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Background: Many medical disorders may contribute to adolescent psychoses. Although guidelines for thorough organicity investigations (OI) exist, their dissemination appears scarce in nonacademic healthcare facilities and some rare disorders remain undiagnosed, many of them presenting without easily recognized phenotypes. This study aims to understand the challenges underlying the implementation of OI in non-academic facilities by practitioners trained in expert centers., Methods: Sixteen psychiatrists working at French non-academic facilities were interviewed about their use of OI for adolescents suspected of early psychosis. Interviews were analyzed with Grounded Theory., Results: Organicity investigations were found to be useful in rationalizing psychiatric care for the young patient all the while building trust between the doctor and the patient's parents. They also are reassuring for psychiatrists confronted with uncertainty about psychosis onset and the consequences of a psychiatric label. However, they commonly find themselves facing the challenges of implementation alone and thus enter a renunciation pathway: from idealistic missionaries, they become torn between their professional ethics and the non-academic work culture. Ultimately, they abandon the use of OI or delegate it to expert centers., Conclusion: Specific hindrances to OI implementation must be addressed., Competing Interests: The authors have declared that no competing interests exist.

To improve the prediction of the individual risk of conversion to psychosis in UHR subjects, by considering all CAARMS' symptoms at first presentation and using a multivariate machine learning method known as logistic regression with Elastic-net shrinkage. 46 young individuals who sought help from the specialized outpatient unit at Sainte-Anne hospital and who met CAARMS criteria for UHR were assessed, among whom 27 were reassessed at follow-up (22.4 ± 6.54 months) and included in the analysis. Elastic net logistic regression was trained, using CAARMS items at baseline to predict individual evolution between converters (UHR-P) and non-converters (UHR-NP). Elastic-net was used to select the few CAARMS items that best predict the clinical evolution. All validations and significances of predictive models were computed with non-parametric re-sampling strategies that provide robust estimators even when the distributional assumption cannot be guaranteed. Among the 25 CAARMS items, the Elastic net selected 'obsessive-compulsive symptoms' and 'aggression/dangerous behavior' as risk factors for conversion while 'anhedonia' and 'mood swings/lability' were associated with non-conversion at follow-up. In the ten-fold stratified cross-validation, the classification achieved 81.8% of sensitivity (P = 0.035) and 93.7% of specificity (P = 0.0016). Non-psychotic prodromal symptoms bring valuable information to improve the prediction of conversion to psychosis. Elastic net logistic regression applied to clinical data is a promising way to switch from group prediction to an individualized prediction.

Background: To what extent Psychotic Like Experiences (PLEs) are associated with nonpsychotic psychiatric disorders and whether the number of PLEs is associated with higher rates of psychiatric disorders remains unclear., Methods: The sample was composed of 34,653 civilian participants, aged 18 years and older from wave 2 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). This was a representative sample of the non-institutionalized U.S., Population: Twenty-two PLEs were assessed. Lifetime prevalence of psychiatric disorders (any mood, anxiety, substance use and personality disorders, PTSD, ADHD, and suicide attempts) according to the number of PLEs were calculated., Results: Almost a third (26.69%) of respondents reported experiencing at least one type of PLEs. There was a gradual association between the number of PLEs and the presence of a nonpsychotic psychiatric disorder (ranging from 5.68%in participants with no PLEs up to 99.53% in those with five or more PLEs). This association with PLE was significant for each of the 25 psychiatric disorders examined regardless of the number of PLEs. Lifetime prevalence of PLEs were significantly higher among the younger respondents, women, non-married, unemployed, high educational level and those with low family income., Conclusion: There is a gradual increase in the magnitude of the association of the numbers of PLEs for each of the 25 nonpsychotic psychiatric disorders examined. Having at least one PLE is strongly associated with the presence of a psychiatric disorder., Competing Interests: Declaration of competing interest The other authors declared no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Gender differences in symptomatology in chronic schizophrenia and first episode psychosis patients have often been reported. However, little is known about gender differences in those at risk of psychotic disorders. This study investigated gender differences in symptomatology, drug use, comorbidity (i.e. substance use, affective and anxiety disorders) and global functioning in patients with an at-risk mental state (ARMS) for psychosis., Methods: The sample consisted of 336 ARMS patients (159 women) from the prodromal work package of the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI; 11 centers). Clinical symptoms, drug use, comorbidity and functioning were assessed at first presentation to an early detection center using structured interviews., Results: In unadjusted analyses, men were found to have significantly higher rates of negative symptoms and current cannabis use while women showed higher rates of general psychopathology and more often displayed comorbid affective and anxiety disorders. No gender differences were found for global functioning. The results generally did not change when corrected for possible cofounders (e.g. cannabis use). However, most differences did not withstand correction for multiple testing., Conclusions: Findings indicate that gender differences in symptomatology and comorbidity in ARMS are similar to those seen in overt psychosis and in healthy controls. However, observed differences are small and would only be reliably detected in studies with high statistical power. Moreover, such small effects would likely not be clinically meaningful., (Copyright © 2019. Published by Elsevier Masson SAS.)

Aim: The aim is to describe a centre operating in Paris that pioneers the early intervention for young people at the onset and at high risk of psychosis in France., Methods: Comprehensive descriptive analysis of different clinical and service measures is used in describing the implementation of the C'JAAD (Evaluation Centre for Young Adults and Adolescents) using data from an ongoing prospective non-interventional research programme., Results: Over a 2-year period, 151 patients were referred to the C'JAAD and included in the ICAAR research programme. After evaluation by the Comprehensive Assessment of the At-Risk Mental States Scale, 53.7% were identified at risk of developing a psychosis, 20.6% presented a full-blown psychosis and 25.7% were considered not at risk of developing a psychosis. A total of 84% of the at-risk subjects suffered from a psychiatric co-morbidity, of which anxiodepressive symptoms being the most frequent (39%). The global functioning of these at-risk subjects was seriously impaired (average Social and Occupational Functioning Assessment Scale score = 48.9). More than one third of the patients was self-referred (33.8%), 22.5% were addressed by a psychiatrist whereas 10.6% were referred by a general practitioner., Conclusions: In this paper, we report for the first time the activities of the C'JAAD, the pioneer unit in France for early detection and treatment of young adults with early psychosis. These observations indicate that such early intervention centre is a feasible and sustainable extension of traditional care for people with mental disorders in this country and offers promising perspective for the development of further centres., (© 2016 John Wiley & Sons Australia, Ltd.)

The onset of psychosis is the consequence of complex interactions between genetic vulnerability to psychosis and response to environmental and/or maturational changes. Epigenetics is hypothesized to mediate the interplay between genes and environment leading to the onset of psychosis. We believe we performed the first longitudinal prospective study of genomic DNA methylation during psychotic transition in help-seeking young individuals referred to a specialized outpatient unit for early detection of psychosis and enrolled in a 1-year follow-up. We used Infinium HumanMethylation450 BeadChip array after bisulfite conversion and analyzed longitudinal variations in methylation at 411 947 cytosine-phosphate-guanine (CpG) sites. Conversion to psychosis was associated with specific methylation changes. Changes in DNA methylation were significantly different between converters and non-converters in two regions: one located in 1q21.1 and a cluster of six CpG located in GSTM5 gene promoter. Methylation data were confirmed by pyrosequencing in the same population. The 100 top CpGs associated with conversion to psychosis were subjected to exploratory analyses regarding the related gene networks and their capacity to distinguish between converters and non-converters. Cluster analysis showed that the top CpG sites correctly distinguished between converters and non-converters. In this first study of methylation during conversion to psychosis, we found that alterations preferentially occurred in gene promoters and pathways relevant for psychosis, including oxidative stress regulation, axon guidance and inflammatory pathways. Although independent replications are warranted to reach definitive conclusions, these results already support that longitudinal variations in DNA methylation may reflect the biological mechanisms that precipitate some prodromal individuals into full-blown psychosis, under the influence of environmental factors and maturational processes at adolescence.

Background: Psychiatric disorders are consistent with the gene x environment model, and non-specific environmental factors such as childhood trauma, urbanity, and migration have been implicated. All of these factors have in common to dysregulate the biological pathways involved in response to stress. Stress is a well-known precipitating factor implicated in psychiatric disorders such as depression, bipolar disorder, anxiety, and possibly schizophrenia. More precisely, psychosocial stress induces dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) and could modify neurotransmission, which raises the question of the involvement of stress-related biological changes in psychotic disorders. Indeed, the literature reveals dysregulation of the HPA axis in schizophrenia. This dysregulation seems to be present in the prodromal phases (UHR subjects for ultra-high risk) and early schizophrenia (FEP for first episode psychosis). Thus, and following the stress-vulnerability model, stress could act directly on psychotic onset and precipitate the transition of vulnerable subjects to a full-blown psychosis., Objective: The present paper reviews the literature on stress and onset of schizophrenia, with consideration for the causal role vs. associated role of HPA axis dysregulation in schizophrenia and the factors that influence it, in particular during prodromal and earlier phases. We also discuss different methods developed to measure stress in humans., Methodology: We performed a bibliographic search using the keywords 'cortisol', 'glucocorticoid', 'HPA' with 'UHR', 'CHR', 'at-risk mental state', 'first episode psychosis', 'schizotypal', 'prodromal schizophrenia' in Medline, Web of Knowledge (WOS), and EBSCO completed by a screening of the references of the selected articles., Results: Stress has been studied for many years in schizophrenia, either by subjective methods (questionnaires), or objective methods (standardized experimental protocols) with biological sampling and/or brain imaging methods. These methods have suggested a link between dysregulation of the HPA axis and psychotic symptoms both through abnormal basal levels of cortisol and flattened reactivity to social stress. Imaging results suggest indirect modifications, including abnormal pituitary or hippocampal volume. Several factors dysregulating the HPA axis have also been highlighted, such as consumption of drugs (i.e. cannabis), childhood trauma or genetic factors (such as COMT, or MTHFR variants). Psychological stress induces subcortical dopaminergic activation attributable to hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This dysregulation is present in the prodromal phase (UHR) in patients who have experienced a first psychotic episode (FEP) and in siblings of schizophrenic patients. Stress dysregulation is a plausible hypothesis to understand the psychosis onset., Discussion: The effect of stress on brain pathways could participate to the mechanisms underlying the onset of psychotic symptoms, both as a precipitating factor and as a marker of a predisposing vulnerability. This dysregulation fits into the gene x environment model: in subjects with genetic predispositions, stressful environmental factors can modify biological pathways implicated in psychiatric disorders, promoting the emergence of symptoms. However, many confounding factors obscure the literature, and further studies are needed in schizophrenic patients, UHR and FEP patients to clarify the precise role of stress in psychotic transition. Identification of stress biomarkers could help diagnosis and prognosis, and pave the way for specific care strategies based on stress-targeted therapies., (Copyright © 2016 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Background: Schizophrenia is a multifactorial disorder and environmental risk factors for it might contribute to hypothalamo-pituitary-adrenal axis (HPA) dysregulation. While increased cortisol levels have been reported in schizophrenia, as well as in early psychosis (compared to healthy controls), a crucial unresolved issue is whether elevated cortisol levels could be related to the distress of an emerging illness, rather than being specific to psychosis. Here, we report new findings from the first French cohort of young help-seekers (ICAAR) including ultra-high risk subjects (UHR), first-episode of psychosis (FEP) and non at-risk help seekers controls (HSC), followed by a meta-analysis of all available reports on salivary basal cortisol levels in early psychosis (UHR and FEP)., Methods: In the ICAAR study, 169 individuals (15-30 years old) had their basal cortisol levels sampled and they were categorized (at baseline) as either UHR, FEP, or HSC using the criteria of the Comprehensive Assessment of At-Risk Mental States (CAARMS). The three groups were compared at baseline, and the UHR and HSC individuals were also included in a one-year longitudinal follow-up. UHRs who converted to psychosis at the follow up (UHR-P) were compared to non-converters (UHR-NP). We also performed a meta-analysis from case-control studies with basal salivary measures of cortisol, drawing from a systematic bibliographic search using the keywords 'cortisol', 'glucocorticoid', 'HPA' with 'UHR', 'CHR', 'at-risk mental state', 'schizotypal ', 'prodromal schizophrenia', 'first-episode psychosis', 'first episode schizophrenia', 'newly diagnosed schizophrenia', 'recent onset schizophrenia' [in Medline, Web of Knowledge (WOS), EBSCO], followed by a systematic screening of the resulting articles., Results: Basal cortisol levels were not significantly different between UHR, FEP, and HSC controls in the ICAAR cohort. Interestingly, initial cortisol levels were correlated with positive symptoms at the one year follow-up in the ICAAR cohort. The meta-analysis revealed a significant elevation of the salivary basal cortisol levels in UHR individuals compared to controls (8 studies--1060 individuals), but not between FEP and controls (6 studies--441 individuals). Indirect comparison of salivary basal cortisol levels between UHR and FEP did not yield significant differences. Finally, no differences were detected between the baseline cortisol of UHR-P and UHR-NP (4 studies--301 individuals)., Conclusion: The meta-analysis (including new data) indicates that basal cortisol levels were increased in UHR compared to controls, but FEP levels were not different from UHR or controls. Many confounding factors could decrease the effect size in FEP especially medication intake. Taken together with our new results (which made use of help-seeker controls, and not merely healthy controls), the findings indicate that basal cortisol levels may not be a reliable biomarker for early psychosis. Further studies are needed to clarify the precise role of the HPA axis in psychotic conversion., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The onset of schizophrenic disorders generally occurs in late adolescence/early adulthood. However, in 75% of the cases, the onset is preceded by a prodromal stage. Subjects concerned by these prodromal symptoms are defined at "high risk" for psychosis (30% of conversion to psychosis in the next year). Early detection programs aim at improving the recognition of the prodromal symptoms in order to develop appropriate early interventions that will delay or prevent conversion to psychosis or reduce the duration of untreated psychosis (DUP). Atypical antipsychotics are not recommended when psychotic symptoms are only attenuated, while they must be rapidly prescribed when a franc psychotic episode is present. Early identification of patients with schizophrenia is a general practitioners' task provided that they can rely on a supportive specialized psychiatric team. Early intervention should be based on a comprehensive assessment of the subject, in order to propose personalized care that include cognitive therapy, psycho-education, and treatment of associated disorders (depression, substance abuse). The reduction of duration of untreated psychosis will also require sensibilization campaigns in the community with the hope to improve access to care and service delivery.