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

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 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

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

•Integrating multiple data to disentangle functioning in schizophrenia is necessary.•A non-linear approach might better capture clinical heterogeneity in schizophrenia .•Four Profiles of functioning emerged, with quantitative and qualitative differences.•Implications of functional profiles encompass both clinical and research fields. 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

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

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

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, 5 years after completion of the intervention, also comparing different durations of the standard rehabilitation. Sixty patients diagnosed with schizophrenia and previously treated with a 6 months 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 5 years after the intervention. Results show that cognitive abilities remained stable after 5 years in both groups, while functional performance significantly decreased in patients treated with the 6 months intervention only. Data thus suggest that cognitive effects persist even after 5 years, while a longer standard rehabilitation following the cognitive remediation program may be needed to achieve a stable functional gain. (C) 2017 Elsevier B.V. All rights reserved

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

Antimicrobial Effect and Cytotoxic Evaluation of Mg-Doped Hydroxyapatite Functionalized with Au-Nano Rods

Hydroxyapatite (HA) is the main inorganic mineral that constitutes bone matrix and represents the most used biomaterial for bone regeneration. Over the years, it has been demonstrated that HA exhibits good biocompatibility, osteoconductivity, and osteoinductivity both in vitro and in vivo, and can be prepared by synthetic and natural sources via easy fabrication strategies. However, its low antibacterial property and its fragile nature restricts its usage for bone graft applications. In this study we functionalized a MgHA scaffold with gold nanorods (AuNRs) and evaluated its antibacterial effect against S. aureus and E. coli in both suspension and adhesion and its cytotoxicity over time (1 to 24 days). Results show that the AuNRs nano-functionalization improves the antibacterial activity with 100% bacterial reduction after 24 h. The toxicity study, however, indicates a 4.38-fold cell number decrease at 24 days. Although further optimization on nano-functionalization process are needed for cytotoxicity, these data indicated that Au-NRs nano-functionalization is a very promising method for improving the antibacterial properties of HA