Adverse childhood experiences differently affect Theory of Mind brain networks in schizophrenia and healthy controls.

Patients with schizophrenia (SZ) show impairments in both affective and cognitive dimensions of theory of mind (ToM). SZ are also particularly vulnerable to detrimental effect of adverse childhood experiences (ACE), influencing the overall course of the disorder and fostering poor social functioning. ACE associate with long-lasting detrimental effects on brain structure, function, and connectivity in regions involved in ToM. Here, we investigated whether ToM networks are differentially affected by ACEs in healthy controls (HC) and SZ, and if these effects can predict the disorder clinical outcome. 26 HC and 33 SZ performed a ToM task during an fMRI session. Whole-brain functional response and connectivity (FC) were extracted, investigating the interaction between ACEs and diagnosis. FC values significantly affected by ACEs were entered in a cross-validated LASSO regression predicting Positive and Negative Syndrome Scale (PANSS), Interpersonal Reactivity Index (IRI), and task performance. ACEs and diagnosis showed a widespread interaction at both affective and cognitive tasks, including connectivity between vmPFC, ACC, precentral and postcentral gyri, insula, PCC, precuneus, parahippocampal gyrus, temporal pole, thalamus, and cerebellum, and functional response in the ACC, thalamus, parahippocampal gyrus and putamen. FC predicted the PANSS score, the fantasy dimension of IRI, and the AToM response latency. Our results highlight the crucial role of early stress in differentially shaping ToM related brain networks in HC and SZ. These effects can also partially explain the clinical and behavioral outcomes of the disorder, extending our knowledge of the effects of ACEs.

The kynurenine pathway in treatment-resistant schizophrenia at the crossroads between pathophysiology and pharmacotherapy.

Two cardinal elements in the complex and multifaceted pathophysiology of schizophrenia (SCZ) are neuroinflammation and dysregulation of glutamatergic neurotransmission, with the latter being especially involved in treatment-resistant schizophrenia (TRS). Interestingly, the Kynurenine (KYN) pathway (KP) is at the crossroad between them, constituting a potential causal link and a therapeutic target. Although there is preclinical and clinical evidence indicating a dysregulation of KP associated with the clinical phenotype of SCZ, clinical studies investigating the possible relationship between changes in biomarkers of the KP and response to pharmacotherapy are still limited. Therefore, we have studied possible differences in the circulating levels of biomarkers of the metabolism of tryptophan along the KP in 43 responders to first-line treatments (FLR) and 32 TRS patients treated with clozapine, and their possible associations with psychopathology in the two subgroups. Plasma levels of KYN were significantly higher in TRS patients than in FLR patients, indicating a greater activation of KP. Furthermore, the levels of quinolinic (NMDA receptor agonist) and kynurenic acid (NMDA negative allosteric modulator) showed a negative and a positive correlation with several dimensions and the overall symptomatology in the whole sample and in FLR, but not in TRS, suggesting a putative modulating effect of clozapine elicited through the NMDA receptors. Despite the cross-sectional design of the study that prevents us from demonstrating causation, these findings show a significant relationship among circulating KP biomarkers, psychopathology, and response to pharmacotherapy in SCZ. Therefore, plasma KP biomarkers should be further investigated for developing personalized medicine approaches in SCZ.

Improving outcome of treatment-resistant schizophrenia: effects of cognitive remediation therapy.

Treatment-Resistant Schizophrenia (TRS) represents a main clinical issue, associated with worse psychopathological outcomes, a more disrupted neurobiological substrate, and poorer neurocognitive performance across several domains, especially in verbal abilities. If cognitive impairment is a major determinant of patients' functional outcomes and quality of life, targeting cognitive dysfunction becomes even more crucial in TRS patients in order to minimize cognitive and functional deterioration. However, although Cognitive Remediation Therapy (CRT) represents the best available tool to treat cognitive dysfunction in schizophrenia, specific evidence of its efficacy in TRS is lacking. Based on these premises, our study aimed at investigating possible differences in CRT outcomes in a sample of 150 patients with schizophrenia, stratified according to antipsychotic response (TRS vs. non-TRS). Subjects were assessed for neurocognition through Brief Assessment of Cognition in Schizophrenia (BACS) and the Wisconsin Card Sorting Test (WCST) at baseline and after CRT. As expected, we observed greater baseline impairment among TRS patients in BACS-Verbal Memory and WCST-Executive Functions. Repeated measures ANCOVAs showed significant within-group pre-/post-CRT differences in the above-mentioned domains, both among non-TRS and TRS subjects. However, after CRT, no differences were observed between groups. This is the first study to indicate that CRT represents a highly valuable resource for TRS patients, since it may be able to fill the cognitive gap between treatment response groups. Our finding further highlights the importance of early implementation of CRT in addition to pharmacotherapy to reduce the cognitive and functional burden associated with the disease, especially for TRS patients.

Belief Inflexibility and Cognitive Biases in Anorexia Nervosa-The Role of the Bias against Disconfirmatory Evidence and Its Clinical and Neuropsychological Correlates.

The aim of this study was to explore, in a sample of patients with a diagnosis of AN, the ability to question their first impression and, in particular, the willingness to integrate their prior ideas and thoughts with additional progressive incoming information. A total of 45 healthy women and 103 patients with a diagnosis of AN, consecutively admitted to the Eating Disorder Padova Hospital-University Unit, underwent a broad clinical and neuropsychological assessment. All participants were administered the Bias Against Disconfirmatory Evidence (BADE) task, which specifically investigates belief integration cognitive bias. Acute AN patients showed a significantly greater bias toward disconfirming their previous judgment, in comparison to healthy women (BADE score, respectively, 2.5 ± 2.0 vs. 3.3 ± 1.6; Mann-Whitney test, p = 0.012). A binge-eating/purging subtype of AN individuals, compared to restrictive AN patients and controls, showed greater disconfirmatory bias and also a significant propensity to uncritically accept implausible interpretations (BADE score, respectively, 1.55 ± 1.6 and 2.70 ± 1.97 vs. 3.33 ± 1.63; Kruskal-Wallis test, p = 0.002 and liberal acceptance score, respectively, 1.32 ± 0.93 and 0.92 ± 1.21 vs. 0.98 ± 0.75; Kruskal-Wallis test p = 0.03). Abstract thinking skills and cognitive flexibility, as well as high central coherence, are neuropsychological aspects positively correlated with cognitive bias, in both patients and controls. Research into belief integration bias in AN population could enable us to shed light on hidden dimensional aspects, facilitating a better understanding of the psychopathology of a disorder that is so complex and difficult to treat.

Schizophrenia and psychedelic state: Dysconnection versus hyper-connection. A perspective on two different models of psychosis stemming from dysfunctional integration processes.

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.

Deconstructing heterogeneity in schizophrenia through language: a semi-automated linguistic analysis and data-driven clustering approach.

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 profiles are associated with outcome in schizophrenia.

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.

Modeling the interplay of age at onset and sex on cognition in Schizophrenia.

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.

It is time to address language disorders in schizophrenia: A RCT on the efficacy of a novel training targeting the pragmatics of communication (PragmaCom).

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Cognitive remediation in schizophrenia: What happens after 10 years?

Cognitive Remediation Therapy (CRT) represents the gold standard treatment for cognitive impairment in schizophrenia, but the permanence of its effects over time have been poorly investigated. Our study aims to evaluate long lasting cognitive and functional effects of CRT together with standard rehabilitation interventions (SRT) in a group of patients diagnosed with schizophrenia, 10 years after the end of the treatment. Forty patients, previously included in a 5-year follow-up study evaluating the effects of CRT combined with SRT, were revalued 10 years after the complete of the intervention. Results revealed that cognitive and functional improvements of combined CRT/SRT interventions are still preserved 10 years after the end of the treatments, with the only exception of psychomotor speed and coordination cognitive subdomain. Moreover, investigating persistence of the influence of SRT, patients that underwent a shorter SRT following CRT (six months vs one year) showed worsened processing speed abilities. This is the first study confirming that cognitive and functional improvements of joint CRT/SRT interventions are still conserved 10 years after the end of the treatments. Preliminary datas suggest that a longer SRT following CRT may lead to significant benefits, in terms of cognitive gains, in patients affected by schizophrenia.

Get up! Functional mobility and metabolic syndrome in chronic schizophrenia: Effects on cognition and quality of life.

Low mobility and poor physical health, especially metabolic syndrome, are frequently reported in patients with schizophrenia and tend to increase with age. Recent evidence suggests that metabolic syndrome may affect cognition and quality of life, while the role functional mobility is still less addressed and their interplay needs to be further explored. This study aims to analyze the effects of functional mobility on cognitive performance, symptoms and quality of life, taking into account age and also modeling it relationship with metabolic syndrome in a sample of 103 adults with chronic schizophrenia. Data were analyzed by means of Pearson's correlations, forward stepwise regressions and mediation models. Results showed that poorer functional mobility is associated with metabolic syndrome and related to more severe negative symptoms, worse cognitive abilities and more disrupted quality of life. Moreover, functional mobility proved to be a significant predictor of cognitive abilities and quality of life, even when other influencing factors were taken into account and independently of age. Finally, analyses showed that functional mobility mediates the effect of metabolic syndrome on both cognition and quality of life. Taken together, these results suggest that functional mobility and metabolic syndrome may represent relevant aspects that further contribute to the evolution of cognitive deficits through all stages of the disease, with also impact on quality of life. In this perspective, the assessment of functional mobility, a non-invasive and quickly performed test may be worth to be implemented in clinical practice, with important implications for treatment and monitoring.

Cognitive dysfunction in schizophrenia: An expert group paper on the current state of the art.

Cognitive impairment in schizophrenia represents one of the main obstacles to clinical and functional recovery. This expert group paper brings together experts in schizophrenia treatment to discuss scientific progress in the domain of cognitive impairment to address cognitive impairments and their consequences in the most effective way. We report on the onset and course of cognitive deficits, linking them to the alterations in brain function and structure in schizophrenia and discussing their role in predicting the transition to psychosis in people at risk. We then address the assessment tools with reference to functioning and social cognition, examining the role of subjective measures and addressing new methods for measuring functional outcomes including technology based approaches. Finally, we briefly review treatment options for cognitive deficits, focusing on cognitive remediation programs, highlighting their effects on brain activity and conclude with the potential benefit of individualized integrated interventions combing cognitive remediation with other approaches.

On the Implementation of Computerized Adaptive Observations for Psychological Assessment.

The use of observational tools in psychological assessment has decreased in recent years, mainly due to its personnel and time costs, and researchers have not explored methodological innovations like adaptive algorithms in observational assessment. In the present study, we introduce the behavior-driven observation procedure to develop, test, and implement observational adaptive instruments. In Study 1, we use a preexisting observational checklist to evaluate nonverbal behaviors related to psychotic symptoms and to specify the adaptive algorithm's model. We fit the model to observational data collected from 114 participants. The results support the model's goodness of fit. In Study 2, we use the estimated model parameters to calibrate the adaptive procedure and test the algorithm for accuracy and efficiency in adaptively reconstructing 58 nonadaptively collected response patterns. The results show the algorithm's good accuracy and efficiency, with a 40% average reduction in the number of administered items. In Study 3, we used real raters to test the adaptive checklist built with behavior-driven observation. The results indicate adequate intrarater agreement and good consistency of the observed response patterns. In conclusion, the results support the possibility of using behavior-driven observation to create accurate and affordable (in terms of resources) observational assessment tools.

Theory of mind and stereotypic behavior promote daily functioning in patients with schizophrenia.

OBJECTIVES: Functional disruption is a main feature of schizophrenia and still represents a major treatment challenge. A more in-depth identification of functional predictors is crucial for the creation of individualized rehabilitation treatments, which can translate into better functional outcomes. In this study, we aimed at pinpointing specific domains that affect different functional profiles, using a data-driven approach. METHODS: We included a comprehensive evaluation of functional predictors, namely demographic, cognitive, sociocognitive and clinical variables, with a focus on constituent subdomains of autistic symptoms that have been associated with functioning in the recent literature. RESULTS: In 123 schizophrenia patients, a two-step cluster analysis identified two groups of patients with different functional profiles (low vs high functioning). A backward stepwise logistic regression analysis showed that the odds of being a member of the high functioning group are significantly higher for individuals with (1) more years of education, (2) better Theory of Mind abilities, (3) higher levels of stereotypies/narrowed interests, (4) lower difficulties in social interaction, (5) lower communication difficulties and with (6) being male. CONCLUSION: Findings raise the intriguing possibility that stereotypic behaviors may have a beneficial effect on functioning in schizophrenia. While the underlying mechanism is currently unknown, we hypothesize that patients may benefit from contexts in which more predictive relationships between environmental entities can systematically be established. This study underscores the potential utility of routinely assessing autistic symptomatology in schizophrenia, which can be instrumental in identifying novel therapeutic targets that can be utilized to improve daily functioning.

Sustained symptomatic remission in schizophrenia: Course and predictors from a two-year prospective study.

BACKGROUND: Although remission is a priority target in psychosis, reported rates show a marked variation across studies and instability over time. Such variability, partly due to methodology, emphasizes the need to define the optimal assessment procedure, as well as to identify reliable predictors. This study aims to: 1. longitudinally compare remission status according to different criteria; 2. identify predictors of duration and stability. METHODS: 112 patients with schizophrenia or schizoaffective disorder underwent comprehensive clinical evaluations, with 24-month follow-up. Remission was assessed using three criteria: Remission in Schizophrenia Working Group (RSWG) vs Positive and Negative Syndrome Scale (PANSS) positive and negative scales (PANSS-PN) vs total score (PANSS-T). Kaplan-Meier survival analysis was used for longitudinal comparison, regression models to identify predictors of duration and stability. RESULTS: At enrolment 50% of patients were in remission according to RSWG, while only 23.2% reached the other criteria. PANSS-T cumulative remission rates showed the greatest stability. Stable remission according to RSWG criteria was predicted by negative symptoms, while no significant predictors emerged for PANSS-T. Remission duration was predicted by negative, positive and cognitive symptoms and treatment dosage for RSWG criteria, while for PANSS-T the predictors were cognitive symptoms and duration of illness. CONCLUSION: Results are in line with previous literature on remission rates and further support the role of basal clinical predictors. In addition, this study shows that more stringent criteria are more stable over time, suggesting their predictive value and the relevance of their use to optimize evaluations also in clinical settings.

Longitudinal course of cognition in schizophrenia: Does treatment resistance play a role?

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.

Disentangling Cognitive Heterogeneity in Psychotic Spectrum Disorders.

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.

Functional benefits of co-occurring autistic symptoms in schizophrenia is delimited by symptom severity.

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.

Clozapine tolerability in Treatment Resistant Schizophrenia: exploring the role of sex.

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.

Communicative-pragmatic abilities mediate the relationship between cognition and daily functioning in schizophrenia.

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).