Influence of polygenic risk scores for schizophrenia and resilience on the cognition of individuals at-risk for psychosis.

Cognitive impairment is a core feature of schizophrenia which precedes the onset of full psychotic symptoms, even in the ultra-high-risk stage (UHR). Polygenic risk scores (PRS) can be computed for many psychiatric disorders and phenotyping traits, including scores for resilience. We explored the correlations between several PRS and neurocognition in UHR individuals. We included 107 UHR individuals; 29.9% of them converted to psychosis (UHR-C) while 57.0% did not (UHR-NC) during the 1-year follow-up. Cognitive performances were assessed with the Wechsler Adult Intelligence Scale estimating the Intelligence Quotient (IQ), the Trail Making Test, the verbal fluency, the Stroop test, and the Wisconsin card sorting test. Linear regression models were used to test their association with the PRS for schizophrenia, bipolar disorder, major depression, ADHD, cross-disorders, cognitive performance, intelligence, education attainment, and resilience to schizophrenia. UHR-C had a lower IQ than UHR-NC. The PRS for schizophrenia negatively correlated with IQ, while the PRS for cognitive performance and for resilience positively correlated with IQ. PRS for schizophrenia showed a significant correlation with working memory and processing speed indices. PRS for schizophrenia showed a higher effect on IQ in UHR-NC, and UHR-NC with high PRS for schizophrenia had a similar IQ as UHR-C. Conversely, UHR-C with a high PRS for resilience performed as well as UHR-NC. Our findings suggest that cognitive deficits may predate the onset of psychosis. The genetic architecture of schizophrenia seems to impacts the cognition in UHR-NC. Cognition is also mediated by PRS for resilience.

Individual factors influencing the duration of untreated psychosis.

AIM: Duration of untreated psychosis (DUP), or the time between onset of psychosis and treatment initiation, is a prognostic factor of schizophrenia. However, few studies evaluated the relative influence of individual-related factors on this duration. The objective of this study was to evaluate the influence of socio-demographic, clinical and cannabis use on DUP. METHODS: This study was part of a large prospective study in help-seeking individuals referred to our specialized early detection / intervention clinic in the Service Hospitalo-Universitaire of Sainte-Anne Hospital in Paris (ICAAR study). We explored 33 consecutive patients who crossed the CAARMS' threshold of psychosis. The DUP and cannabis consumption history were explored during the baseline comprehensive assessment using all available sources (direct interviews of patients, parents, practitioners). Correlations between socio-demographic, clinical and cannabis use, and DUP were studied. A multiple linear regression model was used to determine the variables that could significantly predict DUP. RESULTS: When considered individually, none of the socio-demographic and disease characteristic factors was associated with DUP, with the exception of level of education. In the multivariate analysis, age at inclusion, negative symptoms and history of cannabis use significantly influenced DUP. CONCLUSION: The determinants of DUP are multi-factorial and include individual centred factors, such as age, cannabis and negative symptoms. The identification of factors resulting in delayed access to care may promote the development of effective strategies to reduce DUP in early psychosis and target effective early intervention.

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.

Oculomotricity and Neurological Soft Signs: Can we refine the endophenotype? A study in subjects belonging to the spectrum of schizophrenia.

Alterations in eye tracking and motor impairments as well as Neurological Soft Signs (NSS) are frequently reported in patients with schizophrenia as well as in their relatives, and are proposed as endophenotype of the disease. This study investigated smooth pursuit eye movement and fixation task with distractors with a gap condition, two markers of inhibitory control mechanism, in 49 patients with schizophrenia, 24 ultra-high risk subjects, 41 full biological clinical siblings of patients and 48 controls. NSS were assessed as a marker of abnormal neurodevelopment. The results revealed more intrusive saccades respectively in smooth pursuit eye movement and in fixation task with distractors with a gap condition in patients, respect to controls and full siblings. Ultra high-risk participants with high NSS committed intrusive saccades compared to controls. Patients with schizophrenia with high NSS also displayed more of these abnormalities, compared to patients with schizophrenia with low NSS and controls. These findings highlight a global inhibitory control defect, and suggested that ultra-high risk subjects and patients with schizophrenia could share oculomotor abnormalities, especially when they express a high neurodevelopmental deviance. These oculomotor alterations might suggest that cerebral structures such as prefrontal and cerebellum could be involved in the expression of this vulnerability.

Phenotypic continuum between autism and schizophrenia: Evidence from the Movie for the Assessment of Social Cognition (MASC).

Schizophrenic (SCZ) and autism (ASD) spectrum disorders share several features including social cognition impairments. In SCZ, the link between symptomatic dimensions and social cognition deficits remains unclear. The Movie for the Assessment of Social Cognition (MASC) test, available in several languages including English, investigates mental state attribution capabilities in complex interpersonal situations. After its translation into French, we used MASC to direct compare social cognition in 36 young participants with SCZ to 19 with ASD and 20 healthy controls (HC) matched for gender, age (18-25y.o.) and level of education. The MASC discriminated each group from the others, patients with SCZ exhibiting difficulties compared to ASD (MASC total score 28.1 (4) and 24.2 (6.6), respectively; p<.001). In the whole sample, MASC scores were inversely correlated with autistic traits, evaluated by autism quotient, and with disorganization symptoms. Finally, in SCZ, over-mentalizing difficulties were correlated with age at disease onset. Our results demonstrate the validity of the French version of the MASC and bring direct evidence supporting the hypothesis of a phenotypic continuum between autism and schizophrenia.

Self-reference recollection effect and its relation to theory of mind: An investigation in healthy controls and schizophrenia.

This study explores the links between the Self-Reference Effect (SRE) and Theory of Mind (ToM) in typical adults and patients with schizophrenia. Participants were assessed with a self-referential memory paradigm investigating the mnemonic effect of both semantic and episodic self-reference with a recognition task associated with the Remember/Know/Guess paradigm. They also completed a self-descriptive scale and shortened versions of the attribution of intention task and the reading the mind in the eyes test as measures of cognitive and affective ToM respectively. Unlike typical adults, the patients showed no semantic SRRE (correct recognition associated with remembering), and there was no episodic SRRE and no SRE (on the number of correct recognitions) in either group. Semantic SRRE was correlated with the affective ToM in patients and with the positivity of the self-concept in the healthy group. We discuss that patients and typical adults use different strategies during self and other-reflection.

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.

The double-H maze test, a novel, simple, water-escape memory task: acquisition, recall of recent and remote memory, and effects of systemic muscarinic or NMDA receptor blockade during training.

To explore spatial cognition in rodents, research uses maze tasks, which differ in complexity, number of goals and pathways, behavioural flexibility, memory duration, but also in the experimenter's control over the strategy developed to reach a goal (e.g., allocentric vs. egocentric). This study aimed at validating a novel spatial memory test: the double-H maze test. The transparent device made of an alley with two opposite arms at each extremity and two in its centre is flooded. An escape platform is submerged in one arm. For experiments 1-3, rats were released in unpredictable sequences from one of both central arms to favour an allocentric approach of the task. Experiment 1 (3 trials/day over 6 days) demonstrated classical learning curves and evidence for recent and nondegraded remote memory performance. Experiment 2 (2 days, 3 trials/day) showed a dose-dependent alteration of task acquisition/consolidation by muscarinic or NMDA receptor blockade; these drug effects vanished with sustained training (experiment 3; 4 days, 3 trials/day). Experiment 4 oriented rats towards a procedural (egocentric) approach of the task. Memory was tested in a misleading probe trial. Most rats immediately switched from response learning-based to place learning-based behaviour, but only when their initial view on environmental cues markedly differed between training and probe trials. Because this simple task enables the formation of a relatively stable memory trace, it could be particularly adapted to study consolidation processes at a system level or/and the interplay between procedural and declarative-like memory systems.