Weighing the role of social cognition and executive functioning in pragmatics in the schizophrenia spectrum: A systematic review and meta-analysis.

Pragmatic impairment is diffused in schizophrenia spectrum disorders, but the literature still debates its neurocognitive underpinnings. This systematic review and meta-analysis aimed to investigate the neurocognitive correlates of pragmatic disorders in schizophrenia and determine the weight of social cognition and executive functioning on such disorders. Of the 2,668 records retrieved from the literature, 16 papers were included in the systematic review, mostly focused on non-literal meanings and discourse production in schizophrenia. Ten studies were included in the meta-analysis: pragmatics was moderately associated with both social cognition and executive functions (especially inhibition), but the link with social cognition was stronger. The mediation analysis showed that social cognition mediated the relationship between executive functions and pragmatics. Based on this, we proposed a hierarchical neurocognitive model where pragmatics stems from social cognition, while executive functions are the fertile ground supporting the other two domains, and we discuss its theoretical and clinical implications.

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.

Mind the past: A systematic review on psychological autopsy.

Psychological Autopsy (PA) has become widespread to the point of being applied in many diverse fields. However, it is difficult to identify a standard model. In this systematic review, we focused on PA studies assessing mental illness as a major risk factor for suicide. The research, performed on Scopus, Embase, and Pubmed to cover the last 20 years led to 321 reports of which 15 met the inclusion criteria. Results confirmed mental illness as the main risk factor for suicide, followed by specific socio-demographic factors and life events. The analysis of methodologies depicted a still highly heterogeneous scenario, especially regarding data collection and variables included. However, concerning psychiatric evaluations, an initial standardization process of PA models emerged. In conclusion, the approach is in evolution, and novel guidelines are needed to promote the application of PA as a fundamental tool to inform suicide prevention efforts and to assist forensic examiners in court.

Importance of the dysregulation of the kynurenine pathway on cognition in schizophrenia: a systematic review of clinical studies.

Schizophrenia is a chronic psychotic disease burdened by cognitive deficits which hamper daily functioning causing disability and costs for society. Biological determinants underlying cognitive impairment are only partially understood and there are no convincing pharmacological targets able to improve cognitive outcome. Mounting evidence has shown the involvement of the kynurenine pathway in the pathophysiology of schizophrenia, also concerning cognitive symptoms. Therefore, the action of specific metabolites of kynurenine could affects cognition in schizophrenia. To evaluate the impact of the metabolites of kynurenine pathway on cognitive functions in schizophrenia spectrum disorders, with a focus on the modulating role of gender, to identify predictors of cognitive functioning and hypothetical pharmacological targets able to resize disability by improving cognition, thus functioning and quality of life. A systematic review was performed in PubMed/MEDLINE and Embase according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. All studies measuring the direct impact of kynurenine metabolites on cognitive performances in living individuals with schizophrenia spectrum disorders were included in the review. Six studies were included. The activation of the kynurenine pathway resulted associated with greater cognitive deficits in patients with schizophrenia and both elevations and reduction of metabolites seemed able to affect cognitive outcome. No modulating role of sex emerged. This systematic review provides evidence that the activation of the kynurenine pathway affects cognition in patients with schizophrenia and highlights this pathway as a possible future target for developing novel drugs toward this still unmet clinical need. However, evidence is still limited and future studies are needed to further clarify the relationship between kynurenine pathway and cognition in schizophrenia.

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.

Machine Learning and Criminal Justice: A Systematic Review of Advanced Methodology for Recidivism Risk Prediction.

Recent evolution in the field of data science has revealed the potential utility of machine learning (ML) applied to criminal justice. Hence, the literature focused on finding better techniques to predict criminal recidivism risk is rapidly flourishing. However, it is difficult to make a state of the art for the application of ML in recidivism prediction. In this systematic review, out of 79 studies from Scopus and PubMed online databases we selected, 12 studies that guarantee the replicability of the models across different datasets and their applicability to recidivism prediction. The different datasets and ML techniques used in each of the 12 studies have been compared using the two selected metrics. This study shows how each method applied achieves good performance, with an average score of 0.81 for ACC and 0.74 for AUC. This systematic review highlights key points that could allow criminal justice professionals to routinely exploit predictions of recidivism risk based on ML techniques. These include the presence of performance metrics, the use of transparent algorithms or explainable artificial intelligence (XAI) techniques, as well as the high quality of input data.

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.

Melatonin and aggressive behavior: A systematic review of the literature on preclinical and clinical evidence.

The melatonin system and circadian disruption have well-established links with aggressive behaviors; however, the biological underpinnings have not been thoroughly investigated. Here, we aimed at examining the current knowledge regarding the neurobiological and psychopharmacological involvement of the melatonin system in aggressive/violent behaviors. To this end, we performed a systematic review on Embase and Pubmed/MEDLINE of preclinical and clinical evidence linking the melatonin system, melatonin, and melatoninergic drugs with aggressive/violent behaviors. Two blinded raters performed an independent screening of the relevant literature. Overall, this review included 38 papers distributed between clinical and preclinical models. Eleven papers specifically addressed the existing evidence in rodent models, five in fish models, and 21 in humans. The data indicate that depending on the species, model, and timing of administration, melatonin may exert a complex influence on aggressive/violent behaviors. Particularly, the apparent contrasting findings on the link between the melatonin system and aggression/violence (with either increased, no, or decreased effect) shown in preclinical models underscore the need for further research to develop more accurate and fruitful translational models. Likewise, the significant heterogeneity found in the results of clinical studies does not allow yet to draw any firm conclusion on the efficacy of melatonin or melatonergic drugs on aggressive/violent behaviors. However, findings in children and in traits associated with aggressive/violent behavior, including irritability and anger, are emerging and deserve empirical attention given the low toxicity of melatonin and melatonergic drugs.

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.