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Competing Interests: R. Joober sits 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 Perdue for CME presentations and royalties from Henry Stewart talks. He is co-editor-in-chief of JPN, but he was not involved in the review of or decision to accept this manuscript for publication. No other competing interests were declared.

Objective: Early life adversity is suspected to play an important role for onset and course of psychosis, but its relationship with longer-term clinical outcome is not entirely clear. In this longitudinal study, we investigated the impact of childhood trauma (CT) on positive and negative symptom remission in first episode psychosis (FEP) patients over two years., Methods: A total of 210 FEP patients were assessed with the Childhood Trauma Questionnaire. Patients reporting moderate to severe trauma (CT; N = 114; 54.3%) were compared to those without trauma (N-CT; N = 96; 45.7%). Positive (PSR) and negative symptom remission (NSR) were determined monthly over 24 months following established criteria using the Scale for Assessment of Positive Symptoms and the Scale for Assessment of Negative Symptoms. Global Functioning was evaluated at baseline and 24 months of follow-up., Results: Compared to N-CT patients, CT patients had achieved significantly lower rates of PSR at 12 months and significantly lower rates of NSR at 24 months. A dose-response relationship was observed between the number of trauma categories fulfilled and the number of patients not achieving PSR and NSR at these time points. Higher trauma scores were significantly associated with poor functioning and higher positive and negative symptom severity at 24 months, but not at baseline and 12 months of follow-up., Conclusion: Differential effects of CT on clinical outcome may not be apparent at psychosis onset, but only become evident through poor symptomatic remission and general functioning over time. Targeted diagnostic and therapeutic efforts after illness onset might limit these detrimental consequences., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: We aimed to investigate whether individuals with first-episode psychosis (FEP) receiving extended early intervention (EI) were less likely to experience suicidal ideation and behaviors than those transferred to regular care after 2 years of EI. Another objective was to examine the 5-year course of suicidality in FEP., Methods: We conducted a secondary analysis of a randomized controlled trial where 220 patients were randomized after 2 years of EI to receive extended EI or regular care for the subsequent 3 years. Suicidality was rated using the Brief Psychiatric Rating Scale. Linear mixed model analysis was used to study time and group effects on suicidality., Results: Extended EI and regular care groups did not differ on suicidality. There was a small decrease in suicidality over time, F (7, 1038) = 1.84, P = 0.077, with an immediate sharp decline within a month of treatment, followed by stability over the remaining 5 years. Patients who endorsed suicidality at entry (46.6%) had higher baseline positive, negative, and depressive symptoms. The 5-year course fell in 3 groups: never endorsed suicidality (33.9%), endorsed suicidality at low-risk levels (43.1%), and endorsed high-risk levels (23.0%). The high-risk group had a higher proportion of affective versus nonaffective psychosis diagnosis; higher baseline positive and depressive symptoms; higher 5-year mean depression scores, and fewer weeks of positive symptom remission over the 5-year course., Conclusions: The first month of treatment is a critical period for suicide risk in FEP. Although early reductions in suicidality are often maintained, our findings make the case for sustained monitoring for suicide risk management.

Prospective population studies suggest that psychotic syndromes may be an emergent phenomenon-a function of severity and complexity of more common mental health presentations and their nonpsychotic symptoms. Examining the relationship between nonpsychotic and subthreshold psychotic symptoms in individuals who later developed the ultimate outcome of interest, a first episode of psychosis (FEP), could provide valuable data to support or refute this conceptualization of how psychosis develops. We therefore conducted a detailed follow-back study consisting of semistructured interviews with 430 patients and families supplemented by chart reviews in a catchment-based sample of affective and nonaffective FEP. The onset and sequence of 27 pre-onset nonpsychotic (NPS) or subthreshold psychotic (STPS) symptoms was systematically characterized. Differences in proportions were analyzed with z-tests, and correlations were assessed with negative binomial regressions. Both the first psychiatric symptom (86.24% NPS) and the first prodromal symptom (66.51% NPS) were more likely to be NPS than STPS. Patients reporting pre-onset STPS had proportionally more of each NPS than did those without pre-onset STPS. Finally, there was a strong positive correlation between NPS counts (reflecting complexity) and STPS counts (β = 0.34, 95% CI [0.31, 0.38], P < 2 e-16). Prior to a FEP, NPS precede STPS, and greater complexity of NPS is associated with the presence and frequency of STPS. These findings complement recent arguments that the emergence of psychotic illness is better conceptualized as part of a continuum-with implications for understanding pluripotential developmental trajectories and strengthening early intervention paradigms., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: During a psychotic episode, patients frequently suffer from severe maladaptive beliefs known as delusions. Despite the abundant literature investigating the simple presence or absence of these beliefs, there exists little detailed knowledge regarding their actual content and severity at the onset of illness., Aims: This study reports on delusions during the initiation of indicated treatment for first-episode psychosis (FEP)., Method: Data were systematically collected from a sample of 636 patients entering a catchment-based early intervention service for FEP. The average severity and frequency of each delusional theme at baseline was reported with the Scale for the Assessment of Positive Symptoms. Delusional severity (globally and per theme) was examined across a number of sociodemographic and clinical variables., Results: Delusions were present in the vast majority of individuals experiencing onset of FEP (94%), with persecutory (77.7%) being the most common theme. Persecutory delusions remained consistent in severity across diagnoses, but were more severe with older age at onset of FEP. No meaningful differences in delusional severity were observed across gender, affective versus non-affective psychosis, or presence/absence of substance use disorder. Globally, delusion severity was associated with anxiety, but not depression. Delusions commonly referred to as passivity experiences were related to hallucinatory experiences., Conclusions: This community sample offers a rare clinical lens into the severity and content of delusions in FEP. Although delusional severity was consistent across certain sociodemographic and clinical variables, this was not always the case. Future research should now consider the course of delusion themes over time.

Cost-effectiveness studies of early intervention services (EIS) for psychosis have not included extension beyond the first 2 years. We sought to evaluate the cost-effectiveness of a 3-year extension of EIS compared to regular care (RC) from the public health care payer's perspective. Following 2 years of EIS in a university setting in Montreal, Canada, patients were randomized to a 3-year extension of EIS (n = 110) or RC (n = 110). Months of total symptom remission served as the main outcome measure. Resource use and cost data for publicly covered health care services were derived mostly from administrative systems. The incremental cost-effectiveness ratio (ICER) and cost-effectiveness acceptability curve were produced. Relative cost-effectiveness was estimated for those with duration of untreated psychosis (DUP) of 12 weeks or less vs longer. Extended early intervention had higher costs for psychiatrist and nonphysician interventions, but total costs were not significantly different. The ICER was $1627 per month in total remission. For the intervention to have an 80% chance of being cost-effective, the decision-maker needs to be willing to pay $5942 per month of total symptom remission. DUP ≤ 12 weeks was associated with a reduction in costs of $12 276 even if no value is placed on additional months in total remission. Extending EIS for psychosis for people, such as those included in this study, may be cost-effective if the decision-maker is willing to pay a high price for additional months of total symptom remission, though one commensurate with currently funded interventions. Cost-effectiveness was much greater for people with DUP ≤12 weeks., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: COMT had been considered a promising candidate gene in pharmacogenetic studies in ADHD; yet the findings from these studies have been inconsistent. Part of these inconsistencies could be related to epigenetic mechanisms (including DNA methylation). Here we investigated the role of genetic variants of the COMT gene on the methylation levels of CpG sites in the same gene and explored the effect of methylation on methylphenidate (MPH) and placebo (PBO) response in children with ADHD., Methods: Two hundred and thirty children with ADHD (6-12 years) participated in a randomized, double-blind, placebo-controlled crossover trial with MPH. Univariate analysis was performed to examine the associations between genotypes in the COMT gene and DNA methylation in the same genetic loci. Association between the DNA methylation of 11 CpG sites and PBO/MPH responses were then assessed using spearman's correlation analysis in 212 children. Multiple linear regression analyses were performed to test the interaction between these factors while accounting for sex., Results: Associations were observed between specific genetic variants and methylation level of cg20709110. Homozygous genotypes of GG (rs6269), CC (rs4633), GG (rs4818), Val/Val (rs4680) and the haplotype (ACCVal/GCGVal) were significantly associated with higher level of methylation. This CpG showed a significant correlation with placebo response (r = -0.15, P = 0.045) according to the teachers' evaluation, and a close-to significance correlation with response to MPH according to parents' evaluation (r = -0.134, p = 0.051). Regression analysis showed that in the model including rs4818, sex and DNA methylation of cg20709110 contributed significantly to treatment response., Conclusions: These preliminary results could provide evidence for the effect of genetic variations on methylation level and the involvement of the epigenetic variation of COMT loci in modulating the response to treatment in ADHD., Trial Registration: clinicaltrials.gov, number NCT00483106., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The genetics care pathway experienced by families affected by autism spectrum disorder (ASD) around the time of diagnosis is currently uncharacterized and potentially variable across contexts. The lack of consensus on outcome measures to capture the impact of genetic services for these families shows a gap in understanding and optimizing this genetics care pathway. The Genetic Counseling Outcome Scale (GCOS-24) is a validated outcome measure of clinical genetics services. The current study aims to adapt and validate the GCOS-24 as an outcome measure in the context routine genetic testing in ASD and related conditions. Families seen for their child's developmental evaluation for ASD and related conditions were invited to participate in a genomics cohort between 2016 and 2018. Families (n = 111) completed the mGCOS-24 (modified GCOS-24), adapted from the original GCOS-24 by clinicians working in the target population's routine care pathway. The mGCOS-24 has acceptable internal consistency (Cronbach's α = 0.84) and high test-retest reliability (ICC = 0.88). It also inversely correlates with stress as measured by Perceived Stress Scale (PSS-10) and distress, as measured by the Distress Thermometer, rs ≥ 0.39, ps < 0.001. The mGCOS-24 had adequate readability, as supported by cognitive interviews completed by a sub-sample of five mothers of a child with ASD. Together, our findings show that the mGCOS-24 has good validity for the target population. Preliminary characterization of the genetics care pathway in this population revealed remarkable variability in pre-test counseling and limited post-test counseling. The use of the mGCOS-24 as an outcome measure is useful in filling some of these gaps by offering a way to assess, and in the future, optimize the genetics care pathway for families affected by autism and related neurodevelopmental conditions., (© 2020 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Competing Interests: R. Joober sits 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 Perdue for CME presentations and royalties from Henry Stewart talks. He is co-editor in chief of JPN, and was not involved in the review of this manuscript or in the decision to accept it for publication. No other competing interests were declared.

Background: COVID-19 was declared a pandemic in March 2020, by the World Health Organization. The pandemic has had unprecedented worldwide implications, in particular on marginalized populations., Aims: The aim of this study is to review the impact of the pandemic on patients with schizophrenia spectrum disorders., Method: A number of databases were searched for this review, including PubMed, EMBASE, PsycINFO and Google Scholar. Search terms included psychosis and COVID-19, schizophrenia and COVID-19, and severe mental illness and COVID-19. We included all English language papers and preprints. The final search was done on 15 July 2020., Results: Forty-seven relevant studies were identified and included in this review. Studies were summarised into five main subcategories: potential impact of the COVID-19 pandemic on physical health outcomes of patients with schizophrenia spectrum disorders, impact on mental health outcomes, review of case reports and case series to date, treatment recommendation guidelines and risk of increased prevalence of psychosis., Conclusions: Patients with schizophrenia spectrum disorders may be vulnerable to the effects of the COVID-19 pandemic. This patient population has a number of risk factors, including psychosocial adversities and illness related factors. Continuous monitoring and long-term studies of the impact of the pandemic on this patient population are required.

Background: Although there is some evidence for a normalization of brain structure following exposure to ADHD medication, literature on the effects of duration and dose of continued use on the brain is scarce. Here, we investigated the association between cumulative exposure to medication (range 1 week to 4.69 years) and cortical structures and subcortical volumes in a clinical sample of children with ADHD taking medication (n = 109). To the best of our knowledge, this is the first structural MRI study investigating the effects of cumulative exposure to medication on subregional volumes in children treated for ADHD., Methods: Cumulative exposure to ADHD medication (CEM) was defined as the product of duration on medication (days) and dose (mg/day), yielding the area under the curve (total mg). Cortical thickness and surface area measurements (CIVET-1.1.12), and subcortical volumes in 51 regions (MAGeT-Brain) were analyzed using general linear modelling., Results: Significant effects of CEM were found in two subregions of the left hippocampus, the CA1 (df = 95; q = 0.003) and the strata radiatum/lacunosum/moleculare (df = 95; q = 0.003). Specifically, higher CEM was associated with smaller volumes within these subregions. No effects of medication exposure were detected on cortical thickness or surface area., Conclusions: Although this study is cross-sectional, the results found within this sample of children show that prolonged ADHD medication use at higher doses is significantly associated with smaller hippocampus volumes in specific subregions. More research is required to determine whether these results are reproduced in other samples of children of ADHD, and further, whether these are beneficial or off-target effects of the medication., (Copyright © 2021. Published by Elsevier Inc.)

Recent evidence suggests that patients with psychotic disorders have metabolic disturbances (e.g., insulin resistance, dyslipidemia) at the onset of the disease and before antipsychotic exposure. Such disturbances are strongly associated with adipose tissue dysregulation. Measuring adipokines, the molecular mediators of adipose function, could provide a picture of the state of metabolic regulation at the onset of psychosis. The present study explores adipokine changes in a population of first-episode psychosis (FEP) patients with minimal prior exposure to antipsychotics. The effects of social determinants of health (childhood trauma and minority status) associated with both metabolic and psychotic disorders were studied as potential determinants of this phenomenon. Data was collected through the Signature project, a biobank of clinical, socio-demographic, and biological markers. Adipokines (leptin, adiponectin, resistin and chemerin) were measured in serum of FEP patients with minimal exposure to antipsychotics (N = 48) and controls (N = 39). Data were analyzed with univariate (t-tests) and multivariate (linear regression) statistical methods. Patients, compared to controls, had significantly higher levels of adiponectin and resistin, and significantly lower levels of leptin and chemerin. These results persisted after controlling for sex, waist-to-height ratio, childhood trauma, and visible minority status. Adiponectin and chemerin retained their effects after further controlling for tobacco and depression. Resistin increased with childhood trauma scores; chemerin was higher in visible minority patients. Adipose tissue dysfunction is present in FEP patients, before exposure to antipsychotics. Social determinants of health contribute to adipose (and metabolic) dysregulation in FEP, but may not be the main determinants of this relationship., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Verbal memory (VM) is one of the most affected cognitive domains in first-episode psychosis (FEP) and is a robust predictor of functioning. Given that healthy females demonstrate superior VM relative to males and that female patients show less-severe illness courses than male patients, this study examined whether normative sex differences in VM extend to FEP and influence functioning. Four hundred and thirty-five patients (299 males, 136 females) with affective or nonaffective psychosis were recruited from a catchment-based specialized FEP intervention service and 138 nonclinical controls (96 males, 42 females) were recruited from the same community. One of the two neurocognitive batteries comprising six cognitive domains (VM, visual memory, working memory, attention, executive function, processing speed) were administered at baseline. In patients, positive and negative symptoms were evaluated at baseline and functioning was assessed at 1-year follow-up. Patients were more impaired than controls on all cognitive domains, but only VM showed sex differences (both patient and control males performed worse than females), and these results were consistent across batteries. In patients, better baseline VM in females was related to better functioning after 1 year, mediated through fewer baseline negative symptoms. Supplemental analyses revealed these results were not driven by affective psychosis nor by age and parental education. Thus, normative sex differences in VM are preserved in FEP and mediate functioning at 1-year follow-up via negative symptoms. This study highlights the importance of investigating sex effects for understanding VM deficits in early psychosis and suggests that sex may be a disease-modifying variable with important treatment implications., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Developing a digital health innovation can require a substantial amount of financial and human resource investment before it can be scaled for implementation across geographical, cultural, and health care contexts. As such, there is an increased interest in leveraging eHealth innovations developed and tested in one country or jurisdiction and using these innovations in local settings. However, limited knowledge exists on the processes needed to appropriately adapt digital health innovations to optimize their transferability across geographical, cultural, and contextual settings., Objective: We report on the results of an adaptation study of Horyzons, a digital health innovation originally developed and tested in Australia. Horyzons is designed to prevent relapses and support recovery in young people receiving services for first-episode psychosis (FEP). The aim of this study is to assess the initial acceptability of Horyzons and adapt it in preparation for pilot testing in Canada., Methods: This research took place in 2 specialized early intervention clinics for FEP, located in 1 urban and 1 urban-rural setting, in 2 Canadian provinces. A total of 26 participants were recruited: 15 clinicians (age range 26-56 years) and 11 patients (age range 19-37 years). Following the digital health adaptation framework developed by our team, we used a mixed methods approach, combining descriptive quantitative and qualitative methods across 3 stages of data collection (focus groups, interviews, and consultations), analysis, and adaptations., Results: Overall, patients and clinicians appreciated the strengths-based approach and social media features of Horyzons. However, participants expressed concerns related to implementation, especially in relation to capacity (eg, site moderation, crisis management, internet speed in rural locations). They also provided suggestions for adapting content and features, for example, in relation to community resources, volume of text, universal accessibility (eg, for individuals with limitations in vision), and optimization of platform accessibility through mobile devices. Additional aspects of the innovation were flagged for adaptation during the final stages of preparing it for live implementation. These included terms of use, time zone configuration to reflect local time and date, safety and moderation protocols, the need help now feature, and the list of trigger words to flag posts indicative of potential risk., Conclusions: In the context of the COVID-19 pandemic and public health guidelines for social distancing, there is an increasing interest and need to leverage the internet and mobile technologies for delivering youth mental health services. As countries look to one another for guidance on how to navigate changing social dynamics, knowledge on how to utilize and adapt existing innovations across contexts is now more important than ever. Using a systematic approach, this study illustrates the methods, processes, results, and lessons learned on adapting a digital health innovation to enhance its local acceptability., International Registered Report Identifier (irrid): RR2-10.2196/resprot.8810., (©Shalini Lal, John Gleeson, Lysanne Rivard, Simon D'Alfonso, Ridha Joober, Ashok Malla, Mario Alvarez-Jimenez. Originally published in JMIR Formative Research (http://formative.jmir.org), 29.10.2020.)

Hippocampal circuitry has been posited to be fundamental to positive symptoms in psychosis, but its contributions to other factors important for outcome remains unclear. We hypothesized that longitudinal changes in the hippocampal circuit and concomitant changes of intracortical microstructure are altered in first episode psychosis (FEP) patients and that such changes are associated with negative symptoms and verbal memory. Longitudinal brain scans (2-4 visits over 3-15 months) were acquired for 27 FEP and 29 age- and sex-matched healthy controls. Quantitative T1 maps, sensitive to myelin content, were used to sample the microstructure of the hippocampal subfields and output circuitry (fimbria, alveus, fornix, mammillary bodies), and intracortical regions. Dynamic anatomical covariance in pair-wise regional trajectories were assessed for each subject, and graph theory was used to calculate a participation coefficient metric that quantifies the similarity/divergence between hippocampal and intracortical microstructure. The mean participation coefficient of the hippocampus was significantly reduced in FEP patients compared with controls, reflecting differences in output hippocampal regions. Importantly, lower participation coefficient of the hippocampal circuit was associated with worse negative symptoms, a relationship that was mediated by changes in verbal memory. This study provides evidence for reduced hippocampal centrality in FEP and concomitant changes in intracortical anatomy. Myelin-rich output regions of the hippocampus may be an important biological trigger in early psychosis, with cascading effects on broader cortical networks and resultant clinical profiles., (© 2020 Wiley Periodicals, Inc.)

Background: Purported superior outcomes for treatment of psychosis in low- and middle-income (LMICs) compared with high-income (HICs) countries have not been examined in the context of early intervention services (EIS)., Aims: To compare 2-year clinical outcomes in first-episode psychosis (FEP) treated in EIS in Chennai (LMIC) and Montreal (HIC) using a similar EIS treatment protocol and to identify factors associated with any outcome differences., Method: Patients with FEP treated in EIS in Chennai (n = 168) and Montreal (n = 165) were compared on change in level of symptoms and rate and duration of positive and negative symptom remission over a 2-year period. Repeated-measures analysis of variance, and logistic and linear regression analyses were conducted., Results: Four patients died in Chennai compared with none in Montreal. Family support was higher for Chennai patients (F = 14.05, d.f. = 1, P < 0.001, ƞp2 = 0.061) and increased over time at both sites (F = 7.0, d.f. = 1.915, P < 0.001, ƞp2 = 0.03). Negative symptom outcomes were significantly better in Chennai for level of symptoms (time × site interaction F = 7.36, d.f. = 1.49, P = 0.002, ƞp2 = 0.03), duration of remission (mean 16.1 v. 9.78 months, t = -7.35, d.f. = 331, P < 0.001, Cohen's d = 0.80) and the proportion of patients in remission (81.5% v. 60.3%, χ2 = 16.12, d.f. = 1, P < 0.001). The site differences in outcome remained robust after adjusting for inter-site differences in other characteristics. Early remission and family support facilitated better outcome on negative symptoms. No significant differences were observed in positive symptom outcomes., Conclusions: Patients with FEP treated in EIS in LMIC contexts are likely to show better outcome on negative symptoms compared with those in HIC contexts. Early remission and family support may benefit patients across both contexts.

Competing Interests: See jpn.ca for R. Joober. He is co-editor in chief of JPN, and was not involved in the review of this manuscript or in the decision to accept it for publication. No other competing interests were declared.

Objective: The aetiology of ADHD is complex, with genetic and environmental factors both implicated in the disorder. The most recent ADHD genome-wide association study identified 12 loci that showed significant association with the disorder. However, as highlighted by the authors, these loci "only capture a tiny fraction" of the risk for ADHD. It has been suggested that it may be important to disentangle: (1) the clinical complexity of the disorder, and (2) the complex interaction between genetic and environmental factors, in order to better dissect the aetiology of the disorder., Method: We have conducted a clinically-relevant Pharmaco-Behavioural Genetic study in a large group of children with ADHD (~850 families) over the last 15 years. The study includes detailed evaluation of quantitative behavioural and neuropsychological phenotypes, as well as short-term response of these phenotypes to treatment with a fixed dose of methylphenidate (0.5mg/kg in a b.i.d. dose). Specific genetic markers and environmental factors were examined for their association with these dimensions., Results: Here we present results that highlight the importance of examining genetic association with quantitative traits, including those constructs having relevance to Research Domain Criteria (RDoC). Further, we demonstrate that by conducting association analysis in groups of children stratified based on exposure to key environmental exposure (maternal smoking or stress during pregnancy), we are able to increase the sensitivity for finding genes involved in the disorder., Conclusion: These results suggest that deep phenotyping and heterogeneity reduction may be imperative in order to uncover the "missing heritability" of the disorder., (Copyright © 2020 Canadian Academy of Child and Adolescent Psychiatry.)

Background: Longitudinal studies of first episode of psychosis (FEP) patients are critical to understanding the dynamic clinical factors influencing functional outcomes; negative symptoms and verbal memory (VM) deficits are two such factors that remain a therapeutic challenge. This study uses white-gray matter contrast at the inner edge of the cortex, in addition to cortical thickness, to probe changes in microstructure and their relation with negative symptoms and possible intersections with verbal memory., Methods: T1-weighted images and clinical data were collected longitudinally for patients (N = 88) over a two-year period. Cognitive data were also collected at baseline. Relationships between baseline VM (immediate/delayed recall) and rate of change in two negative symptom dimensions, amotivation and expressivity, were assessed at the behavioral level, as well as at the level of brain structure., Results: VM, particularly immediate recall, was significantly and positively associated with a steeper rate of expressivity symptom decline (r = 0.32, q = 0.012). Significant interaction effects between baseline delayed recall and change in expressivity were uncovered in somatomotor regions bilaterally for both white-gray matter contrast and cortical thickness. Furthermore, interaction effects between immediate recall and change in expressivity on cortical thickness rates were uncovered across higher-order regions of the language processing network., Conclusions: This study shows common neural correlates of language-related brain areas underlying expressivity and VM in FEP, suggesting deficits in these domains may be more linked to speech production rather than general cognitive capacity. Together, white-gray matter contrast and cortical thickness may optimally inform clinical investigations aiming to capture peri-cortical microstructural changes.

Individuals with sub-threshold psychotic symptoms (STPS) are considered at clinical high risk for psychosis (CHR). Imaging studies comparing CHR and patients shortly after a first episode of psychosis (FEP) support progressive cortical thinning by illness stage. However, at least 30% of FEP patients deny pre-onset STPS, suggesting no history of CHR. This calls into question the generalizability of previous imaging findings. To better understand the physiology of early psychosis symptomology, we investigated the relationship between pre-onset STPS and cortical thickness (CT) among FEP patients, examining regional CT and structural covariance (SC). Patients (N = 93) were recruited from PEPP-Montreal, a FEP clinic at the Douglas Mental Health University Institute. The Circumstances of Onset and Relapse Schedule was administered to retrospectively identify patients who recalled at least one of nine expert-selected STPS prior to their FEP (STPS+, N = 67) and to identify those who did not (STPS-, N = 26). Age and sex-matched healthy controls (HC) were recruited (N = 84) for comparison. Participants were scanned between one and three times over the course of two years. CT values of 320 scans (143 HC, 123 STPS+, 54 STPS-) that passed quality control were extracted for group analysis. Linear mixed effects models accounting for effects of age, sex, education, and mean thickness were applied for vertex-wise, group comparisons of cortical thickness and SC. Multiple comparison corrections were applied with Random Field Theory (p-cluster = 0.001). Compared to controls, only STPS- patients exhibited significantly reduced CT in a cluster of the right ventral lateral prefrontal cortex. The vertex with the highest t-statistic within this cluster was employed as a seed in the subsequent SC analysis. After RFT-correction, STPS+ patients exhibited significantly stronger SC between the seed and right pars orbitalis compared to STPS- patients, and HC exhibited significantly stronger SC between the seed and right middle temporal gyrus compared to STPS- patients. Our results revealed patterns of SC that differentiated patient subgroups and patterns of cortical thinning unique to STPS- patients. Our study demonstrates that the early course of sub-threshold psychotic symptoms holds significance in predicting patterns of CT during FEP., Competing Interests: Declaration of Competing Interest M.L. reports grants from Otsuka Lundbeck Alliance, personal fees from Otsuka Canada, personal fees from Lundbeck Canada, grants and personal fees from Janssen, and personal fees from MedAvante-Prophase, outside the submitted work. R.J. reports receipt of grants, speaker's and consultant's honoraria from Janssen, Lundbeck, Otsuka, Pfizer, Shire, Perdue, HLS and Myelin and royalties from Henry Stewart Talks. In the last three years, A.M. reports honoraria for lectures given at conferences funded directly or indirectly by Lundbeck and Otsuka (Global) and consulting activities (e.g. research studies, advisory board participation) with Otsuka and Lundbeck Global and Canada, all unrelated to the present article. M.C. is a member of the editorial board of Progress in Neuropsychopharmacology and Biological Psychiatry., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: This study aims at characterizing the extent of correlation of treatment response (TR) obtained in various observation settings (home, school, clinic) by different observers (parents, teachers, clinicians)., Methods: Children with attention deficit hyperactivity disorder (ADHD) underwent a 2-week double-blind, randomized, cross-over clinical trial with methylphenidate and placebo, and various measures were obtained during the 2 weeks. Interrelationships of TR were examined using Pearson's correlation coefficients., Results: The study included 526 children (420 male, 106 female) with ADHD. TR between different observers shows a variable correlation between parents and teachers. No correlation is seen between parents/teacher evaluation of TR and laboratory-based measures (Continuous Performance Task; Restricted Academic Situation Scale)., Conclusion: The results firmly support the need to synthesize information from many sources in evaluating TR in ADHD.

Background: The clinical integration of chromosomal microarray testing promises improvements in diagnostic yields in Autism Spectrum Disorder (ASD). While the impact on clinical management is promising for some families, the utility perceived by families, including the majority for whom results are negative, is unclear. With next generation genomic sequencing technologies poised for integration, along with promising ASD biomarkers being developed, there is a need to understand the extent to which genomic and other biological testing would have utility for the target recipients of these tests and their families. The purpose of the present cross-sectional study was to examine the predictors of perceived utility of biological testing among parents of a child with ASD., Methods: The Perceived Utility of Biotesting (PUB) Questionnaire was developed based on literature review and integrating family review. Following their child's diagnosis, families participating in an ongoing prospective study completed the PUB questionnaire along with self-reported measures of parent stress, child and family functioning, and family-centered care prior to undergoing genetic testing for both clinical and research purposes., Results: Based on n = 85 families, psychometric properties of the Perceived Utility of Biotesting questionnaire suggest a reliable and valid instrument. A stepwise regression analysis reveals that lower levels of child emotional and behavioural functioning and higher levels of family functioning correlated with higher perceived utility for biological testing., Limitations: A main limitation in the study is the participation rate of 50 %, thus the possibility of self-selection bias cannot be ruled out. We also chose to assess perceived utility among parents rather than the individuals with ASD themselves: modifying the questionnaire to capture perceived utility from autistic individuals across the lifespan would prove essential in future studies. Finally, ongoing validation of the PUB by assessing the PUB's discriminant and convergent validity is still needed., Conclusions: We conclude that the utility of biological testing perceived by families whose child is undergoing genetic testing around ASD diagnosis depends on their unique child and family characteristics. This signifies that engaging families in biomarker discovery for improving the impact of research and care requires systematic input from a representative sample of families., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Cognitive difficulties are a core deficit for people with schizophrenia and are generally assessed with neuropsychological tests. Self-report assessments are also useful in understanding difficulties from the service user's perspective. This study aims to introduce and test the shorter version of the Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS) to improve its acceptability and comprehensibility. Methods: In consultation with service users and clinicians, we identified items from the original 21-item SSTICS that were found difficult and these were excluded. The reduced scale was explored with Confirmatory Factor Analysis (CFA) in two independent samples in the UK and Canada. Convergent validity with symptoms and IQ was assessed and compared between the original and the reduced scale. Results: Six-hundred and seven people with schizophrenia and first-episode psychosis took part in this study. Seven items were removed to produce the SSTICS-Brief. This had good reliability and the CFA confirmed a unidimensional structure. Convergent validity with symptoms and IQ were optimal between the long and short versions. Conclusions: The SSTICS-B has better acceptability than its longer form and could be administered in less time. The resulting measure is likely to be a valuable short self-assessment of cognitive complaints for people with schizophrenia.

Objective: Cognitive insight represents the capacity to self-reflect and consider external feedback when re-evaluating faulty beliefs. It is associated with specific cognitive capacities such as verbal memory, of which there is substantial evidence for sex differences in psychotic disorders. Like more general cognitive capacities, cognitive insight might too be modulated by sex differences., Method: One hundred and seventy-one first episode psychosis (FEP; 123 males, 48 females), and 203 multiple episode psychosis (MEP; 147 males, 56 females) participants completed the Beck Cognitive Insight Scale (BCIS). A two-way MANOVA was conducted on the three BCIS measures (self-reflectiveness, self-certainty, composite index) with sex (male, female) and illness stage (FEP, MEP) as factors, followed by two-way ANOVAs and a post hoc test of simple effects., Results: The only significant interaction to emerge was between sex and illness stage in self-certainty (F(1, 373) = 5.88, p = .016). A test of simple effects revealed that self-certainty group means were significantly different for males and females in FEP, where females had lower self-certainty than males (p = .053) but not during MEP (p = .119)., Conclusion: Sex differences do not modulate cognitive insight in MEP, which may be attributable to females having greater positive symptom severity than males. In FEP however, results revealed that females were significantly less self-certain than males. Lower self-certainty relative to self-reflectiveness predicts treatment response in psychological interventions, and as such future FEP studies should explore sex differences in psychological interventions., Competing Interests: Declaration of competing interest M.L. reports grants work from Otsuka Lundbeck Alliance, personal fees from Otsuka Canada, Lundbeck Canada, and MedAvante-Prophase, and grants and personal fees from Janssen. R.J. reports grants, speaker's and consultant's honoraria from Janssen, Lundbeck, Otsuka, Pfizer, Shire, Perdue, HLS and Myelin, and royalties from Henry Stewart Talks. A.M. reports research funding for an investigator-initiated project from BMS Canada and honoraria for lectures and consulting activities (e.g. advisory board participation) with Otsuka and Lundbeck. Grants, personal fees, and honoraria for all authors are unrelated to the present article., (Copyright © 2019. Published by Elsevier B.V.)

Objective: This study aims to examine the interaction between the gender of the child and the gender of the observers (teachers, parents) on the therapeutic response (TR) noted with methylphenidate (MPH) in children with ADHD., Method: Children with ADHD participated in a two week double-blind, randomized, cross-over clinical trial with MPH and placebo, and the difference between the week of treatment with MPH and placebo was calculated for each measure to obtain the treatment response (TR) with MPH. The TR for differences based on the gender of child and the observer was examined by using a univariate analysis of covariance (ANCOVA)., Results: 299 children (269-male, 30-female; average age 8.9±1.8 years) were evaluated by 52 male teachers, 212 female teachers; 269 female parents and 30 male parents. For the baseline week, the ANCOVA analysis for teachers yielded a significant teacher's gender x child's gender interaction. For the evaluation of TR, the ANCOVA analysis revealed a significant teacher's gender x child's gender interaction whereas no parent's gender x child's gender interactions were noted, all noted interactions were of a small effect size (eta squared <0.02)., Conclusions: These results suggest that there are differences in symptom assessment between parents and teachers at baseline and with TR based on the gender of the observer and the child. While clinicians need to be aware of these interactions, it remains unclear if these interactions will be clinically useful due to the small effect sizes., (Copyright © 2020 Canadian Academy of Child and Adolescent Psychiatry.)

Background: The influence of socioeconomic deprivation on the cardiovascular health of patients with psychosis-spectrum disorders (PSD) has not been investigated despite the growing recognition of social factors as determinants of health, and the disproportionate rates of cardiovascular mortality observed in PSD. Discordant results have been documented when studying dyslipidemia -a core cardiovascular risk factor- in first-episode psychosis (FEP), before chronic exposure to antipsychotic medications. The objective of the present study is to determine the extent to which socioeconomic deprivation affects blood lipids in patients with FEP, and examine its implications for cardiovascular risk in PSD., Methods: Linear regression models, controlling for age, sex, exposure to pharmacotherapy, and physical anergia, were used to test the association between area-based measures of material and social deprivation and blood lipid levels in a sample of FEP patients (n = 208)., Results: Social, but not material deprivation, was associated with lower levels of total and HDL cholesterol. This effect was statistically significant in patients with affective psychoses, but not in schizophrenia-spectrum disorders., Conclusions: Contrary to other reports from the literature, the relationship between socioeconomic disadvantage and blood lipid levels was contingent on the social rather than the material aspects of deprivation. Furthermore, this association also depended on the main diagnostic category of psychosis, suggesting a complex interaction between the environment, psychopathology, and physical health. Future studies exploring health issues in psychosis might benefit from taking these associations into consideration. A better understanding of the biology of blood lipids in this context is necessary., Competing Interests: Declaration of competing interest Dr. Malla has received grants from Roche and Bristol-Myers Squibb, and other funding support for consulting and conference lectures from Otsuka, Lundbeck, and Janssen-Ortho, all of it outside the submitted work. Dr. Joober has received grants from BMS, Otsuka, Lundbeck, Astra Zeneca and HLS, has made part of consulting committees for Pfizer, Janssen, BMS, Sunovian and Myelin, has been a speaker for Pfizer, Janssen Myelin, Otsuka, Lundbeck, Shire and Perdue, and has received royalties from Henry Stewart talks, all of it outside the submitted work. Drs. Iyer, Rho and Veru-Lesmes have no conflicts of interest to disclose., (Copyright © 2019. Published by Elsevier B.V.)

This exploratory study aims to determine whether the change in systolic blood pressure (sBP) after acute methylphenidate (MPH) administration (ΔBP MPH ) is associated with the neurocognitive response to MPH in the Conners Continuous Performance Test (CPT) in 513 children with ADHD (aged 6 to 12 years old). We noted that higher increases in sBP were associated with larger improvement in CPT performance with MPH. In the univariate regression model, the ΔBP MPH accounted for an additional 2% of the variance in the change in CPT-Overall Index (OI) after controlling for covariates (p < .001). Linear regression analysis also indicated that ΔBP MPH significantly contributed to predict a change in omission errors, reaction time, and reaction time variability (p < .001, p < .01, p = .001, respectively), but not in commission errors or detectability index (d`). Participants with a clinically meaningful sBP increase of at least 5 mmHg (n = 191) improved by 4.8 points on the CPT-OI score (p < .001), compared to an improvement of only 0.6 points for participants whose sBP declined by at least 5 mmHg (n = 121). In conclusion, larger sBP increases after MPH administration were associated with greater enhancement in CPT performance. These results could be useful in informing MPH dosing in clinical practice., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: To examine whether the duration of unremitted psychotic symptoms after the onset of a first episode of psychosis (FEP) is associated with cortical thickness and hippocampal volume, as well as structural covariance of these measures., Method: Longitudinal MRI scans were obtained for 80 FEP patients shortly after entry to FEP clinic (baseline), and then 12 months and 24 months later. The proportion of time patients experienced unremitted positive symptoms for 2 interscan intervals (baseline to 12 mo, 12 mo to 24 mo) was calculated. Changes in cortical thickness and hippocampal volumes were calculated for each interscan interval and associated with duration of unremitted psychotic symptoms. Significant regions were then used in seed-based structural covariance analyses to examine the effect of unremitted psychotic symptoms on brain structural organization. Importantly, analyses controlled for antipsychotic medication., Results: Cortical thinning within the left medial/orbitofrontal prefrontal cortex and superior temporal gyrus were significantly associated with the duration of unremitted psychotic symptoms during the first interscan interval (ie, baseline to 12 mo). Further, changes in cortical thickness within the left medial/orbitofrontal cortex positively covaried with changes in thickness in the left dorsal and ventrolateral prefrontal cortex during this period. No associations were observed during the second interscan interval, nor with hippocampal volumes., Conclusions: These results demonstrate that cortical thickness change can be observed shortly after an FEP, and these changes are proportionally related to the percentage of time spent with unremitted psychotic symptoms. Altered structural covariance in the prefrontal cortex suggests that unremitted psychotic symptoms may underlie reorganization in higher-order cortical regions., (© The Author(s) 2020. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

There is growing evidence that psychosis is characterized by brain network abnormalities. Analyzing morphological abnormalities with T1-weighted structural MRI may be limited in discovering the extent of deviations in cortical associations. We assess whether structural associations of either cortical white-gray contrast (WGC) or cortical thickness (CT) allow for a better understanding of brain structural relationships in first episode of psychosis (FEP) patients. Principal component and structural covariance analyses were applied to WGC and CT derived from T1-weighted MRI for 116 patients and 88 controls, to explore sets of brain regions that showed group differences, and associations with symptom severity and cognitive ability in patients. We focused on 2 principal components: one encompassed primary somatomotor regions, which showed trend-like group differences in WGC, and the second included heteromodal cortices. Patients' component scores were related to general psychopathology for WGC, but not CT. Structural covariance analyses with WGC revealed group differences in pairwise correlations across widespread brain regions, mirroring areas derived from PCA. More group differences were uncovered with WGC compared with CT. WGC holds potential as a proxy measure of myelin from commonly acquired T1-weighted MRI and may be sensitive in detecting systems-level aberrations in early psychosis, and relationships with clinical/cognitive profiles., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Patients who have recently experienced a first of episode psychosis (FEP) exhibit considerable heterogeneity in subcortical brain volumes. These results become even more divergent when exploring the effect of antipsychotic medication among other clinical and cognitive features. We aimed to contrast volumetric measures in basal ganglia and thalamus in patients with a FEP treated with different second-generation antipsychotics. T1-weighted magnetic resonance images were obtained and subcortical structures were extracted with MAGeT-Brain. Relationships with cognitive functioning were also explored with a Global Cognitive Index obtained, on average, within one month from the scan. Subgroups included: risperidone (n = 26), aripiprazole (n = 22), olanzapine (n = 19) and controls (n = 80). The olanzapine subgroup displayed significant enlargement of the right globus pallidus volume compared with all other groups. Moreover, despite not exhibiting poorer cognitive capacity than the rest of patients, results from a stepwise multiple-regression linear regression analysis identified a significant negative association between right globus pallidus volume and scores on the Global Cognitive Index among these patients. To our knowledge, this is the first study to associate treatment with olanzapine with an increase in globus pallidus volume in a sample of FEP patients with a relatively short time of antipsychotic monotherapy. Such enlargement was also found to be associated with poorer global cognitive functioning. Exploration of the biological underpinnings of this early medication-induced enlargement should be the focus of future investigations since it may lend insight towards achieving a better clinical outcome for these patients., (Copyright © 2019. Published by Elsevier B.V.)

Competing Interests: None declared by N. Garel. R. Joober sits 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 Perdue for CME presentations and royalties from Henry Stewart talks. He is coeditor-inchief of JPN, but was not involved in the review of this manuscript or the decision to accept it for publication.

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental psychiatric disorder. Genome-wide association studies (GWAS) have identified several loci associated with ADHD. However, understanding the biological relevance of these genetic loci has proven to be difficult. Here, we conduct an ADHD transcriptome-wide association study (TWAS) consisting of 19,099 cases and 34,194 controls and identify 9 transcriptome-wide significant hits, of which 6 genes were not implicated in the original GWAS. We demonstrate that two of the previous GWAS hits can be largely explained by expression regulation. Probabilistic causal fine-mapping of TWAS signals prioritizes KAT2B with a posterior probability of 0.467 in the dorsolateral prefrontal cortex and TMEM161B with a posterior probability of 0.838 in the amygdala. Furthermore, pathway enrichment identifies dopaminergic and norepinephrine pathways, which are highly relevant for ADHD. Overall, our findings highlight the power of TWAS to identify and prioritize putatively causal genes.

Objective: It has been shown that men with a longstanding psychotic disorder have worse clinical and functional outcomes than women. Our objectives were to examine whether these sex differences are also present among patients treated in an early intervention service (EIS) for psychosis and to determine if these differences are related to risk factors other than sex., Method: Patients ( N = 569) were assessed for demographic/clinical characteristics at entry and for symptoms/functioning over 2 years of treatment. Clinical outcomes included remission of positive, negative, and total symptoms. Functional outcomes included good functioning and functional remission. Logistic regression models examined the relationship between sex and outcomes after 1 and 2 years of treatment while controlling for the influence of other risk factors., Results: Men reported to be less educated and have a longer duration of untreated psychosis, poorer childhood and early adolescent premorbid functioning, higher rates of substance abuse/dependence disorders, greater severity of baseline negative symptoms, and poorer baseline social/occupational functioning than women. Women were more likely to achieve symptom remission than men after 2 years of treatment (negative odds ratio [OR], 1.69; 95% confidence interval [CI], 1.02 to 2.78; total OR, 1.79; 95% CI, 1.08 to 2.98). Women were also more likely than men to exhibit good functioning (OR, 1.61; 95% CI, 1.04 to 2.49) after 1 but not after 2 years of treatment. These results did not persist after controlling for other risk factors that could confound these associations (i.e., childhood premorbid functioning and age at onset of psychosis)., Conclusions: Sex differences seen in outcomes among patients treated in an EIS for psychosis may be largely influenced by the disparity of other risk factors that exist between the 2 sexes.

Understanding the overall utility of biological testing for autism spectrum disorder (ASD) is essential for the development and integration of biomarkers into routine care. One measure related to the overall utility of biological testing is the knowledge that a person has about the condition he/she suffers from. However, a major gap towards understanding the role of knowledge in overall utility is the absence of studies that have assessed knowledge of autism along with its predictors within a representative sample of families within the context of routine care. The objective of this study was to measure knowledge of ASD among families within the routine care pathway for biological testing in ASD by examining the association between knowledge with potential correlates of knowledge namely sociodemographic factors, parental stress and distress, and time since diagnosis among parents whose child with ASD is undergoing clinical genetic testing. Parents of a child diagnosed with ASD (n = 85, Mage = 39.0, SD = 7.7) participating in an ongoing prospective genomics study completed the ASD Quiz prior to undergoing genetic testing for clinical and research purposes. Parents also completed self-reported measures of stress and distress. Parent stress and distress was each independently correlated with knowledge of ASD, rs ≥ 0.26, ps < 0.05. Stepwise regression analysis revealed a significant model accounting for 7.8% of the variance in knowledge, F (1, 82) = 8.02, p = 0.006. The only factor significantly associated with knowledge was parental distress, β = 0.30, p = 0.006. Parental stress, time since diagnosis, and sociodemographic factors were not significant predictors in this model. We concluded that families require tailored support prior to undergoing genetic testing to address either knowledge gaps or high distress. Ongoing appraisal of the testing process among families of diverse backgrounds is essential in offering optimal care for families undergoing genetic testing., Competing Interests: The authors have declared that no competing interests exist.

Background: Many Canadian adolescents and young adults with mental health problems face delayed detection, long waiting lists, poorly accessible services, care of inconsistent quality and abrupt or absent inter-service transitions. To address these issues, ACCESS Open Minds, a multi-stakeholder network, is implementing and systematically evaluating a transformation of mental health services for youth aged 11 to 25 at 14 sites across Canada. The transformation plan has five key foci: early identification, rapid access, appropriate care, the elimination of age-based transitions between services, and the engagement of youth and families., Methods: The ACCESS Open Minds Research Protocol has multiple components including a minimum evaluation protocol and a stepped-wedge cluster randomized trial, that are detailed in this paper. Additional components include qualitative methods and cost-effectiveness analyses. The services transformation is being evaluated at all sites via a minimum evaluation protocol. Six sites are participating in the stepped-wedge trial whereby the intervention (a service transformation along the key foci) was rolled out in three waves, each commencing six months apart. Two sites, one high-population and one low-population, were randomly assigned to each of the three waves, i.e., randomization was stratified by population size. Our primary hypotheses pertain to increased referral numbers, and reduced wait times to initial assessment and to the commencement of appropriate care. Secondary hypotheses pertain to simplified pathways to care; improved clinical, functional and subjective outcomes; and increased satisfaction among youth and families. Quantitative measures addressing these hypotheses are being used to determine the effectiveness of the intervention., Discussion: Data from our overall research strategy will help test the effectiveness of the ACCESS Open Minds transformation, refine it further, and inform its scale-up. The process by which our research strategy was developed has implications for the practice of research itself in that it highlights the need to actively engage all stakeholder groups and address unique considerations in designing evaluations of complex healthcare interventions in multiple, diverse contexts. Our approach will generate both concrete evidence and nuanced insights, including about the challenges of conducting research in real-world settings. More such innovative approaches are needed to advance youth mental health services research., Trial Registration Number: Clinicaltrials.gov, ISRCTN23349893 (Retrospectively registered: 16/02/2017).

Objectives: In low- and middle-income countries (LMIC), major mental disorders often remain untreated because of barriers related to access and resources. In rural areas and in conflict-ridden regions, the problem can be exacerbated by increased rates of mental illness and by reduced access to care. This paper describes a project designed to provide mental health services for major mental disorders among youth using a low-cost model in a rural district of the troubled Kashmir valley., Methods: We describe the geographic and political context, the guiding principles and adaptation of the service model (through partnership with a voluntary organization and use of technology), and the implementation of the model using Theory of Change framework. The core of the intervention was to train a pool of lay health workers (LHWs) to provide mental health services to young (aged 14-30 years) people with major mental disorders in their own communities, supported by clinical professionals., Results: Despite political turmoil and major floods, 40 (male and female) LHWs were trained. The LHWs efficiently engaged in case identification, basic interventions, and data collection on outcomes. Several different stakeholders were engaged in activities relevant to the objectives of the project; however, the use of technologies was moderated by several challenges, including access to internet services and patient preference for personal contact., Conclusions: This service model is applicable in an environment where protracted political and armed conflict, low resources, and geographical isolation make exclusive reliance on scarce professional services impractical.

Objectives: To report the outcomes of young people (aged 14-30 years) treated for major mental disorders in a lay health worker (LHW) intervention model in a rural district of conflict-ridden Kashmir, India., Methods: Over a 12-month follow-up, LHWs collected data on symptoms, functioning, quality of life and disability, and patients' and families' service engagement and satisfaction., Results: Forty trained LHWs (18 males and 22 females) identified 262 individuals who met the criteria for a diagnosis of a major mental disorder, connected them with specialists for treatment initiation (within 14 days), and provided follow-up and support to patients and families. Significantly more patients (14-30 years) were identified during the 14 months of the project than those in all age groups in the preceding 2 years. At 12 months, 205 patients (78%) remained engaged with the service and perceived it as very helpful. Repeated measures ANOVA showed significant improvements in scores on the global assessment of functioning (GAF) scale (F[df, 3.449] = 104.729, p < 0.001) and all 4 domains of the World Health Organization quality of life (WHOQOL) brief version (WHOQOL-BREF) of the survey-Physical F(df, 1.861) = 40.82; Psychological F(df, 1.845) = 55.490; Social F(df, 1.583) = 25.189; Environment F(df, 1.791) = 40.902, all ps < 0.001-and a decrease in disability (F[df, 1.806] = 4.364, p = 0.016). An interaction effect between time and sex was observed for the physical health domain of the WHOQOL-BREF., Discussion and Conclusions: Our results show that an LHW-based service model, implemented in a rural setting of a low-to-middle income region plagued by long-term conflict, benefits young people with major mental disorders. We discuss the implications of our findings in the context of similar environments and the challenges encountered.

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia, defined as having an onset before the age of 13. The male COS cases have a slightly younger age of onset than female cases. They also present with a higher rate of comorbid developmental disorders. These sex differences are not explained by the frequency of chromosomal abnormalities, and the contribution of other forms of genetic variations remains unestablished. Using a whole-exome sequencing approach, we examined 12 COS trios where the unaffected parents had an affected male child. The sequencing data enabled us to test if the hemizygous variants, transmitted from the unaffected carrying mother, could mediate the phenotype (X-linked recessive inheritance model). Our results revealed that affected children have a significantly greater number of X-linked rare variants than their unaffected fathers. The variants identified in the male probands were mostly found in genes previously linked to other neuropsychiatric diseases like autism, intellectual disability, and epilepsy, including LUZP4, PCDH19, RPS6KA3, and OPHN1. The level of expression of the genes was assessed at different developmental periods in normal brain using the BrainSpan database. This approach revealed that some of them were expressed earlier in males than in females, consistent with the younger age of onset in male COS. In conclusion, this article suggests that X-linked genes might play a role in the pathophysiology of COS. Candidate genes detailed here could explain the higher level of comorbidities and the earlier age of onset observed in a subset of the male COS cases., (© 2018 Wiley Periodicals, Inc.)

Objective: The study objective was to examine whether and when antipsychotic-induced weight gain in first episode psychosis (FEP) stabilizes over a 12-month exposure to the same antipsychotic in a sample of previously untreated FEP patients., Methods: In this prospective naturalistic outcome study, 109 patients diagnosed with non-affective or affective psychosis (DSM-IV) were treated with the same antipsychotic medication (olanzapine n = 45, risperidone n = 39, or aripiprazole n = 25) throughout the first year of treatment. Body weight was measured and body mass index calculated at baseline and 1, 2, 3, 6, 9, and 12 months. Additional weight data over the second year were available, making extending the comparison for a second year possible., Results: Linear mixed model analysis showed a significant main effect of time (Type III test P < .001) after adjusting for baseline weight values. Post hoc pairwise comparisons showed that incremental weight changes subsequent to month 6 were insignificant, suggesting weight stabilization by month 9. No significant difference (P = .243) between groups or time × group interaction (P = .111) was observed. Similar findings were obtained with BMI. A follow-up analysis, of a subsample who continued treatment with the same antipsychotic for an additional 12 months (n = 57), confirmed weight stabilization in the second year. There was no significant main effect of time (P = .641), group (P = .539), or time × group interaction (P = .250)., Conclusions: Antipsychotic-induced weight gain occurs mostly in the first few months of treatment. Preventive interventions concurrent to second-generation antipsychotic treatment initiation in medication-naive FEP patients might be warranted., (© Copyright 2019 Physicians Postgraduate Press, Inc.)

Aims: To explore the impact of a targeted case identification intervention, with training and education regarding first-episode psychosis and clinical high-risk syndromes, on the referral and identification of those at high risk., Methods: Using a historical control design, referral information from pre-intervention and post-intervention periods was collected via administrative data and clinician notes from a catchment-based early psychosis service., Results: A significant increase in the number of referrals sent to the service's clinical high-risk unit was observed following the intervention (P = 0.01). The proportion of referrals eligible was significantly higher post-intervention (P = 0.03), with the majority (26/44, 59.1%) referred via the first-episode psychosis service unit., Conclusions: An integrated outreach intervention for both first-episode psychosis and the clinical high-risk state was effective in increasing referrals of eligible cases to the service's at-risk unit. Rather than being stage-specific, targeted case identification strategies and service integration should span across the early stages of psychosis., (© 2018 John Wiley & Sons Australia, Ltd.)

Objectives: Dopamine plays an important role in modulating attention and motor behaviours, dimensions altered in attention deficit/hyperactivity disorder (ADHD). Numerous association studies have linked dopamine receptor 4 ( DRD4 ) to increased risk of ADHD. This study investigated the effect of DRD4 exon 3 polymorphism on child behaviours in response to treatment with methylphenidate. Methods: A total of 374 children diagnosed with ADHD (ages 6-12 years) were evaluated under three experimental conditions: baseline, placebo and MPH (0.5 mg/kg/day). This was a 2-week prospective within-subject, placebo-controlled, crossover trial. The Conners' Global Index for parents and for teachers was used to evaluate the behaviours of the children. One-way repeated measures analysis of variance was used to test the effect of the interaction between DRD4 genotype and experimental conditions. Results: A significant interaction between DRD4 genotype and treatment was detected when the child's behaviour was evaluated by the parents ( P  = 0.035, effect size of 0.014), driven by a better treatment response in children homozygous for long 7-repeat allele. Conclusions: According to the parent assessment, children homozygous for the long 7-repeat allele were more responsive to experimental condition. This is the largest pharmacogenetic investigation of the effect of DRD4 exon 3 polymorphism in childhood ADHD. Trial Registration: clinicaltrials.gov, identifier NCT00483106.

Objective: To test whether duration of untreated psychosis (DUP) < 3 months, recommended by the World Health Organization/International Early Psychosis Association, enhances the effects of an extended early intervention service (EEIS) on symptom remission., Method: We examined data from a randomized controlled trial in which patients who received 2 years of treatment in EIS for psychosis were subsequently randomized to either 3 years of EEIS or 3 years of regular care (RC). Using a DUP cut-off ≤ 12 weeks (approximately < 3 months), patients were split into two groups. Length of positive, negative and total symptom remission were the outcomes., Results: Patients (N = 217) were mostly male (68%) with schizophrenia spectrum disorder (65%); 108 (50%) received EEIS (58 had DUP ≤12 weeks; 50 had DUP >12 weeks). Interaction between treatment condition (EEIS vs. RC) and DUP cut-off ≤ 12 weeks was only significant in multiple linear regression model examining length of negative symptom remission as the outcome (adjusted β = 36.88 [SE = 15.88], t = 2.32, P = 0.02). EEIS patients with DUP ≤12 weeks achieved 25 more weeks of negative symptom remission than EEIS patients with DUP >12 weeks., Conclusion: Having a short DUP may be critical in deriving long-term benefits from EIS for psychosis, including EEIS settings. This work empirically supports policy recommendations of reducing DUP <3 months., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Psychosis has been associated with abnormalities in hypothalamic-pituitary-adrenal axis functioning, which may emerge through heightened stress sensitivity following early life adversity - ultimately resulting in illness onset and progression. The present study assessed cortisol levels during an established psychosocial stress task and their association with current stress perception, putative protective factors and adverse childhood experiences in patients with a first episode of psychosis (FEP). A total of 100 volunteers participated in the study, 57 of whom were patients with a FEP (mean age 23.9 ± 3.8) and 43 healthy community controls (mean age 23.2 ± 3.9). Salivary cortisol, heart rate and blood pressure were measured at eight time points before and after the Trier Social Stress Test. Subjective stress and protective factors were assessed with the Perceived Stress Scale, the Self-Esteem Rating Scale and the Brief COPE. Early life adversity was assessed with the Childhood Trauma Questionnaire. Patients compared to controls showed significantly lower cortisol levels (F = 7.38; p = .008) throughout the afternoon testing period, but no difference in the cortisol response to the TSST. Heart rate was elevated and protective factors were lower in patients compared to controls. Attenuated cortisol levels were associated with higher levels of perceived stress, poor protective factors and more physical neglect during childhood. Our results suggest that attenuated baseline cortisol levels and not a blunted response during an acute stress task might be an indicator of heightened stress vulnerability and poor resilience in psychosis. The possible influence of childhood adversity and antipsychotic medication is discussed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: In many parts of the world, there is growing concern about youth homelessness. Homeless youth are particularly vulnerable to psychological distress, substance use and mental disorders, and premature mortality caused by suicide and drug overdose. However, their access to and use of mental health care is very limited., Methods: The Réseau d'intervention de proximité auprès des jeunes (RIPAJ), a Montreal network of over 20 community stakeholders providing a wide array of cohesive services, was created to ease homeless youth's access to mental health and psychosocial services. Its philosophy is that there should be no "wrong door" or "wrong timing" for youth seeking help. In 2014, the network partnered with the pan-Canadian transformational research initiative, ACCESS Esprits ouverts., Results: Created through this partnership, ACCESS Esprits ouverts RIPAJ has been promoting early identification through outreach activities targeting homeless youth and agencies that serve them. An ACCESS Clinician was hired to promote and rapidly respond to help-seeking and referrals. By strengthening connections within RIPAJ and using system navigation, the site is working to facilitate youth's access to timely appropriate care and eliminate age-based transitions between services. A notable feature of our program, that is not usually evident in homelessness services, has been the engagement of the youth in service planning and design and the encouragement of contact with families and/or friends., Conclusion: Challenges remain including eliminating any remaining age-related transitions of care between adolescent and adult services; and the sustainability of services transformation and network coordination. Nonetheless, this program serves as an example of an innovative, much-needed, community-oriented model for improving access to mental health care for homeless youth., (© 2019 The Authors Early Intervention in Psychiatry Published by John Wiley & Sons Australia, Ltd.)

Aim: To describe a community-specific and culturally coherent approach to youth mental health services in a small and remote northern Indigenous community in Canada's Northwest Territories, under the framework of ACCESS Open Minds (ACCESS OM), a pan-Canadian youth mental health research and evaluation network., Methods: As 1 of the 14 Canadian communities participating in a 5-year, federally funded service transformation and evaluation project, the arctic Inuit community of Ulukhaktok has undertaken culturally relevant adjustments in their delivery of youth mental wellness services and related community wellness initiatives. These enhancement activities highlight connections to culture and traditional skills, honour youth- and community-expressed desires to incorporate Inuvialuit-specific approaches to wellness, and strengthen the support systems to improve access to mainstream mental healthcare, when needed. The adaptation of a Lay Health Worker model from Global Mental Health to the local circumstances resulting in creation of lay community health workers is central to this approach in meeting contextual needs., Results: Community leaders identified key activities for sustainable change, including human capital development, authentic collaboration and diversified engagement strategies. Building around five ACCESS OM objectives, the local site team in Ulukhaktok has identified its youth programming and mental wellness service gaps through an ongoing process of community mapping., Conclusions: Information from service providers, youth and other community members demonstrates attuning of the ACCESS OM framework to Inuit paradigms in Ulukhaktok. It could prove to be a sustainable prototype for delivering youth mental health services in other communities in the Inuvialuit Settlement Region and possibly across the entire Inuit Nunangat. It needs, however, to be further supported by easier access to specialized mental health services when needed., (© 2019 The Authors Early Intervention in Psychiatry Published by John Wiley & Sons Australia, Ltd.)

Aim: Demands for mental health services in post-secondary institutions are increasing. This paper describes key features of a response to these needs: ACCESS Open Minds University of Alberta (ACCESS OM UA) is focused on improving mental health services for first-year students, as youth transition to university and adulthood., Methods: The core transformation activities at ACCESS OM UA are described, including early case identification, rapid access, appropriate and timely connections to follow-up care and engagement of students and families/carers. In addition, we depict local experiences of transforming existing services around these objectives., Results: The ACCESS OM UA Network has brought together staff with diverse backgrounds in order to address the unique needs of students. Together with the addition of ACCESS Clinicians these elements represent a systematic effort to support not just mental health, but the student as a whole. Key learnings include the importance of community mapping to developing networks and partnerships, and engaging stakeholders from design through to implementation for transformation to be sustainable., Conclusions: Service transformation grounded in principles of community-based research allows for incorporation of local knowledge, expertise and opportunities. This approach requires ample time to consult, develop rapport between staff and stakeholders across diverse units and develop processes in keeping with local opportunities and constraints. Ongoing efforts will continue to monitor changing student needs and to evaluate and adapt the transformations outlined in this paper to reflect those needs., (© 2019 The Authors Early Intervention in Psychiatry Published by John Wiley & Sons Australia, Ltd.)