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Background: Shared biological factors may play a role in both the cognitive deficits and the increased prevalence of metabolic syndrome observed in individuals with Schizophrenia (SCZ). These factors could entail disturbances in tryptophan (Trp) to both melatonin (MLT) and kynurenine (Kyn) metabolic pathways, as well as inflammation and alterations in the gut microbiome composition., Methods: The present research project aims to investigate this hypothesis by recruiting 170 SCZ patients from two different recruitment sites, assessing their cognitive functions and screening for the presence of metabolic syndrome. Additionally, we plan to assess the impact of a 3-month cognitive remediation therapy on 30 of these patients. We will analyze clinical data alongside serum biomarkers and gene expression related to the Trp- to MLT and Kyn metabolic pathways, markers of inflammatory and composition of the gut microbiome. The association between Trp-MLT-Kyn levels, expression levels of selected genes, inflammatory markers and clinical phenotypes will be analyses in the context of general linear models., Discussion: This project has the potential to identify some typical SCZ symptomatic clusters that will be more stringently associated with variations in the Trp-MLT-Kyn/inflammatory system and with a better response to cognitive remediation therapy. Moreover, in a future perspective, it may highlight a group of patients who may benefit from a pharmacological treatment aiming at reinstating the physiological Trp to MLT and Kyn system. Therefore, it has the potential to move research toward a personalized approach for SCZ management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Mercuriali, Lodde, Paribello, Sapienza, Corona, Ave, Pacini, Nocera, Corrias, El Kacemi, D'Incalci, Frau, Monzani, Valtorta, Congiu, Meloni, Scherma, Fadda, Dedoni, Siddi, Sut, Dall’Acqua, Nasini, Barzon, Squassina, Cavallaro, Manchia, Pisanu, Bosia and Comai.)

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: In the last decade, the kynurenine pathway (KP) has gained attention in the pathogenesis of cognitive impairment in schizophrenia being at the croassroad between neuroinflammation and glutamatergic and cholinergic neurotransmission. However, clinical findings are scarse and conflicting, and the specific contributions of these two systems to the neurobiology of cognitive symptoms are far from being elucidated. Furthermore, little is known about the molecular underpinnings of non-pharmacological interventions for cognitive improvement, including rehabilitation strategies., Methods: The current study examined 72 patients with schizophrenia, divided in two clusters depending on the severity of the cognitive impairment, with the aim to evaluate the impact of inflammatory biomarkers and KP metabolites depending on cognitive functioning. Moreover, we studied their possible link to the cognitive outcome in relation to sessions of cognitive remediation therapy (CRT) and aerobic exercise (AE) in a longitudinal arm of 42 patients., Results: Neuroinflammation appeared to exert a more pronounced influence on cognition in patients exhibiting a higher cognitive functioning, contrasting with the activation of the KP, which had a greater impact on individuals with a lower cognitive profile. Cognitive improvements after the treatments were negatively predicted by levels of TNF-α and positively predicted by the 3-hydroxykynurenine (3-HK)/kynurenine (KYN) ratio, an index of the kynurenine-3-monooxygenase (KMO) enzyme activity., Conclusion: Overall, these findings add novel evidence on the biological underpinnings of cognitive impairment in schizophrenia pointing at a differential role of neuroinflammation and KP metabolites in inducing cognitive deficits depending on the cognitive reserve and predicting outcomes after rehabilitation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Inc.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Previous literature showed that people with schizophrenia have difficulties in humor comprehension and might differ from controls in the appreciation of humor, i.e., in perceived funniness. However, the cognitive architecture that underlies humor impairment in this population remains unclear, with humorous items sometimes assessed in the context of the communicative-pragmatic profiling and sometimes included in Theory of Mind (ToM) tasks. Here we enrolled 116 people with schizophrenia and 116 healthy controls, who were administered a task including jokes based on sound aspects and jokes based on mental aspects (Phonological and Mental Jokes task). Both comprehension accuracy (ability to select the funny ending of the joke) and appreciation (ratings of funniness) were evaluated, together with other linguistic, cognitive, and clinical measures. Results highlighted a diffuse impairment in humor comprehension in schizophrenia compared to controls, with mental jokes being more difficult for both groups. Humor comprehension was robustly associated with the patients' global pragmatic and linguistic profile, while the association with ToM was negligible. Another remarkable finding was the increased appreciation of humor in individuals with schizophrenia, who rated jokes (both correctly and incorrectly completed) as funnier than controls did. Funniness ratings were not predicted by any measure, pointing to a dimension untied from cognition or psychopathology. Overall, this study offers evidence - on a considerably large sample - of altered humor understanding and appreciation in schizophrenia, sketching a cognitive architecture where humor impairment stands together with communicative impairment, rather than with social cognition. This has implications not only for the assessment of humor, but also for how to treat it in patients to improve their ability to navigate the social world., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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., (© 2023 John Wiley & Sons Ltd.)

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., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

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., Competing Interests: Declaration of Competing Interest The authors report no potential conflict of interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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., (© 2022. The Author(s).)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., Competing Interests: None., (© 2022 The Authors. Published by Elsevier Inc.)

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., Competing Interests: Dr. Harvey has received consulting fees or travel reimbursements from Alkermes, Bio Excel, Boehringer Ingelheim, Karuna Pharma, Merck Pharma, Minerva Pharma, SK Pharma, and Sunovion Pharma (DSP/Angelini) during the past year. He receives royalties from the Brief Assessment of Cognition in Schizophrenia (Owned by Verasci, Inc. and contained in the MCCB). He is chief scientific officer of i-Function, Inc. Dr. Cavallaro has received honoraria as for lectures from Angelini. Dr. Bosia has received research grants from the Italian Ministry of Education and the Italian Ministry of Health but does not have financial relationship to any pharmaceutical company. Dr. Leucht has received honoraria as a consultant/advisor and/or for lectures from Angelini, Böhringer Ingelheim, Geodon&Richter, Janssen, Johnson&Johnson, Lundbeck, LTS Lohmann, MSD, Otsuka, Recordati, SanofiAventis, Sandoz, Sunovion, TEVA, Eisai, Rovi, Medichem. Dr. Howes is a part-time employee of H. Lundbeck A/S and has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Rand, Recordati, Roche and Viatris/Mylan. Neither Dr. Howes or his family have holdings/a financial stake in any pharmaceutical company. Dr. Howes has a patent for the use of dopaminergic imaging. Dr. Mueller has been supported by the Swiss National Foundation but does not have financial relationship to any pharmaceutical company. Dr. Penadés has been supported by the Health Research Fund of the Ministry of Health of the Government of Spain but does not have financial relationship to any pharmaceutical company. Dr.Kahn has no recent biomedical conflicts of interest. Dr. Vita received, during the past years, directly or indirectly, support for clinical studies or trials, conferences, consultancies, Congress presentations, advisory boards from: Angelini, Boehringer Ingelheim, Innovapharma, Janssen- Cilag, Lundbeck, Otsuka, Pfizer, Recordati, Roche, Rovi Pharma, Takeda., (© 2022 The Authors.)

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., Competing Interests: The authors declare that there is no conflict of interest., (© 2022 The Authors.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sleep quality has been highlighted as a significant predictor of violent behavior through lifespan and across pathologies and a causal link has also been suggested. Despite the high prevalence of insomnia and its potential impact as a modifiable risk factor for aggressive behavior, a comprehensive synthesis of the literature is lacking. We aimed to systematically review the published works exploring the role of sleep in aggressive behaviors, especially focusing on forensic contexts. We performed a systematic review searching the electronic databases PubMed and Scopus through December 2020 and selected articles that compared sleep of offenders and controls and articles that studied the association between sleep and aggression. Ten articles were selected: 2 compared sleep in offenders and controls and 8 studied the association between sleep and aggression. Offenders showed worse sleep features than control both objectively and subjectively measured. Sleep quality was associated with aggression, but sleep quantity was less studied. Sleep seems to have a prominent role in aggressive behaviors but studies concerning this topic are few; samples and methods were highly heterogeneous and most studies were cross-sectional. Future studies are needed to clarify the association between sleep disturbances and aggression, adopting a more systematized approach. Sleep assessment and treatment and might be particularly useful, especially in high-risk populations., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)