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Purpose: High rates of Not in Education, Employment or Training (NEET) are seen in people with first episode of psychosis (FEP). Sociodemographic and clinical factors were reported to be associated with NEET status in FEP patients. This study follows Intersectionality to examine the independent and additive effects, and most importantly the intersections of sociodemographic and clinical variables concerning NEET status in FEP patients. It was hypothesized that NEET status in FEP patients would be described by the intersection between at least two predictor variables., Methods: Secondary analyses with chi-square tests, multiple logistic regression and Chi-squared Automatic Interaction Detection (CHAID) analyses were performed on 440 participants with FEP., Results: Chi-square tests indicated that patient socioeconomic status and negative symptom severity were significantly and independently associated with their NEET status. Multiple logistic regression suggested additive effects of age (odds ratio = 1.61), patient socioeconomic status (odds ratio = 1.55) and negative symptom severity (odds ratio = 1.75) in predicting patients' NEET status. CHAID detected an intersection between patients' negative symptom severity and socioeconomic status in shaping their NEET status., Conclusion: This study explored how the NEET status of patients with FEP was explained not only by the separate effects of negative symptom severity and socioeconomic status but also by the unique intersections of their clinical and social identities. Findings indicated that functional outcomes of patients appear co-constructed by the intersections of multiple identities. Crucial clinical implications of complementing care for negative symptom severity with vocational resources to improve functional outcomes of patients are discussed., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Importance: Despite growing interest in the phenomenology of delusions in psychosis, at present little is known about their content and evolution over time, including whether delusion themes are consistent across episodes., Objective: To examine the course of delusions and thematic delusion content across relapse episodes in patients presenting to an early intervention service for psychosis., Design, Setting, and Participants: This longitudinal, observational study used clinical data systematically collected from January 2003 to March 2018 from a cohort of consenting patients with affective or nonaffective first-episode psychosis, followed up naturalistically for up to 2 years in an early intervention service for psychosis in Montréal, Quebec, Canada. Data included the thematic content and severity of delusions (scores ≥3 using the Scale for the Assessment of Positive Symptoms) and associated psychotic and nonpsychotic symptoms, both across an initial episode and, in the event of remission, a potential relapse. Data were analyzed from September 2021 to February 2023., Exposure: An early intervention service for psychosis, organized around intensive case management and a multidisciplinary team approach, which observed each patient for up to 2 years of care., Main Outcomes and Measures: The primary outcome was positive symptom relapse and remission, including the presence and content of delusions, which was coded per the Scale for the Assessment of Positive Symptoms and accepted definitions. The main statistical measures included repeated paired-sample t tests and binary logistic regression analyses., Results: Of 636 consenting patients, mean (SD) age was 23.8 (4.75) years; 191 patients were female, 444 were male, and 1 patient was nonbinary. Remission rates were high, and relapse rates were relatively low: 591 individuals had baseline delusions, of which 558 (94.4%) achieved remission. Of these 558 patients, only 182 (32.6%) had a subsequent relapse to a second or later episode of psychosis. Of the 182 patients who did relapse, however, a large proportion (115 [63.2%]) reported threshold-level delusions. Of these 115, 104 patients (90.4%) had thematic delusion content consistent with that reported during the index (first) episode. Those who relapsed with delusions had fewer delusion themes present during subsequent episodes of psychosis compared with the index episode and lower levels of other psychotic and nonpsychotic symptoms., Conclusions and Relevance: Specialized early intervention services for psychosis can achieve high rates of sustained remission. However, in this study, the minority of individuals with delusions who later relapsed experienced similar delusion themes during subsequent episodes. These findings raise important considerations for the conceptualization of delusions and have clinical implications for trajectories of illness and care.

Background: Neurocognitive impairment is a core feature of schizophrenia spectrum disorders (SSDs), and the relationship between cognition and symptoms in SSDs has been widely researched. Negative symptoms are related to a wide range of cognitive impairments; however, the aspects of negative symptoms that underpin this relationship have yet to be specified., Study Design: We used iterative Constrained Principal Component Analysis (iCPCA) to explore the relationship between 18 cognitive measures (including processing speed, attention, working, spatial and verbal memory and executive functions) and 46 symptoms in schizophrenia at the individual item level while minimizing the risk of Type I errors. ICPCA was conducted on a sample of SSD patients in the early stages of psychiatric treatment (n = 121) to determine the components of cognition overlapping with symptoms measured by the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS)., Results: We found that a verbal memory component was associated with items from SANS and SAPS related to impoverished and disorganized emotional communication, language, and thought. In contrast, a working memory component was associated with SANS items related to motor system impoverishment., Conclusions: The iCPCA allowed us to explore the associations between individual items, optimized to understand the overlap between symptoms and cognition. The specific symptoms linked to verbal and working memory impairments imply distinct brain networks, which further investigation may lead to our deeper understanding of the illness and the development of treatment methods., Competing Interests: Declaration of competing interest There are no financial or other conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cross-cultural psychosis research has mostly focused on outcomes, rather than patient and family experiences. Therefore, our aim was to examine differences in patients' and families' experiences of their treating teams in early intervention services for psychosis in Chennai, India [low- and middle-income country] and Montreal, Canada [high-income country]., Methods: Patients (165 in Chennai, 128 in Montreal) and their families (135 in Chennai, 110 in Montreal) completed Show me you care, a patient- and family-reported experience measure, after Months 3, 12, and 24 in treatment. The measure assesses the extent to which patients and families view treating teams as being supportive. A linear mixed model with longitudinal data from patient and family dyads was used to test the effect of site (Chennai, Montreal), stakeholder (patient, family), and time on Show me you care scores. This was followed by separate linear mixed effect models for patients and families with age and gender, as well as symptom severity and functioning as time-varying covariates., Results: As hypothesized, Chennai patients and families reported more supportive behaviours from their treating teams (β=4.04; β= 9, respectively) than did Montreal patients (Intercept =49.6) and families (Intercept=42.45). Higher symptom severity over follow-up was associated with patients reporting lower supportive behaviours from treating teams. Higher levels of positive symptoms (but lower levels of negative symptoms) over follow-up were associated with families reporting lower supportive behaviours from treating teams. There was no effect of time, age, gender and functioning., Conclusions: The levels to which treating teams are perceived as supportive may reflect culturally shaped attitudes (e.g., warmer attitudes towards healthcare providers in India vis-à-vis Canada) and actual differences in how supportive treating teams are, which too may be culturally shaped. Being expected to be more involved in treatment, Chennai families may receive more attention and support, which may further reinforce their involvement. Across contexts, those who improve over follow-up may see their treating teams more positively., Competing Interests: Declaration of Competing Interest The authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Hypothesis: Symptoms that precede a first episode of psychosis (FEP) can ideally be targeted by early intervention services with the aim of preventing or delaying psychosis onset. However, these precursor symptoms emerge in combinations and sequences that do not rest fully within traditional diagnostic categories. To advance our understanding of illness trajectories preceding FEP, we aimed to investigate combinations and temporal associations among precursor symptoms., Study Design: Participants were from PEPP-Montréal, a catchment-based early intervention program for FEP. Through semistructured interviews, collateral from relatives, and a review of health and social records, we retrospectively measured the presence or absence of 29 precursor symptoms, including 9 subthreshold psychotic and 20 nonpsychotic symptoms. Sequences of symptoms were derived from the timing of the first precursor symptom relative to the onset of FEP., Study Results: The sample included 390 participants (68% men; age range: 14-35 years). Combinations of precursor symptoms most frequently featured depression, anxiety, and substance use. Of 256 possible pairs of initial and subsequent precursor symptoms, many had asymmetrical associations: eg, when the first symptom was suspiciousness, the incidence rate ratio (IRR) of subsequent anxiety was 3.40 (95% confidence interval [CI]: 1.79, 6.46), but when the first symptom was anxiety, the IRR of subsequent suspiciousness was 1.15 (95% CI: 0.77, 1.73)., Conclusions: A detailed examination of precursor symptoms reveals diverse clinical profiles that cut across diagnostic categories and evolve longitudinally prior to FEP. Their identification may contribute to risk assessments and provide insights into the mechanisms of illness progression., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Cognitive symptoms, among the core symptoms of schizophrenia, are associated with poor functional outcome and burden of illness. To date, there is no effective pharmacological treatment for these symptom clusters. Augmentation with psychostimulants has been proposed as a potential treatment option., Objectives: The present study aims to assess off-label use of adjunctive methylphenidate extended release (ER) in patients with schizophrenia who are stable on antipsychotic medications, and to assess its efficacy on functioning and cognitive outcome., Methods: This is a single centre study at the Royal Ottawa Mental Health Centre. An open-label fixed dose controlled cross-over trial is planned. Eligible participants will be randomized into one of two arms of the study: 1) four weeks of add-on methylphenidate ER 36 mg, or 2) four weeks of treatment as usual. At 4 weeks, participants will switch arms. The duration of the study includes 8 weeks of treatment and a follow-up visit at 12 weeks. Primary outcome measures include tablet-based tests of functioning and cognition (VRFCAT and BAC) and will be administered at baseline and every 4 weeks. We are aiming to recruit a total of 24 participants., Expected Outcomes: The proposed project intends to assess a potential treatment option for cognitive deficits of schizophrenia, for which there are no recommendations by current treatment guidelines. The novelty and significance of the current study is that it investigates this intervention and assess applicability of it in a "real world setting" in a tertiary care hospital., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Harvey has received consulting fees or travel reimbursements from Alkermes, Bio Excel, Boehringer Ingelheim, Karuna Pharma, Merck Pharma, Minerva Pharma, and WCG Endpoint Solutions during the past year. He receives royalties from the Brief Assessment of Cognition in Schizophrenia (Owned by WCG, Inc. and contained in the MCCB). He is chief scientific officer of i-Function, Inc. Other authors have no conflict of interest to declare., (© 2024 The Authors.)

Hallucinations are a core feature of psychosis, and their severity during the acute phase of illness is associated with a range of poor outcomes. Various clinical and sociodemographic factors may predict hallucinations and other positive psychotic symptoms in first episode psychosis (FEP). Despite this, the precise factors associated with hallucinations at first presentation to an early intervention service have not been extensively researched. Through detailed interviews and chart reviews, we investigated sociodemographic and clinical predictors in 636 minimally-medicated patients who entered PEPP-Montréal, an early intervention service for FEP, between 2003 and 2018. Hallucinations were measured using the Scale for the Assessment of Positive Symptoms (SAPS), while negative symptoms were assessed using the Scale for the Assessment of Negative symptoms (SANS). Depressive symptoms were evaluated through the Calgary Depression Scale for Schizophrenia (CDSS), and anxiety symptoms via the Hamilton Rating Scale for Anxiety (HAS). A majority (n = 381, 59.9 %) of the sample presented with clinically significant hallucinations (SAPS global hallucinations score ≥ 3) at program entry. These patients had an earlier age at onset, fewer years of education, and a higher severity of delusions, depression and negative symptoms than those without clinical-level hallucinations. These results suggest that individuals with clinically significant hallucinations at admission tend to be younger and have a greater overall symptom burden. This makes it especially important to monitor hallucinations alongside delusions, depression and negative symptoms in order to identify who might benefit from targeted interventions. The implications of these findings for early intervention and person-centered care are discussed., Competing Interests: Declaration of competing interest A.M. reports no funding from industry in >3 years. R. J. reports no funding from industry in >3 years. M.L. reports grants from Otsuka Lundbeck Alliance and personal fees from Otsuka Canada, Lundbeck Canada, and MedAvante-Prophase, as well as grants and personal fees from Janssen. These interests had no relation to the present study. Other co-authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The stress-vulnerability model has been repeatedly highlighted in relation to the risk, onset and course of psychosis, and has been independently studied in clinical high-risk (CHR) and first-episode psychosis (FEP) populations. Notable in this literature, however, is that there are few studies directly comparing markers of stress response across progressive stages of illness. Here we examined the psychobiological response to the Trier Social Stress Test in 28 CHR (mean age 19.1) and 61 FEP (age 23.0) patients, in order to understand the stage(s) or trajectories in which differences in subjective stress or physiological response occur. The overall clinical sample had greater perceived stress and blunted cortisol (FEP + CHR, n = 89, age 21.7) compared with healthy controls ( n = 45, age 22.9). Additional analyses demonstrated elevated heart rate and systolic blood pressure in FEP compared with CHR, but there were no further differences in physiological parameters (cortisol, heart rate, or blood pressure) between stage- or trajectory-based groups. Together, this suggests that individual stress response markers may differentially emerge at particular stages en route to psychosis - and demonstrates how stage-based analyses can shed light on the emergence and evolution of neurobiological changes in mental illness.

Purpose: Cross-cultural psychosis research has typically focused on a limited number of outcomes (generally symptom-related). It is unknown if the purported superior outcomes for psychosis in some low- and middle-income countries extend to fundamental treatment processes like trust. Addressing this gap, we studied two similar first-episode psychosis programs in Montreal, Canada, and Chennai, India. We hypothesized higher trust in healthcare institutions and providers among patients and families in Chennai at baseline and over follow-up., Methods: Upon treatment entry and at months 3, 12 and 24, trust in healthcare providers was measured using the Wake Forest Trust scale and trust in the healthcare and mental healthcare systems using two single items. Nonparametric tests were performed to compare trust levels across sites and mixed-effects linear regression models to investigate predictors of trust in healthcare providers., Results: The study included 333 patients (Montreal = 165, Chennai = 168) and 324 family members (Montreal = 128, Chennai = 168). Across all timepoints, Chennai patients and families had higher trust in healthcare providers and the healthcare and mental healthcare systems. The effect of site on trust in healthcare providers was significant after controlling for sociodemographic characteristics known to impact trust. Patients' trust in doctors increased over follow-up., Conclusion: This study uniquely focuses on trust as an outcome in psychosis, via a comparative longitudinal analysis of different trust dimensions and predictors, across two geographical settings. The consistent differences in trust levels between sites may be attributable to local cultural values and institutional structures and processes and underpin cross-cultural variations in treatment engagement and outcomes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: Despite their acknowledged value, patient-reported outcome measures (PROMs) are infrequently used in psychosis, particularly in low-and middle-income countries. We compared ratings on two single-item PROMs, Self-Rated Health (SRH) and Self-Rated Mental Health (SRMH), of persons receiving similar early psychosis services in Chennai, India and Montreal, Canada. We hypothesized greater improvements in SRH and SRMH in the Chennai (compared to the Montreal) sample., Methods: Participants (Chennai N = 159/168 who participated in the larger study; Montreal N = 74/165 who participated in the larger study) completed the SRH and SRMH during at least two out of three timepoints (entry, months 12 and 24). Repeated measures proportional odds logistic regressions examined the effects of time (baseline to month 24), site, and relevant baseline (e.g., gender) and time-varying covariates (i.e., symptoms) on SRH and SRMH scores., Results: SRH (but not SRMH) scores significantly differed between the sites at baseline, with Chennai patients reporting poorer health (OR: 0.33; CI: 0.18, 0.63). While Chennai patients reported similar significant improvements in their SRH (OR: 7.03; CI: 3.13; 15.78) and SRMH (OR: 2.29, CI: 1.03, 5.11) over time, Montreal patients only reported significant improvements in their SRMH. Women in Chennai (but not Montreal) reported lower mental health than men. Higher anxiety and longer durations of untreated psychosis were associated with poorer SRH and SRMH, while negative symptoms were associated with SRH., Conclusions: As hypothesized, Chennai patients reported greater improvements in health and mental health. The marked differences between health and mental health in Montreal, in contrast to the overlap between the two in Chennai, aligns with previous findings of clearer distinctions between mind and body in Western societies. Cross-context (e.g., anxiety) and context-specific (e.g., gender) factors influence patients' health perceptions. Our results highlight the value of integrating simple PROMs in early psychosis., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Data from high-income countries (HICs) show a high risk of suicidal thoughts and behaviors (STBs) in first-episode psychosis (FEP). It is unknown, however, whether rates and associated factors differ in low- and middle-income countries (LMICs)., Aims: We therefore aimed to compare the 2-year course of STBs and associated factors in persons with FEP treated in two similarly structured early intervention services in Chennai, India and Montreal, Canada., Method: To ensure fit to the data that included persons without STBs and with varying STBs' severity, a hurdle model was conducted by site, including known predictors of STBs. The 2-year evolution of STBs was compared by site with mixed-effects ordered logistic regression., Results: The study included 333 FEP patients (168 in Chennai, 165 in Montreal). A significant decrease in STBs was observed at both sites (OR = 0.87; 95% CI [0.84, 0.90]), with the greatest decline in the first 2 months of follow-up. Although three Chennai women died by suicide in the first 4 months (none in Montreal), Chennai patients had a lower risk of STBs over follow-up (OR = 0.44; 95% CI [0.23, 0.81]). Some factors (depression, history of suicide attempts) were consistently associated with STBs across contexts, while others (gender, history of suicidal ideation, relationship status) were associated at only one of the two sites., Conclusions: This is the first study to compare STBs in FEP between two distinct geo-sociocultural contexts (an HIC and an LMIC). At both sites, STBs reduced after treatment initiation, suggesting that early intervention reduces STBs across contexts. At both sites, for some patients, STBs persisted or first appeared during follow-up, indicating need for suicide prevention throughout follow-up. Our study demonstrates contextual variations in rates and factors associated with STBs. This has implications for tailoring suicide prevention and makes the case for more research on STBs in FEP in diverse contexts., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Multiscale neuroscience conceptualizes mental illness as arising from aberrant interactions across and within multiple biopsychosocial scales. We leverage this framework to propose a multiscale disease progression model of psychosis, in which hippocampal-cortical dysconnectivity precedes impairments in episodic memory and social cognition, which lead to more severe negative symptoms and lower functional outcome. As psychosis represents a heterogeneous collection of biological and behavioral alterations that evolve over time, we further predict this disease progression for a subtype of the patient sample, with other patients showing normal-range performance on all variables. We sampled data from two cross-sectional datasets of first- and multi-episode psychosis, resulting in a sample of 163 patients and 119 non-clinical controls. To address our proposed disease progression model and evaluate potential heterogeneity, we applied a machine-learning algorithm, SuStaIn, to the patient data. SuStaIn uniquely integrates clustering and disease progression modeling and identified three patient subtypes. Subtype 0 showed normal-range performance on all variables. In comparison, Subtype 1 showed lower episodic memory, social cognition, functional outcome, and higher negative symptoms, while Subtype 2 showed lower hippocampal-cortical connectivity and episodic memory. Subtype 1 deteriorated from episodic memory to social cognition, negative symptoms, functional outcome to bilateral hippocampal-cortical dysconnectivity, while Subtype 2 deteriorated from bilateral hippocampal-cortical dysconnectivity to episodic memory and social cognition, functional outcome to negative symptoms. This first application of SuStaIn in a multiscale psychiatric model provides distinct disease trajectories of hippocampal-cortical connectivity, which might underlie the heterogeneous behavioral manifestations of psychosis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Competing Interests: Competing interests:: Lena Palaniyappan has received research support from the Monique H. Bourgeois Chair in Developmental Disorders; grants from the Graham Boeckh Foundation (Douglas Research Centre, McGill University) and the Canadian Institutes of Health Research; royalties from Oxford University Press and SPMM Course, UK; and speaker’s honoraria from Janssen Canada and Otsuka Canada. He reports a salary award from the Fonds de recherche du Québec-Santé. He is a member of the editorial board of the Canadian Journal of Psychiatry. He is the coeditor in chief of JPN; he had no role in editorial decision-making for this article. No other competing interests were declared.

Preventing relapse in schizophrenia improves long-term health outcomes. Repeated episodes of psychotic symptoms shape the trajectory of this illness and can be a detriment to functional recovery. Despite early intervention programs, high relapse rates persist, calling for alternative approaches in relapse prevention. Predicting imminent relapse at an individual level is critical for effective intervention. While clinical profiles are often used to foresee relapse, they lack the specificity and sensitivity needed for timely prediction. Here, we review the use of speech through Natural Language Processing (NLP) to predict a recurrent psychotic episode. Recent advancements in NLP of speech have shown the ability to detect linguistic markers related to thought disorder and other language disruptions within 2-4 weeks preceding a relapse. This approach has shown to be able to capture individual speech patterns, showing promise in its use as a prediction tool. We outline current developments in remote monitoring for psychotic relapses, discuss the challenges and limitations and present the speech-NLP based approach as an alternative to detect relapses with sufficient accuracy, construct validity and lead time to generate clinical actions towards prevention., Competing Interests: Declaration of competing interest LP reports personal fees from Janssen Canada, Otsuka Canada, SPMM Course Limited, UK, Canadian Psychiatric Association; book royalties from Oxford University Press; investigator-initiated educational grants from Sunovion, Janssen Canada, Otsuka Canada outside the submitted work. M. L. reports grants from Otsuka Lundbeck Alliance and Roche, personal fees from Otsuka Canada, personal fees from Lundbeck Canada, personal fees from Boehringer Ingelheim, and grants and personal fees from Janssen. KL reports grants from Otsuka Lundbeck Alliance and personal fees from Otsuka Canada and Lundbeck Canada. SL and RJ reports none in the last 3 yrs. MAR reports personal honoraria from Janssen, Otsuka-Lundbeck Alliance, Viatris; research grants from Janssen; Research contracts from Lundbeck, Boehringer-Ingelheim, Otsuka-Lundbeck Alliance. FZ, MD, AA, MFD, P Subramanian, DG, IZ, KD, MM, P Sabesan, and AV report no conflicts., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Maternal smoking during pregnancy (MSDP) is considered a risk factor for ADHD. While the mechanisms underlying this association are not well understood, MSDP may impact the developing brain in ways that lead to ADHD. Here, we investigated the effect of prenatal smoking exposure on cortical brain structures in children with ADHD using two methods of assessing prenatal exposure: maternal recall and epigenetic typing. Exposure groups were defined according to: (1) maternal recall (+MSDP: n = 24; -MSDP: n = 85) and (2) epigenetic markers (EM) (+EM: n = 14 -EM: n = 21). CIVET-1.1.12 and RMINC were used to acquire cortical brain measurements and perform statistical analyses, respectively. The vertex with highest significance was tested for association with Continuous Performance Test (CPT) dimensions. While no differences of brain structures were identified between +MSDP and -MSDP, +EM children (n = 10) had significantly smaller surface area in the right orbitofrontal cortex (ROFc), middle temporal cortex (RTc) and parahippocampal gyrus (RPHg) (15% FDR) compared to -EM children (n = 20). Cortical surface area in the RPHg significantly correlated with CPT commission errors T-scores. This study suggests that molecular markers may better define exposure to environmental risks, as compared to human recall., Competing Interests: Declaration of competing interest Dr B. Chaumette has received research funding from the foundation Bettencourt Schueller, speaking fees from Janssen-Cilag, Lundbeck, and Eisai outside the submitted work. Dr N. Grizenko is a member of the advisory board of Purdue and Shire. Dr R. Joober is on the advisory boards and speakers’ bureaus of Pfizer, Janssen, Ortho, BMS, Sunovion, Otsuka, Lundbeck, Perdue and Myelin. He has received grant funding from them and from AstraZeneca and HLS. He has received honoraria from Janssen Canada, Shire, Lundbeck, Otsuka, Pfizer, and from Perdue for CME presentations and royalties for Henry Stewart talks. The other authors report no biomedical financial interests nor potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

There is widespread overlap across major psychiatric disorders, and this is the case at different levels of observations, from genetic variants to brain structures and function and to symptoms. However, it remains unknown to what extent these commonalities at different levels of observation map onto each other. Here, we systematically review and compare the degree of similarity between psychiatric disorders at all available levels of observation. We searched PubMed and EMBASE between January 1, 2009 and September 8, 2022. We included original studies comparing at least four of the following five diagnostic groups: Schizophrenia, Bipolar Disorder, Major Depressive Disorder, Autism Spectrum Disorder, and Attention Deficit Hyperactivity Disorder, with measures of similarities between all disorder pairs. Data extraction and synthesis were performed by two independent researchers, following the PRISMA guidelines. As main outcome measure, we assessed the Pearson correlation measuring the degree of similarity across disorders pairs between studies and biological levels of observation. We identified 2975 studies, of which 28 were eligible for analysis, featuring similarity measures based on single-nucleotide polymorphisms, gene-based analyses, gene expression, structural and functional connectivity neuroimaging measures. The majority of correlations (88.6%) across disorders between studies, within and between levels of observation, were positive. To identify a consensus ranking of similarities between disorders, we performed a principal component analysis. Its first dimension explained 51.4% (95% CI: 43.2, 65.4) of the variance in disorder similarities across studies and levels of observation. Based on levels of genetic correlation, we estimated the probability of another psychiatric diagnosis in first-degree relatives and showed that they were systematically lower than those observed in population studies. Our findings highlight that genetic and brain factors may underlie a large proportion, but not all of the diagnostic overlaps observed in the clinic., (© 2024. The Author(s).)

Background: Although both pharmacotherapy and psychological treatments are considered to be efficacious in the treatment of major depressive disorder (MDD), one third of patients do not respond to treatment and many experience residual symptoms post-treatment. In this double-blind placebo-controlled randomized control trial (RCT), we assessed whether intranasal oxytocin (OT) augments the therapeutic efficacy of psychotherapy for MDD and improves the therapeutic alliance., Methods: Twenty-three volunteers (12 female) with MDD underwent 16 sessions of interpersonal therapy. Prior to each session, volunteers self-administered 24 International Units of intranasal OT ( n = 12; Syntocinon ) or placebo ( n = 11). Depressive symptoms were assessed with the Inventory of Depressive Symptomatology at pre- and post-treatment, and at a six month follow-up., Results: Multilevel modeling found a significant effect of OT on the negative slope of depressive symptoms over time ( p < 0.05), with medium-large effect sizes at post-treatment (Cohen's d = 0.75) and follow-up (Cohen's d = 0.82). Drug intervention also predicted the intercept when examining the weekly ratings of the therapeutic alliance ( p < 0.05), such that volunteers receiving OT, relative to placebo, reported improved therapeutic alliance at session 1. The agreement of goals between therapists and participants, a facet of the therapeutic alliance, mediated the relationship between drug intervention and clinical outcome., Conclusion: In this pilot study, the administration of intranasal OT, relative to placebo, improved the therapeutic alliance at the beginning of therapy and therapeutic efficacy of psychotherapy in persons with MDD. Future RCTs should attempt to replicate these findings in larger samples with different therapeutic modalities ( ClinicalTrials.gov: NCT02405715 ).

Background: Cognitive impairment are among the core features of schizophrenia, experienced by up to 75% of patients. Available treatment options for schizophrenia including dopamine antagonists and traditional antipsychotic medications have not been shown to confer significant benefits on cognitive deficits. Contrary to the focus on management of positive symptoms in schizophrenia, cognitive abilities are main predictor of independent living skills, functional abilities, employment, engagement in relapse prevention, and patients' subjective sense of well-being and quality of life. This review aims to provide a summary of recent literature on pharmacological options for the treatment of cognitive deficits in schizophrenia., Methods: We conducted a literature search of studies from 2011 to 2021 across four electronic databases including PubMed, PsycInfo, MEDLINE, and Embase. Human studies using a pharmacological treatment for cognitive impairment in schizophrenia were included., Results: Fifty-eight eligible publications, representing 11 pharmacological classes, were included in this review. Major limitations involved small sample size, methodological limitations as well as heterogeneity of participants and outcome measures., Conclusions: Overall evidence remains inconclusive for any pharmacological classes studied for the treatment of cognitive deficits in schizophrenia. Methodological limitations in a majority of the studies rendered their findings preliminary. We further discuss possible explanations for these findings that could guide future research., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Background: Although attention-deficit hyperactivity disorder (ADHD) is often comorbid with schizophrenia spectrum and other psychotic disorders (SZSPD), concerns about an increased risk of psychotic events have limited its treatment with either psychostimulants or atomoxetine., Aims: To examine whether the risk of hospital admission for psychosis in people with SZSPD was increased during the year following the introduction of such medications compared with the year before., Method: This was a retrospective cohort study using Quebec (Canada) administrative health registries, including all Quebec residents with a public prescription drug insurance plan and a diagnosis of psychotic disorder, defined by relevant ICD-9 or ICD-10 codes, who initiated either methylphenidate, amphetamines or atomoxetine, between January 2010 and December 2016, in combination with antipsychotic medication. The primary outcome was time to hospital admission for psychosis within 1 year of initiation. State sequence analysis was also used to visualise admission trajectories for psychosis in the year following initiation of these medications, compared with the previous year., Results: Out of 2219 individuals, 1589 (71.6%) initiated methylphenidate, 339 (15.3%) amphetamines and 291 (13.1%) atomoxetine during the study period. After adjustment, the risk of hospital admission for psychosis was decreased during the 12 months following the introduction of these medications when used in combination with antipsychotics (adjusted HR = 0.36, 95% CI 0.24-0.54; P < 0.0001)., Conclusions: These findings suggest that, in a real-world setting, when used concurrently with antipsychotic medication, methylphenidate, amphetamines and atomoxetine may be safer than generally believed in individuals with psychotic disorders.

Objectives: Antipsychotics are widely used to treat first-episode psychosis but may have an anticholinergic burden, that is, a cumulative effect of medications that block the cholinergic system. Studies suggest that a high anticholinergic burden negatively affects memory in psychosis, where cognitive deficits, particularly those in verbal memory, are a core feature of the disease. The present study sought to replicate this in a large cohort of well-characterized first-episode psychosis patients. We expected that patients in the highest anticholinergic burden group would exhibit the poorest verbal memory compared to those with low anticholinergic burden and healthy controls at baseline (3 months following admission). We further hypothesized that over time, at month 12, patients' verbal memory performance would improve but would remain inferior to controls., Methods: Patients ( n   =  311; low anticholinergic burden [ n   =  241] and high anticholinergic burden [ n   =  70], defined by a Drug Burden Index cut-off of 1) and healthy controls ( n   =  128) completed a clinical and neurocognitive battery including parts of the Wechsler Memory Scale at months 3 and 12., Results: Cross-sectionally, using an analysis of variance, patients in the highest anticholinergic burden group had the poorest performance in verbal memory when compared to the other groups at month 3, F (2,430)  =  52.33, P  < 0.001. Longitudinally, using a Generalized Estimating Equation model, the verbal memory performance of all groups improved over time. However, patients' performance overall remained poorer than the controls., Conclusion: These findings highlight the importance of considering the anticholinergic burden when prescribing medications in the early stages of the disease., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Attention deficit/hyperactivity disorder (ADHD) is a highly prevalent childhood disorder. Maternal smoking during pregnancy is a replicated environmental risk factor for this disorder. It is also a robust modifier of gene methylation during the prenatal developmental period. In this study, we sought to identify loci differentially methylated by maternal smoking during pregnancy and relate their methylation levels to various behavioural and physical outcomes relevant to ADHD., Methods: We extracted DNA from blood samples from children diagnosed with ADHD and deeply phenotyped. Genome-wide DNA methylation was assessed using Infinium MethylationEPIC BeadChip. Maternal smoking during pregnancy was self-declared and assessed retrospectively., Results: Our sample included 231 children with ADHD. Statistically significant differences in DNA methylation between children exposed or not to maternal smoking during pregnancy were detected in 3457 CpGs. We kept 30 CpGs with at least 5% of methylation difference between the 2 groups for further analysis. Six genes were associated with varied phenotypes of clinical relevance to ADHD. The levels of DNA methylation in RUNX1 were positively correlated with the CBCL scores, and DNA methylation in MYO1G correlated positively with the score at the Conners rating scale. Methylation level in a CpG located in GFI1 correlated with birthweight, a risk factor for ADHD. Differentially methylated regions were also identified and confirmed the association of RUNX1 methylation levels with the CBCL score., Limitations: The study has several limitations, including the retrospective recall with self-report of maternal smoking during pregnancy as well as the grouping of individuals of varying age and developmental stage and of both males and females. In addition, the correlation design prevents the building of causation models., Conclusion: This study provides evidence for the association between the level of methylation at specific loci and quantitative dimensions highly relevant for ADHD as well as birth weight, a measure that has already been associated with increased risk for ADHD. Our results provide further support to public health educational initiatives to stop maternal smoking during pregnancy., Competing Interests: Competing interests: B. Chaumette has received research funding from the Fondation Bettencourt Schueller (180 000€/4 yr) and speaking fees from Janssen-Cilag, Lundbeck and Eisai, outside the submitted work. He has no direct employment in profit organizations nor consultancies. N. Grizenko reports receiving research funding from the Canadian Institutes of Health Research (CIHR) and is a member of the advisory board for Purdue and Shire. A. Labbe is an associate editor of JPN. She was not involved in the review or decision to accept this manuscript for publication. R. Joober reports having received research funding from CIHR. He is on the advisory boards and speakers’ bureaus of Pfizer, Janssen Ortho, BMS, Sunovion, Otsuka, Lundbeck, Perdue and Myelin. He has received grant funding from them and from AstraZeneca and HLS. He has received honoraria from Janssen Canada, Shire, Lundbeck, Otsuka, Pfizer and from Perdue for CME presentations and royalties for Henry Stewart talks. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

Background and Hypothesis: Suicide is a leading cause of death in first-episode psychosis (FEP), with an elevated risk during the first year following illness onset. The association between negative symptoms and suicidality remains contentious. Some studies suggest that negative symptoms may be associated with lower suicidality, while others fail to find an association between the two. No previous studies have specifically investigated suicidality in Persistent Negative Symptoms (PNS) and its associated subgroups., Study Design: In a large cohort of FEP patients (n = 515) from an early intervention service, we investigated suicidality in those with PNS, secondary PNS (ie, sPNS; PNS with clinical-level positive, depressive, or extrapyramidal symptoms), and non-PNS (all other patients) over 24 months. Patients were categorized into PNS groups based on symptoms from month 6 to month 12, and suicidality was evaluated using the Brief Psychiatric Rating Scale (BPRS)., Study Results: Covarying for age and sex, we found that sPNS had higher suicidality relative to PNS and non-PNS throughout the 24-month period, but PNS and non-PNS did not differ. These differences were maintained after adjusting for depressive symptoms., Conclusion: We observed that PNS did not significantly differ from non-PNS. However, we identified sPNS as a group with elevated suicidality above and beyond depression, suggesting that sPNS would benefit from targeted intervention and that PNS categorization identifies a subgroup for whom negative symptoms are not associated with lower suicidality., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: 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., Methods: 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., Results: 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%)., Conclusion: 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.

Aim: Dropping out of psychological interventions is estimated to occur in up to a third of individuals with psychosis. Given the high degree of attrition in this population, identifying predictors of attrition is important to develop strategies to retain individuals in treatment. We observed a particularly high degree of attrition (48%) in a recent randomized controlled study assessing cognitive health interventions for first-episode psychosis participants with comorbid social anxiety. Due to the importance of developing interventions for social anxiety in first episode psychosis, the aim of the present study was to identify putative predictors of attrition through a secondary analysis of data., Methods: Participants (n = 96) with first episode psychosis and comorbid social anxiety were randomized to receive cognitive behavioural therapy for social anxiety or cognitive remediation. Differences between completers and non-completers (<50% intervention completed) were compared using t-tests or chi-square analyses; statistically significant variables were entered into a multivariate logistic regression model., Results: Non-completers tended to be younger, had fewer years of education and had lower levels of social anxiety compared to completers. Lower baseline social anxiety and younger age were statistically significant predictors of non-completion in the logistic regression model., Conclusions: Age and social anxiety were predictors of attrition in cognitive health interventions in first episode psychosis populations with comorbid social anxiety. In the ongoing development of social anxiety interventions for this population, future studies should investigate specific engagement strategies, intervention formats and outcome monitoring to improve participant retention in treatment., (© 2023 John Wiley & Sons Australia, Ltd.)

Background: Identifying risk factors for suicidal ideation and attempt among first-episode psychosis patients is essential to prevent suicide in this high-risk population. We investigated risk factors at admission for suicidal ideation and attempt during a 2-year early intervention program., Methods: Our sample included patients aged 18-35 years who were consecutively admitted to an early intervention program (2003-2017). Sociodemographic and clinical variables were obtained from a longitudinal study, while data on suicidal ideation and attempt were collected via systematic file review. Univariable and multivariable logistic regressions assessed the association of these variables with suicide ideation and attempt., Results: Of 446 participants, 35 (7.8 %) attempted suicide during the 2-year follow up, including two resulting in death (0.45 %), and 168 (37.7 %) reported solely suicidal ideation. Multivariable analyses indicated living alone (OR = 4.01, CI = 2.11-7.63), affective psychosis (OR = 1.95, CI = 1.22-3.14) and depressive symptomatology (OR = 1.45, CI = 1.13-1.86) were associated with increased risk for suicidal ideation. Attempting suicide close to admission (OR = 10.29, CI = 3.63-29.22), living alone (OR = 4.17, CI = 1.40-12.35), and depressive (OR = 1.67, CI = 1.06-2.63) and positive symptomatology (OR = 1.60, CI = 1.02-2.50) were associated with increased risk for suicide attempt. Attempting suicide close to admission (OR = 11.65, CI = 4.08-33.30), being part of an ethnic minority (OR = 3.71, CI = 1.59-8.63), and presenting lower anxiety (OR = 0.58, CI = 0.36-0.94) were the only factors specifically associated with suicide attempt compared to ideation., Conclusion: Close monitoring of patients who recently attempted suicide, live alone, are part of an ethnic minority, and present with affective and positive symptomatology may help reduce the risk of suicide-related outcomes during early intervention programs., Competing Interests: Declaration of competing interest ML reports grants from Roche Canada, grants from Otsuka Lundbeck Alliance, grants and personal fees from Janssen, and personal fees from Otsuka Canada, and Lundbeck Canada, outside the submitted work. RJ reports receipt of grants, speaker and consultant honoraria from Janssen, Lundbeck, Otsuka, Pfizer, Shire, Perdue, HLS, and Myelin, and royalties from Henry Stewart Talks. AM reports honoraria for research consultations, lectures at conferences, and advisory board participation with Otsuka and Lundbeck, all unrelated to this study. The other authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests: Lena Palaniyappan has received personal fees from Janssen Canada, Otsuka Canada, SPMM Course Limited UK and the Canadian Psychiatric Association, and book royalties from Oxford University Press. No other competing interests were declared. Funding: Lena Palaniyappan acknowledges research support from Monique H. Bourgeois Chair in Developmental Disorders and Graham Boeckh Foundation through the Douglas Research Centre, McGill University and a salary award from the Fonds de recherche du Québec - Santé.

Background: 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)., Study Design: 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., Study Results: 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., Conclusions: 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Differences in subjective quality of life among persons receiving early intervention for psychosis in varying geo-sociocultural contexts have rarely been examined. Our prospective longitudinal study compared the quality of life of persons with first-episode psychosis receiving two years of similar early intervention in Chennai, India and Montreal, Canada. We hypothesized that general life satisfaction would be higher in Chennai compared to Montreal, and that social relations (a specific quality of life component) would also be higher in Chennai and positively contribute to general life satisfaction. Participants completed the general satisfaction and social relations domains of the Wisconsin Quality of Life Index at baseline, months 12 and 24. Baseline weighted mean general satisfaction and social relations scores were in the low to moderate range. Generalized estimating equation analyses showed that general satisfaction scores increased with time [Wald χ 2 (1) = 125.28, p < 0.001] and were higher in Chennai than in Montreal [Wald χ 2 (1) = 7.50, p = 0.006]. Social relations scores showed the highest association with general satisfaction scores (B = 0.52), followed by positive symptom remission (B = 0.24) and gender (B = 0.18) with Chennai males having the highest general satisfaction scores. Social relations weighted mean scores increased with time [Wald χ 2 (1) = 87.30, p < 0.001] and were positively associated with years of education [Wald χ 2 (1) = 4.76, p = 0.029] and early negative symptom remission [Wald χ 2 (1) = 7.38, p = 0.007]. Our results suggest that subjective quality of life may improve following early intervention for psychosis across contexts. Our findings advance knowledge about the role of sociocultural (e.g., gender) and clinical factors in influencing subjective outcomes in psychosis, and point to social support networks and symptom remission as avenues to boost quality of life., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest in to the submitted work. Unrelated to this manuscript, in the last three years, Dr. Margolese reports grants from Aifred, SyneuRx and the Montreal General Hospital Foundation; and served as speaker and/or member of an advisory board committee for AbbVie, HLS, Janssen, Lundbeck, Otsuka, Teva and Sunovion. All other authors declare no conflicts of interest. Unrelated to this manuscript and prior to the past three years, Dr. Joober served as speaker and member of advisory board committees for Pfizer, Janssen, BMS, Sunovian, Myelin, Otsuka, Lundbeck, Shire and Perdue, and received grants from Janssen, BMS, Otsuka, Lundbeck, Astra Zeneca and HLS., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Diagnostic criteria used in autism research have undergone a shift towards the inclusion of a larger population, paralleled by increasing, but variable, estimates of autism prevalence across clinical settings and continents. A categorical diagnosis of autism spectrum disorder is now consistent with large variations in language, intelligence, comorbidity, and severity, leading to a heterogeneous sample of individuals, increasingly distant from the initial prototypical descriptions. We review the history of autism diagnosis and subtyping, and the evidence of heterogeneity in autism at the cognitive, neurological, and genetic levels. We describe two strategies to address the problem of heterogeneity: clustering, and truncated-compartmentalized enrollment strategy based on prototype recognition. The advances made using clustering methods have been modest. We present an alternative, new strategy for dissecting autism heterogeneity, emphasizing incorporation of prototypical samples in research cohorts, comparison of subgroups defined by specific ranges of values for the clinical specifiers, and retesting the generality of neurobiological results considered to be acquired from the entire autism spectrum on prototypical cohorts defined by narrow specifiers values., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Social anxiety (SA), a prevalent comorbid condition in psychotic disorders with a negative impact on functioning, requires adequate intervention relatively early. Using a randomized controlled trial, we tested the efficacy of a group cognitive-behavioral therapy intervention for SA (CBT-SA) that we developed for youth who experienced the first episode of psychosis (FEP). For our primary outcome, we hypothesized that compared to the active control of group cognitive remediation (CR), the CBT-SA group would show a reduction in SA that would be maintained at 3- and 6-month follow-ups. For secondary outcomes, it was hypothesized that the CBT-SA group would show a reduction of positive and negative symptoms and improvements in recovery and functioning., Method: Ninety-six patients with an FEP and SA, recruited from five different FEP programs in the Montreal area, were randomized to 13 weekly group sessions of either CBT-SA or CR intervention., Results: Linear mixed models revealed that multiple measures of SA significantly reduced over time, but with no significant group differences. Positive and negative symptoms, as well as functioning improved over time, with negative symptoms and functioning exhibiting a greater reduction in the CBT-SA group., Conclusions: While SA decreased over time with both interventions, a positive effect of the CBT-SA intervention on measures of negative symptoms, functioning, and self-reported recovery at follow-up suggests that our intervention had a positive effect that extended beyond symptoms specific to SA.ClinicalTrials.gov identifier: NCT02294409.

Language is an important aspect of communication and language status is known to impact healthcare accessibility, its perceived suitability, and outcomes. However, its influence on treatment engagement and/or disengagement is unknown. Our study therefore sought to investigate the impact of language on service disengagement in an early intervention psychosis program in Montreal, Quebec (a province with French as the official language). We aimed to compare service disengagement between a linguistic minority group (i.e., English) vis-à-vis those whose preferred language was French and to explore the role of language in service engagement. Using a mixed methods sequential design, we tested preferred language and several sociodemographic characteristics associated with service disengagement in a time-to-event analysis with Cox proportional hazards regression models ( N  = 338). We then conducted two focus groups with English (seven patients) and French speakers (five patients) to further explore differences between the two linguistic groups. Overall, 24% ( n  = 82) disengaged from the service before the two-year mark. Those whose preferred language was English were more likely to disengage ( n  = 47, 31.5%) than those whose preferred language was French ( n  = 35, 18.5%; χ2 = 9.11, p  < .01). This remained significant in the multivariate regression. In focus groups, participants identified language as one aspect of a complex communication process between patients and clinicians and highlighted the importance of culture in the clinical encounter. Language status of patients plays an important role in their engagement with early psychosis services. Our findings underscore the value of establishing communication and cultural understanding in creating clinical/therapeutic alliance.

Competing Interests: Competing interests: Christina Rigas is supported by a CGS-CIHR Master’s Award. Mona Ben m’rad has received honoraria from the Régie de l’assurance maladie du Québec; speaker fees and consulting fees from Otsuka; speaker fees from GSK; and equipment, materials, gifts or “other” from Amgen and Otsuka. She has also received consulting fees from Creative Research Design and has contributed to the e-learning platform Nephrons and Neurons, which is funded by Otsuka. She serves as an unpaid consultant to Health Canada on the advisory board on renal adverse effects of COVID-19 immunization. Harmehr Sekhon is supported by postdoctoral fellowship awards from CIHR, Mitacs and AGE-WELL. Soham Rej receives salary support from a Fonds de Recherche Quebec – Santé (FRQS) clinician-scientist salary award, has received operating grants from Mitacs, is on a steering committee for AbbVie, and has shares in Aifred Health. No other competing interests were declared.

Horyzons is a digital health intervention designed to support recovery in young people receiving specialized early intervention services for first-episode psychosis (FEP). Horyzons was developed in Australia and adapted for implementation in Canada based on input from clinicians and patients (Horyzons-Canada Phase 1) and subsequently pilot-tested with 20 young people with FEP (Horyzons-Canada Phase 2)., Objective: To understand the experiences of young adults with FEP who participated in the pilot study based on focus group data., Methods: Among the twenty individuals that accessed the intervention, nine participated across four focus groups. Three team members were involved in data management and analysis, informed by a thematic analysis approach. A coding framework was created by adapting the Phase 1 framework to current study objectives, then revised iteratively by applying it to the current data. Once the coding framework was finalized, it was systematically applied to the entire dataset., Results: Four themes were identified: (1) Perceiving Horyzons-Canada as helpful for recovery; (2) Appreciating core intervention components (i.e., peer networking; therapeutic content; moderation) and ease of use; (3) Being unaware of its features; and (4) Expressing concerns, suggestions, and future directions., Conclusions: Horyzons-Canada was well received, with participants wanting it to grow in scale, accessibility, and functionality.

Digital health innovations may help to improve access to psychosocial therapy and peer support; however, the existence of evidence-based digital health interventions for individuals recovering from a first-episode psychosis (FEP) remains limited. This study aims to investigate the feasibility, acceptability, safety, and pre-post outcomes of Horyzons-Canada (HoryzonsCa), a Canadian adaptation of a digital mental health intervention consisting of psychosocial interventions, online social networking, and clinical and peer support moderation. Using a convergent mixed-methods research design, we recruited participants from a specialized early intervention clinic for FEP in Montreal, Canada. Twenty-three participants (mean age = 26.8) completed baseline assessments, and 20 completed follow-up assessments after 8 weeks of intervention access. Most participants provided positive feedback on general experience (85%, 17/20) and the utility of Horyzons for identifying their strengths (70%, 14/20). Almost all perceived the platform as easy to use (95%, 19/20) and felt safe using it (90%, 18/20). There were no adverse events related to the intervention. Participants used HoryzonsCa to learn about their illness and how to get better (65%, 13/20), receive support (60%, 12/20), and access social networking (35%, 7/20) and peer support (30%, 6/20). Regarding adoption, 65% (13/20) logged in at least 4 times over 8 weeks. There was a nonsignificant increase in social functioning and no deterioration on the Clinical Global Impression Scale. Overall, HoryzonsCa was feasible to implement and perceived as safe and acceptable. More research is needed with larger sample sizes and using in-depth qualitative methods to better understand the implementation and impact of HoryzonsCa., (© 2023. The Author(s).)

Background: Rapid progression from the first identifiable symptom to the onset of first-episode psychosis (FEP) allows less time for early intervention. The aim of this study was to examine the association between the first identifiable symptom and the subsequent speed of illness progression., Methods: Data were available for 390 patients attending a catchment-based early intervention service for FEP. Exposure to non-psychotic and subthreshold psychotic symptoms was retrospectively recorded using semi-structured interviews. Outcomes following the onset of the first identifiable symptom were (1) time to onset of FEP and (2) symptom incidence rate (i.e. number of symptoms emerging per person-year until FEP onset). These outcomes were respectively analyzed with Cox proportional hazards and negative binomial regressions., Results: After Bonferroni correction, having a subthreshold psychotic ( v. non-psychotic) symptom as the first symptom was not associated with time to FEP onset [hazard ratio (HR) = 1.39; 95% CI 0.94-2.04] but was associated with higher symptom incidence [incidence rate ratio (IRR) = 1.92; 95% CI 1.10-3.48]. A first symptom of suspiciousness was associated with shorter time to FEP onset (HR = 2.37; 95% CI 1.38-4.08) and higher symptom incidence rate (IRR = 3.20; 95% CI 1.55-7.28) compared to other first symptoms. In contrast, a first symptom of self-harm was associated with lower symptom incidence rate (IRR = 0.06; 95% CI 0.01-0.73) compared to other first symptoms. Several associations between symptoms and illness progression were moderated by the age at symptom onset., Conclusions: Appreciating the content and timing of early symptoms can identify windows and treatment targets for early interventions in psychosis.

Introduction: Although extensively studied in high-income countries (HICs) and less so in low- and middle-income countries (LMICs), pathways to care and treatment delays in early psychosis have not been compared across contexts. We compared pathways to early intervention for psychosis in an HIC (Montreal, Canada) and an LMIC (Chennai, India). We hypothesised that the duration of untreated psychosis (DUP) would be longer in Chennai., Methods: The number of contacts preceding early intervention, referral sources, first contacts, and DUP and its referral and help-seeking components of first-episode psychosis patients at both sites were similarly measured and compared using chi-square analyses and t tests/one-way ANOVAs., Results: Overall and help-seeking DUPs of Chennai (N = 168) and Montreal (N = 165) participants were not significantly different. However, Chennai patients had shorter referral DUPs [mean = 12.0 ± 34.1 weeks vs. Montreal mean = 13.2 ± 28.7 weeks; t(302.57) = 4.40; p < 0.001] as the early intervention service was the first contact for 44% of them (vs. 5% in Montreal). Faith healers comprised 25% of first contacts in Chennai. Those seeing faith healers had significantly shorter help-seeking but longer referral DUPs. As predicted, most (93%) Montreal referrals came from medical sources. Those seeing psychologists/counsellors/social workers as their first contact had longer DUPs., Conclusion: Differences in cultural views about mental illnesses and organizational structures shape pathways to care and their associations with treatment delays across contexts. Both formal and informal sources need to be targeted to reduce delays. Early intervention services being the first portal where help is sought can reduce DUP especially if accessed early on in the illness course., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Psychotic disorders are highly heterogeneous. Understanding relationships between symptoms will be relevant to their underlying pathophysiology. We apply dimensionality-reduction methods across two unique samples to characterize the patterns of symptom organization. We analyzed publicly-available data from 153 participants diagnosed with schizophrenia or schizoaffective disorder (fBIRN Data Repository and the Consortium for Neuropsychiatric Phenomics), as well as 636 first-episode psychosis (FEP) participants from the Prevention and Early Intervention Program for Psychosis (PEPP-Montreal). In all participants, the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) were collected. Multidimensional scaling (MDS) combined with cluster analysis was applied to SAPS and SANS scores across these two groups of participants. MDS revealed relationships between items of SAPS and SANS. Our application of cluster analysis to these results identified: 1 cluster of disorganization symptoms, 2 clusters of hallucinations/delusions, and 2 SANS clusters (asocial and apathy, speech and affect). Those reality distortion items which were furthest from auditory hallucinations had very weak to no relationship with hallucination severity. Despite being at an earlier stage of illness, symptoms in FEP presentations were similarly organized. While hallucinations and delusions commonly co-occur, we found that their specific themes and content sometimes travel together and sometimes do not. This has important implications, not only for treatment, but also for research-particularly efforts to understand the neurocomputational and pathophysiological mechanism underlying delusions and hallucinations., (© 2023. The Author(s).)

Objectives: Recent studies have reported altered methylation levels at disorder-relevant DNA sites in people who are ill with Anorexia Nervosa (AN) compared to findings in people with no eating disorder (ED) or in whom AN has remitted. The preceding implies state-related influences upon gene expression in people with AN. This study further examined this notion., Methods: We measured genome-wide DNA methylation in 145 women with active AN, 49 showing stable one-year remission of AN, and 64 with no ED., Results: Comparisons revealed 205 differentially methylated sites between active and no ED groups, and 162 differentially methylated sites between active and remitted groups ( Q  < 0.01). Probes tended to map onto genes relevant to psychiatric, metabolic and immune functions. Notably, several of the genes identified here as being differentially methylated in people with AN (e.g. SYNJ2, PRKAG2, STAT3 , CSGALNACT1, NEGR1 , NR1H3 ) have figured in previous studies on AN. Effects also associated illness chronicity and lower BMI with more pronounced DNA methylation alterations, and remission of AN with normalisation of DNA methylation., Conclusions: Findings corroborate earlier results suggesting reversible DNA methylation alterations in AN, and point to particular genes at which epigenetic mechanisms may act to shape AN phenomenology.

Aim: Childhood trauma increases social functioning deficits in first-episode psychosis (FEP) and is negatively associated with higher-order social cognitive processes such as emotion recognition (ER). We investigated the relationship between childhood trauma severity and ER capacity, and explored sex as a potential factor given sex differences in childhood trauma exposure., Methods: Eighty-three FEP participants (52 males, 31 females) and 69 nonclinical controls (49 males, 20 females) completed the CogState Research Battery. FEP participants completed the Childhood Trauma Questionnaire. A sex × group (FEP, controls) ANOVA examined ER differences and was followed by two-way ANCOVAs investigating sex and childhood trauma severity (none, low, moderate, and severe) on ER and global cognition in FEP., Results: FEP participants had significantly lower ER scores than controls (p = .035). No significant sex × group interaction emerged for ER F(3, 147) = .496, p = .438 [95% CI = -1.20-0.57], partial η 2  = .003. When controlling for age at psychosis onset, a significant interaction emerged in FEP between sex and childhood trauma severity F(3, 71) = 3.173, p = .029, partial η 2  = .118. Males (n = 9) with severe trauma showed ER deficits compared to females (n = 8) (p = .011 [95% CI = -2.90 to -0.39]). No significant interaction was observed for global cognition F(3, 69) = 2.410, p = .074, partial η 2  = .095., Conclusions: These preliminary findings provide support for longitudinal investigations examining whether trauma severity differentially impacts ER in males and females with FEP., (© 2022 John Wiley & Sons Australia, Ltd.)

Across subthreshold psychotic and nonpsychotic syndromes, symptoms experienced before the onset of a first episode of psychosis (FEP) may index distinct illness trajectories. We aimed to examine the associations between three types of pre-onset symptoms (self-harm, suicide attempts, and subthreshold psychotic) and outcome trajectories during FEP. Participants with FEP were recruited from PEPP-Montreal, a catchment-based early intervention service. Pre-onset symptoms were systematically assessed through interviews with participants (and their relatives) and reviews of health and social records. Over 2 years of follow-up at PEPP-Montreal, 3-8 repeated measures were collected for positive, negative, depressive, and anxiety symptoms, as well as functioning. We applied linear mixed models to examine associations between pre-onset symptoms and outcome trajectories. We found that on average over follow-up, participants with pre-onset self-harm had more severe positive, depressive, and anxiety symptoms compared with other participants (standardized mean differences: 0.32-0.76), while differences in negative symptoms and functioning were not significant. Associations did not differ by gender and remained similar after adjusting for the duration of untreated psychosis, substance use disorder, or baseline diagnosis of affective psychosis. Over time, depressive and anxiety symptoms improved among individuals with pre-onset self-harm, such that they converged with other individuals by the end of the follow-up. Similarly, pre-onset suicide attempts were associated with elevated depressive symptoms that improved over time. Pre-onset subthreshold psychotic symptoms were not associated with outcomes, except for a slightly different trajectory of functioning. Individuals with pre-onset self-harm or suicide attempts may benefit from early interventions that target their transsyndromic trajectories. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Competing Interests: Competing interests: R. Joober served as speaker and member of advisory board committees for Pfizer, Janssen, BMS, Sunovian, Myelin, Otsuka, Lundbeck, shire and Perdue. He also received grants from Janssen, BMS, Otsuka, Lundbeck, Astra Zeneca and HLS. P. Sabesan has received speaker fees from Lundbeck Canada. L. Palaniyappan is co-editor in chief of the Journal of Psychiatry and Neuroscience but was not involved in the review of or decision to accept the manuscript for publication. He has received personal fees from Janssen Canada, Otsuka Canada, SPMM Course Limited UK, and the Canadian Psychiatric Association; book royalties from Oxford University Press; and investigator- initiated educational grants from Sunovion, Janssen Canada, and Otsuka Canada. All of these are unrelated to the present work. No other competing interests were declared.

Purpose: While the prevalence of delusional themes appears to be consistent across geographic contexts, little is known about the relative prevalence of such themes within a given setting over periods of time. We therefore investigated delusional themes across 12 years of presentation to a catchment-based early intervention service for first episode psychosis (FEP)., Methods: Systematically collected data from 500 patients at an early intervention service for FEP were analyzed. Four cohorts of 3 years each, from 2006 to 2017, were used to compare the frequency of delusion themes across cohorts. We also integrated into the analysis baseline sociodemographic factors such as gender, age, and highest level of education and clinical factors such as anxiety, depression, suicidality, hallucinations, and primary diagnosis (affective or non-affective psychosis)., Results: Sex and education level were stable across cohorts, while patient age varied (p = 0.047). Clinical anxiety, depression, and suicidality at entry were also stable. Across cohorts, the proportion of patients with affective versus non-affective diagnosis differed (p = 0.050), with no differences in global rating of delusion severity or theme prevalence except for delusions of guilt or sin (p = 0.001). This single theme difference was not correlated with age or diagnosis., Conclusion: Our study suggests relatively stable prevalence of delusion themes across cohorts of individuals experiencing FEP. This demonstrates the potential utility of studying thematic content both for understanding delusions in clinical populations and in research. Future explorations of the relationships between delusion themes and across individual patient episodes should be conducted., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Relapse after first-episode psychosis (FEP) is a major clinical challenge for specialized early intervention services. Understanding patient perspectives on factors contributing to relapse can inform the development of risk assessments and preventive interventions. The objective of this study was to identify factors that may contribute to and prevent relapse from the perspectives of patients receiving services for FEP. Data from 25 participants across four focus groups in Canada were analyzed with a descriptive content analysis approach. Twelve factors were identified, of which four (social environment, technology use, medication, and lifestyle behaviors) had both contributory and preventive roles. In descending order of frequency, risk factors for relapse included substance use; unsupportive social environment; technology use; taking and not taking medication; lack of sleep; work, career, or school stress; significant life events; symptoms of depression or mania; generalized worry; and financial stress. Preventive factors consisted of having a supportive social environment, using technology, taking medication, using coping strategies, and engaging in healthy lifestyle behaviors and meaningful activities. These findings extend the literature on relapse vulnerability and protective factors. Importantly, the factors identified in this study are modifiable, and thereby provide insights for the development and optimization of relapse risk assessments and preventive interventions.

Background: In people with schizophrenia, major areas of everyday life are impaired, including independent living, productive activities, social relationships and overall quality of life. Enhanced understanding of factors that hinder real-life functioning is vital for treatments to translate into more positive outcomes., Aim: The goal of the present study was to identify factors associated with motivation deficits in real-life schizophrenia, and to assess its contribution to impaired functioning and quality of life., Methods: Based on previous literature and clinical experience, several factors were selected and grouped into factors potentially explaining motivation deficits. Some of these variables were never investigated before in relationship with motivation deficits., Results: In 561 patients with schizophrenia of the national FACE-SZ cohort living in the community, 235 (41.9%) reported severe motivation deficits. These deficits were found to be significantly associated with impaired socially useful activities, psychological and physical quality of life (in almost all domains), alcohol use disorder (aOR = 2.141, p  = 0.021), severe nicotine dependence (aOR = 2.906, p  < 0.001) independently of age and sex. No significant association was found for body mass index, metabolic syndrome or physical activity level. In the second model, we identified the following modifiable factors associated with motivation deficits: history of suicide attempt (aOR = 2.297, p  = 0.001), positive symptoms (aOR = 1.052, p  = 0.006), current major depressive episode (aOR = 2.627, p  < 0.001), sleep disorders (aOR = 1.474, p  = 0.024) and lower medication adherence (aOR = 0.836, p  = 0.001) independently of gender, current alcohol use disorder, second-generation antipsychotics and akathisia. No significant association was found for negative symptoms, childhood trauma and inflammation. These results were maintained after removing patients with schizoaffective disorders or those with major depressive disorder., Interpretation: Motivation deficits are frequent and remain persistent unmet need in real-world schizophrenia that should be addressed in future guidelines. Based on our results, literature and clinical experience, we recommend to address in priority major depression, sleep, suicide, positive symptoms (when present and as early as possible) and medication adherence to improve motivation deficits of schizophrenia.

Schizophrenia is an illness characterized by positive symptoms, negative symptoms, and cognitive impairments. Cognitive impairments occur before the onset of psychosis and could reflect glutamatergic dysregulation. Thus, identifying associations between genetic variations in genes coding for glutamatergic receptors and cognitive impairment in schizophrenia may help in understanding the basis of these deficits and in identifying potential drug targets. In a discovery cohort of 144 first-episode of psychosis patients (FEP), we genotyped 58 candidate Single Nucleotide Polymorphisms (SNPs) located in NMDA and metabotropic glutamatergic receptors. These SNPs were selected according to the results from the Psychiatric Genomic Consortium and were tested for association with intellectual quotient (IQ) as assessed with the Wechsler Intelligence Scales. For replication, we used the ICAAR cohort including 121 ultra-high-risk patients (UHR) with the same cognitive assessment. A polymorphism located in GRM7, rs1396409, was significantly associated with performance IQ in the discovery cohort of FEP. This association was replicated in the UHR cohort. This polymorphism is also associated with total IQ and verbal IQ in the merged dataset, with a predominant effect on the arithmetic subtest. The rs1396409 polymorphism is significantly associated with cognitive impairment during the onset of psychosis. This genetic association highlights the possible impact of glutamatergic genes in cognitive deficits in the early phases of psychosis and enforces the interest for new therapeutic interventions targeting the glutamatergic pathway., Competing Interests: Declaration of competing interest Dr. Joober reports to be a speaker and/or consulting committee member for Pfizer, Janssen, BMS, Sunovian, Myelin, Otsuka, Lundbeck, shire and Perdue, and to have received grants from Janssen, BMS, Otsuka, Lundbeck, Astra Zeneca and HLS, and to have royalties from Henry Stewart talks, all outside the submitted work. Dr. Malla served as a research consultant to and gave lectures at conferences supported by Lundbeck and Otsuka and was on an advisory board meeting for the same two companies for which he received honoraria. Pr. Krebs has received honoraria from and participated in advisory boards or did educational conference for F. Hoffmann-La Roche, Janssen Cilag and Otsuka-Lundbeck. She received financial support for investigator-driven educational initiative from Eisai, Janssen Cilag and Otsuka-Lundbeck. Dr. Lepage reports grants from Otsuka Lundbeck Alliance, personal fees from Otsuka Canada, personal fees from Lundbeck Canada, grants and personal fees from Janssen, personal fees from MedAvante-Prophase, personal fees from Amplexor, outside the submitted work. Dr. Chaumette has received speaking fees from Janssen Cilag, outside the submitted work. All authors declare they have no conflict of interest related to this article. The contributing Group members (ICAAR study group) declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The neural orphan G protein coupled receptor GPR88 is predominant in the striatum and cortex of both rodents and humans, and considered a potential target for brain disorders. Previous studies have shown multiple behavioral phenotypes in Gpr88 knockout mice, and human genetic studies have reported association with psychosis. Here we tested the possibility that GPR88 contributes to Attention Deficit Hyperactivity Disorder (ADHD). In the mouse, we tested Gpr88 knockout mice in three behavioral paradigms, best translatable between rodents and humans, and found higher motor impulsivity and reduced attention together with the reported hyperactivity. Atomoxetine, a typical ADHD drug, reduced impulsivity in mutant mice. Conditional Gpr88 knockout mice in either D1R-type or D2R-type medium spiny neurons revealed distinct implications of the two receptor populations in waiting and stopping impulsivity. Thus, animal data demonstrate that deficient GPR88 activity causally promotes ADHD-like behaviors, and identify circuit mechanisms underlying GPR88-regulated impulsivity. In humans, we performed a family-based genetic study including 567 nuclear families with DSM-IV diagnosis of ADHD. There was a minor association for SNP rs2036212 with diagnosis, treatment response and cognition. A stronger association was found for SNP rs2809817 upon patient stratification, suggesting that the T allele is a risk factor when prenatal stress is involved. Human data therefore identify GPR88 variants associated with the disease, and highlight a potential role of life trajectories to modulate GPR88 function. Overall, animal and human data concur to suggest that GPR88 signaling should be considered a key factor for diagnostic and treatment of ADHD., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)