was assessed with functional MRI. OCD severity was assessed with the Yale-Brown Obsessive Compulsive Scale before, during, and after treatment. Usable fMRI and longitudinal symptom data were obtained from 116 patients (68 female; 54 adolescents; 60 medicated).
ERP produced greater decreases in symptom scores than SMT. ERP was selectively associated with less vmPFC-subcortical (caudate and thalamus) connectivity in both age groups and primarily in unmedicated participants. Greater symptom improvement with both ERP and SMT was associated with greater cognitive-control (cingulo-opercular and frontoparietal) and subcortical (putamen) connectivity across age groups. Developmental specificity was observed across ERP and SMT treatments, such that greater improvements with ERP than SMT were associated with greater frontoparietal-subcortical (nucleus accumbens) connectivity in adolescents but greater connectivity between frontoparietal regions in adults. Comparison of response-predictive connections revealed no significant differences compared with a matched healthy control group.
The results suggest that less vmPFC-subcortical connectivity related to affect-influenced behavior may be important for ERP engagement, whereas greater cognitive-control and motor circuit connectivity may generally facilitate response to psychotherapy. Finally, neural predictors of treatment response may differ by age.
Cognitive Behavioral Therapy (CBT); Functional Connectivity; Obsessive-Compulsive Disorder (OCD); Psychotherapy; Ventromedial Prefrontal Cortex (vmPFC); fMRI.
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Review
Mara Parellada et al.
American Journal of Psychiatry.
The aim of this study was to catalog and evaluate response biomarkers correlated with autism spectrum disorder (ASD) symptoms to improve clinical trials. A systematic review of MEDLINE, Embase, and Scopus was conducted in April 2020. Seven criteria were applied to focus on original research that includes quantifiable response biomarkers measured alongside ASD symptoms. Interventional studies or human studies that assessed the correlation between biomarkers and ASD-related behavioral measures were included.
A total of 5,799 independent records yielded 280 articles for review that reported on 940 biomarkers, 755 of which were unique to a single publication. Molecular biomarkers were the most frequently assayed, including cytokines, growth factors, measures of oxidative stress, neurotransmitters, and hormones, followed by neurophysiology (e.g., EEG and eye tracking), neuroimaging (e.g., functional MRI), and other physiological measures. Studies were highly heterogeneous, including in phenotypes, demographic characteristics, tissues assayed, and methods for biomarker detection. With a median total sample size of 64, almost all of the reviewed studies were only powered to identify biomarkers with large effect sizes. Reporting of individual-level values and summary statistics was inconsistent, hampering mega- and meta-analysis. Biomarkers assayed in multiple studies yielded mostly inconsistent results, revealing a “replication crisis.”
There is currently no response biomarker with sufficient evidence to inform ASD clinical trials. This review highlights methodological imperatives for ASD biomarker research necessary to make definitive progress: consistent experimental design, correction for multiple comparisons, formal replication, sharing of sample-level data, and preregistration of study designs. Systematic “big data” analyses of multiple potential biomarkers could accelerate discovery.
Autism Spectrum Disorder; Biological Markers; Clinical Drug Studies; Clinical Trials; Endophenotypes; Pharmacodynamic Biomarkers; Response Biomarkers; Symptom Severity; Translational Research.
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Hermela Shimelis et al.
American Journal of Psychiatry.
Autism, schizophrenia, and other clinically distinct neurodevelopmental psychiatric disorders (NPDs) have shared genetic etiologies, including single-gene and multigenic copy number variants (CNVs). Because rare variants are primarily investigated in clinical cohorts, population-based estimates of their prevalence and penetrance are lacking. The authors determined the prevalence, penetrance, and NPD risk of pathogenic single-gene variants in a large health care system population. The authors analyzed linked genomic and electronic health record (EHR) data in a subset of 90,595 participants from Geisinger’s MyCode Community Health Initiative, known as the DiscovEHR cohort. Loss-of-function pathogenic variants in 94 high-confidence NPD genes were identified through exome sequencing, and NPD penetrance was calculated using preselected EHR diagnosis codes. NPD risk was estimated using a case-control comparison of DiscovEHR participants with and without NPD diagnoses. Results from single-gene variant analyses were also compared with those from 31 previously reported pathogenic NPD CNVs.
Pathogenic variants were identified in 0.34% of the DiscovEHR cohort and demonstrated a 34.3% penetrance for NPDs. Similar to CNVs, sequence variants collectively conferred a substantial risk for several NPD diagnoses, including autism, schizophrenia, and bipolar disorder. Significant NPD risk remained after participants with intellectual disability were excluded from the analysis, confirming the association with major psychiatric disorders in individuals without severe cognitive deficits.
Collectively, rare single-gene variants and CNVs were found in >1% of individuals in a large health care system population and play an important contributory role in mental health disorders. Diagnostic genetic testing for pathogenic variants among symptomatic individuals with NPDs could improve clinical outcomes through early intervention and anticipatory therapeutic support.
Bipolar and Related Disorders; Genetics/Genomics; Neurodevelopmental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders.
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Ying Duan et al.
PNAS.
As a critical node connecting the forebrain with the midbrain, the lateral habenula (LHb) processes negative feedback in response to aversive events and plays an essential role in value-based decision-making. Compulsive drug use, a hallmark of substance use disorder, is attributed to maladaptive decision-making regarding aversive drug-use-related events and has been associated with dysregulation of various frontal-midbrain circuits. To understand the contributions of frontal-habenula-midbrain circuits in the development of drug dependence, we employed a rat model of methamphetamine self-administration (SA) in the presence of concomitant footshock, which has been proposed to model compulsive drug-taking in humans. In this longitudinal study, functional MRI data were collected at pretraining baseline, after 20 d of long-access SA phase, and after 5 d of concomitant footshock coupled with SA (punishment phase). Individual differences in response to punishment were quantified by a “compulsivity index (CI),” defined as drug infusions at the end of punishment phase, normalized by those at the end of SA phase. Functional connectivity of LHb with the frontal cortices and substantia nigra (SN) after the punishment phase was positively correlated with the CI in rats that maintained drug SA despite receiving increasing-intensity footshock. In contrast, functional connectivity of the same circuits was negatively correlated with CI in rats that significantly reduced SA. These findings suggest that individual differences in compulsive drug-taking are reflected by alterations within frontal-LHb-SN circuits after experiencing the negative consequences from SA, suggesting these circuits may serve as unique biomarkers and potential therapeutic targets for individualized treatment of addiction.
compulsive drug-taking; footshock; lateral habenula; orbitofrontal cortex; substantia nigra.
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Juan P Ramirez-Mahaluf et al.
Schizophrenia Bulletin.
Abnormal functional connectivity between brain regions is a consistent finding in schizophrenia, including functional magnetic resonance imaging (fMRI) studies. Recent studies have highlighted that connectivity changes in time in healthy subjects. We here examined the temporal changes in functional connectivity in patients with a first episode of psychosis (FEP). Specifically, we analyzed the temporal order in which whole-brain organization states were visited. Two case-control studies, including in each sample a subgroup scanned a second time after treatment. Chilean sample included 79 patients with a FEP and 83 healthy controls. Mexican sample included 21 antipsychotic-naïve FEP patients and 15 healthy controls. Characteristics of the temporal trajectories between whole-brain functional connectivity meta-states were examined via resting-state functional MRI using elements of network science. We compared the cohorts of cases and controls and explored their differences as well as potential associations with symptoms, cognition, and antipsychotic medication doses.
We found that the temporal sequence in which patients’ brain dynamics visited the different states was more redundant and segregated. Patients were less flexible than controls in changing their network in time from different configurations, and explored the whole landscape of possible states in a less efficient way. These changes were related to the dose of antipsychotics the patients were receiving. We replicated the relationship with antipsychotic medication in the antipsychotic-naïve FEP sample scanned before and after treatment.
We conclude that psychosis is related to a temporal disorganization of the brain’s dynamic functional connectivity, and this is associated with antipsychotic medication use.
antipsychotic; brain networks; dynamic connectivity; graph analysis; meta-states; schizophrenia.
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Charles N Bernstein et al.
Gastroenterology.
We estimated the incidence and prevalence of benzodiazepine and Z-drug (separately and jointly as BZD) use in the inflammatory bowel disease (IBD) population compared with matched controls without IBD and examined the association of mood/anxiety disorders (M/ADs) with the use of BZD from 1997 to 2017. Using administrative data from Manitoba, Canada, we identified 5,741 persons with incident IBD who were matched in a 1:5 ratio to controls on sex, birth year, and region. Validated case definitions were used to identify M/AD. Dispensations of BZD were identified. Multivariable generalized linear models were used to assess the association between IBD, M/AD, and BZD use.
In 2016, the incident age/sex-standardized benzodiazepine use rates per 1,000 were 28.06 (95% confidence interval [CI] 26.41-29.81) in the IBD cohort and 16.83 (95% CI 16.28-17.39) in controls (adjusted rate ratio = 1.69 [95% CI 1.56-1.79]). Benzodiazepine incidence rates were higher for women with IBD than men, but the RR between cases and controls were similar for men and women. The incident age/sex-standardized Z-drug use rate per 1,000 was 21.07 (95% CI 19.69-22.41) in the IBD cohort. This was 1.87-fold higher than in controls (95% CI 1.73-2.01). In 2017, approximately 20% of persons with IBD used benzodiazepines and 20% used Z-drugs. There was a subadditive effect of both benzodiazepine and Z-drug uses between IBD and M/AD after adjusting for covariates.
The use of BZD is more common in people with IBD than in population controls. Strategies to reduce the use of BZDs in persons with IBD and to offer alternative management strategies for M/ADs, sleep disorders, and other symptomatic concerns are needed.
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Rubén López-Bueno et al.
The British Journal of Psychiatry.
Prior research has solely focused on the association between handgrip strength and risk of depression in single countries or general populations, but more knowledge is required from wider-spread cohorts and target populations. This study aimed to investigate the association between handgrip strength and risk of depression using repeated measures in adults aged 50 years and over.
Data on handgrip strength and risk of depression were retrieved from the Survey of Health, Ageing and Retirement in Europe (SHARE) waves 1, 2, 4, 5, 6 and 7, using a hand dynamometer (Smedley, S Dynamometer, TTM) and the EURO-D 12-item scale, respectively. Time-varying exposure and covariates were modelled using both Cox regression and restricted cubic splines.
A total of 115 601 participants (mean age 64.3 years (s.d. = 9.9), 54.3% women) were followed-up for a median of 7.3 years (interquartile range: 3.9-11.8) and 792 459 person-years. During this period, 30 208 (26.1%) participants experienced a risk of depression. When modelled as a continuous variable, we observed an inverse significant association for each kg increase of handgrip strength and depression up to 40 kg in men and up to 27 kg in women.
Being physically strong may serve as a preventive factor for depression in older adults, but this is limited up to a maximum specific threshold for men and women.
Muscle; burden of disease; epidemiology; mental disorder; prevention.
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Anika Varma et al.
Gastroenterology.
Patients with Crohn’s disease (CD) experience a variety of symptoms that significantly affect their lives. In this study, we (i) ascertain the most prevalent and impactful symptoms in CD and (ii) identify modifying factors that are associated with a higher disease burden in CD. We conducted semistructured interviews with adult participants with CD to determine what issues have the greatest impact on their lives. Next, we conducted a large cross-sectional study of individuals with CD to determine the prevalence and relative importance of those symptoms and themes and to identify the demographic features that are associated with a higher disease burden.
Sixteen individuals with CD provided 792 direct quotes regarding their symptomatic burden. Four hundred three people with CD participated in our cross-sectional study. The symptomatic themes with the highest prevalence in CD were gastrointestinal issues (93.0%), fatigue (86.4%), dietary restrictions (77.9%), and impaired sleep or daytime sleepiness (75.6%). The symptomatic themes that had the greatest impact on patients’ lives (0-4 scale) related to fatigue (1.82), impaired sleep or daytime sleepiness (1.71), gastrointestinal issues (1.66), and dietary restrictions (1.61). Symptomatic theme prevalence was strongly associated with a higher number of soft stools per day, greater number of bowel movements per day, missed work, employment and disability status, and having perianal disease.
Patients with CD experience numerous symptoms that affect their daily life. These symptoms, some underrecognized, vary based on disease and demographic characteristics and represent potential targets for future therapeutic interventions.
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https://psychiatry.dev/wp-content/uploads/speaker/post-11069.mp3?cb=1669985866.mp3 Playback speed: 0.8x 1x 1.3x 1.6x 2x Download: Autism attenuates the perception of the mind-body divide – PubMed Iris Berent et al. PNAS. 2022. People are intuitive Dualists-they tacitly considerFull EntryAutism attenuates the perception of the mind-body divide – PubMed
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https://psychiatry.dev/wp-content/uploads/speaker/post-11016.mp3?cb=1669811105.mp3 Playback speed: 0.8x 1x 1.3x 1.6x 2x Download: Factors Impacting Access and Engagement of Cognitive Remediation Therapy for People with Schizophrenia: A Systematic Review – Review Rosalie Ariane EvaFull EntryFactors Impacting Access and Engagement of Cognitive Remediation Therapy for People with Schizophrenia: A Systematic Review –
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https://psychiatry.dev/wp-content/uploads/speaker/post-11004.mp3?cb=1669707197.mp3 Playback speed: 0.8x 1x 1.3x 1.6x 2x Download: No safety without emotional safety – Review David Veale et al. Lancet Psychiatry. 2022. This Personal View highlights how emotional safety isFull EntryNo safety without emotional safety –
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https://psychiatry.dev/wp-content/uploads/speaker/post-10996.mp3?cb=1669659225.mp3 Playback speed: 0.8x 1x 1.3x 1.6x 2x Download: Cross-Modality Evidence for Reduced Choice History Biases in Psychosis-Prone Individuals – Anna-Lena Eckert et al. Schizophrenia Bulletin. 2022. Predictive processing posits thatFull EntryCross-Modality Evidence for Reduced Choice History Biases in Psychosis-Prone Individuals –
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https://psychiatry.dev/wp-content/uploads/speaker/post-10890.mp3?cb=1669103593.mp3 Playback speed: 0.8x 1x 1.3x 1.6x 2x Download: Personality traits and coping strategies in recent-onset psychosis: Associations with symptom severity and psychosocial functioning – Matej Djordjevic et al. Schizophrenia Research.Full EntryPersonality traits and coping strategies in recent-onset psychosis: Associations with symptom severity and psychosocial functioning –
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https://psychiatry.dev/wp-content/uploads/speaker/post-10852.mp3?cb=1669015154.mp3 Playback speed: 0.8x 1x 1.3x 1.6x 2x Download: Treatment of schizophrenia with catatonic symptoms: A narrative review – Stanley N Caroff et al. Schizophrenia Research. 2022. Catatonia is a neuropsychiatricFull EntryTreatment of schizophrenia with catatonic symptoms: A narrative review –
https://psychiatry.dev/wp-content/uploads/speaker/post-10848.mp3?cb=1669011445.mp3 Playback speed: 0.8x 1x 1.3x 1.6x 2x Download: Brain mechanisms underlying catatonia: A systematic review – Giulia Cattarinussi et al. Schizophrenia Research. 2022. Catatonia is a complex psychomotor disorder characterizedFull EntryBrain mechanisms underlying catatonia: A systematic review –
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