Carmelo Guglielmino

Combined social cognitive and neurocognitive rehabilitation strategies in schizophrenia: neuropsychological and psychopathological influences on Theory of Mind improvement.

BACKGROUND Neurocognitive and social cognitive impairments represent important treatment targets in schizophrenia, as they are significant predictors of functional outcome. Different rehabilitative interventions have recently been developed, addressing both cognitive and psychosocial domains. Although promising, results are still heterogeneous and predictors of treatment outcome are not yet identified. In this study we evaluated the efficacy of two newly developed social cognitive interventions, respectively based on the use of videotaped material and comic strips, combined with domain-specific Cognitive Remediation Therapy (CRT). We also analysed possible predictors of training outcome, including basal neurocognitive performance, the degree of cognitive improvement after CRT and psychopathological variables. METHOD Seventy-five patients with schizophrenia treated with CRT, were randomly assigned to: social cognitive training (SCT) group, Theory of Mind Intervention (ToMI) group, and active control group (ACG). RESULTS ANOVAs showed that SCT and ToMI groups improved significantly in ToM measures, whereas the ACG did not. We reported no influences of neuropsychological measures and improvement after CRT on changes in ToM. Both paranoid and non-paranoid subjects improved significantly after ToMI and SCT, without differences between groups, despite the better performance in basal ToM found among paranoid patients. In the ACG only non-paranoid patients showed an improvement in non-verbal ToM. CONCLUSION Results showed that both ToMI and SCT are effective in improving ToM in schizophrenia with no influence of neuropsychological domains. Our data also suggest that paranoid symptoms may discriminate between different types of ToM difficulties in schizophrenia.

COMT Val158Met and 5-HT1A-R -1019 C/G polymorphisms: effects on the negative symptom response to clozapine

AIM Clozapine is still considered the gold standard for treatment-resistant schizophrenia patients; however, up to 40% of patients do not respond adequately. Identifying potential predictors of clinical response to this last-line antipsychotic could represent an important goal for treatment. Among these, functional polymorphisms involved in dopamine system modulation, known to be disrupted in schizophrenia, may play a role. We examined the COMT Val158Met polymorphism, which plays a key role in dopamine regulation at the prefrontal level, and the 5-HT1A-R -1019 C/G polymorphism, a target of clozapine activity involved in the interaction between the serotonin and dopamine systems. MATERIALS & METHODS 107 neuroleptic-refractory, biologically unrelated Italian patients (70 males and 37 females) with a DSM-IV diagnosis of schizophrenia who were being treated with clozapine were recruited. Psychopathology was assessed by the Positive and Negative Symptoms Scale (PANSS) at the beginning of treatment, and at weeks 8 and 12. Genomic DNA was extracted from venous blood samples. COMT rs4680 (Val158Met) and 5-HT1A-R rs6295 (-1019 C/G) polymorphisms were analyzed by PCR-based restriction fragment length and direct sequencing, respectively. RESULTS We found a significant effect of COMT and 5-HT1A-R on the PANSS Negative Subscale variation, with greater improvement among COMT Val/Val and 5-HT1A-R G/G subjects. CONCLUSION The findings support the hypothesis that COMT rs4680 and 5-HT1A-R rs6295 polymorphisms could influence the negative symptom response to clozapine, probably through modulation of the dopaminergic system.

Exploring functioning in schizophrenia: Predictors of functional capacity and real-world behaviour

Impairment in daily functioning still represents a major treatment issue in schizophrenia and a more in-depth knowledge of underlying constructs is crucial for interventions to translate into better outcomes. This study aims to model factors influencing both functional capacity and real-life behaviour in a sample of outpatients with chronic schizophrenia, through a comprehensive assessment including evaluations of psychopathology, cognitive and social cognitive abilities, premorbid adjustment, family environment and early childhood experiences. No significant correlation was observed between functional capacity and real-life behaviour. Functional capacity was significantly predicted by IQ, while real-life behaviour was significantly predicted by empathy, affect recognition and symptoms. Functional capacity seems mainly related to neurocognition, whereas real-life behaviour appears more complex, requiring the integration of different factors including symptoms, with a major role of empathy. Results thus support a divergence between the two constructs of functioning and their underlying components and highlight the need to target both dimensions through individualized sequential rehabilitation programs in order to optimize functional outcome.

COMT and STH polymorphisms interaction on cognition in schizophrenia

Abstract 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.

Combined neurocognitive and metacognitive rehabilitation in schizophrenia: Effects on bias against disconfirmatory evidence.

BACKGROUND A Metacognitive Training for Schizophrenia patients (MCT) was developed to target the cognitive biases that characterize the illness. Results suggest positive MCT effects encompassing several aspects of psychopathology and subjective well-being. There are still open questions concerning the effect on different cognitive biases and the interplay between them and both psychopathology and neurocognition. Specifically, the bias against disconfirmatory evidence (BADE) has never been tested in previous trials on MCT. In this study we evaluated the feasibility of MCT combined with a cognitive remediation therapy (CACR) in schizophrenia and its effect on BADE. Moreover, we investigated the relationships between BADE and both neuropsychology and psychopathology, taking into account mutual influences on the degree of improvement. METHODS Fifty-seven schizophrenia outpatients were randomly assigned to CACR + control group or MCT+CACR and assessed at baseline and after treatment for psychopathology, neurocognition and BADE. RESULTS After MCT+CACR patients showed significantly greater improvements on BADE. Although BADE baseline performances correlated with several cognitive domains, no association was found between BADE improvement and neurocognitive nor psychopathological measures. CONCLUSIONS This study enlightened for the first time the efficacy of MCT+CACR on BADE in schizophrenia, suggesting the importance to develop a more specific intervention tailored on individual needs of patients.

Integrated cognitive remediation and standard rehabilitation therapy in patients of schizophrenia: persistence after 5 years

Cognitive remediation, often used in combination with standard rehabilitation programs, represents the best available tool to treat cognitive impairments in patients with schizophrenia. However, there are still open questions about durability of effects and generalization of cognitive improvements to functional outcome. This study aims to investigate the persistence of both cognitive and functional effects of combined cognitive remediation plus standard rehabilitation interventions, 5years after completion of the intervention, also comparing different durations of the standard rehabilitation. Sixty patients diagnosed with schizophrenia and previously treated with a 6months intervention, consisting of standard rehabilitation plus 3-months of cognitive remediation, either followed by another year of standard rehabilitation or routine psychiatric treatment, were reassessed with neuropsychological and functional measures 5years after the intervention. Results show that cognitive abilities remained stable after 5years in both groups, while functional performance significantly decreased in patients treated with the 6months intervention only. Data thus suggest that cognitive effects persist even after 5years, while a longer standard rehabilitation following the cognitive remediation program may be needed to achieve a stable functional gain.

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

ABSTRACT 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.

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.

Is longer treatment better? A comparison study of 3 versus 6 months cognitive remediation in schizophrenia.

Objective: Despite its extensive use for treating cognitive deficits in schizophrenia, computer-assisted cognitive remediation (CACR) currently lacks a standardized protocol. Duration is an important feature to be defined, as it may contribute to heterogeneous outcome. This study compares 2 treatment durations, 3 versus 6 months, to analyze their effects on both cognition and daily functioning. Method: Fifty-seven outpatients with schizophrenia received 3 months of CACR and 41 received 6 months of CACR. All patients were assessed at baseline and after 3 and 6 months with the Brief Assessment for Cognition in Schizophrenia and with the Quality of Life Scale (QLS). Results: Repeated measures ANOVA showed significant improvements in all cognitive domains after 3 months. A significant effect of treatment duration was observed only for executive functions, with significantly higher scores among patients treated for 6 months. Significant improvements in QLS were also observed after 6 months in both groups, with a significant time by treatment interaction for QLS Total Score. Conclusions: Results confirm the efficacy of 3-months CACR in terms of both cognitive and functional improvements, suggesting that an extended intervention may lead to further benefits in executive functions and daily functioning.

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.