Asynchronous neural maturation predicts transition to psychosis.

AIM: Neuroimaging-based machine-learning predictions of psychosis onset rely on the hypothesis that structural brain anomalies may reflect the underlying pathophysiology. Yet, current predictors remain difficult to interpret in light of brain structure. Here, we combined an advanced interpretable supervised algorithm and a model of neuroanatomical age to identify the level of brain maturation of the regions most predictive of psychosis. METHODS: We used the voxel-based morphometry of a healthy control dataset (N = 2024) and a prospective longitudinal UHR cohort (N = 82), of which 27 developed psychosis after one year. In UHR, psychosis was predicted at one year using Elastic-Net-Total-Variation (Enet-TV) penalties within a five-fold cross-validation, providing an interpretable map of distinct predictive regions. Using both the whole brain and each predictive region separately, a brain age predictor was then built and validated in 1605 controls, externally tested in 419 controls from an independent cohort, and applied in UHR. Brain age gaps were computed as the difference between chronological and predicted age, providing a proxy of whole-brain and regional brain maturation. RESULTS: Psychosis prediction was performant with 80 ± 4% of area-under-curve and 69 ± 5% of balanced accuracy (P < 0.001), and mainly leveraged volumetric increases in the ventromedial prefrontal cortex and decreases in the left precentral gyrus and the right orbitofrontal cortex. These regions were predicted to have delayed and accelerated maturational patterns, respectively. CONCLUSION: By combining an interpretable supervised model of conversion to psychosis with a brain age predictor, we showed that inter-regional asynchronous brain maturation underlines the predictive signature of psychosis.

Association between family functioning and psychotic transition in ultra-high risk adolescents and young adults.

Background: Psychotic transition (PT) is a crucial stage in schizophrenia. The Comprehensive Assessment of At-Risk Mental States (CAARMS) scale can be used to identify individuals at ultra-high risk (UHR) for psychosis and to evaluate their risk of PT. Many environmental and genetic factors have been identified as contributing to the development and decompensation of schizophrenia. This study aimed to determine if the quality of family functioning is associated with PT risk in UHR individuals aged between 11 and 25 years after 1 year of follow-up. Methods: From January to November 2017, 45 patients aged 12 to 25 consulting for psychiatric reasons were included. Twenty-six were classified as UHR of PT at the CAARMS. Family functioning was assessed by the Family Assessment Device-Global Functioning (FAD-GF). Thirty-seven of these patients (30% men, mean age 16 ± 2.5) were reassessed at 8-14 months of recruitment. Survival analysis was used to examine the impact of family functioning on PT risk. Results: A total of 40% of UHR patients were classified as psychotic at reassessment. Survival analysis showed that better family functioning is a significant protective factor for PT in this population. Discussion: This result suggests that the global family functioning has an impact at 1 year on the risk of PT in the population of adolescents and young adults who consult the hospital for psychiatric reasons. A family intervention may be effective in reducing PT risk in this population and should be considered as a potential therapeutic option.

Validation of the Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) questionnaire for adults.

BACKGROUND: The Collaborative Outcome study on Health and Functioning during Infection Times (COH-FIT; www.coh-fit.com) is an anonymous and global online survey measuring health and functioning during the COVID-19 pandemic. The aim of this study was to test concurrently the validity of COH-FIT items and the internal validity of the co-primary outcome, a composite psychopathology "P-score". METHODS: The COH-FIT survey has been translated into 30 languages (two blind forward-translations, consensus, one independent English back-translation, final harmonization). To measure mental health, 1-4 items ("COH-FIT items") were extracted from validated questionnaires (e.g. Patient Health Questionnaire 9). COH-FIT items measured anxiety, depressive, post-traumatic, obsessive-compulsive, bipolar and psychotic symptoms, as well as stress, sleep and concentration. COH-FIT Items which correlated r ≥ 0.5 with validated companion questionnaires, were initially retained. A P-score factor structure was then identified from these items using exploratory factor analysis (EFA) and confirmatory factor analyses (CFA) on data split into training and validation sets. Consistency of results across languages, gender and age was assessed. RESULTS: From >150,000 adult responses by May 6th, 2022, a subset of 22,456 completed both COH-FIT items and validated questionnaires. Concurrent validity was consistently demonstrated across different languages for COH-FIT items. CFA confirmed EFA results of five first-order factors (anxiety, depression, post-traumatic, psychotic, psychophysiologic symptoms) and revealed a single second-order factor P-score, with high internal reliability (ω = 0.95). Factor structure was consistent across age and sex. CONCLUSIONS: COH-FIT is a valid instrument to globally measure mental health during infection times. The P-score is a valid measure of multidimensional mental health.

The collaborative outcomes study on health and functioning during infection times in adults (COH-FIT-Adults): Design and methods of an international online survey targeting physical and mental health effects of the COVID-19 pandemic.

BACKGROUND: . High-quality comprehensive data on short-/long-term physical/mental health effects of the COVID-19 pandemic are needed. METHODS: . The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is an international, multi-language (n=30) project involving >230 investigators from 49 countries/territories/regions, endorsed by national/international professional associations. COH-FIT is a multi-wave, on-line anonymous, cross-sectional survey [wave 1: 04/2020 until the end of the pandemic, 12 months waves 2/3 starting 6/24 months threreafter] for adults, adolescents (14-17), and children (6-13), utilizing non-probability/snowball and representative sampling. COH-FIT aims to identify non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to improve social/health outcomes in the general population/vulnerable subgrous during/after COVID-19. In adults, co-primary outcomes are change from pre-COVID-19 to intra-COVID-19 in well-being (WHO-5) and a composite psychopathology P-Score. Key secondary outcomes are a P-extended score, global mental and physical health. Secondary outcomes include health-service utilization/functioning, treatment adherence, functioning, symptoms/behaviors/emotions, substance use, violence, among others. RESULTS: . Starting 04/26/2020, up to 14/07/2021 >151,000 people from 155 countries/territories/regions and six continents have participated. Representative samples of ≥1,000 adults have been collected in 15 countries. Overall, 43.0% had prior physical disorders, 16.3% had prior mental disorders, 26.5% were health care workers, 8.2% were aged ≥65 years, 19.3% were exposed to someone infected with COVID-19, 76.1% had been in quarantine, and 2.1% had been COVID 19-positive. LIMITATIONS: . Cross-sectional survey, preponderance of non-representative participants. CONCLUSIONS: . Results from COH-FIT will comprehensively quantify the impact of COVID-19, seeking to identify high-risk groups in need for acute and long-term intervention, and inform evidence-based health policies/strategies during this/future pandemics.

Physical and mental health impact of COVID-19 on children, adolescents, and their families: The Collaborative Outcomes study on Health and Functioning during Infection Times - Children and Adolescents (COH-FIT-C&A).

BACKGROUND: The COVID-19 pandemic has altered daily routines and family functioning, led to closing schools, and dramatically limited social interactions worldwide. Measuring its impact on mental health of vulnerable children and adolescents is crucial. METHODS: The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT - www.coh-fit.com) is an on-line anonymous survey, available in 30 languages, involving >230 investigators from 49 countries supported by national/international professional associations. COH-FIT has thee waves (until the pandemic is declared over by the WHO, and 6-18 months plus 24-36 months after its end). In addition to adults, COH-FIT also includes adolescents (age 14-17 years), and children (age 6-13 years), recruited via non-probability/snowball and representative sampling and assessed via self-rating and parental rating. Non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to promote health and prevent mental and physical illness in children and adolescents will be generated by COH-FIT. Co-primary outcomes are changes in well-being (WHO-5) and a composite psychopathology P-Score. Multiple behavioral, family, coping strategy and service utilization factors are also assessed, including functioning and quality of life. RESULTS: Up to June 2021, over 13,000 children and adolescents from 59 countries have participated in the COH-FIT project, with representative samples from eleven countries. LIMITATIONS: Cross-sectional and anonymous design. CONCLUSIONS: Evidence generated by COH-FIT will provide an international estimate of the COVID-19 effect on children's, adolescents' and families', mental and physical health, well-being, functioning and quality of life, informing the formulation of present and future evidence-based interventions and policies to minimize adverse effects of the present and future pandemics on youth.

Implementing organicity investigations in early psychosis: Spreading expertise.

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.

Prevalence and correlates of psychotic-like experiences in the general population.

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.

Predicting the individual risk of psychosis conversion in at-risk mental state (ARMS): a multivariate model reveals the influence of nonpsychotic prodromal symptoms.

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.

The C'JAAD: a French team for early intervention in psychosis in Paris.

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.

Salivary cortisol in early psychosis: New findings and meta-analysis.

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.

[Early detection and early intervention in first episode psychosis]. / Dépistage précoce de la schizophrénie et prise en charge des premiers épisodes psychotiques.

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.

[Early diagnosis in schizophrenia: a mission for the general practitioners?]. / Diagnostic précoce dans la schizophrénie: une mission pour les médecins généralistes?

Schizophrenia represents a relatively frequent disease within the population with a prevalence of 1 %. Despite a consistent therapeutic equipment at doctors' disposal, the evolution of this disease remains globally rather unfavourable. For a long time, the classic concept from Magnan "bouffée délirante aiguë" was considered as the main mode of entrance of the schizophrenia. Now, in most cases, the beginning of the disease is progressive and insidious. Two phases in the evolution of the disease before appearance of true psychotic symptoms are described: a premorbid phase and a prodromic phase. The early care of this disease has a major impact for the prognosis. The Duration of Untreated Psychosis (DUP) is correlated to an unfavourable evolution of the disease. It is advisable to reduce the delay of first care by locating prematurely the patients developing a psychosis. Because of their central place in our health care system, the general practitioners have a major role in this screening. The clinical symptoms of the prodromic phase are rather heterogeneous and little specific. The general practitioners must be made sensitive to search the symptoms suggesting an entrance to the psychosis and to allow a care adapted to these patients. But they are relatively little exposed to the psychotic disorders and must be supported in their mission by specialized centers.