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Previous works highlighted the relevance of automated language analysis for predicting diagnosis in schizophrenia, but a deeper language-based data-driven investigation of the clinical heterogeneity through the illness course has been generally neglected. Here we used a semiautomated multidimensional linguistic analysis innovatively combined with a machine-driven clustering technique to characterize the speech of 67 individuals with schizophrenia. Clusters were then compared for psychopathological, cognitive, and functional characteristics. We identified two subgroups with distinctive linguistic profiles: one with higher fluency, lower lexical variety but greater use of psychological lexicon; the other with reduced fluency, greater lexical variety but reduced psychological lexicon. The former cluster was associated with lower symptoms and better quality of life, pointing to the existence of specific language profiles, which also show clinically meaningful differences. These findings highlight the importance of considering language disturbances in schizophrenia as multifaceted and approaching them in automated and data-driven ways.

Cognitive reserve (CR), the brain's ability to cope with brain pathology to minimize symptoms, could explain the heterogeneity of outcomes in neuropsychiatric disorders, however it is still rarely investigated in schizophrenia. Indeed, this study aims to classify CR in this disorder and evaluate its impact on neurocognitive and socio-cognitive performance and daily functioning. A group of 106 patients diagnosed with schizophrenia was enrolled and assessed in these aereas: neurocognition, Theory of Mind (ToM) and daily functioning. A composite CR score was determined through an integration of the intelligence quotient and education and leisure activities. CR profiles were classified with a two-step cluster analysis and differences among clusters were determined with an analysis of variance (ANOVA). The cluster analysis was identified with three CR profiles characterized, respectively, by high, medium and low CR. ANOVA analysis showed significant differences on neurocognition, ToM and daily functioning between the clusters: people with higher CR reached significantly superior scores. This study suggests that greater general cognitive resources could act as a buffer against the effect of brain pathology, allowing patients to have a better cognitive performance, social outcome and quality of life.

Cognition remains one of the most critical features of the schizophrenia. A wide range of factors has been associated to neurocognition and, among these, sex and age of onset are two of the most consistently reported to influence the functional and cognitive outcome. This work aims to evaluate the effects of sex and age of onset and their interaction on cognition in 419 subjects with schizophrenia. Analyses of variance and analyses of covariance were performed to evaluate the effect of sex and age at onset on cognition. To model the possible interaction sex-onset on cognition, a separate slope regression analysis was performed. Analyses of variance showed significant differences between sexes for age and age at onset, both significantly higher among females, as well as for Executive Functions, with higher performance among males. When compared according to age at onset, late-onset patients performed better than both early- and intermediate-onset ones in Verbal Memory subtest, with a significant effect of length of illness. Moreover, early-onset patients showed a significantly lower IQ compared to both intermediate and late-onset ones, with no significant effect of length of illness. Finally, the separate slope regression revealed a significant interaction between sex and age at onset, with early-onset being associated to a worse global cognition only among male patients. Our finding of a significant sex-onset interaction effect on neurocognition sheds new light on the complex issue of cognitive heterogeneity in schizophrenia. Our data may help towards the development of personalized programs for preventive and rehabilitative purposes.

Objective Daily functional impairment is a main target of treatment in schizophrenia. Multiple rehabilitation treatments have been developed to improve patients' sociocognitive and neurocognitive abilities and to generalize the benefits to functioning. However, whether the effects of these treatments can be generalized and maintained remains equivocal. Our study aims to evaluate the stability and generalization of benefits, following combined Theory of Mind (ToM) and cognitive remediation (CR) trainings, compared with an active control group + CR, at a 3-year follow-up. Method Sixty-seven outpatients with schizophrenia who had completed an earlier study of ToM and CR were recruited for a 3-year follow-up assessment. We examined changes in ToM and functioning, at baseline, after treatment, and at follow-up. Results ANOVAs showed significant Time × Group interactions on ToM and functioning. ANOVAs showed significant differences between groups in effect sizes of ToM and functioning from before treatment to follow-up. Conclusions and implications for practice Posttraining ToM improvement was maintained at follow-up, and ToM + CR participants experienced greater functional improvement than participants in the control condition. This study represents the first attempt to report the stability and generalization of treatment effects obtained by combining CR and ToM interventions after 3 years. Combined sociocognitive and neurocognitive treatments can enhance rehabilitation practice for people with schizophrenia to achieve good results on both cognitive and functional outcomes and to maintain positive outcomes. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Psychotic symptoms are a cross-sectional dimension affecting multiple diagnostic categories, despite schizophrenia represents the prototype of psychoses. Initially, dopamine was considered the most involved molecule in the neurobiology of schizophrenia. Over the next years, several biological factors were added to the discussion helping to constitute the concept of schizophrenia as a disease marked by a deficit of functional integration, contributing to the formulation of the Dysconnection Hypothesis in 1995. Nowadays the notion of dysconnection persists in the conceptualization of schizophrenia enriched by neuroimaging findings which corroborate the hypothesis. At the same time, in recent years, psychedelics received a lot of attention by the scientific community and astonishing findings emerged about the rearrangement of brain networks under the effect of these compounds. Specifically, a global decrease in functional connectivity was found, highlighting the disintegration of preserved and functional circuits and an increase of overall connectivity in the brain. The aim of this paper is to compare the biological bases of dysconnection in schizophrenia with the alterations of neuronal cyto-architecture induced by psychedelics and the consequent state of cerebral hyper-connection. These two models of psychosis, despite diametrically opposed, imply a substantial deficit of integration of neural signaling reached through two opposite paths.

Language and communication disruptions in schizophrenia are at the center of a large body of investigation. Yet, the remediation of such disruptions is still in its infancy. Here we targeted what is known to be one of the most damaged language domains in schizophrenia, namely pragmatics, by conducting a pragmatics-centered intervention with a randomized controlled trial design and assessing also durability and generalization. To the best of our knowledge, this is the first study with these characteristics.Inspired by the Gricean account of natural language use, we tailored a novel treatment addressing the pragmatics of communication (PragmaCom) and we tested its efficacy in a sample of individuals with schizophrenia randomized to the experimental group or to an active control group. The primary outcome with respect to the efficacy of the PragmaCom was measured by changes in pragmatic abilities (as evaluated with the global score of the Assessment of Pragmatic Abilities and Cognitive Substrates test) from baseline to 12 weeks and at 3-month follow-up. The secondary outcome was measured by changes in metaphor comprehension, abstract thinking, and global functioning from baseline to 12 weeks and at 3-month follow-up.Relative to the control group, at post-test the PragmaCom group showed greater and enduring improvement in global pragmatic skills and in metaphor comprehension. At follow-up, these improvements persisted and the PragmaCom exerted beneficial effects also on functioning.Despite the limited sample size, we believe that these findings offer initial yet encouraging evidence of the possibility to improve pragmatic skills with a theoretically grounded approach and to obtain durable and clinically relevant benefits. We argue that it is time that therapeutic efforts embrace communicative dysfunctions in order to improve illness outcome.

The relationship between neurocognition and functioning among patients with schizophrenia is well documented. However, integrating neuropsychological, clinical and psychopathological data to better investigate functional outcome still constitutes a challenge. Artificial neural network-based modeling might help to better capture clinical heterogeneity by analyzing the non-linear relationships among multiple variables. Two hundred and fourteen clinically stabilized patients with schizophrenia were recruited and assessed for neurocognition, psychopathology and functioning. Artificial neural network analyses were conducted to yield significant predictors of functional outcome among clinical and cognitive variables and to build distinct functional Profiles, each characterized by a different medley of cognitive and clinical features. Twenty-two key predictors of daily functioning emerged, encompassing neurocognitive and clinical domains, with major roles for processing speed and attention. Four Profiles were constructed based on specific levels of functioning, each characterized by a distinct distribution of key clinical and neurocognitve measures. This study highlights the importance of a more in-depth investigation of cognitive and clinical heterogeneity. A better understanding of the building blocks of these Profiles would lead to more individualized rehabilitation treatments.

Cognitive deficits represent core features of schizophrenia, affecting quality of life and functioning. The excitatory amino acid transporter 2 (EAAT2) is responsible for the majority of glutamate reuptake and its activity is crucial for glutamatergic neurotransmission, prevention of excitotoxic damage and cerebral metabolism. Different studies reported that EAAT2 rs4354668 (−181 T/G) influences cognitive functions and brain structures in patients with schizophrenia. Specifically, the G allele, linked to lower EAAT2 expression, was associated with impaired prefrontal cognitive performance and reduced grey matter volumes. Cognitive remediation therapy (CRT) is one of the best available tool to treat cognitive deficits in schizophrenia, able to induce a neuroplastic modulation of cognitive functions. The present study aims to investigate the effects of rs4354668 on CRT outcome, also considering possible genotype interaction with antipsychotic (AP) treatment, since EAAT2 expression is negatively influenced by clozapine. We examined rs4354668 in 88 clinically stabilized patients with schizophrenia, treated with CRT and assessed at enrolment, at the end of CRT and after 3 months. We observed greater working memory improvements among patients carrying the T/T genotype, regardless of AP treatment. Moreover, we reported a significant interaction between pharmacological treatment and rs4354668 on executive functions, with greater improvements among T/T patients treated with APs other than clozapine. These observations suggest that impaired EAAT2 expression may attenuate CRT outcome. Moreover, our results indicate the possibility that rs4354668 could also differentially influence the response to CRT depending on the AP treatment.

Background Impairments in daily functioning characterize both autism spectrum disorder and schizophrenia. Research has shown that a subsample of schizophrenia patients presents autistic symptoms, leading to the hypothesis that their co-occurrence would be associated with a ‘double dose’ of deficit. A growing body of research examined this hypothesis by looking at the joint effect of autistic and positive psychotic symptoms, and yielded contrasting results, ranging from benefits to adverse effects. We hypothesized that the interactive effect of autistic and positive symptoms on functioning in schizophrenia might depend on the patients' symptom severity. Method In 170 schizophrenia patients, a two-step cluster analysis identified two groups of patients with different levels of autistic and positive symptom severity. Using general linear models, we examined the interactions of groups, autistic and positive symptoms on functioning. Results Autistic and positive symptoms were interactively associated with better functioning, but only in the symptomatically less severe patients. In contrast, autistic and positive symptoms were independently associated with worse functioning in the symptomatically more severe patients. These associations were observed above and beyond the effects of I.Q. and illness duration. Conclusions The findings highlight the complex role played by co-occurring autistic symptoms in schizophrenia, whose beneficial effects on functioning appear to depend on patients’ psychopathological severity. Our findings may help to reconcile the seemingly contrasting results from previous studies, and to understand the heterogeneity of behavior and functional outcomes in schizophrenia. This study underscores the potential utility of routinely assessing autism in schizophrenia, in order to better formulate individualized rehabilitative programs.

Treatment-resistant schizophrenia (TRS) represents a main clinical issue, associated with worse functional outcome and higher healthcare costs. Clozapine is the most effective antipsychotic for TRS, although 40% of resistant patients, defined as ultra-treatment resistant (UTR), are clozapine-refractory. Previous literature suggests that TRS is characterized by worse cognitive functioning and a more disrupted neurobiological substrate, but only few studies focused on UTR schizophrenia. Moreover, despite this evidence and the central role of cognition, to date no study has investigated long-term cognitive outcome in TRS. Based on these premises, this study aims to analyze cross-sectional and long-term cognitive functioning of patients with schizophrenia, stratified according to antipsychotic response: first-line responders (FLRs), clozapine responders (CRs) and UTRs. We analyzed cross-sectional and retrospective cognitive evaluations of 93 patients with schizophrenia (32 FLRs, 42 CRs, 19 UTRs) over a mean follow-up period of 9 years, also taking into account possible influencing factors such as clinical severity and antipsychotic load. Analyses showed that UTR is associated with overall impaired cognitive functioning and represents the main predictor of long-term cognitive decline. We observed no significant differences between FLR and CR patients, which showed moderate cognitive improvement over time. This is the first study to report an association of treatment resistance with longitudinal cognitive course in schizophrenia, indicating that UTR is correlated with cognitive decline over time. This decline may either be a consequence of the persistence of psychotic symptoms or depend on a distinct and more disrupted neurobiological substrate affecting both cognition and antipsychotic response.

Clozapine is the only evidence-based drug indicated for Treatment Resistant Schizophrenia but it is largely underprescribed, partially due to its life-threatening adverse effects (AEs). However, clozapine treatment is burdened by other common AEs as constipation, hypersalivation, postural hypotension, tachycardia and metabolic abnormalities. Few studies have investigated sex-related differences in clozapine's tolerability, reporting women to experience more frequently weight gain, hyperglycemia and constipation, while men hypertension and dyslipidemia. Based on these premises, we investigated clinical, psychopathological and metabolic sex-related differences among 147 treatment-resistant patients treated with clozapine, with a specific focus on non-life-threatening AEs. We observed significant higher prevalence of tachycardia in men, and of orthostatic hypotension and constipation in women. Concerning metabolic alterations, we observed significant lower levels of HDL-cholesterol and higher prevalence of hypertriglyceridemia among men, whereas females showed higher prevalence of abdominal obesity. Consistently with previous studies, our data confirm the presence of sex-related differences in clozapine tolerability, with a main effect of sex especially for tachycardia, postural hypotension and constipation. Although non-life-threatening, these common AEs significantly affect patients' quality of life, undermine compliance and cause treatment discontinuation. A better understanding of this topic could contribute to tailor therapeutic approaches, thus improving tolerability, compliance and clinical stability.

Introduction: Cognitive deficits and metabolic disturbances are among the main determinants of functional impairment and reduced life expectancy in patients with schizophrenia, and they may share underlying biological mechanisms. Among these, interleukin-1β (IL-1β), a key mediator of inflammatory response, is of particular interest. IL-1β C-511T polymorphism has been associated with neuropsychiatric conditions and, in the general population, with cognitive and metabolic alterations. This study aims to evaluate the effects of the IL-1β C-511T polymorphism on both cognition and metabolic syndrome in a sample of patients affected by schizophrenia, with a focus on sex differences. Methods: 138 patients with schizophrenia were assessed for metabolic parameters and neurocognitive measures by means of the Brief Assessment of Cognition Scale. The effects of IL-1β C-511T polymorphism on cognition and metabolic syndrome were evaluated in the context of general linear models. Results: The analysis showed a significant interaction between IL-1β genotype and sex on 2 core cognitive domains. In detail, among CC homozygous, females outperformed males on processing speed, while among T carriers, males outperformed females on executive functions. A significant interaction also emerged between metabolic syndrome, sex, and IL-1β genotype for executive functions, with worse performance for T carrier females with metabolic syndrome. No significant direct effect was observed for metabolic syndrome on cognition. Conclusion: These findings support the hypothesis that IL-1β polymorphism could play a key role in mediating the complex and refined relationship between metabolic syndrome and cognitive performance.

OBJECTIVE: Pragmatics refers to the capacity to understand the speaker's meaning and thus to appropriately engage in a conversation. This study aims at establishing the role of communicative-pragmatic abilities in functioning, defined as a set of daily activities, in schizophrenia. This would contribute to enrich current models of the neurocognitive predictors of functioning, which have so far neglected pragmatics. METHOD: One hundred people with schizophrenia underwent a comprehensive assessment including functioning, cognition, theory of mind (ToM), and pragmatics. We tested the effects of cognition as a predictor of functioning, first mediated by ToM, then sequentially mediated by ToM and pragmatics. Next, we explored the predictive effect of cognition, sequentially mediated by ToM and pragmatics, on different functional domains (i.e., interpersonal relations, instrumental role, and personal autonomy). RESULTS: The first model confirmed that ToM acts as a mediator between cognition and functioning. Importantly, the second model highlighted also the main mediating role of pragmatics. The mediation models on different functional domains showed that, when considered together, both pragmatics and ToM significantly influenced all aspects of functioning. When considered separately, pragmatics was significantly related to interpersonal functioning, while ToM to personal autonomy. CONCLUSIONS: Innovatively, our findings highlight that pragmatics has a main role, both direct and indirect, in affecting functioning. Of particular interest is that the impact of pragmatics encompasses different functional domains, and especially interpersonal functioning. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Computer-assisted cognitive remediation (CACR) is a computer-based rehabilitation treatment aimed at improving cognition and at developing strategies that can be applied to various functional areas. Different protocols are currently used with great variability over the intensity and duration of treatments. In this study, we evaluated the effects of a brief and intensive CACR training (i.e., 15 sessions for 3 weeks) on cognitive domains, as well as the durability of cognitive gains and their generalization to functional areas, 3 months after CACR training. Thirty-eight patients with schizophrenia were recruited and assessed for psychopathology, cognitive performance, and functioning before the rehabilitative intervention. Patients were reassessed for cognition after CACR rehabilitation. Moreover, a subsample of 13 patients was evaluated for cognition and functioning 3 months after CACR completion. Results show significant improvements in multiple cognitive domains after CACR. Furthermore, 3 months after CACR completion, significant improvements were also detected in executive functions and daily functioning. This study suggests that a brief and intense CACR training is effective on cognitive and functional domains and that it could be feasible and affordable for health care services, thus offering patients the best options for fulfilling recovery goals.

Anxiety is among the least studied features of schizophrenia, despite evidence of its significant impact on disease outcome. This work aims to investigate the anxiety construct in a sample of outpatients with schizophrenia, exploring the interplay of clinical, neurocognitive and social cognitive domains, as well as adverse childhood experiences and their relative contribute in determining anxiety. A forward stepwise regression model was performed on a sample of 68 outpatients with schizophrenia, to examine the predictive effect of different variables on anxiety. Predictors have been selected based on previous literature and include psychopathological, neurocognitive and social cognitive measures, as well as premorbid environmental factors. The analysis showed a significant contribution of childhood adverse experiences, followed by personal distress, while no significant effect was found for symptom's severity, nor global cognitive efficiency. The results show that anxiety is mainly determined by early environmental factors, as well as by socio-cognitive dimensions, such as personal distress. Data also suggest that anxiety can be considered as an independent construct, rather than as a mere epiphenomenon of the illness. The study has clinical implications as it highlights the importance of implementing both standardized assessments and group interventions specifically targeting anxiety in schizophrenia.

OBJECTIVE Theory of Mind (ToM) is a multifaceted construct that involves mental states attribution in social interactions. Patients with schizophrenia are impaired in ToM abilities, but recent studies showed that a non-negligible number of patients perform within normal ranges or close to normal, whereas other patients are very impaired in ToM tasks. The present study aims to comprehensively analyze differences between patients with "poor" and "fair" mentalizing abilities, as identified through a median-split procedure on mental state attribution task, and healthy controls, as well as to explore the role of clinical, demographical, and neurocognitive predictors of ToM performance within groups. METHOD One hundred twenty-two patients with schizophrenia and 67 healthy controls were assessed for ToM, attention, and executive functioning. In addition, patients' daily functioning and psychopathological profiles were also rated. RESULTS "Fair" mentalizers perform significantly better than "poor" mentalizers on cognitive abilities and quality of life and they differ from healthy controls in neurocognition and cognitive ToM performance, even though the global ToM performance is similar. Furthermore, regression models showed distinct contributing factors in each sub group: ToM is related to neurocognitive abilities and education in healthy subjects, while it is mainly associated with attention in "fair" group and it is related to clinical variables and executive functions in "poor" mentalizers. CONCLUSIONS Although preliminary, these data shed new light on the heterogeneity of ToM deficit among patients with schizophrenia and could reflect on daily clinical practice, as they are important to develop individualized step-by-step rehabilitative programs. (PsycINFO Database Record

Objectives: Cognitive reserve (CR), defined as individual differences in the ability to cope with brain damage, seem to be associated to the several psychopathological features in psychiatric patients, such as the functional outcome. This study aims to identify different profiles of CR by combining intelligence quotient (IQ) and premorbid functioning, two measures independently associated to CR in previous works, as well as to explore CR effect on both Theory of Mind (ToM) baseline performance and improvement after socio-cognitive trainings. Methods: Sixty patients with chronic schizophrenia underwent a socio-cognitive rehabilitation. All patients were assessed for psychopathology, neurocognition, and ToM at baseline and post-treatment. CR profiles were explored with K-means cluster analysis, while differences between clusters in both baseline assessments and post-treatment ToM improvement, were analyzed by means of analysis of variance and repeated measures analysis of covariance. Results: The analysis revealed three CR profiles, respectively, characterized by low early premorbid functioning and mild intellectual impairment, average/high early premorbid functioning trend with moderate intellectual impairment and good early premorbid functioning associated to IQ within normal limits. Analyses showed a significant effect of CR on both baseline ToM performance and treatment outcome: patients with higher CR reached significantly better ToM scores. Conclusions: These results underline the clinical relevance of defining CR profiles of patients to customize trainings: subjects with a lower CR may benefit from more intensive programs. A deeper knowledge about CR may considerably increase our understanding of individual differences and thus potentiate treatment outcome. (JINS, 2018, 24, 563–571)

Neuropsychological impairments represent a central feature of psychosis-spectrum disorders. It is characterized by a great both within- and between-subjects variability (i.e. cognitive heterogeneity), which needs to be better disentangled. The present study aimed to describe the distribution of performance on the Brief Assessment of Cognition in Schizophrenia (BACS) by using the Equivalent Scores, in order to balance statistical methodological problems. To do so, cognitive performance groups were branded, identifying the main factors contributing to cognitive heterogeneity. A sample of 583 patients with a diagnosis of Schizophrenia or Psychotic Disorder Not Otherwise Specified was enrolled and assessed for neurocognition and intellectual level. K-means cluster analysis was performed based on BACS Equivalent Scores. Differences among clusters were analyzed throughout Analysis of Variance and Discriminant Function Analysis in order to identify the most significant predictors of cluster membership. For each cognitive task, roughly 40% of patients displayed poor performance, while up to 63% displayed a symbol-coding deficit. K-means cluster analysis depicted three profiles characterized by "near-normal" cognition, widespread impairment, and "borderline" profile. Discriminant analysis selected Verbal IQ and diagnosis as predictors of cluster membership. Our findings support the usefulness of Equivalent Scores and cluster analysis to explain cognitive heterogeneity, and tailor better interventions.

Aim Recovery, or functional remission represents the ultimate treatment goal in schizophrenia. Despite its importance, a standardized definition of remission is still lacking, thus reported rates significantly vary across studies. Moreover, the effects of rehabilitative interventions on recovery are still poorly investigated. This study aims to evaluate recovery in a sample of patients with chronic schizophrenia engaged in rehabilitation programs and to explore contributing factors, with a focus on of socio-cognitive rehabilitative interventions. Methods Data from 104 patients with schizophrenia treated either with a standard rehabilitation program including cognitive remediation (n = 46) or the latter plus a specific socio-cognitive intervention (n = 58) and assessed for psychopathology, cognition, social cognition and Quality of Life Scale (QLS), were retrospectively analyzed for this study. Results Recovery, evaluated with QLS, was achieved by 56.76% of patients in our sample. While no effects were observed for clinical, cognitive and socio-cognitive variables, the participation to the socio-cognitive rehabilitative interventions was positively associated to recovery. Conclusion Results point out that high rates of recovery can be achieved in patients treated with psycho-social interventions and suggest that rehabilitative programs targeting social cognition may further facilitate the process of recovery. If confirmed, these results may have relevant implications for daily clinical practice and service provision, allowing clinicians to develop and optimize specific rehabilitation programs in order to promote recovery.

Impairment in daily functioning still represents a major treatment issue in schizophrenia and a more in-depth knowledge of underlying constructs is crucial for interventions to translate into better outcomes. This study aims to model factors influencing both functional capacity and real-life behaviour in a sample of outpatients with chronic schizophrenia, through a comprehensive assessment including evaluations of psychopathology, cognitive and social cognitive abilities, premorbid adjustment, family environment and early childhood experiences. No significant correlation was observed between functional capacity and real-life behaviour. Functional capacity was significantly predicted by IQ, while real-life behaviour was significantly predicted by empathy, affect recognition and symptoms. Functional capacity seems mainly related to neurocognition, whereas real-life behaviour appears more complex, requiring the integration of different factors including symptoms, with a major role of empathy. Results thus support a divergence between the two constructs of functioning and their underlying components and highlight the need to target both dimensions through individualized sequential rehabilitation programs in order to optimize functional outcome.

In schizophrenia employment rate is dramatically low, also among patients receiving job support interventions. Recent studies showed a direct relationship between neurocognitive deficits and work functioning, as well as proving the benefits of combined neurocognitive and work interventions. Current evidence also supports a role of Theory of Mind (ToM), on work functioning. However, the effect of integrated rehabilitation programmes including a social cognitive training on job outcome is still less explored. The aim of this pilot study is to investigate the relationship between work competence and clinical factors, neurocognitive and ToM abilities, as well as to explore the effect of neurocognitive and ToM treatments combined with work therapy. Thirty-seven outpatients with schizophrenia were assigned to either a Computer-assisted Cognitive Remediation (CACR) plus work therapy group (WTG) or to CACR and WTG added to ToM Intervention, both followed by a job support programme. All patients were assessed for psychopathology, neurocognition, ToM and work functioning. Work outcome was significantly predicted by age at onset, neurocognitive abilities and the degree of ToM improvement after the specific intervention. This study provides preliminary insight on predictors of work competence in schizophrenia, highlighting the importance of ToM abilities.

Objectives:Premorbid dysfunction during childhood and adolescence is well documented in patients with schizophrenia. Literature pointed out multiple premorbid trajectories leading to different patients’ cognitive status, symptomatology, and global functioning after disease onset. This study aimed at identifying groups of premorbid trajectories and disentangling between group differences in clinical and cognitive measures, focusing on theory of mind (ToM) and autistic traits (ATs).Methods:Ninety-seven patients with schizophrenia were recruited and assessed for cognitive and ToM abilities, psychopathology, and ATs. A two-step cluster analysis identified three different groups of patients based on premorbid adjustment during childhood, adolescence, and late adolescence (i.e., stable-good, stable-poor, and “deteriorating”).Results:Compared to 66 healthy controls, results showed a widespread impairment in cognitive and ToM abilities among all groups of patients, except for affective ToM and executive functions in the stable-good group. Moreover, the stable-poor group exhibited more pronounced ATs and a more severe ToM impairment, compared to the other two groups of patients.Conclusions:Our findings highlight the existence of a group of patients with poor premorbid adjustment since childhood, more pronounced ATs and a severe ToM impairment affecting those basic mentalizing skills that are usually preserved in schizophrenia. Results might have intriguing implications in identifying underpinning endophenotypes and implementing cutting-edge rehabilitation programs.

The present study aims at evaluating the impact of anxiety on functional outcome in patients with schizophrenia, also taking into account the other main predictors of functioning identified by literature, to disentangle specific subcomponents which contribute to functional outcome. One hundred five patients with DSM-IV-TR schizophrenia were recruited and underwent a broad functional, psychopathological, and clinical-neuropsychological battery. A forward stepwise regression model was used to assess the predictive effect of anxiety and other factors on daily functioning, showing significant results only for global neurocognitive status and anxiety. These results confirm the role of neurocognition and are also in line with the hypothesis that trait anxiety has a direct impact on functional outcome. Overall, the findings support the role of anxiety as a core feature of schizophrenia pathology, with important implications for both research and clinical settings.

Intellectual abilities display high heterogeneity in patients with schizophrenia that might depend on the interaction among neurodevelopmental processes, environmental factors and neurocognitive decline. This study aimed to disentangle the interplay between intellectual level, cognitive status and each cognitive domain, with a focus on speed-related abilities, also including pre-morbid factors. In details, by means of cluster analysis, we identified both in global sample of 452 patients affected by schizophrenia and in a subsample with high pre-morbid functioning, different profiles based on current intellectual level and global cognitive status, analysing the distribution of deficits in each cognitive domains between groups. Then, through regression models, we analysed the contribution of speed-related domains and global cognitive profile to each other cognitive function. Considering the whole sample, results highlight three groups (high, medium and low cognitive level), while among patients with high pre-morbid level, the heterogeneity was best captured by two groups (high and medium level). Still, within each group, a small to high percentage of patients achieved normal score in neurocognitive abilities depending on the cluster they belong to. Speed of processing and psychomotor coordination resulted impaired in all clusters, even in patients with high pre-morbid functioning. The regression analyses revealed significant effects of both cognitive profile and speed-dependent domains on the other cognitive abilities. This study confirms, in a large sample, previous data about the heterogeneity of intellectual and neurocognitive functioning in schizophrenia and highlights the main role of speed-dependent neurocognitive functioning, also as an important target of rehabilitation.

Cognitive impairments are considered core features of schizophrenia and are recognized as the most important predictors of functional outcome and quality of life. A better study of the mechanisms underlying the cognition is of extreme relevance. Literature has shown that several genetic and environmental factors affect cognitive performance. In particular, the interaction between Catechol-O-Methyltransferase (COMT) gene and cannabis use has gained increasing attention in the past years. Based on these premises, the present study, aimed to analyze the interplay between cannabis use and COMT polymorphism on cognitive performance in a sample of 135 patients with chronic schizophrenia. Patients were assessed for neurocognitive measures with a broad battery, genotyped for COMT Val158Met polymorphism from peripheral blood sample, and evaluated with a semi-structured interview in order to establish the history of cannabis abuse. Results showed a significant interaction effect between COMT polymorphism and cannabis use on verbal fluency and speed of processing. The analysis revealed significant differences between subjects COMT Val/Val homozygous and Met carriers with history of cannabis use, with a better performance on both tasks among the Met carriers group. These data are in line with literature on healthy subjects that suggests a more detrimental effect of cannabis among subjects with Val/Val genotype. In conclusions, results highlight the need to better disentangle the biological pathways in which cannabis use and COMT are converging, as possible treatment targets, as well as the importance to assess these factors in clinical to optimize individualized interventions.

Literature has recently identified a discrete subgroup of patients affected by schizophrenia that also present autistic traits (ATs), showing a peculiar cognitive, clinical and functional profile. Theory of Mind (ToM) represents a core, impaired feature in both schizophrenia and Autism Spectrum Disorder (ASD), ToM in patients with schizophrenia and ATs has yet to be investigated. Thus, this study aims, on the one hand, to assess differences among patients with and without ATs on clinical, cognitive and ToM abilities as well as in daily functioning; on the other hand, to compare the efficacy on mentalizing abilities of a specific ToM training in these two groups.Ninety-six patients with schizophrenia were enrolled and underwent a broad cognitive, social-cognitive and functional assessment before and after the ToM training.ANOVAs revealed that patients with schizophrenia and ATs are more impaired in cognition, ToM, in premorbid and daily functioning as well as in clinical features, as compared to patients without ATs. This latter group also showed a general improvement in mentalizing abilities after ToM training, while patients with schizophrenia and ATs did not, with a significant time × group interaction on ToM abilities.These data shed new light on the relation among schizophrenia and ATs, highlighting that patients with these traits are highly impaired in ToM abilities. Thus, ATs seem to limit the effectiveness of ToM training, having implications in clinical and rehabilitative practice. Keywords: Schizophrenia, Autistic traits, Social cognition, Rehabilitation

Premorbid adjustment has been associated with several outcomes in schizophrenia and has been proposed as an index of cognitive reserve. This study aims to comprehensively analyse the relation between premorbid adjustment and clinical, neurocognitive, socio-cognitive and functional assessments, as well as to investigate the effect of premorbid adjustment on cognitive improvements after a cognitive remediation therapy protocol. Seventy-nine clinically stabilised outpatients with schizophrenia underwent a combined intervention consisting of cognitive remediation therapy added to standard rehabilitation therapy. All patients were assessed at baseline for psychopathology, premorbid adjustment, intellectual level, cognition and functioning. Cognitive evaluations were also repeated after the intervention. At baseline, significant correlations were observed between premorbid adjustment and working memory. The global cognitive improvement after treatment was significantly predicted by age and premorbid adjustment. This study confirms the association between premorbid adjustment and cognitive impairment and is the first to highlight the possible role of premorbid adjustment on the capacity to recover from cognitive deficits through a cognitive remediation therapy protocol. The data suggest that cognitive remediation may be particularly effective for people in the early course and that the assessment of premorbid adjustment could be of value to design individualised interventions.

BackgroundNeurocognitive and social cognitive impairments represent important treatment targets in schizophrenia, as they are significant predictors of functional outcome. Different rehabilitative interventions have recently been developed, addressing both cognitive and psychosocial domains. Although promising, results are still heterogeneous and predictors of treatment outcome are not yet identified. In this study we evaluated the efficacy of two newly developed social cognitive interventions, respectively based on the use of videotaped material and comic strips, combined with domain-specific Cognitive Remediation Therapy (CRT). We also analysed possible predictors of training outcome, including basal neurocognitive performance, the degree of cognitive improvement after CRT and psychopathological variables.MethodSeventy-five patients with schizophrenia treated with CRT, were randomly assigned to: social cognitive training (SCT) group, Theory of Mind Intervention (ToMI) group, and active control group (ACG).ResultsANOVAs showed that SCT and ToMI groups improved significantly in ToM measures, whereas the ACG did not. We reported no influences of neuropsychological measures and improvement after CRT on changes in ToM. Both paranoid and non-paranoid subjects improved significantly after ToMI and SCT, without differences between groups, despite the better performance in basal ToM found among paranoid patients. In the ACG only non-paranoid patients showed an improvement in non-verbal ToM.ConclusionResults showed that both ToMI and SCT are effective in improving ToM in schizophrenia with no influence of neuropsychological domains. Our data also suggest that paranoid symptoms may discriminate between different types of ToM difficulties in schizophrenia.

Recovery, or functional remission, represents the ultimate treatment goal in schizophrenia. Despite its importance, a standardized definition of remission is still lacking, thus reported rates significantly vary across studies. Moreover, the effects of rehabilitative interventions on recovery have not been thoroughly investigated. This study aimed to evaluate recovery in a sample of patients with chronic schizophrenia engaged in rehabilitation programs and to explore contributing factors, with a focus on sociocognitive rehabilitative interventions.Data from 104 patients with schizophrenia treated either with a standard rehabilitation program, including cognitive remediation (n = 46), or the latter plus a specific sociocognitive intervention (n = 58), and assessed for psychopathology, cognition, social cognition, and Quality of Life Scale, were retrospectively analyzed for this study.Recovery, evaluated with the Quality of Life Scale, was achieved by 56.76% of patients in our sample. While no effects were observed for clinical, cognitive, or sociocognitive variables, participation in the sociocognitive rehabilitative interventions was positively associated with recovery.Our results indicate that high rates of recovery can be achieved in patients treated with psychosocial interventions and suggest that rehabilitative programs targeting social cognition may further facilitate the process of recovery. If confirmed, these results may have relevant implications for daily clinical practice and service provision, allowing clinicians to develop and optimize specific rehabilitation programs in order to promote recovery.

OBJECTIVE Despite its extensive use for treating cognitive deficits in schizophrenia, computer-assisted cognitive remediation (CACR) currently lacks a standardized protocol. Duration is an important feature to be defined, as it may contribute to heterogeneous outcome. This study compares 2 treatment durations, 3 versus 6 months, to analyze their effects on both cognition and daily functioning. METHOD Fifty-seven outpatients with schizophrenia received 3 months of CACR and 41 received 6 months of CACR. All patients were assessed at baseline and after 3 and 6 months with the Brief Assessment for Cognition in Schizophrenia and with the Quality of Life Scale (QLS). RESULTS Repeated measures ANOVA showed significant improvements in all cognitive domains after 3 months. A significant effect of treatment duration was observed only for executive functions, with significantly higher scores among patients treated for 6 months. Significant improvements in QLS were also observed after 6 months in both groups, with a significant time by treatment interaction for QLS Total Score. CONCLUSIONS Results confirm the efficacy of 3-months CACR in terms of both cognitive and functional improvements, suggesting that an extended intervention may lead to further benefits in executive functions and daily functioning. (PsycINFO Database Record

Background:Several studies suggested that anxiety can significantly affect the outcome of schizophrenia. Despite this evidence, non-pharmacological interventions targeting anxiety are still heterogenous. This study aims to test the efficacy of a novel training specifically designed to target anxiety in patients with schizophrenia. Innovatively, this training, beyond psychoeducation and problem solving, also targets Theory of Mind, as it provides coping strategies.Method:Twenty-seven outpatients with schizophrenia received a novel rehabilitative training targeting anxiety (Anxiety Management Group [AMG]) combined with a Computer-Assisted Cognitive Remediation (CACR), and twenty received CACR plus a control intervention (Control Newspaper discussion Group [CNG]). All patients were assessed at baseline and after treatment for quality of life, neurocognition and anxiety.Results:After training, patients treated with AMG + CACR showed significantly greater improvements on anxiety. A significant increase in quality of life was observed only for AMG + CACR group. Moreover, the participants’ appraisal showed a significant difference between treatment groups with higher ratings among patients who received the AMG + CACR.Conclusions:This study thus suggests feasibility and efficacy of the proposed intervention, that could be implemented in rehabilitative programs for patients with schizophrenia with potential benefits also on disease course and outcome.

Cognitive remediation therapy (CRT) has been proved to improve cognitive deficits in schizophrenia and to enhance functional outcomes of classical rehabilitation. However, CRT outcomes are heterogeneous and predictors of response are still unknown. Genetic variability, especially in the dopaminergic system, has been hypothesized to affect CRT. We previously reported that rs4680 of the catechol-O-methyltrasferase (COMT) influences improvements in executive functions in patients treated with CRT, but this result was not confirmed by other studies. Such inconsistent findings may depend, other than on clinical variables, also on other genes involved in cognition. Recent studies proved that serotonin 1A receptor (5-HT1A-R) regulates dopamine in the prefrontal cortex (PFC), and clinical works suggested a 5-HT1A-R role in cognition. We then analysed possible effects of COMT rs4680 and 5-HT1A-R rs6295 on CRT outcomes, taking into account also clinical and demographic factors. Eighty-six clinically stabilized schizophrenia patients treated with three months CRT were assessed with the Wisconsin Card Sorting Test, as a measure of executive functions, at enrolment and after CRT treatment, and underwent COMT and 5-HT1A-R genotyping. We found a significant main effect of COMT genotype and an interaction with 5-HT1A-R on executive function improvement after CRT. The results suggest that these two polymorphisms may have an additive effect on individual capacity to recover from cognitive deficit, probably through their role on PFC dopaminergic transmission modulation, known to be critical for modulating cognitive functions.

Cognitive remediation, often used in combination with standard rehabilitation programs, represents the best available tool to treat cognitive impairments in patients with schizophrenia. However, there are still open questions about durability of effects and generalization of cognitive improvements to functional outcome. This study aims to investigate the persistence of both cognitive and functional effects of combined cognitive remediation plus standard rehabilitation interventions, 5. years after completion of the intervention, also comparing different durations of the standard rehabilitation. Sixty patients diagnosed with schizophrenia and previously treated with a 6. months intervention, consisting of standard rehabilitation plus 3-months of cognitive remediation, either followed by another year of standard rehabilitation or routine psychiatric treatment, were reassessed with neuropsychological and functional measures 5. years after the intervention. Results show that cognitive abilities remained stable after 5. years in both groups, while functional performance significantly decreased in patients treated with the 6. months intervention only. Data thus suggest that cognitive effects persist even after 5. years, while a longer standard rehabilitation following the cognitive remediation program may be needed to achieve a stable functional gain.

Social disability is one of the critical areas known to be a predictor of daily functioning in schizophrenia. Recent studies showed that impairments in Theory of Mind (ToM) contribute to real-world social functioning and are more strongly associated with community outcomes than other neuropsychological domains of cognition. Several experiments revealed an improving potential of social cognition targeted training, particularly through introduction of verbalisation and explicit manipulation of information about others' mental states. Based on these data, we evaluated longitudinally, with a controlled trial, the feasibility and efficacy of ToM training and the possible influences of daily functioning and IQ on the enhancement of ToM abilities. Thirty outpatients with schizophrenia were recruited and randomly allocated to two groups: ToM Intervention (ToMI), based on verbalisation of selected comic strips representing ToM scenarios, or active control group (ACG). Results showed a significant improvement of ToM abilities among subjects allocated to ToMI compared to ACG, confirming the hypothesis of the enhancing potential of training methods targeting ToM functions. Moreover, we observed no influences of neuropsychological and functional variables on ToM improvement. Development of future studies should take into account possible effects of ToM training on functional outcome, according to the strong associations between ToM abilities and real-world social functioning.

Deficits in emotion processing (EP) represent a target of rehabilitation in schizophrenia, as they have been related to poor personal and social functioning. To date neither the relationship between these deficits and the generalised cognitive impairment, nor the involvement of specific mechanisms of perception (visual or auditory) are fully comprehended. We developed two treatments targeting EP, through visual or auditory channels, with the aim of disentangling possible differences and/or interactions between the two modalities in schizophrenia-related impairments, also taking into account the role of cognition and social functioning. Thirty five outpatients with schizophrenia were assessed for neurocognition, social functioning and EP (visual and auditory channel) and participated in either visual or auditory EP training or in an active control group. Results showed a significant improvement in EP through the specific channel trained for both groups, with an extended effect also on vocal stimuli for the visual training group. Positive correlations were found between working memory, social functioning and EP. Our findings help to shed light on the possible different involvement of perceptual channels in schizophrenia, as well as supporting previous evidence that emotion recognition may be inter-related but does not overlap with neurocognition and can be specifically trained.

BackgroundCognitive Remediation represents the best available tool to treat cognitive deficits in schizophrenia and evidence suggests an effect also on global functioning. However, the relationship between cognitive and functional improvement is not yet fully elucidated: do cognitive changes need to be of a definite size and/or encompass a certain number of domains in order to impact on daily functioning? This study aims to explore the role of cognitive improvement, evaluated both quantitatively and qualitatively through the use of Italian equivalent scores, on the daily functioning of patients. As secondary goal, the influence of demographic, clinical and neuropsychological variables on functional outcome was also systematically investigated.MethodsOne hundred subjects with a diagnosis of schizophrenia underwent 36 sessions of Cognitive Remediation and were evaluated at baseline and after the training with the Brief Assessment of Cognition in Schizophrenia and the Quality of Life Scale.ResultsA total of 70% of patients improved in at least one cognitive domain and over 50% obtained a normalized score. Among the clinical and neurocognitive factors examined, the only significant predictor of quality of life’s improvement was the proportion of cognitive functions that reached an equivalent score of “normal”.ConclusionsThis study suggests that improvements in daily functioning depend on the achievement of a cognitive profile as much as possible “normal”, harmonious and balanced, supporting the idea that a qualitative leap in cognition is needed in order to gain an advantage in real life activities.

Impairments in social cognition are critical predictors of social functioning in patients with schizophrenia. Emotion processing (EP) and theory of mind (ToM) are hypothesized to influence real-world behavior more directly than basic cognition and represent important targets of intervention. The use of video scenes depicting human interactions could constitute an appropriate tool to enhance understanding of the characters' behavior and stimulate inferences on mental states. The aim of our pilot study was to evaluate longitudinally, with a controlled trial, the feasibility and the efficacy of a single-paradigm emotion recognition and ToM training designed for outpatients affected by schizophrenia, with the goal to create an ecological treatment, overcoming artificial laboratory biases, by the use of specific videotaped material. Fifty-two outpatients were randomly assigned to an EP and ToM video-based training (n=27) or to a standard social cognitive rehabilitation treatment (n=24). They were assessed before and after 12 weeks of intervention and compared to a time-matched control group (n=24). Our results show a statistically significant improvement in ToM abilities, confirming the hypothesis of the enhancing potential of social cognitive interventions, but no changes with respect to EP; despite the need for a deeper examination, these data support further development of this treatment approach.

Catechol-O-methyltransferase (COMT) gene, a key regulator of prefrontal cortex (PFC) dopamine (DA) availability, has been extensively studied in relation to cognitive domains, mainly executive functions, that are impaired in schizophrenia, but results are still controversial. Since recent studies in patients affected by neurodegenerative and psychiatric disorders suggested a role of saitohin (STH) gene as a concurring factor in hypofrontality, we hypothesize that STH and COMT polymorphisms could have an additive effect on cognition in schizophrenia. Three forty three clinically stabilized patients with schizophrenia were assessed with a broad neuropsychological battery including the Brief Assessment of Cognition in Schizophrenia, the Wisconsin Card Sorting Test and the Continuous Performance Test and were genotyped for COMT Val108/158Met and STH Q7R polymorphisms. We observed the effects of COMT on speed of processing and executive functions, as well as a significant effect of STH on executive functions performances. Moreover, a significant interaction between COMT and STH polymorphisms was found on executive functions, with COMT Val/Val and STH R carriers performing worse. Our results showed a significant interaction effect of COMT and STH polymorphisms on cognitive performances, strengthening the involvement of STH in cognitive impairments, especially in the domains commonly impaired in schizophrenia.

BackgroundA Metacognitive Training for Schizophrenia patients (MCT) was developed to target the cognitive biases that characterize the illness. Results suggest positive MCT effects encompassing several aspects of psychopathology and subjective well-being. There are still open questions concerning the effect on different cognitive biases and the interplay between them and both psychopathology and neurocognition. Specifically, the bias against disconfirmatory evidence (BADE) has never been tested in previous trials on MCT. In this study we evaluated the feasibility of MCT combined with a cognitive remediation therapy (CACR) in schizophrenia and its effect on BADE. Moreover, we investigated the relationships between BADE and both neuropsychology and psychopathology, taking into account mutual influences on the degree of improvement.MethodsFifty-seven schizophrenia outpatients were randomly assigned to CACR + control group or MCT+CACR and assessed at baseline and after treatment for psychopathology, neurocognition and BADE.ResultsAfter MCT+CACR patients showed significantly greater improvements on BADE. Although BADE baseline performances correlated with several cognitive domains, no association was found between BADE improvement and neurocognitive nor psychopathological measures.ConclusionsThis study enlightened for the first time the efficacy of MCT+CACR on BADE in schizophrenia, suggesting the importance to develop a more specific intervention tailored on individual needs of patients.

The aim of this study was to evaluate the efficacy and tolerability of risperidone versus haloperidol in subchronic schizophrenia, using psychopathological subgroups of patients with negative or positive and mixed symptoms to analyse the possible differential efficacy of the drugs. A total of 33 patients diagnosed using DSM-IV criteria entered the 6 week double-blind study with either risperidone or haloperidol 5 mg/day. Twenty-nine patients completed at least 2 weeks of treatment and entered the last observation carried-forward analysis. Both treatments were effective in reducing total scores and positive and negative subscale scores on the Positive and Negative Scale for Schizophrenia (PANSS), with a significantly better extrapyramidal profile in the risperidone-treated group. When analysis was repeated in each treatment group by psychopathological subtype (negative vs positive-mixed subgroups based on the PANSS composite index), risperidone was significantly superior to haloperidol in the intention to treat analysis in the negative subgroup. Repeated measures multivariate analysis of variance showed a significantly greater improvement in the PANSS negative subscale scores of risperidone-treated patients in the negative subgroup and a significant improvement in the PANSS positive subscale scores in both psychopathological subtypes. Haloperidol was significantly effective only in reducing positive symptoms in the positive subtype. Our results indicate that risperidone may be proposed for first-line treatment of subchronic schizophrenia, in particular the negative subtype. Copyright (C) 2001 John Wiley & Sons, Ltd.

Cognitive remediation is the best available tool to treat cognitive deficits in schizophrenia and has evidence of biological validity; however results are still heterogeneous and significant predictors are lacking. Previous studies showed that cognitive remediation is able to induce changes in PFC function and dopaminergic transmission and thus the study of possible sources of variability at these levels (i.e. antipsychotic treatments and genetic variability) might help to gain a deeper understanding of neurobiological correlates and translate into optimization and personalization of interventions. In the present study, we analyzed the interaction between pharmacological treatment (clozapine vs typical/atypical D2 blockers) and COMT rs4680 polymorphism on cognitive changes after cognitive remediation therapy, in a sample of 98 clinically stabilized patients with schizophrenia. The General Linear Model showed a significant interaction of pharmacological treatment and COMT polymorphism on the improvement in "Symbol Coding" subtest, a global measure of speed of processing. Post-hoc analysis revealed a significant difference between COMT genotypes, when treated with D2 blockers, with worse results among Val/Val patients. These preliminary results suggest that genetic variability, influencing prefrontal dopamine, might affect individual capacity to improve with different patterns, depending on antipsychotic treatment. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

A disturbance of glutamatergic transmission has been suggested to contribute to the development of schizophrenic pathophysiology, based primarily on the ability of glutamate receptor antagonists to induce schizophrenic-like symptoms. The excitatory amino acid transporter 2 (EAAT2) is responsible for the majority of glutamate uptake. It also contributes to energy metabolism in the brain, by transporting glutamate into astrocytes for conversion into glutamine. A dysregulation of its level of expression has been associated with multiple neurological disorders. Blocking glutamate uptake by EAAT2 in cultured oligodendrocytes leads to cell death, demyelination and axonal damage, suggesting that it is crucial for normal oligodendrocyte function. Different studies focused on EAAT2 alterations among subjects affected by schizophrenia, reporting a decreased expression in the parahippocampal region and in the dorsolateral prefrontal cortex. Moreover, subjects with the high-risk metabotropic glutamate receptor 3 (GRM3) haplotype associated with schizophrenia had lower EAAT2 expression in the prefrontal cortex and also showed impaired cognitive performances for measures of verbal list learning and verbal fluency. EAAT2 protein activity is regulated by a SNP rs4354668 (−181 T/G) which falls in the gene promoter region, with the G allele resulting in a lower activity of the transporter. Based on these data, we assessed possible effects of the −181 T/G EAAT2 polymorphism on two core prefrontal cognitive performances, known to be impaired in schizophrenia, in a sample of 211 clinically stabilized patients. We observed better executive functions (WCST, no. of categories) and working memory (N-back: 1-back, 2-back) performances in subjects homozygous for the T allele, compared to the G carriers group. These observations suggest that the presence of the G allele is associated, among patients with schizophrenia, with a disadvantageous effect on core cognitive functions that depend on prefrontal cortex activity. These results are preliminary and need to be replicated by future and larger studies, however they suggest that EAAT2 inefficiency may represent a target of interest for development of pharmacological strategies aimed to improve prefrontal performances by compensating the impaired glutamate reuptake.