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.

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.

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.

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.

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.

Cognitive Reserve Profiles in Chronic Schizophrenia: Effects on Theory of Mind Performance and Improvement after Training.

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

Achieving recovery in patients with schizophrenia through psychosocial interventions: A retrospective study.

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

Visual and audio emotion processing training for outpatients with schizophrenia: an integrated multisensory approach.

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

COMT and STH polymorphisms interaction on cognition in schizophrenia.

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

Neuroinflammation and kynurenines in schizophrenia: Impact on cognition depending on cognitive functioning and modulatory properties in relation to cognitive remediation and aerobic exercise.

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.

Theory of Mind intervention for outpatients with schizophrenia.

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

The cognitive architecture of verbal humor in schizophrenia.

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.

Saitohin polymorphism and executive dysfunction in schizophrenia.

Saitohin (STH) is an intronless gene nested within the human tau gene, which contains a single nucleotide polymorphism (A/G), suggested to be involved in the physiopathology and clinical course of several neurodegenerative and neuropsychiatric diseases. Recently, an association between this polymorphism and frontal hypoperfusion and clinical prognosis in frontotemporal dementia was reported. The present study sought to evaluate the possible role of the STH polymorphism as a concurring factor of cognitive decline in schizophrenia, a disease sharing both early psychotic manifestations, a core deficit of executive functions and hypofrontality with frontotemporal lobe dementia. 220 clinically stabilized patients with schizophrenia were assessed with the Wisconsin Card Sorting Test (WCST) for evaluation of executive functions and compared for STH allele frequency with 48 patients affected by frontotemporal dementia and 47 healthy subjects. There was no significant difference in allelic distribution between the healthy controls and all other groups, while we observed a significantly greater frequency of G allele among both patients with frontotemporal dementia (p = 0.037) and schizophrenia patients with poor performances of WCST (p = 0.044), compared to schizophrenia patients with best WCST performances. Among the patients with schizophrenia, stratified for age and gender, the STH polymorphism resulted in a significant predictor of WCST performance (p = 0.007). These results suggest a possible contribution of STH gene products on the heterogeneity of core frontal executive functions deterioration, probably through complex interactions with mechanism involved in neurodevelopment and neurodegeneration.

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 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.

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.

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).

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.

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).