Negative symptoms represent a fundamental aspect of schizophrenia: they have a substantial impact on patients’ real-life functioning and do not respond satisfactorily to currently available treatments. Therefore, a better understanding of the pathophysiological mechanisms underlying these symptoms could favor the development of new treatments.

To date, the most validated pathophysiological hypothesis indicates an association between the Motivational domain (consisting of avolition, anhedonia and asociality) and alterations in the neuronal circuits involved in motivation. The Expressive Deficit domain (consisting of blunted affect and alogia) would be subtended by widespread alterations of cortical connectivity and associated with impaired neurocognition, social cognition, and the presence of neurological soft signs.

The aim of the present study is to examine the neurobiological correlates of the two domains of negative symptoms, starting from the brain areas that have been most commonly found in the literature to be associated with negative symptoms.

Resting-state (rs) fMRI data were acquired in 62 subjects with schizophrenia (SZ) and 46 healthy controls (HC). The two negative symptom domains were assessed using the Brief Negative Symptom Scale. In addition, the following assessment tools were used: the Positive and Negative Syndrome Scale for the assessment of positive symptoms and disorganization, the Calgary Depression Scale for Schizophrenia for depression and the St. Hans Rating Scale for extrapyramidal symptoms. The study of the possible relationships between rs-brain activity and the negative symptoms domains was conducted through partial correlations, checking for possible confounding factors (positive, depressive, extrapyramidal symptoms and disorganization).

The SZ, compared to the HC, showed higher rs-brain activity of the right inferior parietal lobule and of the right temporoparietal junction and lower rs-brain activity of the right dorsolateral prefrontal cortex, bilateral anterior dorsal cingulate cortex, bilateral ventral caudate and bilateral dorsal caudate. Furthermore, in the group of patients, the rs-brain activity of the left ventral caudate showed a moderate negative correlation with the Expressive deficit domain (r = -0.401; p = 0.003), but not with the Motivational domain.

The results of the present study, in line with the literature, demonstrated how the two domains of negative symptomatology are subtended by different pathophysiological mechanisms. Given the role played by the ventral caudate in neurocognitive processes, these results are in line with the hypothesis that Expressive deficit may have a common etiopathogenesis with cognitive deficits. A better understanding of the neurobiology of negative symptoms could foster the development of innovative treatment strategies targeting the two negative symptom domains.

None Declared

Negative symptoms (NS) represent a heterogeneous construct of schizophrenia, whose conceptualization is still to be clarified. In the last decade, the conceptualization model that has received the most support from the literature has described 2 NS domains: the expressive deficit (EXP), which includes blunted affect and alogia, and the motivational deficit (MAP), which includes avolition, asociality, and anhedonia. However, different confirmatory factor-analytic studies suggest that the bi-dimensional model may not capture the complexity of this construct, which could be better defined by a 5-factor model (5 individual negative symptoms) or a hierarchical model (5 individual negative symptoms as first-order factors, and the 2 domains, MAP and EXP domains, as second-order factors). However, to our knowledge, no study has investigated associations between negative symptom models with social cognition and functional capacity, which are largely documented to correlate with negative symptoms, nor the associations with external validators over time, looking at the potential stability of negative symptom models validity through the course of the illness.

In the light of this observations, we investigated, the external validity of the five-factor model and the hierarchical model of the BNSS in subjects with schizophrenia, looking at associations with cognition, social cognition, functioning and functional capacity at baseline and at four years follow-up.

NS were assessed in 612 subjects with schizophrenia using the Brief Negative Symptom Scale at the baseline and after 4-year follow-up. State of the art assessment instruments were used to assess cognitive and functioning related variables. Structural equation models (SEM) that included the NS models and 4 external variables were used to our aim.

According to recent multicenter studies, our results confirmed the validity of the 5-factor- and the hierarchical-model of negative symptoms. In particular, these 2 models proved to be equivalent in terms of fit to the data at baseline and follow-up. As regard to the relationship of the two BNSS models with external variables, we found that there was a similar pattern of associations at the two time points despite minor variations.

The five factor and the hierarchical models provide an optimal conceptualization of negative symptoms in relation to external variables. The similar pattern of associations with external variables of the two models at the two time points despite minor variations, suggests that the simple and widely used 5-factor solution provides the best balance between parsimony and granularity to summarize BNSS structure. This data is of important relevance with consequent implications in the study of pathophysiological mechanisms and the development of targeted treatments for NS.

None Declared

Negative symptoms (NS) represent an unmet need of treatment in schizophrenia (SCZ). As a result, these symptoms pose a significant burden on patients, their families, and the health care system. In the last decade, the conceptualization model that has received the most support from the literature has described 2 domains of NS: the expressive deficit (EXP), which includes blunted affect and alogia, and the motivational deficit (MAP), which includes avolition, asociality, and anhedonia. However, different confirmatory factor-analytic studies suggest that the bi-dimensional model may not capture the complexity of this construct, which could be better defined by the 5-factor model. To date no study exploiting innovative tools and state of the art assessment instruments has yet been conducted to evaluate the NS structure stability over time.

The aim of this study was to investigate the stability of the latent structure of NS in subjects with SCZ.

NS were assessed in 612 subjects with SCZ using the Brief Negative Symptom Scale (BNSS) at the baseline and after 4-year follow-up. A network invariance analysis was conducted for the data collected longitudinally.

Results showed that the BNSS’ items aggregated to form 5 distinct domains (avolition, asociality, blunted affect, alogia and anhedonia). The result of the network invariance test indicated that the network structure remained unchanged over time (network invariance test = 0.13; p = 0.169) while its overall strength decreased significantly (6.28 baseline, 5.79 at follow-up; global strength invariance test = 0.48; p = 0.016).

The results of this study show how the construct of NS can be better explained by the 5 individual negative symptoms and that this model is almost stable over time. Therefore the 2-dimensional model may be insufficient to describe the characteristics of NS. This data is of important relevance with consequent implications in the study of pathophysiological mechanisms and the development of targeted treatments for NS.

None Declared

Honoraria, advisory board, or consulting fees from Angelini, Astra Zeneca, Bristol-Myers Squibb, Gedeon Richter Bulgaria, Innova-Pharma, Janssen Pharmaceuticals, Lundbeck, Otsuka, Pfizer, and Pierre Fabre, for services not related to this abstract

An extensive literature regarding gender differences relevant to several aspects of schizophrenia is nowadays available. It includes some robust findings as well as some inconsistencies. The identification of gender differences and the understanding of their explanations may help to clarify the underlying etiopathogenetic mechanisms of specific aspects of the disorder.

The present study aimed at investigating gender differences on premorbid, clinical, cognitive and outcome indices, as well as their impact on recovery, in a large sample of patients with schizophrenia recruited within the multicenter study of the Italian Network for Research on Psychoses.

State-of-the-art instruments were used to assess the investigated domains. Group comparisons between male and female patients were performed on all considered indices. The associations of premorbid, clinical and cognitive indices with recovery in the two patient groups were investigated by means of multiple regressions.

Males with respect to females had a worse premorbid adjustment – limited to the academic dimension – an earlier age of onset, a higher frequency of history of substance and alcohol abuse, more severe negative symptoms (both avolition and expressive deficit), positive symptoms and impairment of social cognition. No gender difference was observed in neurocognition nor in the rates of recovery.

Although males showed some disadvantages in the clinical picture, this was not translated into a worse outcome. This finding may be related to the complex interplay of several factors acting as predictors or mediators of outcome.

No significant relationships.

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.

Characterizing neuroanatomical markers of different stages of schizophrenia (SZ) to assess of how the disorder develops is extremely important for the clinical practice. It still remains uncertain how abnormalities are formed as SZ progresses.

We reviewed and analyzed 113 voxel based morphometry studies on people at risk of or with schizophrenia to assess GM alterations at different stages of the disorder and to functionally characterize these GM variations.

We performed a meta-analysis of voxel-based morphometry studies of genetic and clinical high-risk subjects (g-/c-HR), recently diagnosed (RDSZ) and chronic SZ patients (ChSZ). We quantified gray matter (GM) changes associated with these four conditions and compared them with contrast and conjunctional data. We performed the behavioral analysis and networks decomposition of alterations to obtain their functional characterization.

Compared to previous investigations, results reveal a robust cortical-subcortical, left-to-right homotopic progression of GM loss. The right anterior cingulate is the only altered region in all conditions. Contrast analyses show left-lateralized insular, amygdalar and parahippocampal GM reduction in RDSZ, which appears bilateral in ChSZ. An overlap between RDSZ and ChSZ is observed in the left insula, amygdala, precentral and inferior frontal gyri. Functional decomposition shows involvement of the salience network, with an enlargement of the sensorimotor network in RDSZ and the thalamus-basal nuclei network in ChSZ.

These results can help the research on diagnostic and neuroimaging biomarkers of SZ staging, as well as on the identification of new therapeutics neuroanotomic targets that could be addressed with focused magnetic or non-invasive electric stimulation.

No significant relationships.

Lack of insight is present in 50-80% of schizophrenic patients and is associated with poorer prognosis and negative outcome. The aim of our study was to evaluate possible differences in symptomatology and functioning between schizophrenic patients with poor or good insight.

One undred twenty one patients with a DSM-IV-TR diagnosis of schizophrenia in a stable phase were evaluated with PANSS, CDSS, GAF, and QLS. The Scale for the Assessment of Unawareness of Mental Disorder, SUMD, was used to assess three domains: awareness of mental illness, the need for treatment, the social consequences of illness. SUMD cut-off of 3 was used to differentiate patients with good insight from those with impaired insight. Independent sample t-test was performed to compare these two groups on clinical profile, quality of life and global functioning.

No significant differences were found between poor and good insight groups on socio-demographic variables. Significant differences (p< .01) were observed between patients with poor and good insight, for all the three dimensions of SUMD, in GAF, PANSS positive and PANSS general symptomatology. Patients with worse awareness of illness presented more severe negative symptoms (p= .001) and less depressive symptomatology (p= .008). Patients with impaired awareness of need for treatment and the social consequences of disorder presented lower scores in QLS occupational role (p< .02).

These findings suggest a link between insight, symptomatology and outcome that can be explained by a clinical model which considers insight related to how a particular symptom is created.

Quality of life (QOL) has been recognized as an important outcome of schizophrenia treatment. We examined whether global functional status, symptomatology and neurocognition would contribute to quality of life in patients with schizophrenia.

Eighty six stable schizophrenic outpatients (DSM-IV-TR criteria) were included. All patients were receiving antipsychotic treatment. Functioning and clinical assessment included the Global Assessment of Functioning scale (GAF), the Clinical Global Impression scale (CGI), the Positive and Negative Syndrome Scale (PANNS) and the Calgary Depression Scale for Schizophrenia (CDSS). Neurocognition assessment evaluated attentive functions, verbal memory-learning, executive functions and perceptual-motor speed. QOL has been evaluated using an objective measure (Schizophrenia Quality of Life Scale, QLS). Indices correlated with QOL (p<0,005) were then included in a multiple regression analysis using QOL as the dependent variable and the Bonferroni correction.

QLS total score was predicted by global functioning and negative symptoms (F=56,47, p<0,001), which accounted for 57% of the variance. Social activity, intrapsychic functioning and use of objects and participation in activities domains were also predicted by global functioning and negative symptoms whereas instrumental functioning domain were predicted only by global functioning.

Our findings suggest that, in outpatients with schizophrenia, global functioning and negative symptoms seem to play a role on modifying QOL while neurocognition doesn't seem to have a direct impact on QOL.

The Brief Negative Symptom Scale (BNSS) was developed to address the main limitations of the existing scales for the assessment of negative symptoms of schizophrenia. The initial validation of the scale by the group involved in its development demonstrated good convergent and discriminant validity, and a factor structure confirming the two domains of negative symptoms (reduced emotional/verbal expression and anhedonia/asociality/avolition). However, only relatively small samples of patients with schizophrenia were investigated. Further independent validation in large clinical samples might be instrumental to the broad diffusion of the scale in clinical research.

The present study aimed to examine the BNSS inter-rater reliability, convergent/discriminant validity and factor structure in a large Italian sample of outpatients with schizophrenia.

Our results confirmed the excellent inter-rater reliability of the BNSS (the intraclass correlation coefficient ranged from 0.81 to 0.98 for individual items and was 0.98 for the total score). The convergent validity measures had r values from 0.62 to 0.77, while the divergent validity measures had r values from 0.20 to 0.28 in the main sample (n = 912) and in a subsample without clinically significant levels of depression and extrapyramidal symptoms (n = 496). The BNSS factor structure was supported in both groups.

The study confirms that the BNSS is a promising measure for quantifying negative symptoms of schizophrenia in large multicenter clinical studies.

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.

The Brief Negative Symptom Scale (BNSS) was designed to address the main limitations of the existing scales for the assessment of negative symptoms in schizophrenia. The first validation of the scale by the same group involved in its development showed good convergent and discriminant validity, and a factor structure which confirmed the two domains of negative symptoms (reduced emotional/verbal expression and anhedonia/asociality/avolition). Nevertheless, the investigated samples of patients with schizophrenia were relatively small.

The present study aimed at providing a further independent validation of the BNSS in a large clinical sample to promote a wider diffusion of the scale in clinical research.

The inter-rater reliability, convergent/discriminant validity and factor structure of the Italian version of the BNSS were evaluated in 912 outpatients with schizophrenia recruited within an Italian multicenter study.

Our results confirmed the strong inter-rater reliability of the BNSS (the intraclass correlation coefficient ranged from 0.81 to 0.98 for individual items and was 0.98 for the total score). The convergent validity measures had r values from 0.62 to 0.77, while the divergent validity measures had r values from 0.20 to 0.28 in the whole sample (N=912) and in a smaller group of patients without clinically significant levels of depression and extrapyramidal symptoms (N=496). The BNSS factor structure was supported in both groups.

According to our results the BNSS is a promising measure for quantifying negative symptoms of schizophrenia in large multicenter clinical studies.

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.

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.

This study aims to empirically identify profiles of functioning, and the correlates of those profiles in a sample of patients with stable schizophrenia in a real-world setting. The second aim was to assess factors associated with best profile membership.

Three hundred and twenty-three outpatients were enrolled in a cross-sectional study. A two-step cluster analysis was used to define groups of patients by using baseline values for the Heinrichs-Carpenter Quality of Life Scale (QLS) total score. Logistic regression was used to construct models of class membership.

Our study identified three distinct clusters: 50.4% of patients were classified in the “moderate” cluster, 27.9% in the “poor” cluster, 21.7% in the “good” cluster. Membership in the “good” cluster versus the “poor” cluster was characterized by less severe negative (OR = .832) and depressive symptoms (OR = .848), being employed (OR = 2.414), having a long-term relationship (OR = .256), and treatment with second-generation antipsychotics (SGAs) (OR = 3.831). Nagelkerke R2 for this model was .777.

Understanding which factors are associated with better outcomes may direct specific and additional therapeutic interventions, such as treatment with SGAs and supported employment, in order to enhance benefits for patients, as well as to improve the delivery of care in the community.

The author has not supplied his declaration of competing 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.