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Background: Delay in treatment of psychosis is associated with poor clinical and social outcome and is measured as the duration of untreated psychosis (DUP) prior to treatment of the first episode. It has been suggested that this may be mediated through toxic effects of psychosis on the structure and function of the brain. Equivocal evidence exists regarding association between longer DUP and neuro-anatomical changes such as, reduced grey matter volume in specific regions in the brain and deficits in neurocognitive functions.Objective: To examine if duration of untreated psychosis (DUP) preceding treatment of a first episode of psychosis is associated with structural brain abnormalities and deficits in neurocognitive functions.Method: We investigated the relationship between DUP and grey matter volume using voxel-based morphometry techniques and with multiple domains of cognition. Eighty patients with a first episode of psychosis were separated into two equal sized groups based on a median split (18 weeks) of their DUP.Results: Compared to the short-DUP group (mean DUP 7.9 weeks ± 5.6), the long-DUP group (mean 113.7 weeks ± 170 .4) showed significant grey matter volume reductions in orbital-frontal regions (bilateral medial frontal gyrus and bilateral rectal gyrus, BA 11) and parietal regions (postcentral gyrus and superior parietal lobule) as well as a significant reduction in whole brain grey matter volume (p<0.04). For schizophrenia spectrum cases only these findings were confined to left rectal gyrus. There were no differences in white matter or cerebral spinal fluid volumes or on cognitive functions. Results are controlled for antipsychotic medication exposure.Limitations: The inherent difficulty in separating slow and insidious onset from long-DUP may limit the interpretation of our results and there may be an overlap between DUP and duration of illness (including the prodrome).Conclusion: Patients with a longer delay in treatment of psychosis show a significant reduction in overall grey matter volume with specific reductions in the inferior-orbital region. These results provide some support to a possible neurotoxic effect of prolonged untreated psychosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Few studies have examined the underlying factor structure of signs and symptoms occurring before the first psychotic episode. Our objective was to determine whether factors derived from early signs and symptoms are differentially associated with non-affective versus affective psychosis.MethodA principal components factor analysis was performed on early signs and symptoms reported by 128 individuals with first-episode psychosis. Factor scores were examined for their associations with duration of untreated illness, drug abuse prior to onset of psychosis, and diagnosis (schizophrenia versus affective psychosis). RESULTS: Of the 27 early signs and symptoms reported by patients, depression and anxiety were the most frequent. Five factors were identified based on these early signs and symptoms: depression, disorganization/mania, positive symptoms, negative symptoms and social withdrawal. Longer duration of untreated illness was associated with higher levels of depression and social withdrawal. Individuals with a history of drug abuse prior to the onset of psychosis scored higher on pre-psychotic depression and negative symptoms. The two mood-related factors, depression and disorganization/mania, distinguished the eventual first-episode diagnosis of affective psychosis from schizophrenia. Individuals with affective psychosis were also more likely to have a 'mood-related' sign and symptom as their first psychiatric change than individuals later diagnosed with schizophrenia. CONCLUSIONS: Factors derived from early signs and symptoms reported by a full diagnostic spectrum sample of psychosis can have implications for future diagnostic trajectories. The findings are a step forward in the process of understanding and characterizing clinically important phenomena to be observed prior to the onset of psychosis. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether detailed assessment of cognitive functions in people suffering from psychotic disorders can assist in their psychosocial rehabilitation while they are living in the community. A case study approach was used. People with a diagnosis of schizophrenia who were experiencing difficulties with vocational educational rehabilitation within the setting of an assertive community treatment program, received a detailed neuropsychological assessment. Feedback from the assessment was provided to the people with mental illness and their case managers, who together had identified referral questions for the neuropsychological testing. Three case vignettes are described as examples of the ways in which the goals of this study were achieved. Neuropsychological assessment can positively influence the process of psychosocial rehabillitation for clients and case managers in select cases. Future research should concentrate on determining the ecological validity of assessment based on specific neuropsylogical test results for the purpose of predicting readiness for vocational training for persons with serious mental disorders. [ABSTRACT FROM AUTHOR]

There continues to be controversy concerning the long term benefits of specialized early intervention programs (SEI) for psychotic disorders. Recent reports of five year outcomes for SEI programs indicate that benefits of early intervention programs at two year follow-up have disappeared at five years. The Prevention and Early Intervention Program for Psychoses (PEPP) in London, Ontario offers continuity of care for five years, with a lower intensity level of specialized intervention after the initial two years. In this paper we examine whether the outcomes observed at two years were maintained at five year follow-up. In addition, it was possible to compare PEPP outcomes with those of the OPUS project at two and five years. Results indicate that improvement of symptoms between entry into PEPP and two year follow-up were maintained at five years. In addition, there was further improvement in global functioning between two and five year follow-up. Comparison of PEPP outcomes at two and five year follow-up to those of OPUS suggest that longer term continuity of care within SEI is associated with continuing benefits at least with respect to level of positive symptoms and functioning. [ABSTRACT FROM AUTHOR]

Background: A history of childhood symptoms of inattention-hyperactivity is often reported in first episode psychosis (FEP) as is cannabis use. In the general population childhood ADHD predicts future cannabis use but the relationship has not been tested in FEP.Method: Parents of patients with a first episode of psychosis (n=75) retrospectively assessed their affected child for symptoms of early-life disorders, namely, attention deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional defiant disorder (ODD) using the Child Behaviour Checklist (CBCL). Assessments were made prospectively of cannabis use over two years following a FEP and of SCID diagnosis of cannabis-use disorder.Results: Childhood hyperactivity-inattention symptoms predicted inability to maintain abstinence from cannabis following treatment (Wald=8.4, p=.004) and lifetime cannabis-use diagnosis (Wald=5.3, p=.022) in a logistic regression controlling for relevant covariates including symptoms of CD and ODD from ages 12 to 18. When the symptom of inattention was considered in place of the hyperactivity-inattention syndrome it predicted cannabis-use diagnosis (Wald=6.4, p=.011) and persistent abstinence from cannabis (Wald=5.3, p=.021). Symptoms of CD and ODD did not predict cannabis use when hyperactivity-inattention symptoms were controlled for.Conclusions: Symptoms of childhood inattention-hyperactivity predict subsequent cannabis use in FEP. [ABSTRACT FROM AUTHOR]

Social anxiety disorder (SAD) is a frequent comorbidity in first-episode psychosis (FEP) and may increase cognitive impairments. Cognitive remediation (CR) is an effective treatment for cognition, particularly in a group format. This study aims to assess the efficacy, acceptability and engagement of group CR on cognitive outcomes in FEP+SAD compared to group cognitive-behavioral therapy (CBT). Participants with FEP+SAD were randomized to group CR (n = 45) or CBT-SAD (n = 51). They were assessed for cognition at baseline, post-therapy and 3- and 6-month follow-up. The CR group additionally completed scale to assess perceived competency and enjoyment in CR. Linear mixed models for repeated measures were used for cognitive scores. Descriptive statistics and t-tests were used to summarize acceptability, perceived competency, and enjoyment, for CR completers and non-completers. The CR group performed significantly better than CBT on executive functions and visual memory at post-therapy compared to baseline. Twenty participants completed CR (44 %; mean 5.5 sessions). At week 1, CR non-completers presented higher levels of perceived competency. Completers reported higher enjoyment scores at the last session compared to the first session. Group CR is effective for cognitive outcomes in FEP+SAD, but acceptability and engagement present a challenge. Future studies are necessary to explore approaches promoting engagement., Competing Interests: Declaration of competing interest There are no conflicts of interest to report., (Copyright © 2024. Published by Elsevier B.V.)

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.)

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.

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: 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.

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: Mental health problems are common globally, and typically have their onset in adolescence and early adulthood-making youth (aged 11-25) an optimal target for prevention and early intervention efforts. While increasing numbers of youth mental health (YMH) initiatives are now underway, thus far few have been subject to economic evaluations. Here we describe an approach to determining the return on investment of YMH service transformation via the pan-Canadian ACCESS Open Minds (AOM) project, for which a key focus is on improving access to mental health care and reducing unmet need in community settings., Approach: As a complex intervention package, it is hoped that the AOM transformation will: (i) enable early intervention through accessible, community-based services; (ii) shift care away toward these primary/community settings and away from acute hospital and emergency services; and (iii) offset at least some of the increased costs of primary care/community-based mental health services with reductions in the volume of more resource-intensive acute, emergency, hospital or specialist services utilized. Co-designed with three diverse sites that represent different Canadian contexts, a return on investment analysis will (separately at each site) compare the costs generated by the intervention, including volumes and expenditures associated with the AOM service transformation and any contemporaneous changes in acute, emergency, hospital or service utilization (vs. historical or parallel comparators). Available data from health system partners are being mobilized to assess these hypotheses., Anticipated Results: Across urban, semi-urban and Indigenous sites, the additional costs of the AOM transformation and its implementation in community settings are expected to be at least partially offset by a reduction in the need for acute, emergency, hospital or specialist care., Discussion: Complex interventions such as AOM aim to shift care "upstream": away from acute, emergency, hospital and specialist services and toward community-based programming which is more easily accessible, often more appropriate for early-stage presentations, and more resource-efficient. Carrying out economic evaluations of such interventions is challenging given the constraints of available data and health system organization. Nonetheless, such analyses can advance knowledge, strengthen stakeholder engagement, and further implementation of this public health priority., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shah, Moinfar, Anderson, Gould, Hutt-Macleod, Jacobs, Mitchell, Nguyen, Rodrigues, Reaume-Zimmer, Rudderham, Rudderham, Smyth, Surood, Urichuk, Malla, Iyer and Latimer.)

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).

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.)

Negative symptoms are present at the onset of psychosis and their persistence is significantly associated with poor psychosocial functioning and lower quality of life. Persistent negative symptoms (PNS) may be idiopathic or secondary to other factors such as depression, positive symptoms, and medication side-effects. Several studies have examined neurocognitive functions in early psychosis patients with PNS relative to non-PNS, but have not systematically controlled for secondary PNS (sPNS). The latter may have a distinct neurocognitive profile that could obscure differences between PNS and non-PNS. Using a large (n = 425) sample, we examined neurocognitive functions in PNS, sPNS, and non-PNS and hypothesized that PNS would be associated with greater impairments relative to non-PNS. Following admission to an early intervention program, a neurocognitive battery was administered after at least 3 months of treatment, and symptom data collected during a subsequent 6-month period were used to classify patients as PNS, sPNS and non-PNS. At month 12, both PNS and sPNS groups had significantly lower level of functioning relative to the non-PNS group but the sPNS group experienced higher levels of depressive and positive symptoms and were on a higher dose of antipsychotics. Relative to non-PNS, PNS patients exhibited significant impairments in verbal memory and working memory, whereas sPNS patients exhibited a trend towards greater impairments in verbal memory. This study confirms that the presence of PNS or sPNS negatively influences functioning with more selective cognitive impairments found in PNS, providing evidence that these groups of patients could benefit from different personalised interventions., Competing Interests: Declaration of Competing Interest Salary awards include: FRSQ to J.L.S., R.J., M.B., and M.L.; a Canada Research Chair to A.M.; and a James McGill Professorship to M.L. M.L. reports grants from Otsuka Lundbeck Alliance, diaMentis 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. 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, all unrelated to the present article. All other authors report no competing interests., (Copyright © 2021. Published by Elsevier B.V.)

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.)

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.)

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.)

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.)

Objectives: Views on who bears how much responsibility for supporting individuals with mental health problems may vary across stakeholders (patients, families, clinicians) and cultures. Perceptions about responsibility may influence the extent to which stakeholders get involved in treatment. Our objective was to report on the development, psychometric properties and usability of a first-ever tool of this construct., Methods: We created a visual weighting disk called 'ShareDisk', measuring perceived extent of responsibility for supporting persons with mental health problems. It was administered (twice, 2 weeks apart) to patients, family members and clinicians in Chennai, India ( N  = 30, 30 and 15, respectively) and Montreal, Canada ( N  = 30, 32 and 15, respectively). Feedback regarding its usability was also collected., Results: The English, French and Tamil versions of the ShareDisk demonstrated high test-retest reliability ( r s = .69-.98) and were deemed easy to understand and use., Conclusion: The ShareDisk is a promising measure of a hitherto unmeasured construct that is easily deployable in settings varying in language and literacy levels. Its clinical utility lies in clarifying stakeholder roles. It can help researchers investigate how stakeholders' roles are perceived and how these perceptions may be shaped by and shape the organization and experience of healthcare across settings.

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.)

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).

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.)

Varying perceptions of who should be responsible for supporting individuals with mental health problems may contribute to their needs remaining unmet. A qualitative descriptive design was used to explore these perceptions among key stakeholders. Focus groups were conducted with 13 service users, 12 family members, and 18 treatment providers from an early psychosis intervention program in Montreal, Canada. Individual interviews were conducted with six mental health policy-/decision-makers. Participants across stakeholder groups assigned a range of responsibilities to individuals with mental health problems, stakeholders in these individuals' immediate and extended social networks (e.g., families), macro-level stakeholders with influence (e.g., government), and society as a whole. Perceived failings of the health care system and the need for greater sharing of roles and responsibilities also emerged as important themes. Our findings suggest that different stakeholders should collectively assume certain responsibilities and that systems-level failings may contribute to unmet needs for mental health support.

Early life adversity is associated with increased risk for psychosis onset and poor clinical outcome. Male compared to female patients often show a more severe course of psychotic illness. The aim of the present study was to investigate gender differences in childhood trauma (CT) and their impact on symptomatic and functional outcome following psychosis onset. The study included 210 patients (144 men, 66 women) diagnosed with a first-episode of psychosis (FEP). Early adversity was assessed with the Childhood Trauma Questionnaire. Psychotic symptoms and general functioning were rated with the Brief Psychiatric Rating Scale and Global Assessment of Functioning scale at baseline, 12 and 24 months of follow-up in an established early intervention service. Male patients reported higher rates of physical or emotional neglect, whereas female patients indicated significantly higher rates of emotional abuse. More severe CT was related to higher levels of depression in women and to negative symptoms in men. Distinct CT effects were observed on positive and negative symptom severity and global functioning in male patients at 24 months. Emotional abuse was the strongest predictor of depression in both genders. In male patients only, emotional abuse predicted positive symptom severity and impaired global functioning, whereas emotional neglect predicted more severe negative symptoms. Our results suggest differences in CT experiences in male and female FEP patients, with a more pronounced impact on longer-term outcome in male patients. The findings support the notion that sex differences in stress vulnerability account for the relatively poor illness course in male psychosis patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Negative symptoms are known to be present in the prodromal stage of psychotic disorders, yet little is known about their prevalence. Studies examining the presence of negative symptoms in ultra-high risk (UHR) populations have shown some limitations, notably failing to control depression. The objective of this study was to examine the prevalence of negative symptoms in the presence of significant levels of depression and in the absence of such symptoms (primary negative symptoms) over 1 year and to examine differences in negative symptoms in psychosis converters and non-converters., Methods: Participants were 123 individuals at UHR for the development of psychosis receiving follow-up for a period of 2 years. Negative symptoms and depression were measured using the Scale for the Assessment of Negative Symptoms and the Montgomery-Asberg Depression Scale at baseline, 6 and 12 months post-admission., Results: At baseline, the prevalence of negative symptoms and primary negative symptoms was 76.4% and 32.7%, respectively. Whereas the prevalence of negative symptoms was significantly decreased at 6 months, the prevalence of primary negative symptoms was similar at all time points. Negative symptoms at baseline were not different between later converters and non-converters to psychosis., Conclusion: Our findings confirm the presence of secondary and primary negative symptoms in individuals at UHR, but suggest a differential trajectory of both measures over time. Future studies should include larger UHR groups and focus on the investigation of intra-individual changes in primary negative symptoms over time and further explore their potential role for psychosis conversion., (© 2016 John Wiley & Sons Australia, Ltd.)

Background: Individuals with mental health problems have many support needs that are often inadequately met; however, perceptions of who should be responsible for meeting these needs have been largely unexplored. Varying perceptions may influence whether, how, and to what extent relevant stakeholders support individuals with mental health problems., Aims: To critically evaluate the literature to determine who different stakeholders believe should be responsible for supporting individuals with mental health problems, what factors shape these perceptions, and how they relate to one another., Method: A critical literature review was undertaken. Following an extensive literature search, the conceptual contributions of relevant works were critically evaluated. A concept map was created to build a conceptual framework of the topic., Results: Views of individual versus societal responsibility for need provision and health; the morality of caring; and attributions of responsibility for mental illness offered valuable understandings of the review questions. Creating a concept map revealed that various interrelated factors may influence perceptions of responsibility., Conclusions: Varying perceptions of who should be responsible for supporting individuals with mental health problems may contribute to unmet support needs among this group. Our critical review helps build a much-needed conceptual framework of factors influencing perceptions of responsibility. Such a framework is essential as these views iteratively shape and reflect the complex divisions of mental healthcare roles and responsibilities. Understanding these perceptions can help define relevant stakeholders' roles more clearly, which can improve mental health services and strengthen stakeholder accountability.

Accurate automated quantification of subcortical structures is a greatly pursued endeavour in neuroimaging. In an effort to establish the validity and reliability of these methods in defining the striatum, globus pallidus, and thalamus, we investigated differences in volumetry between manual delineation and automated segmentations derived by widely used FreeSurfer and FSL packages, and a more recent segmentation method, the MAGeT-Brain algorithm. In a first set of experiments, the basal ganglia and thalamus of thirty subjects (15 first episode psychosis [FEP], 15 controls) were manually defined and compared to the labels generated by the three automated methods. Our results suggest that all methods overestimate volumes compared to the manually derived "gold standard", with the least pronounced differences produced using MAGeT. The least between-method variability was noted for the striatum, whereas marked differences between manual segmentation and MAGeT compared to FreeSurfer and FSL emerged for the globus pallidus and thalamus. Correlations between manual segmentation and automated methods were strongest for MAGeT (range: 0.51 to 0.92; p<0.01, corrected), whereas FreeSurfer and FSL showed moderate to strong Pearson correlations (range 0.44-0.86; p<0.05, corrected), with the exception of FreeSurfer pallidal (r=0.31, p=0.10) and FSL thalamic segmentations (r=0.37, p=0.051). Bland-Altman plots highlighted a tendency for greater volumetric differences between manual labels and automated methods at the lower end of the distribution (i.e. smaller structures), which was most prominent for bilateral thalamus across automated pipelines, and left globus pallidus for FSL. We then went on to examine volume and shape of the basal ganglia structures using automated techniques in 135 FEP patients and 88 controls. The striatum and globus pallidus were significantly larger in FEP patients compared to controls bilaterally, irrespective of the method used. MAGeT-Brain was more sensitive to shape-based group differences, and uncovered widespread surface expansions in the striatum and globus pallidus bilaterally in FEP patients compared to controls, and surface contractions in bilateral thalamus (FDR-corrected). By contrast, after using a recommended cluster-wise thresholding method, FSL only detected differences in the right ventral striatum (FEP>Control) and one cluster of the left thalamus (Control>FEP). These results suggest that different automated pipelines segment subcortical structures with varying degrees of variability compared to manual methods, with particularly pronounced differences found with FreeSurfer and FSL for the globus pallidus and thalamus., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Although the negative consequences associated with first-episode psychosis (FEP) have been well investigated, relatively less is known about positive changes that people may experience after FEP. Existing literature is disparate and in need of synthesis. Such a synthesis can inform the design of mental health services that foster strengths, hope, and optimism. The objective of this study was to synthesize the literature on how positive change is experienced after FEP by affected persons and their families and friends and to delineate the individual, social, and structural factors facilitating positive change., Methods: A librarian-assisted systematic review of quantitative, qualitative, and mixed-methods studies published in English between 1970 and 2015 was conducted. Articles identified from three databases (PubMed, PsycINFO, and Embase) and through additional search strategies were screened. Results sections were open coded and analyzed by using thematic synthesis., Results: Of the 2,777 studies identified, 40 were retained. The synthesis of findings showed that after FEP, service users and their families and friends experienced positive changes at the individual (for example, more insight and clarity), interpersonal (for example, improved relationships), and spiritual levels (for example, greater religiosity). In addition to being facilitated by mental health services, these positive changes were enabled by personal (for example, motivation), social (for example, family support), and spiritual (for example, prayer) factors., Conclusions: Suffering is a core experience of FEP from which a range of positive changes can follow among service users and their families and friends. It may be beneficial for mental health services to specifically strive to promote these positive changes.

Objective: One reason for worldwide interest in the clinical high-risk (CHR) state for psychosis is its potential as a target for prevention. However, the feasibility and utility of early intervention initiatives that are focused on this stage involve an untested assumption: that most patients with a first episode of psychosis (FEP) experience earlier CHR symptoms. The objective of this study was to identify and characterize the proportion of FEP patients who had experienced such symptoms prior to the onset of their psychosis., Methods: Semistructured interviews of 351 patients and families with the Circumstances of Onset and Relapse Schedule were supplemented by chart reviews in a catchment area-based sample of FEP patients. Information was extracted regarding pathways to care and psychiatric and behavioral changes over time. Experts (N=30) working in FEP and CHR settings identified which of 27 early signs and symptoms constitute attenuated positive or subthreshold psychotic symptoms (APSPS) if they appear prior to a syndromal-level psychotic episode., Results: Nine early signs and symptoms were endorsed by the experts as representing APSPS. More than half of consenting patients, and two-thirds (68%) of those who completed all assessments, had experienced at least one such sign or symptom prior to their FEP. The groups with and without APSPS were similar in social, demographic, and clinical characteristics., Conclusions: Most consenting patients with an FEP had experienced previous signs and symptoms consistent with a CHR state prior to the onset of threshold-level psychotic symptoms, although a substantial minority had not. This finding validates the viability of the CHR construct as a potential target for early case identification and preventive and therapeutic interventions.

Early persistent negative symptoms (PNS) following a first episode of psychosis (FEP) are linked to poor functional outcome. Reports of reduced amygdalar and hippocampal volumes in early psychosis have not accounted for heterogeneity of symptoms. Age is also seldom considered in this population, a factor that has the potential to uncover symptom-specific maturational biomarkers pertaining to volume and shape changes within the hippocampus and amygdala. T1-weighted volumes were acquired for early (N=21), secondary (N=30), non-(N=44) PNS patients with a FEP, and controls (N=44). Amygdalar-hippocampal volumes and surface area (SA) metrics were extracted with the Multiple Automatically Generated Templates (MAGeT)-Brain algorithm. Linear mixed models were applied to test for a main effect of group and age × group interactions. Early PNS patients had significantly reduced left amygdalar and right hippocampal volumes, as well as similarly lateralized negative age × group interactions compared to secondary PNS patients (P<0.017, corrected). Morphometry revealed decreased SA in early PNS compared with other patient groups in left central amygdala, and in a posterior region when compared with controls. Early and secondary PNS patients had significantly decreased SA as a function of age compared with patients without such symptoms within the right hippocampal tail (P<0.05, corrected). Significant amygdalar-hippocampal changes with age are linked to PNS after a FEP, with converging results from volumetric and morphometric analyses. Differential age trajectories suggest an aberrant maturational process within FEP patients presenting with PNS, which could represent dynamic endophenotypes setting these patients apart from their non-symptomatic peers. Studies are encouraged to parse apart such symptom constructs when examining neuroanatomical changes emerging after a FEP.

Aim: In the context of an increasing focus on indicated prevention of psychotic disorders, we describe the operation of the Clinic for Assessment of Youth at Risk (CAYR) over 10 years, a specialized service for identification, monitoring and treatment of young individuals who meet ultra-high risk (UHR) criteria for psychosis, and its integration within the Prevention and Early Intervention Program for Psychosis (PEPP) in Montreal, Canada., Methods: We outline rationale, development, inclusion and exclusion criteria, assessment, services offered, community outreach and liaison with potential referral sites, and our research focus on risk and protective factors related to the neural diathesis-stress model of psychosis., Results: Between January 2005 and December 2014, CAYR has received 370 referrals and accepted 177 patients who met UHR criteria based on the Comprehensive Assessment for At Risk Mental States. Conversion rates to a first episode of psychosis were 11%. Our research findings point to high subjective stress levels, poor self-esteem, social support and coping skills, and a dysregulation of the hypothalamus-pituitary-adrenal axis during the high-risk phase., Conclusions: Our efforts at community outreach have resulted in increasing numbers of referrals and patients accepted to CAYR, highlighting the relevance of and need for a high-risk programme in the Montreal area. Patients with psychotic symptoms can be immediately assigned to the first-episode psychosis clinic within PEPP, which has likely contributed to the low conversion rates observed in the UHR group. Our research findings on stress and protective factors emphasize the importance of psychosocial interventions for high-risk patients., (© 2015 Wiley Publishing Asia Pty Ltd.)

Background: Altered hypothalamus-pituitary-adrenal (HPA) axis function and reduced hippocampal volume (HV) are established correlates of stress vulnerability. We have previously shown an attenuated cortisol awakening response (CAR) and associations with HV specifically in male first-episode psychosis patients. Findings in individuals at ultra-high risk (UHR) for psychosis regarding these neurobiological markers are inconsistent, and assessment of their interplay, accounting for sex differences, could explain incongruent results., Method: Study participants were 42 antipsychotic-naive UHR subjects (24 men) and 46 healthy community controls (23 men). Saliva samples for the assessment of CAR were collected at 0, 30 and 60 min after awakening. HV was determined from high-resolution structural magnetic resonance imaging scans using a semi-automatic segmentation protocol., Results: Cortisol measures and HV were not significantly different between UHR subjects and controls in total, but repeated-measures multivariate regression analyses revealed reduced cortisol levels 60 min after awakening and smaller left HV in male UHR individuals. In UHR participants only, smaller left and right HV was significantly correlated with a smaller total CAR (ρ = 0.42, p = 0.036 and ρ = 0.44, p = 0.029, respectively), corresponding to 18% and 19% of shared variance (medium effect size)., Conclusions: Our findings suggest that HV reduction in individuals at UHR for psychosis is specific to men and linked to reduced post-awakening cortisol concentrations. Abnormalities in the neuroendocrine circuitry modulating stress vulnerability specifically in male UHR subjects might explain increased psychosis risk and disadvantageous illness outcomes in men compared to women.

Elevated rates of cigarette smoking are observed prior to the onset of psychosis and remain stable early in the illness. Cannabis use frequently co-occurs with cigarette smoking and is independently associated with distinct clinical outcomes. However, past research has not controlled for cannabis use in cigarette smokers with first episode psychosis (FEP), limiting conclusions on the unique relationship of cigarette smoking to the demographic and clinical profiles of these patients. The present study therefore aimed to: (1) Determine the prevalence and patterns of cigarette smoking and its co-use with cannabis in FEP, and (2) Examine the demographic, clinical, cognitive, and functional characteristics associated with cigarette smoking status, after adjusting for frequency of cannabis use. Patients entering specialized treatment for FEP (N = 140) were divided into groups according to their current smoking status: 66 non-smokers (0 cigarettes/day), 47 light/moderate smokers (1-19 cigarettes/day; M = 9.81, SD = 3.93), and 27 heavy smokers (≥20 cigarettes/day; M = 26.39, SD = 6.31). The prevalence of cigarette smoking was 53% and smoking status was highly associated with frequency of cannabis use. After adjusting for cannabis use, significant between-group differences emerged. Heavy smokers were older at program entry and had a later age of onset of psychosis than light/moderate and non-smokers. Non-smokers had more education, better neurocognitive performance, and higher levels of functioning than light/moderate and heavy smokers. Prospective, longitudinal studies are needed to better understand the clinical significance of tobacco use and factors that contribute to the initiation and continuation of smoking behaviours in FEP., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Recent work has clearly established that early persistent negative symptoms (ePNS) can be observed following a first episode of psychosis (FEP), and can negatively affect functional outcome. There is also evidence for cortical changes associated with ePNS. Given that a FEP often occurs during a period of ongoing complex brain development and maturation, neuroanatomical changes may have a specific age-related component. The current study examines cortical thickness (CT) and trajectories with age using longitudinal structural imaging. Structural T1 volumes were acquired at three time points for ePNS (N=21), PNS due to secondary factors (N=31), non-PNS (N=45) patients, and controls (N=48). Images were processed using the CIVET pipeline. Linear mixed models were applied to test for the main effects of (a) group, (b) time, and interactions between (c) time and group membership, and (d) age and group membership. Compared with the non-PNS and secondary PNS patient groups, the ePNS group showed cortical thinning over time in temporal regions and a thickening with age primarily in prefrontal areas. Early PNS patients also had significantly different linear and quadratic age relationships with CT compared with other groups within cingulate, prefrontal, and temporal cortices. The current study demonstrates that FEP patients with ePNS show significantly different CT trajectories with age. Increased CT may be indicative of disruptions in cortical maturation processes within higher-order brain regions. Individuals with ePNS underline a unique subgroup of FEP patients that are differentiated at the clinical level and who exhibit distinct neurobiological patterns compared with their non-PNS peers., Competing Interests: M.L. reports having received financial assistance/compensation for research and educational events from Janssen-Ortho, Eli Lilly, Roche, and Otsuka/Lundbeck Alliance. A.K.M. reports having received financial assistance/compensation for research and educational activities from Pfizer, Janssen-Ortho, AstraZeneca, and Bristol-Myers Squibb. R.J. reports having received consultancy honorariums from Pfizer and Janssen-Ortho. The remaining authors declare no conflict of interest.

Social anxiety has received scant attention in studies of schizophrenia and related psychoses. However, some data suggest it may be an obstacle to vocational and functional outcome. This pilot study investigated the feasibility of a group-based cognitive behavioral therapy (CBGT) to reduce social anxiety in those at risk for developing psychosis or in the early phase. Twenty-nine patients with first-episode psychosis (FEP) or at ultra high risk for developing psychosis or often referred to as at-risk mental state (ARMS) with comorbid social anxiety attended a CBGT intervention weekly for 14 weeks in 90-minute sessions. Baseline, post-treatment, and follow-up ratings of social anxiety were measured using the Social Interaction Anxiety Scale, the Social Phobia Inventory, and the Brief Social Phobia Scale. Psychotic symptoms and general psychopathology were also measured before and after the intervention. Results suggest that the proposed CBGT is feasible and beneficial for socially anxious patients at risk, or with experience of, psychosis. Participants significantly improved on three outcome measures of social anxiety after completing this intervention (all p's < .002). Participants who completed treatment also showed a significant reduction on measures of depression and negative symptoms. Future research should examine the relative efficacy of this brief manualized CBGT intervention for the treatment of social anxiety and psychotic symptoms in a larger randomized controlled trial.

Background: Current neuroscience literature has related treatment with aripiprazole to improved memory performance and subcellular changes in the hippocampus., Aims: To explore the volumetric changes in hippocampal grey matter in people with a first episode of psychosis (FEP) treated with second-generation antipsychotics., Method: Baseline and 1-year follow-up magnetic resonance images were obtained. Hippocampal volumes were estimated by using FreeSurfer and MAGeT-Brain. Subgroups included: aripiprazole ( n =13), olanzapine ( n =12), risperidone/paliperidone ( n =24), refused-antipsychotics ( n =13) and controls ( n =44)., Results: Aripiprazole subgroup displayed significant increases in bilateral hippocampal volume compared with all other subgroups (FreeSurfer: all P 's<0.012; MAGeT-Brain: all P 's<0.040)., Conclusions: Aripiprazole is a first-line, second-generation treatment option that may provide an added benefit of pro-hippocampal growth. The biological underpinnings of these changes should be the focus of future investigations and may be key towards achieving a better clinical outcome for more individuals., Declaration of Interest: M.L. received financial assistance/compensation for research and educational events from Janssen-Ortho, Eli Lilly, Roche and Otsuka/Lundbeck Alliance. A.K.M. received financial assistance/compensation for research and educational activities from Pfizer, Janssen-Ortho, AstraZeneca and Bristol-Myers Squibb. R.J. received consultancy honorariums from Pfizer and Janssen-Ortho., Copyright and Usage: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Many objects seen for the first time look familiar because they resemble known objects. To overcome this feeling of familiarity and detect novelty, memories of known objects must be recollected and compared to new objects. This experiment examines whether recollection performed when perceiving new items (i.e., recollection rejection) is abnormal in people who experienced a first episode of psychosis (FEP). Recollection of old items is impaired in this clinical population but it has not yet been demonstrated that this impairment influences the processing of new items. Eighteen FEP participants and 19 healthy controls completed an episodic memory task consisting of a study phase and a recognition phase. All the new objects looked familiar because they resembled the studied objects. Brain activity underlying false recognition and correct rejection of new objects was measured with functional resonance magnetic imaging and compared across groups. Behavioral responses to new items were not significantly different between the 2 groups. However, the between-groups analysis revealed significant differences in brain activity in the left middle frontal gyrus, the left inferior parietal lobule, the right superior parietal lobule, and the right temporal fusiform gyrus during the correct rejection of new items. This activity seems related to recollection rejection and suggests that FEP patients do not normally recollect information of past events when they process new items., ((c) 2016 APA, all rights reserved.)

Aberrant white matter structures in fronto-temporal regions have previously been identified in patients with schizophrenia. However, scant research has focused on white matter integrity in patients presenting with a first episode of psychosis (FEP) with persistent negative symptoms (PNS). This study aimed to explore microstructure in the neurocircuitry proposed to be involved in PNS, by using a region-of-interest approach. Secondly, the relationship between individual negative symptoms and white matter were explored. Fractional anisotropy (FA) was measured in the fornix and three other tracts bilaterally including the uncinate fasciculus, superior longitudinal fasciculus and the cingulum bundle. Twelve patients with PNS were compared to a non-PNS group (52) and a healthy control group (51). Results showed that the PNS group had significantly lower FA values in the fornix when compared to healthy controls and that the non-PNS group had significantly lower FA values in the right uncinate fasciculus compared to healthy controls. Significant correlations were observed between SANS global score for anhedonia-asociality and lower FA values in the right cingulum bundle. Our results suggest that fronto-temporal white matter might be more closely related to PNS and that this relationship may possibly be mediated by greater anhedonia in PNS patients., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The computer-based CogState Research Battery (CSRB) proposes a test structure which follows MATRICS recommended cognitive domains but lacks direct comparison to pen and paper batteries in first-episode psychosis (FEP). The aim of this study was to compare performances obtained with the CSRB and a pen and paper battery in a historical cohort of FEP patients. Among patients entering an early intervention program between 2003 and 2014, separate cohorts completed the traditional pen and paper cognitive battery (n = 182) and the CSRB (n = 97). Composite z-scores were derived using normative data of matched controls (n = 64 pen and paper, n = 69 CSRB) and were compared between the two batteries for the 7 cognitive domains. The cohort tested using the CSRB performed better on the domains of processing speed, attention, visual memory, and verbal memory than the cohort tested using the pen and paper battery (all p  < 0.001). Performance did not differ between the two types of batteries for the working memory, executive functions, and social cognition domains. Cognitive profiles identified in the two patient cohorts were similar, with verbal memory being the most impaired domain. Better performances on the CSRB may be primarily due to the minimal demand of the computerized tests on graphomotor abilities and reading speed compared to the pen and paper tests. Our investigation offers a better understanding on how the results obtained with computerized batteries may compare to earlier work done with traditional tests.

Objectives: In the context of a stress-vulnerability framework, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis is thought contribute to the risk, onset and course of psychotic illness. However, recent reports regarding static and dynamic features of the HPA axis suggest a more complex set of phenomena at play in the early phases of psychosis., Methods: We review literature regarding structural and functional aspects of the HPA axis in subjects at risk for or experiencing the first episode of psychosis, including evidence favoring as well as that which contradicts a model of HPA axis hyperactivation., Results: Static measures of diurnal cortisol and hippocampal/pituitary volumes suggest that the HPA axis is in a hyperactivated state in early phases of psychosis. In contrast, the dynamic cortisol response to encountered or anticipated stress is blunted in the same populations. These incongruent findings need to be better understood., Conclusions: We consider potential explanations for the seemingly contradictory elevation and blunting of HPA biomarkers in the early course of psychosis. Finally, we propose and explore implications of a conceptual model of tonic HPA hyperactivation and phasic HPA blunting that integrates and reconciles these data., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In most mental illnesses, onset occurs before the age of 25 and the earliest stages are critical. The youth bear a large share of the burden of disease associated with mental illnesses. Yet, Canadian youths with mental health difficulties face delayed detection; long waiting lists; inaccessible, unengaging services; abrupt transitions between services; and, especially in remoter regions, even a complete lack of services. Responding to this crisis, the Canadian Institutes of Health Research announced a 5-year grant that was awarded to ACCESS, a pan-Canadian network of youths, families, clinicians, researchers, policymakers, community organisations and Indigenous communities. Using strategies developed collaboratively by all stakeholders, ACCESS will execute a youth mental healthcare transformation via early detection, rapid access and appropriate, high-quality care. The project includes an innovative, mixed-methods service research component. Similar in many respects to other national youth mental health initiatives, ACCESS also exhibits important differences of scale, scope and approach.

Background: Hippocampal volume (HV) decline is an important marker of psychosis and has been associated with hypothalamus-pituitary-adrenal (HPA) axis dysregulation in various disorders. Given recent findings of sex differences in HPA axis function in psychosis, the current study investigated differences in HV in male and female first episode psychosis (FEP) patients and controls and the interaction of HV with the cortisol awakening response (CAR) and symptoms., Methods: Fifty-eight patients with a diagnosis of FEP (39 men, 19 women) and 27 healthy community controls (15 men, 12 women) underwent structural magnetic resonance imaging (MRI) on a 1.5 T scanner. Hippocampal volume was determined using previously established segmentation protocols. Saliva samples for cortisol assessment were collected at 0, 30 and 60 min after awakening. Psychotic symptoms were assessed with the Scale for Assessment of Positive Symptoms (SAPS), the Scale for Assessment of Negative Symptoms (SANS) and the Global Assessment of Functioning (GAF) scale., Results: Male patients had significantly smaller left and right HVs compared to male controls, which appeared to be secondary to global brain volume differences. However, even when controlling for overall brain size, male patients showed smaller HV compared to female patients. The CAR was significantly lower in male patients compared to male controls and female patients. Only in male patients, smaller left HV was significantly associated with a blunted CAR, and smaller HV bilaterally was related to positive psychotic symptoms and lower levels of functioning., Conclusions: We propose that reduced hippocampal volume and an attenuated cortisol awakening response are related markers of increased stress vulnerability in male psychosis patients and that both contribute to the unfavorable clinical picture in men.