The European impact of the clinical high risk for psychosis (CHR-P) paradigm is constrained by the lack of critical mass (detection) to power prognostic and preventive interventions.

An ITAlian partnership for psychosis prevention (ITAPP) was created across CHR-P centers, which were surveyed to describe: (a) service, catchment area, and outreach; (b) service users; and (c) interventions and outcomes. Descriptive statistics and Kaplan–Meier failure function complemented the analyses.

The ITAPP included five CHR-P clinical academic centers established from 2007 to 2018, serving about 13 million inhabitants, with a recruitment capacity of 277 CHR-P individuals (mean age: 18.7 years, SD: 4.8, range: 12–39 years; 53.1% females; 85.7% meeting attenuated psychotic symptoms; 85.8% without any substance abuse). All centers were multidisciplinary and included adolescents and young adults (transitional) primarily recruited through healthcare services. The comprehensive assessment of at-risk mental state was the most widely used instrument, while the duration of follow-up, type of outreach, and preventive interventions were heterogeneous. Across 205 CHR-P individuals with follow up (663.7 days ± 551.7), the cumulative risk of psychosis increased from 8.7% (95% CI 5.3–14.1) at 1 year to 15.9% (95% CI 10.6–23.3) at 2 years, 21.8% (95% CI 14.9–31.3) at 3 years, 34.8% (95% CI 24.5–47.9) at 4 years, and 51.9% (95% CI 36.3–69.6) at 5 years.

The ITAPP is one of the few CHR-P clinical research partnerships in Europe for fostering detection, prognosis, and preventive care, as well as for translating research innovations into practice.

No significant relationships.

Central to recovery-oriented approaches in schizophrenia are treatment integration and personalization, targeting key variables beyond symptom reduction. The Italian network for research on psychoses conducted a study demonstrating, using network analysis, the central role of community activities in bridging the effects of symptoms, cognition, functional capacity and service engagement on real-word functioning. A 4-year follow-up study was recently completed and the presentation will illustrate the findings. Network analysis was used to test whether relationships among all variables at baseline were similar at follow-up. In addition, the network structure was compared between subjects classified as recovered or non-recovered at follow-up. Six hundred eighteen subjects were assessed at both baseline and 4-year follow-up. Results showed that the network structure was stable from baseline to follow-up, and the overall strength of the connections among variables did not significantly change. Functional capacity and everyday life skills were the most central variables in the network at both baseline and follow-up, while psychopathological variables were more peripheral. The network structure of non-recovered patients was similar to the one observed in the whole sample, but very different from that of recovered subjects, showing few connections among the different nodes. These data strongly suggest that connections among symptoms/dysfunctions tend to maintain over time, contributing to poor outcome in schizophrenia. Early treatment plans, targeting variables with high centrality, might prevent the emergence of self-reinforcing networks of symptoms and dysfunctions in people with schizophrenia.

Armida Mucci has been a consultant and/or advisor to or has received honoraria from Gedeon Richter Bulgaria, Janssen Pharmaceuticals, Lundbeck, Otsuka, Pfizer and Pierre Fabre. None of these has any impact on this abstract and on the presented study.

Genome-Wide Association Studies (GWASs) have identified several genes associated with Schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. In addition, products of GWAS genes interact with neuronal factors coded by genes lacking association, such that this interaction may confer risk for specific phenotypes of this brain disorder. In this regard, fragile X mental retardation syndrome-related 1 (FXR1) gene has been GWAS associated with SCZ. FXR1 protein is regulated by glycogen synthase kinase-3β (GSK3β), which has been implicated in pathophysiology of SCZ and response to antipsychotics (APs). rs496250 and rs12630592, two eQTLs (Expression Quantitative Trait Loci) of FXR1 and GSK3β, respectively, interact on emotion stability and amygdala/prefrontal cortex activity during emotion processing. These two phenotypes are associated with Negative Symptoms (NSs) of SCZ suggesting that the interaction between these SNPs may also affect NS severity and responsiveness to medication.

To test this hypothesis, in two independent samples of patients with SCZ, we investigated rs496250 by rs12630592 interaction on NS severity and response to APs. We also tested a putative link between APs administration and FXR1 expression, as already reported for GSK3β expression.

We found that rs496250 and rs12630592 interact on NS severity. We also found evidence suggesting interaction of these polymorphisms also on response to APs. This interaction was not present when looking at positive and general psychopathology scores. Furthermore, chronic olanzapine administration led to a reduction of FXR1 expression in mouse frontal cortex.

Our findings suggest that, like GSK3β, FXR1 is affected by APs while shedding new light on the role of the FXR1/GSK3β pathway for NSs of SCZ.

Autism spectrum disorders (ASDs) and schizophrenia spectrum disorders (SSDs), although conceptualized as separate entities, may share some clinical and neurobiological features. ASD symptoms may have a relevant role in determining a more severe clinical presentation of schizophrenic disorder but their relationships with cognitive aspects and functional outcomes of the disease remain to be addressed in large samples of individuals.

To investigate the clinical, cognitive, and functional correlates of ASD symptoms in a large sample of people diagnosed with schizophrenia.

The severity of ASD symptoms was measured with the PANSS Autism Severity Scale (PAUSS) in 921 individuals recruited for the Italian Network for Research on Psychoses multicenter study. Based on the PAUSS scores, three groups of subjects were compared on a wide array of cognitive and functional measures.

Subjects with more severe ASD symptoms showed a poorer performance in the processing speed (p = 0.010), attention (p = 0.011), verbal memory (p = 0.035), and social cognition (p = 0.001) domains, and an overall lower global cognitive composite score (p = 0.010). Subjects with more severe ASD symptoms also showed poorer functional capacity (p = 0.004), real-world interpersonal relationships (p < 0.001), and participation in community-living activities (p < 0.001).

These findings strengthen the notion that ASD symptoms may have a relevant impact on different aspects of the disease, crucial to the life of people with schizophrenia. Prominent ASD symptoms may characterize a specific subpopulation of individuals with SSD.

Rasd2 is a striatal GTP-binding protein that modulates Akt and mTOR signaling cascades, well known to be highly vulnerable pathways in psychiatric disorders.

We investigated the association of Rasd2 and its genetic variation with a series of prefronto-striatal phenotypes related to psychosis in rodents and humans.

We want to provide evidence that Rasd2 controls the vulnerability to schizophrenia-related behavior induced by psychothomimetic drugs in mice. Moreover, we aim to find genetic variations within the Rasd2 gene that influence a series of brain schizophrenia-related phenotypes in human.

Rasd2 knockout mice were employed to evaluate schizophrenia-like behaviors induced by psychotomimetic drugs like amphetamine and phencyclidine. Furthermore, we investigated if RASD2genetic variations in humans are associated with mRNA expression in post-mortem prefrontal cortex, as well as prefrontal and striatal grey matter volume and physiology during working memory as measured with MRI in healthy subjects. Finally, we assessed RASD2mRNA expression levels in post-mortem brains of patients with schizophrenia and bipolar disorder.

We found that both psychotomimetics triggered greater vulnerability to motor stimulation and to prepulse inhibition deficits in Rasd2 mutants. In humans, we found that a genetic variation (rs6518956) within RASD2 predicts prefrontal mRNA expression as well as prefrontal grey matter volume and prefronto-striatal activity during working memory. Finally, we reported that RASD2 mRNA expression is slightly reduced in post-mortem prefrontal cortex of patients with schizophrenia.

Collectively, our data suggests that RASD2represents a gene of potential interest in psychiatric disorders for its ability to modulate prefronto-striatal phenotypes related to schizophrenia.

Negative symptoms have been associated with functional outcome of patients with schizophrenia by a large body of literature. However, in previous studies negative symptoms were regarded as a unitary construct, while recent literature data suggest that they include at least two factors, ‘Avolition” and ‘Poor Emotional Expression” (EE), that might show different relationships to functional outcome; moreover, the inter-relationships of negative symptoms, neurocognition, social cognition and real-life functioning are poorly understood.

A large multicenter study was carried out by the Italian Network for Research on Psychoses to model relationship between the negative symptom domains and real-life functioning, taking into account the role of other psychopathological dimensions including depression, neurocognition, functional capacity and social cognition.

A structural equation model was used to investigate direct and indirect effects of the 2 negative symptoms domains, other psychopathological dimensions, including depression, and neurocognition on real-life functioning. Social cognition and functional capacity were modeled as mediators.

In 921 patients with schizophrenia we found that the considered variables explained about 50% of real-life functioning variance. Avolition and functional capacity were the strongest independent predictors, followed by positive and disorganization dimensions, neurocognition and social cognition. EE had only a modest indirect effect on functioning. Neurocognition strongly predicted functional capacity and social cognition, which mediated its effects on functioning.

Our results support the heterogeneity of the two negative symptom domains. Only avolition is a strong predictor of functioning in real-life of patients with schizophrenia independent of social cognition, neurocognition and functional capacity.

The study was carried out within the project ‘Multicenter study on factors influencing real-life social functioning of people with a diagnosis of schizophrenia” of the Italian Network for Research on Psychoses.

D-aspartate (D-Asp) is an atypical amino acid that binds to and activates NMDARs. D-Asp occurs abundantly in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the enzyme D-Aspartate Oxidase (DDO). The agonistic activity of D-Asp on NMDARs and its neurodevelopmental occurrence make this D-amino acid a potential mediator for NMDAR-related alterations observed in schizophrenia. Consistently, substantial reduction of D-Asp was observed in post-mortem schizophrenia brains.

We evaluated the potential contribution of D-Asp as neurodevelopmental modulator of brain circuits and behaviors relevant to schizophrenia.

We analyzed DDO mRNA expression in the post-mortem prefrontal cortex of schizophrenic patients. Moreover, we treated knockout mice for Ddo gene (Ddo-/-) with the NMDAR antagonist phencyclidine to evaluate their schizophrenia-relevant behaviors and circuits. Finally, we assessed cortico-hippocampal connectivity of these mice.

DDO mRNA detection was performed by quantitative PCR. Phencyclidine-induced schizophrenia-like behaviours were assessed through motor activity and prepulse inhibition paradigms. Resting-state and pharmacological fMRI were used to evaluate functional circuits and connectivity.

DDO mRNA expression is increased in frontal samples of schizophrenic patients. In mice, the absence of Ddo gene produces a significant reduction in phencyclidine-induced motor hyper-activity and prepulse inhibition deficit. Furthermore, increased levels of D-Asp in Ddo-/- animals significantly inhibit functional circuits activated by phencyclidine, and affect the development of cortico-hippocampal connectivity networks potentially involved in schizophrenia.

Our data suggest that D-Asp, through the regulation exerted by DDO, may have a role in the pathophysiology of schizophrenia.

The genetic architecture of schizophrenia is based on polygenic trajectories. Indeed, genes converge on molecular co-expression pathways, which may be associated with heritable characteristics of patients and their siblings, called intermediate phenotypes, such as prefrontal anomalies and thalamic dysconnectivity during attentional control [2].

Here, we investigated in healthy humans association between co-expression of genes with coordinated thalamo-prefrontal (THA-PFC) expression and functional connectivity during attentional control.

We used Brainspan dataset to characterize a coordinated THA-PFC expression gene list by correlating post-mortem gene expression in both areas (Kendall's Tau>.76, Bonferroni P < .05). Then, we identified a PFC co-expression network1 and tested all gene sets for THA-PFC and PGC loci [3] enrichments (P < .05). SNPs associated with the first principal component of the resulting enriched gene set were combined in a Polygenic Co-Expression Index (PCI) [1]. We conducted Independent Component Analysis (ICA) on attentional control fMRI data (n = 265) and selected Independent Components (ICs) including the thalamus and being highly correlated with an attentional control network2. Multiple regressions were conducted (predictor: PCI) using a thalamic cluster previously associated with familial risk for schizophrenia [2] as ROI (FWE P < .05).

In one of the 8 ICs of interest there was a positive effect of PCI on thalamic connectivity strength in a cluster overlapping with our ROI (Z = 4.3).

Decreased co-expression of genes included in PCI predicts thalamic dysconnectivity during attentional control, suggesting a novel co-regulated molecular pathway potentially implicated in genetic risk for schizophrenia.

The authors have not supplied their declaration of competing interest.

Social cognition is a complex construct that refers to the functions required to understand other people's mental states and behavior. In people with schizophrenia, social cognition deficits account for a proportion of variance in functional outcome, independent of symptomatology. However, the relationships among social cognition, neurocognitive functioning and functional outcome are still unclear. Previous investigations had several limitations including small sample size, heterogeneous and limited measures of social cognition and neurocognitive functions.

Within the study of the Italian Network for Research on Psychoses, we investigated factors influencing outcome in patients with schizophrenia and their unaffected relatives. Psychopathology, including depression, neurocognition, social cognition and outcome were assessed using instruments designed to overcome some of the previous limitations.

Structural equation modeling was used to test direct and indirect effects of neurocognition, social cognition and functional capacity on vocational and interpersonal functioning. Tests of facial emotion recognition, emotional intelligence and theory of mind were included to assess social cognition. The MATRICS Consensus Cognitive Battery (MCCB) was used to investigate neurocognition.

In both subjects with schizophrenia and their first-degree relatives, social cognition was found to be independent of negative symptoms and to have a direct impact on outcome. Neurocognition was a predictor of functional capacity and social cognition, which both mediated its impact on outcome. Social cognition was independent of functional capacity and negative symptoms.

Better understanding of how neurocognitive dysfunction and social cognition deficits relate to one another may guide efforts toward targeted treatment approaches.

AM received honoraria or advisory board/consulting fees from the following companies: Janssen Pharmaceuticals, Otsuka, Pfizer and Pierre Fabre SG received honoraria or advisory board/consulting fees from the following companies: Lundbeck, Janssen Pharmaceuticals, Hoffman-La Roche, Angelini-Acraf, Otsuka, Pierre Fabre and Gedeon-Richter.

All other Authors declare no potential conflict of interest.

An impairment of premorbid adjustment (PA) has been regarded among poor prognostic indicators of schizophrenia. Some discrepancies in the literature suggest the usefulness of further characterizations of its impact on different aspects of the disease.

The present study aimed to investigate the association of poor PA with psychopathology, neurocognition and real-life functioning in patients with schizophrenia recruited within the multicenter study of the Italian network for research on psychoses. functioning during childhood and adolescence (early adjustment) was assessed also in a group of healthy controls (HC) and one of unaffected relatives of patients (UR).

Group comparisons were performed between patients with poor and those with good PA. Differences in frequency of poor early adjustment were investigated among patients, HC and UR.

Patients with poor PA, as compared to those with good PA, showed earlier age of onset, more severe negative symptoms and disorganization, greater impairment on all cognitive domains with the exception of attention/vigilance and worse real-life functioning in the considered areas (interpersonal relationships, community activities and work abilities). The pattern of poor early adjustment was more frequent in patients with respect to UR and HC and, to a less degree, in UR with respect to HC.

Our findings confirm that poor PA in schizophrenia is associated with poorer illness outcome, and offer a further characterization of PA impact on different psychopathological and cognitive domains. They also suggest that poor early adjustment is a candidate endophenotype of schizophrenia, occurring in patients and their unaffected relatives.

The authors have not supplied their declaration of competing interest.

The inter-relationships of neurocognition, social cognition, residual psychopathology and real-life functioning are poorly understood. A large multicenter study was carried out by the Italian Network for Research on Psychoses to model relationships between neurocognitive deficits, psychopathology and real-life functioning, taking into account the role of functional capacity and social cognition.

A structural equation model was used to investigate direct and indirect effects of neurocognition and psychopathology on real-life functioning. Social cognition and functional capacity were modeled as mediators.

In 921 patients with schizophrenia, neurocognition had both direct and indirect effects, through functional capacity and social cognition, on real-life functioning. Neurocognition predicted to a large extent social cognition on which depression and disorganization had a modest effect. Social cognition showed a significant direct impact on real-life functioning.

Our results support a strong link between neurocognition and functional outcome, independent of psychopathology. Social cognition accounted for unique incremental variance in real-life functioning.

The authors have not supplied their declaration of competing interest.

Neurocognition may represent an indicator of genetic risk and poor outcome in schizophrenia patients (SCZ) predicting real life functioning.

As cognitive performance of unaffected first-degree relatives (UR) is intermediate between SCZ and healthy controls (HC), neurocognitive impairment may represent a marker of vulnerability to schizophrenia.

To investigate social and neurocognition in all subjects and their impact on functional capacity of patients as markers of vulnerability.

Sample: 922 SCZ, 379 UR and 780 HC. Assessment: MATRICS Consensus Cognitive Battery (neurocognition), Facial Emotion Identification Test and Awareness of Social Inference Test (social cognition) and Specific Level of Functioning Scale (social functioning). Analyses: Structural Equation Model (SEM) analyses to model the impact of all variables on functional outcome.

SCZ scored worse in all domains than UR and HC. UR had significant impairments in all cognitive domains with respect to HC. Cognitive functioning had direct and indirect impacts on functional outcome mainly through social cognition and functional capacity. Social cognition had a direct impact on outcome, independent of neurocognition.

SCZ and UR display similar patterns of social and neurocognition deficits. Our results confirm a strong impact of neurocogniton on functional outcome. Social cognition has become an interesting object of study and its conceptualization as trait variable and the existence of a continuum between SCZ and UR are hypotheses for further research.

The study was carried out within the project “Multicenter study on factors influencing real-life social functioning of people with a diagnosis of schizophrenia” of the Italian Network for Research on Psychoses.

The authors have not supplied their declaration of competing interest.

Neuroimaging studies have identified several candidate biomarkers of schizophrenia. However, it is unclear whether the considerable variability in these neurobiological correlates between patients can be translated into the clinical setting.

We aimed to identify neuroimaging predictors of clinical course in patients with schizophrenia. Combined with the identification of genetically determined markers of schizophrenia risk, our studies aimed to elucidate the biological basis and the clinical relevance of inter-individual variability between patients.

We included over 150 patients with schizophrenia and 279 healthy volunteers across five neuroimaging centers in the framework of the IMAGEMEND project [1]. We performed multiple studies on MRI scans using random forests and ROC curves to predict clinical course. Data from healthy controls served to normalize the data from the clinical population and to provide a benchmark for the findings.

We identified ensembles of neuroimaging markers and of genetic variants predictive of clinical course. Results highlight that (i) brain imaging carries significant clinical information, (ii) clinical information at baseline can considerably increase prediction accuracy.

The methodological challenges and the results will be discussed in the context of recent findings from other multi-site studies. We conclude that brain imaging data on their own right are relevant to stratify patients in terms of clinical course; however, complementing these data with other modalities such as genetics and clinical information is necessary to further develop the field towards clinical application of the predictions.

Giulio Pergola is the academic supervisor of a Hoffmann-La Roche Collaboration grant that partially funds his salary.

Schizotypy refers to a set of temporally stable traits that are observed in the general population and that resemble, in attenuated form, the symptoms of schizophrenia. In a previous work, we identified volumetric patterns in thalamic subregions which were associated with disease status, and trained a random forests classifier, accounting for such thalamic volumetric patterns, that discriminated healthy controls (HC) from patients with schizophrenia (SCZ) (81% accuracy) [1].

i) to assess performance of random forests classifier developed by Pergola and coworkers [1], in an independent sample of healthy subjects; ii) to test whether false positives (FP), i.e. HC classified as SCZ based on such classifier would be associated with greater schizotypy compared with true negatives (TN), i.e. HC classified as such.

A total of 167 HC participated in the MRI study and filled the Schizotypal Personality Questionnaire (SPQ). We pre-processed MRI data with SPM8 and DARTEL. Then, we used thalamic grey matter volumes (GMV) as features in the random forests prediction of disease status at the single subject level. Finally, we tested SPQ scores differences between FP and TN with Mann-Whitney test.

The classification accuracy was 71%. FP had greater SPQ scores compared to TN (P = 0.007).

Classification accuracy of our classifier in an independent sample suggests that thalamic GMV patterns are reproducible markers of disease status. Furthermore, the present results also suggest that variability of thalamic GMV patterns in HC may have relevance for subclinical phenotypes related to schizophrenia spectrum.

The authors have not supplied their declaration of competing interest.