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Davide Palumbo,1 Armida Mucci,1 Giulia Maria Giordano,1 Giuseppe Piegari,1 Carmen Aiello,1 Daria Pietrafesa,1 Nicola Annarumma,1 Marcello Chieffi,1 Matteo Cella,2 Silvana Galderisi1 1Department of Psychiatry, University of Campania Luigi Vanvitelli, Naples, Italy; 2Institute of Psychiatry, Psychology and Neuroscience (ioppn), King’s College London, London, UKCorrespondence: Armida MucciDepartment of Psychiatry, University of Campania Luigi Vanvitelli, L.go Madonna delle Grazie 1, 80138 Naples, ItalyTel +39-81-5665153Email armida.mucci@gmail.comIntroduction: The Computerized Interactive Remediation of Cognition – Training for Schizophrenia (CIRCuiTS) is a form of cognitive remediation therapy developed to target neurocognitive and metacognitive deficits of people with schizophrenia, which have a detrimental impact on real-life functioning. The English version of CIRCuiTS demonstrated good acceptability and feasibility. A recent randomized controlled trial provided evidence that the program improves memory and functioning, and that the impact on functional outcome is mediated by metacognition. The next steps in the development of CIRCuiTS include both: 1) the translation and adaptation of the program in different cultural settings; and 2) the demonstration of feasibility, acceptability and effectiveness of a standardized method to administer CIRCuiTS remotely.Purpose: To implement the CIRCuiTS Italian version and to assess acceptability, feasibility and efficacy of a standardized method to administer CIRCuiTS remotely.Methods: Participants were assessed at baseline and received up to 40 CIRCuiTS therapy sessions, three times a week, for about 1 hr over a three-month period. Participants were reassessed post-treatment.Results: The program demonstrated good feasibility and high acceptability when assessed by the number of dropouts and evaluation of patients’ satisfaction. Participants improved in learning, speed of processing, working memory and executive control. They showed a reduction in disorganization and improvement in self-esteem, functional capacity, and real-life functioning.Conclusion: In this study, a standardized protocol for using CIRCuiTS from home was implemented. The first set of data showed in the paper is encouraging. The proposed procedure could lead to a dropout reduction while maintaining the efficacy of the program.Keywords: cognition, cognitive training, metacognition, real-life functioning

BACKGROUND: Negative symptoms represent an unmet need of schizophrenia treatment, occurring since the early phases of the disorder. Primary and persistent negative symptoms are associated with the worst outcome in terms of treatment response and psychosocial functioning. The prevalence of these symptoms in first episode patients, especially early after onset (within 2 years), has not been systematically studied. METHODS: In the present study we investigated the prevalence of negative symptoms of moderate severity, unconfounded by depression and extrapyramidal symptoms at baseline (U-NEG), and their persistence over the three phases of the OPTIMISE trial (i.e., after 4, 10 and 22 weeks of treatment). The impact on remission and psychosocial functioning of persistent negative symptoms (PNS) was also assessed. RESULTS: U-NEG were observed in 263/446 subjects (59% of the whole cohort of first-episode, recent-onset subjects). U-NEG were associated with worse psychosocial functioning and duration of psychosis at intake in the study. At the end of phase2 they were associated with poor psychosocial functioning (controlling for the severity of all other psychopathological dimensions and demographic variables). However, the attrition and remission rates did not differ with respect to subjects without negative symptoms of moderate severity. U-NEG persisted in 49 subjects (11% of the whole cohort and 18.6% of cases with U_NEG) at the end of phase1 (after 4 weeks of amisulpride treatment). The 49 early PNS subjects did not differ at baseline on measures of functioning and global severity of illness from non-persistent U-NEG subjects (NPNS), although the latter group had more severe depression and positive symptoms. At the end of phase1, PNS subjects had higher global severity of illness, were less frequently remitted and showed a worse psychosocial functioning than NPNS. During phase2 (6 weeks double-blind olanzapine vs amisulpride), 22/49 PNS subjects dropped (44.9%) vs 45/214 (21%) of NPNS. Among the 27 PNS who completed phase2, 13 (48.1%) were non-remitted and started phase3, representing 72% of all subjects entering phase3 (N=18). Only 10 subjects completed phase3 and 7 were non-remitted. These latter subjects had persistent negative symptoms across all treatment phases. CONCLUSIONS: Unconfounded negative symptoms predicted poor psychosocial functioning. Persistent negative symptoms were associated with the worse psychosocial functioning at all phases and were the most resistant to antipsychotic treatment including clozapine.

OBJECTIVE: Negative symptoms are currently viewed as having a 2-dimensional structure, with factors reflecting diminished expression (EXP) and motivation and pleasure (MAP). However, several factor-analytic studies suggest that the consensus around a 2-dimensional model is premature. The current study investigated and cross-culturally validated the factorial structure of BNSS-rated negative symptoms across a range of cultures and languages. METHOD: Participants included individuals diagnosed with a psychotic disorder who had been rated on the Brief Negative Symptom Scale (BNSS) from 5 cross-cultural samples, with a total N = 1691. First, exploratory factor analysis was used to extract up to 6 factors from the data. Next, confirmatory factor analysis evaluated the fit of 5 models: (1) a 1-factor model, 2) a 2-factor model with factors of MAP and EXP, 3) a 3-factor model with inner world, external, and alogia factors; 4) a 5-factor model with separate factors for blunted affect, alogia, anhedonia, avolition, and asociality, and 5) a hierarchical model with 2 second-order factors reflecting EXP and MAP, as well as 5 first-order factors reflecting the 5 aforementioned domains. RESULTS: Models with 4 factors or less were mediocre fits to the data. The 5-factor, 6-factor, and the hierarchical second-order 5-factor models provided excellent fit with an edge to the 5-factor model. The 5-factor structure demonstrated invariance across study samples. CONCLUSIONS: Findings support the validity of the 5-factor structure of BNSS-rated negative symptoms across diverse cultures and languages. These findings have important implications for the diagnosis, assessment, and treatment of negative symptoms.

Negative symptoms represent an unmet need of treatment in schizophrenia. Although a consensus exists on negative symptom construct, and second generation assessment instruments reflecting the consensus are available, studies still rely upon old assessment instruments, that do not reflect recent conceptualizations and might limit progress in the search for effective treatments. This is often the case in the European context, where one of the challenges encountered in designing large studies is the availability of validated instruments in the many languages of the continent. To address this challenge and promote sound research on negative symptoms in Europe, the ECNP Schizophrenia Network coordinated a large multicenter, multinational validation study of the Brief Negative Symptom Scale (BNSS). Clinically-stable subjects with schizophrenia (SCZ, N = 249) were recruited from 10 European Countries. Apart from BNSS, subjects were administered the Positive and Negative Syndrome Scale (PANSS) and standardized instruments for depression, extrapyramidal symptoms and psychosocial functioning. Results showed an excellent internal consistency, convergent and discriminant validity of BNSS and replicated a 5 factor-model. A larger number of subjects with predominant negative symptoms, i.e. the target population for clinical trials, was identified by using the BNSS compared to the PANSS. Regression analysis showed that BNSS-avolition, a key negative symptom poorly assessed by PANSS, explained 23.9% of psychosocial functioning, while no combination of the PANSS core negative symptoms showed the same impact on functioning. The study demonstrated that BNSS has substantial advantages with respect to PANSS for the identification of the avolition domain and subjects with predominant negative symptoms. (C) 2019 The Author(s). Published by Elsevier B.V.

Recently, neuroimaging research has substantially increased our understanding of the pathophysiology of psychotic disorders by detailing their association with distributed, complex, multimodal patterns of brain aberrations. Several studies have reported differences between subjects with psychotic disorders and healthy controls in structural, functional, and neurochemical neuroimaging measures. However, the clinical utility of these findings is not yet clear.

Background:Negative symptoms in schizophrenia are heterogeneous and multidimensional; effective treatments are lacking. Cariprazine, a dopamine D3-preferring D3/D2receptor partial agonist and serotonin 5-HT1Areceptor partial agonist, was significantly more effective than risperidone in treating negative symptoms in a prospectively designed trial in patients with schizophrenia and persistent, predominant negative symptoms.Methods:Using post hoc analyses, we evaluated change from baseline at week 26 in individual items of the Positive and Negative Syndrome Scale (PANSS) and PANSS-derived factor models using a mixed-effects model for repeated measures (MMRM) in the intent-to-treat (ITT) population (cariprazine = 227; risperidone = 227).Results:Change from baseline was significantly different in favor of cariprazine versus risperidone on PANSS items N1-N5 (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking) (PPPConclusions:Since items representing different negative symptom dimensions may represent different fundamental pathophysiological mechanisms, significant improvement versus risperidone on most PANSS Negative Subscale items and across all PANSS-derived factors suggests broad-spectrum efficacy for cariprazine in treating negative symptoms of schizophrenia.

Different medical disciplines have adopted biomarkers in order to establish a diagnosis and predict clinical and functional outcome of a disease. In psychiatry, the search for biomarkers could lead to substantial improvement in mental disorder diagnosis and care. Different neuroimaging techniques have contributed to improve our understanding of brain structure and functioning in patients with psychotic disorders. However, though a large number of studies have reported differences between patients with psychotic disorders and healthy controls in structural and functional neuroimaging measures, only few results are robust and consistent. In addition, so far, even robust and consistent findings have differences at group level, which so far did not translate into applications at the individual level. The heterogeneity of psychotic disorders, the use of medications, and the infrequent replication of findings in independent patient cohorts from different centers have limited the identification of reliable neuroimaging biomarkers for diagnosis and outcome prediction of psychotic disorders. Machine-learning algorithms might represent a good opportunity for the progress in this field.

A major goal for the revision of the International Classification of Diseases and Related Health Problems, Tenth Edition (ICD-10) is to increase the clinical utility of the diagnostic system. Schizoaffective disorder has a history of poor diagnostic reliability due to the similarities and overlap in symptoms that it shares with other disorders, especially primary psychotic and mood disorders. The present study was part of the case-controlled field trials for ICD-11 and examines how the proposed changes for schizoaffective disorder may improve differential diagnosis and diagnostic accuracy. Clinicians from around the globe (n = 873) were provided with either ICD-10 or ICD-11 diagnostic guidelines and asked to apply them to case vignettes comparing schizoaffective disorder to schizophrenia and mood disorders with psychotic symptoms. Participants were asked to respond to follow-up diagnostic questions to determine which components of the diagnostic guidelines affected diagnostic accuracy. Overall, clinicians showed small improvements in accurately diagnosing vignettes using ICD-11 over ICD-10. Results suggest the discrepancy in diagnosing schizoaffective disorder is related primarily to the presence of mood symptoms and discrepancies about whether those symptoms are more consistent with schizoaffective disorder or a mood disorder diagnosis. Continuing to identify ways to more accurately capture this symptom picture will be important in the future as well as systematic efforts to educate clinicians about differential diagnosis.

Prior studies using exploratory factor analysis provide evidence that negative symptoms are best conceptualized as 2 dimensions reflecting diminished motivation and expression. However, the 2-dimensional model has yet to be evaluated using more complex mathematical techniques capable of testing structure. In the current study, network analysis was applied to evaluate the latent structure of negative symptoms using a community-detection algorithm. Two studies were conducted that included outpatients with schizophrenia (SZ; Study 1: n = 201; Study 2: n = 912) who were rated on the Brief Negative Symptom Scale (BNSS). In both studies, network analysis indicated that the 13 BNSS items divided into 6 negative symptom domains consisting of anhedonia, avolition, asociality, blunted affect, alogia, and lack of normal distress. Separation of these domains was statistically significant with reference to a null model of randomized networks. There has been a recent trend toward conceptualizing the latent structure of negative symptoms in relation to 2 distinct dimensions reflecting diminished expression and motivation. However, the current results obtained using network analysis suggest that the 2-dimensional conceptualization is not complex enough to capture the nature of the negative symptom construct. Similar to recent confirmatory factor analysis studies, network analysis revealed that the latent structure of negative symptom is best conceptualized in relation to the 5 domains identified in the 2005 National Institute of Mental Health consensus development conference (anhedonia, avolition, asociality, blunted affect, and alogia) and potentially a sixth domain consisting of lack of normal distress. Findings have implications for identifying pathophysiological mechanisms and targeted treatments.

Primary psychotic disorders are characterized by clinical heterogeneity in terms of psychopathological manifestations, course, and outcome. Several data demonstrated that symptoms cluster in psychopathological dimensions which are more accurate than diagnostic categories in predicting risk factors, course, response to treatment, and functional outcome. The dimensions might be related to distinct pathophysiological mechanisms which can coexist in individual subjects.

IntroductionSocial cognition and skill deficits have been largely documented in subjects with schizophrenia (SCZs), and have a strong influence on the functional outcome of these subjects. Different behavioural interventions have been developed to target and improve social skills in SCZs. For instance, the Social Skills Training (SST) focuses on improving communication skills and assertiveness to facilitate disease management, independent living and real-life functioning of SCZs. SST seems also to have an impact on negative symptoms and social cognition.ObjectivesThe study aims to evaluate the effectiveness of SST in improving social cognition and negative symptoms in SCZs.MethodsThe sample included 8 chronic SCZs (age between 18 and 60), who completed 6 months of SST. The intervention consisted of two weekly group sessions of 2 hours each. We assessed psychopathology, neurocognition, real-life functioning, functional capacity and social cognition at baseline and after training. Paired samples t-tests were performed to evaluate the differences of the variables considered after completing the treatment.ResultsSignificant improvements in negative symptoms (pConclusionsThe present findings suggest that SST might ameliorate social cognition and negative symptoms which are generally not influenced by antipsychotic treatment. The integration of pharmacological and SST interventions might have an impact on major determinants of poor real-life functioning in SCZs.

IntroductionDespite innovative treatments, the impairment in real-life functioning in subjects with schizophrenia (SCZ) remains an unmet need in the care of these patients. Recently, real-life functioning in SCZ was associated with abnormalities in different electrophysiological indices. It is still not clear whether this relationship is mediated by other variables, and how the combination of different EEG abnormalities influences the complex outcome of schizophrenia.ObjectivesThe purpose of the study was to find EEG patterns which can predict the outcome of schizophrenia and identify recovered patients.MethodsIllness-related and functioning-related variables were measured in 61 SCZ at baseline and after four-years follow-up. EEGs were recorded at the baseline in resting-state condition and during two auditory tasks. We performed Sparse Partial Least Square (SPLS) Regression, using EEG features, age and illness duration to predict clinical and functional features at baseline and follow up. Through a Linear Support Vector Machine (Linear SVM) we used electrophysiological and clinical scores derived from SPLS regression, in order to classify recovered patients at follow-up.ResultsWe found one significant latent variable (pConclusionsA combination of electrophysiological markers, age and illness-duration might predict clinical and functional outcome of schizophrenia after 4 years of follow-up.

Negative symptoms are considered a core feature of schizophrenia. They are present since the prodromal phase and tend to persist more than other psychopathological dimensions in the chronic stages. The domain of apathy has attracted research efforts for the strong association with poor functional outcome. This negative symptom domain is observed in a number of neuropsychiatric disorders and might have both overlapping and distinct pathophysiological mechanisms. In schizophrenia it can be secondary to other aspects of the disorder, such as positive symptoms and depression, to drug side effects and/or social isolation, often observed in affected subjects. When primary to schizophrenia, apathy is conceptualized in terms of a reduction of the voluntary activity due to a lack of interest and motivation for goal-directed behavior initiation and persistence. In a percentage of subjects, apathy tend to persist and do not respond to available pharmacological and psychosocial treatments. The assessment of this domain in patients with schizophrenia using internationally recognized criteria for its definition, as were recently developed in other neuropsychiatric disorders, might help disentangle the different pathophysiological mechanisms. In the presentation, studies of apathy in schizophrenia will be illustrated to highlight the relationships with cognitive dysfunction, other psychopathological dimensions and functional outcome using state of the art instruments to assess the construct in schizophrenia.DisclosureProf. 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.

IntroductionCognitive deficits are considered a key feature of schizophrenia due to their substantial influence on the psychosocial outcome of subjects affected by this disorder. Several studies showed that moderate to severe cognitive impairments, including dysfunctions of social cognition, are already present during the early phases of the illness, in subjects with first-episode psychosis (FEPs). Psychosocial interventions, such as social skill training (SST), could therefore be implemented already upon occurrence of the first episode of psychosis to improve the overall functional outcome of schizophrenia, which represents to date an unmet need in the care of these patients.ObjectivesThe study aims to evaluate the use of SST to enhance social skills and real-life functioning in FEPs.MethodsThe sample included 7 FEPs (age between 15 and 40). The SST intervention included 30 sessions lasting 2 hours and delivered twice a week. Psychopathology, neurocognition, real life functioning, functional capacity and social cognition were assessed at baseline ad after training. Paired samples t-tests were performed to evaluate the effects of the intervention. All subjects were treated with second generation antipsychotics.ResultsSignificant improvements were observed in negative symptoms, social cognition, problem solving skills, as well as in global functioning (all pConclusionsThese preliminary findings suggest that SST might complement pharmacological treatment in FEPs to improve functional outcome in these subjects. Further studies with a higher sample size and a longer follow-up are required in order to confirm the present results.

IntroductionDifferent electrophysiological indices have been investigated to identify diagnostic and prognostic markers of schizophrenia (SCZ). However, these indices have limited use in clinical practice, since both specificity and association with illness outcome remain unclear. In recent years, machine learning techniques, through the combination of multidimensional data, have been used to better characterize SCZ and to predict illness course.ObjectivesThe aim of the present study is to identify multimodal electrophysiological biomarkers that could be used in clinical practice in order to improve precision in diagnosis and prognosis of SCZ.MethodsIllness-related and functioning-related variables were measured at baseline in 113 subjects with SCZ and 57 healthy controls (HC), and after four-year follow-up in 61 SCZ. EEGs were recorded at baseline in resting-state condition and during two auditory tasks (MMN-P3a and N100-P3b). Through a Linear Support Vector Machine, using EEG data as predictors, four models were generated in order to classify SCZ and HC. Then, we combined unimodal classifiers’ scores through a stacking procedure. Pearson’s correlations between classifiers score with illness-related and functioning-related variables, at baseline and follow-up, were performed.ResultsEach EEG model produced significant classification (p < 0.05). Global classifier discriminated SCZ from HC with accuracy of 75.4% (p < 0.01). A significant correlation (r=0.40, p=0.002) between the global classifier scores with negative symptoms at follow-up was found. Within negative symptoms, blunted affect showed the strongest correlation.ConclusionsAbnormalities in electrophysiological indices might be considered trait markers of schizophrenia. Our results suggest that multimodal electrophysiological markers might have prognostic value for negative symptoms.

BackgroundFirst rank symptoms (FRS) of schizophrenia have been used for decades for diagnostic purposes. In the new version of the DSM-5, the American Psychiatric Association (APA) has abolished any further reference to FRS of schizophrenia and treats them like any other “criterion A” symptom (e.g. any kind of hallucination or delusion) with regard to their diagnostic implication. The ICD-10 is currently under revision and may follow suit. In this review, we discuss central points of criticism that are directed against the continuous use of first rank symptoms (FRS) to diagnose schizophrenia.MethodsWe describe the specific circumstances in which Schneider articulated his approach to schizophrenia diagnosis and discuss the relevance of his approach today. Further, we discuss anthropological and phenomenological aspects of FRS and highlight the importance of self-disorder (as part of FRS) for the diagnosis of schizophrenia. Finally, we will conclude by suggesting that the theory and rationale behind the definition of FRS is still important for psychopathological as well as neurobiological approaches today.ResultsResults of a pivotal meta-analysis and other studies show relatively poor sensitivity, yet relatively high specificity for FRS as diagnostic marker for schizophrenia. Several methodological issues impede a systematic assessment of the usefulness of FRS in the diagnosis of schizophrenia. However, there is good evidence that FRS may still be useful to differentiate schizophrenia from somatic causes of psychotic states. This may be particularly important in countries or situations with little access to other diagnostic tests. FRS may thus still represent a useful aid for clinicians in the diagnostic process.ConclusionIn conclusion, we suggest to continue a tradition of careful clinical observation and fine-grained psychopathological assessment, including a focus on symptoms regarding self-disorders, which reflects a key aspect of psychosis. We suggest that the importance of FRS may indeed be scaled down to a degree that the occurrence of a single FRS alone should not suffice to diagnose schizophrenia, but, on the other hand, absence of FRS should be regarded as a warning sign that the diagnosis of schizophrenia or schizoaffective disorder is not warranted and requires specific care to rule out other causes, particularly neurological and other somatic disorders. With respect to the current stage of the development of ICD-11, we appreciate the fact that self-disorders are explicitly mentioned (and distinguished from delusions) in the list of mandatory symptoms but still feel that delusional perceptions and complex hallucinations as defined by Schneider should be distinguished from delusions or hallucinations of “any kind”. Finally, we encourage future research to explore the psychopathological context and the neurobiological correlates of self-disorders as a potential phenotypic trait marker of schizophrenia.

Importance Detection, prognosis, and indicated interventions in individuals at clinical high risk for psychosis (CHR-P) are key components of preventive psychiatry. Objective To provide a comprehensive, evidence-based systematic appraisal of the advancements and limitations of detection, prognosis, and interventions for CHR-P individuals and to formulate updated recommendations. Evidence Review Web of Science, Cochrane Central Register of Reviews, and Ovid/PsychINFO were searched for articles published from January 1, 2013, to June 30, 2019, to identify meta-analyses conducted in CHR-P individuals. MEDLINE was used to search the reference lists of retrieved articles. Data obtained from each article included first author, year of publication, topic investigated, type of publication, study design and number, sample size of CHR-P population and comparison group, type of comparison group, age and sex of CHR-P individuals, type of prognostic assessment, interventions, quality assessment (using AMSTAR [Assessing the Methodological Quality of Systematic Reviews]), and key findings with their effect sizes. Findings In total, 42 meta-analyses published in the past 6 years and encompassing 81 outcomes were included. For the detection component, CHR-P individuals were young (mean [SD] age, 20.6 [3.2] years), were more frequently male (58%), and predominantly presented with attenuated psychotic symptoms lasting for more than 1 year before their presentation at specialized services. CHR-P individuals accumulated several sociodemographic risk factors compared with control participants. Substance use (33% tobacco use and 27% cannabis use), comorbid mental disorders (41% with depressive disorders and 15% with anxiety disorders), suicidal ideation (66%), and self-harm (49%) were also frequently seen in CHR-P individuals. CHR-P individuals showed impairments in work (Cohen d = 0.57) or educational functioning (Cohen d = 0.21), social functioning (Cohen d = 1.25), and quality of life (Cohen d = 1.75). Several neurobiological and neurocognitive alterations were confirmed in this study. For the prognosis component, the prognostic accuracy of CHR-P instruments was good, provided they were used in clinical samples. Overall, risk of psychosis was 22% at 3 years, and the risk was the highest in the brief and limited intermittent psychotic symptoms subgroup (38%). Baseline severity of attenuated psychotic (Cohen d = 0.35) and negative symptoms (Cohen d = 0.39) as well as low functioning (Cohen d = 0.29) were associated with an increased risk of psychosis. Controlling risk enrichment and implementing sequential risk assessments can optimize prognostic accuracy. For the intervention component, no robust evidence yet exists to favor any indicated intervention over another (including needs-based interventions and control conditions) for preventing psychosis or ameliorating any other outcome in CHR-P individuals. However, because the uncertainty of this evidence is high, needs-based and psychological interventions should still be offered. Conclusions and Relevance This review confirmed recent substantial advancements in the detection and prognosis of CHR-P individuals while suggesting that effective indicated interventions need to be identified. This evidence suggests a need for specialized services to detect CHR-P individuals in primary and secondary care settings, to formulate a prognosis with validated psychometric instruments, and to offer needs-based and psychological interventions. Question What is the status of current clinical knowledge in the detection, prognosis, and interventions for individuals at risk of psychosis? Findings In this review of 42 meta-analyses encompassing 81 outcomes, detecting individuals at risk for psychosis required knowledge of their specific sociodemographic, clinical, functional, cognitive, and neurobiological characteristics, and predicting outcomes was achieved with good accuracy provided that assessment tools were used in clinical samples. Evidence for specific effective interventions for this patient population is currently insufficient. Meaning Findings of this review suggest that, although clinical research knowledge for psychosis prevention is substantial and detecting and formulating a prognosis in individuals at risk for psychosis are possible, further research is needed to identify specific effective interventions in individuals with sufficient risk enrichment. This review synthesizes research findings from 42 meta-analyses that assessed detection, prognosis, and interventions for the prevention of psychosis and offers updated practice recommendations.

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Avolition, a deficit in goal-directed behavior, is a key aspect of negative symptoms. It is highly prevalent in schizophrenia and is associated to poor functional outcome and to measures of real life motivation, indicating that central to the concept is the lack of interest and motivation. In this study we tested the hypothesis that avolition is related to altered connectivity within dopaminergic cortico-striatal circuits involved in motivation processes. Since dopamine input to these circuits derives mostly from the ventro-tegmental area (VTA), we investigated the relationships between the resting-state functional connectivity (RS-FC) of the VTA and avolition in twenty-six subjects with schizophrenia (SCZ), treated with second-generation antipsychotics only, compared to twenty-two healthy controls (HC). SCZ, in comparison to HC, showed significantly reduced RS-FC of the VTA with bilateral ventro-lateral prefrontal cortex (VLPFC), bilateral insular cortex (IC) and right (R) lateral occipital complex (LOC) and increased RS-FC of the VTA with bilateral dorso-lateral prefrontal cortex (DLPFC). Significant negative correlations were found between avolition and RS-FC of the VTA with the bilateral IC, R VLPFC and R LOC. According to our findings, avolition is linked to a disconnectivity of the VTA from several key cortical regions involved in the integration of value information with action selection. These findings are in line with translational animal models of “auto-activation apathy”.

Objective: Previous studies have proposed music therapy (MT) as a useful rehabilitation approach for patients with psychosis, but few studies have focused on acute settings. The aim of the study was to evaluate the effects of a structured MT program on clinical and social functioning indices of patients with psychosis while hospitalized in an emergency psychiatric ward. Method: The intervention followed a modified approach to Benenzon's MT model and was delivered biweekly to 61 patients with psychosis consecutively admitted to our ward. Before and after the MT program, all subjects were administered the Brief Psychiatric Rating Scale (BPRS) for assessment of general psychopathology, the Hospital Anxiety and Depression Scale (HADS) for affective symptomatology, the Clinical Global Impression (CGI) scale for severity of symptoms, and the Global Assessment of Functioning (GAF) scale for psychosocial functioning. Results: A repeated-measures analysis of variance revealed that patients who underwent the MT intervention had a statistically significant reduction of BPRS and CGI scores, compared to the control group; furthermore, the BPRS anxiety/depression factor and the HADS scores for affective symptomatology significantly decreased after the observation period compared to controls. Conclusion: Our results are in line with previous studies showing favorable effects of MT in patients with psychosis, in particular on affective symptomatology, but extend this observation to an emergency setting with short periods of hospital stay.

Background:Positive findings on early detection and early intervention services have been consistently reported from many different countries. The aim of this study, conducted within the European Brain Council project “The Value of Treatment”, was to estimate costs and the potential cost- savings associated with adopting these services within the context of the Czech mental health care reform.Methods:Czech epidemiological data, probabilities derived from meta-analyses, and data on costs of mental health services in the Czech Republic were used to populate a decision analytical model. From the health care and societal perspectives, costs associated with health care services and productivity lost were taken into account. One-way sensitivity analyses were conducted to explore the uncertainty around the key parameters.Results:It was estimated that annual costs associated with care as usual for people with the first episode of psychosis were as high as 46 million Euro in the Czech Republic 2016. These annual costs could be reduced by 25% if ED services were adopted, 33% if EI services were adopted, and 40% if both, ED and EI services, were adopted in the country. Cost-savings would be generated due to decreased hospitalisations and better employment outcomes in people with psychoses.Conclusions:Adopting early detection and early intervention services in mental health systems based on psychiatric hospitals and with limited access to acute and community care could generate considerable cost- savings. Although the results of this modelling study needs to be taken with caution, early detection and early intervention services are recommended for multi-centre pilot testing accompanied by full economic evaluation in the region of Central and Eastern Europe.

The avolition/apathy domain of negative symptoms includes motivation- and pleasure-related impairments. In people with schizophrenia, structural and functional abnormalities were reported in key regions within the motivational reward system, including ventral-tegmental area (VTA), striatum (especially at the level of the nucleus accumbens, NAcc), orbitofrontal cortex (OFC), as well as amygdala (Amy) and insular cortex (IC). However, the association of the reported abnormalities with avoliton-apathy is still controversial. In the present study, we investigated white matter connectivity patterns within these regions, using a probabilistic analysis of diffusion tensor imaging (DTI) data, in male subjects with schizophrenia. Thirty-five male subjects with schizophrenia (SCZ) and 17 male healthy controls (HC) matched for age, underwent DTI. SCZ were evaluated using the Schedule for Deficit Syndrome (SDS), the Positive and Negative Syndrome Scale (PANSS), and the MATRICS Consensus Cognitive Battery (MCCB). Probabilistic tractography was applied to investigate pathways connecting the Amy and the NAcc with the OFC and IC. Reduced fractional anisotropy (FA) was observed in left Amy–ventral anterior IC connections, in SCZ compared with controls. This abnormality was negatively correlated with avolition/apathy but not with expressive deficit scores. SCZ showed also a reduced connectivity index between right NAcc and medial OFC, as compared with controls. Finally, the left NAcc-dorsal anterior IC connectivity index was negatively correlated with working memory scores. Our results indicate that only the avolition/apathy domain of negative symptoms is related to abnormal connectivity in the motivation-related circuits. The findings also demonstrate that distinct alterations underlie cognitive impairment and avolition/apathy.

Davide Palumbo,* Armida Mucci,* Giuseppe Piegari, Valentina D’Alise, Annapaola Mazza, Silvana Galderisi Department of Psychiatry, University of Campania Luigi Vanvitelli, Naples, Italy *These authors contributed equally to this work Abstract: The purpose of this pilot study was to assess the efficacy of a new social cognition (SC) remediation intervention, the Social Cognition Individualized Activities Lab (SoCIAL), for subjects with schizophrenia. The training includes a module for emotion recognition and one for theory of mind. A comparison with a validated cognitive remediation intervention, the Social Skills And Neurocognitive Individualized Training (SSANIT), was conducted to verify the efficacy of the SoCIAL in improving SC. Ten stabilized patients with schizophrenia accepted to participate. Five patients were randomized to SoCIAL and five to SSANIT. The SoCIAL intervention includes individual sessions of neurocognitive individualized training (NIT) and group sessions of SC training. SSANIT includes individual sessions of NIT and group sessions of social skills individualized training. The interventions were matched for the overall treatment duration (20 weeks) and for the frequency of the sessions (two times a week, one for SoCIAL or social skills individualized training and one for NIT, with a duration of 80 minutes for each session). Results showed a significant treatment effect (effect size: Cohen’s d 0.32) on the primary outcome; in fact, only the SoCIAL intervention improved theory of mind. Patients receiving the SoCIAL intervention also showed an improvement of avolition. These preliminary findings support further development of the SoCIAL and suggest that cognitive remediation should include an SC module. Keywords: cognitive remediation, psychiatric rehabilitation, negative symptoms, avolition, MATRICS consensus cognitive battery, MCCB

Negative symptoms of schizophrenia are associated with poor functional outcome and place a substantial burden on people with this disorder, their families, and health-care systems. We summarise the evolution of the conceptualisation of negative symptoms, the most important findings, and the remaining open questions. Several studies have shown that negative symptoms might be primary to schizophrenia or secondary to other factors, and that they cluster in the domains of avolition–apathy and expressive deficit. Failure to take this heterogeneity into account might hinder progress in research on neurobiological substrates and discoveries of treatments for primary or enduring negative symptoms. Improvement in recognition and routine assessment of negative symptoms is instrumental for correct management of secondary negative symptoms that are amenable to treatment. If substantial progress is to be made in the understanding and treatment of negative symptoms, then advances in concepts and assessment should be integrated into the design of future studies of these symptoms.

IntroductionNegative symptoms are a core feature of schizophrenia but their pathophysiology remains elusive. They cluster in a motivation-related domain, including apathy, anhedonia, asociality and in an expression-related domain, including alogia and blunted affect.AimOur aim was to investigate the different neurobiological underpinnings of the two domains using the brain electrical microstates (MS), which reflect global patterns of functional connectivity with high temporal resolution.MethodWe recorded multichannel resting EEGs in 142 schizophrenia patients (SCZ) and in 64 healthy controls (HC), recruited to the Italian network for research on psychoses study. Four microstates (MS) classes were computed from resting EEG data using the K-Mean clustering algorithm. Pearson's coefficient was used to investigate correlations of microstates measures with negative symptom domains, assessed by the Brief Negative Symptoms Scale (BNSS).ResultsSCZ, in comparison to HC, showed increased contribution and duration of MS-C. Only the avolition domain of BNSS correlated with the contribution and occurrence of MS-A. Within the same domain, anticipatory anhedonia, apathy and asociality, but not consummatory anhedonia, were positively correlated with contribution and occurrence of microstate A. Asociality was also negatively correlated with contribution and occurrence of MS-D.ConclusionOur findings support different neurobiological underpinnings of the negative symptom domains, avolition and expressive deficit. Furthermore, our results lend support to the hypothesis that only anticipatory anhedonia is linked to the avolition domain of the negative symptoms. Mixed results in the literature concerning the presence of MS-A and D abnormalities in schizophrenia might be related to the syndrome heterogeneity.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Negative symptoms have long been conceptualized as a core aspect of schizophrenia. They play a key role in the functional outcome of the disorder, and their management represents a significant unmet need. Improvements in definition, characterization, assessment instruments and experimental models are needed in order to foster research aimed at developing effective interventions. A consensus has recently been reached on the following aspects: a) five constructs should be considered as negative symptoms, i.e. blunted affect, alogia, anhedonia, asociality and avolition; b) for each construct, symptoms due to identifiable factors, such as medication effects, psychotic symptoms or depression, should be distinguished from those regarded as primary; c) the five constructs cluster in two factors, one including blunted affect and alogia and the other consisting of anhedonia, avolition and asociality. In this paper, for each construct, we report the current definition; highlight differences among the main assessment instruments; illustrate quantitative measures, if available, and their relationship with the evaluations based on rating scales; and describe correlates as well as experimental models. We conclude that: a) the assessment of the negative symptom dimension has recently improved, but even current expert consensus‐based instruments diverge on several aspects; b) the use of objective measures might contribute to overcome uncertainties about the reliability of rating scales, but these measures require further investigation and validation; c) the boundaries with other illness components, in particular neurocognition and social cognition, are not well defined; and d) without further reducing the heterogeneity within the negative symptom dimension, attempts to develop successful interventions are likely to lead to great efforts paid back by small rewards.

IntroductionThe effects of chronic antipsychotic administration on the human brain are debated. In particular, first-generation (FGAs) and second-generation antipsychotics (SGAs) seem to have different impacts on brain function and structure in subjects with schizophrenia. Few studies have investigated the effect of chronic administration of FGAs and SGAs on indices of brain function, such as event-related potentials (ERP) or neuropsychological performance.ObjectivesWithin the Italian Network for Research on Psychoses study, subjects stabilized on FGAs or SGAs were compared on P300, an ERP component, thought to reflect attention, working memory and context integration and on neurocognitive indices.MethodsERPs were recorded in 110 chronic, stabilized patients with Schizophrenia (28 used FGAs) during a standard auditory oddball task. P300 latency and amplitude were assessed at Pz channel. MATRICS Consensus Cognitive Battery (MCCB) was used for cognitive assessment.ResultsCompared with the SGAs group, patients on FGAs showed significant increased P300 latency (P = 0.003; Cohen's d = 0.67) and significant decreased P300 amplitudes (P = 0.023; Cohen's d = 0.38). The two groups did not differ on psychopathology and MCCB scores. Multiple linear regressions revealed that “FGAs vs. SGAs” (β = 0.298, P = 0.002) and MCCB neurocognitive composite T-score (β = –0.273, P = 0.004) were independent predictors of P300 latency, whereas only age (β = –0.220, P = 0.027) was an independent predictor of P300 amplitude.ConclusionsFGAs seem to affect the functional brain activity more than SGAs, particularly slowing cortical processing. Our results suggest that discrepant findings concerning P300 latency in schizophrenia might be related to the type of antipsychotic treatment used. Longitudinal studies are needed to further address this issue.Disclosure of interestThe authors have not supplied their declaration of competing interest.

IntroductionSocial 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.AimsWithin 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.MethodsStructural 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.ResultsIn 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.ConclusionsBetter understanding of how neurocognitive dysfunction and social cognition deficits relate to one another may guide efforts toward targeted treatment approaches.Disclosure of interestAM 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.

IntroductionImpairment of neurocognitive functions, such as attention, memory or executive functions, as well as of social cognition, particularly of affect recognition and theory of mind, are frequently observed in people with Schizophrenia or other psychotic disorders. These dysfunctions are associated with poor real-life functioning. Social cognition deficits mediate in part the impact of neurocognitive dysfunction on functional outcome.AimsTo review literature findings on prevalence, severity and association with functional outcome of neurocognitive and social cognitive deficits in schizophrenia and other psychotic disorders.MethodsWe searched PubMed for English/Italian or French full-text publications with the keywords.schizophr*/psychosis/psychot*/AND neurocognitive/cognitive/neuropsychological/memory/attention/”executive function”/learning/”social cognition”/”theory of mind”/”affect recognition”/”acial emotion recognition”/”emotional intelligence”/”emot* recognition”. Furthermore, we manually searched the reference lists of relevant papers, systematic reviews and meta-analyses.ResultsIn people with schizophrenia, schizoaffective disorder or bipolar disorder with psychotic features, neurocognitive and social cognition deficits were observed in all phases of the disorders, even after symptom remission. Some of these deficits were observed in subjects at high-risk to develop schizophrenia before psychotic onset. In all these subjects, cognitive deficits are associated with worse psychosocial functioning and poor quality of life. Pharmacological treatments do not alleviate cognitive deficits, which can also limit the benefit of other psychological or psychosocial interventions.ConclusionsNeurocognitive and social cognition deficits need to be targeted by specific interventions to improve real-life functioning and quality of life of people with schizophrenia or psychotic disorders.Disclosure of interestAM 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.