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.

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.

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.

Cognition in Schizophrenia: Modeling the Interplay between Interleukin-1ß C-511T Polymorphism, Metabolic Syndrome, and Sex.

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

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).

Cognitive Remediation for Inpatients With Schizophrenia: Effects of a Brief and Intensive Training.

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

The Influence of Premorbid Adjustment and Autistic Traits on Social Cognitive Dysfunction in Schizophrenia.

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

Stability and generalization of combined theory of mind and cognitive remediation interventions in schizophrenia: Follow-up results.

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

The association of autistic traits with Theory of Mind and its training efficacy in patients with schizophrenia.

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

Daily Functioning in Schizophrenia: Is There Room for Anxiety?

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

Schizophrenia, cannabis use and Catechol-O-Methyltransferase (COMT): Modeling the interplay on cognition.

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

Exploring predictors of work competence in schizophrenia: The role of theory of mind.

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

Intellectual and cognitive profiles in patients affected by schizophrenia.

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

The role of premorbid adjustment in schizophrenia: Focus on cognitive remediation outcome.

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

From cognitive and clinical substrates to functional profiles: Disentangling heterogeneity in schizophrenia.

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

Improving Cognition to Increase Treatment Efficacy in Schizophrenia: Effects of Metabolic Syndrome on Cognitive Remediation's Outcome.

Cognitive impairment, typically more severe in treatment resistant patients, is considered a hallmark of schizophrenia and the prime driver of functional disability. Recent evidence suggests that metabolic syndrome may contribute to cognitive deficits in schizophrenia, possibly through shared underlying mechanisms. However, results are still contradictory and no study has so far examined the influence of metabolic syndrome on cognitive outcome after cognitive remediation therapy (CRT). Based on these premises, this study aims to investigate the relationship between metabolic syndrome and cognition, specifically considering cognitive outcome after treatment. Secondary objectives include the analysis of the association between cognitive impairment and psychopathological status and, in a subgroup of patients, the evaluation of the effect of Sterol Regulatory Element Binding Transcription Factor 1 (SREBF-1) rs11868035 genetic polymorphism, previously associated with metabolic alterations, on both cognition and metabolic syndrome. One-hundred seventy-two outpatients with schizophrenia were assessed for metabolic parameters and neurocognitive measures and 138 patients, who completed CRT, were re-evaluated for cognition. A subsample of 51 patients was also genotyped for rs11868035 from peripheral blood sample. Results show a negative impact of metabolic syndrome on executive functions and global cognitive outcome after CRT. Data also revealed a significant effect of SREBF-1 polymorphism, with a higher prevalence of metabolic syndrome and worse processing speed performance among G/G homozygous subjects, compared the A allele carriers. Overall these findings support the hypothesis that metabolic alterations may hamper the capacity to restore cognitive deficits, as well as they highlight the need to further explore possible converging mechanisms underlying both cognitive and metabolic dysfunction. At the clinical level, results point to the importance of a comprehensive assessment including the metabolic status of patients and of individualized strategies addressing metabolic dysfunction in order to potentiate treatment outcome in schizophrenia.

Neurobiology of cognitive remediation in schizophrenia: Effects of EAAT2 polymorphism.

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

Exploring anxiety in schizophrenia: New light on a hidden figure.

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

Can patients with schizophrenia have good mentalizing skills? Disentangling heterogeneity of theory of mind.

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