Publications by authors named "Margherita Bechi"

41 Publications

Functional benefits of co-occurring autistic symptoms in schizophrenia is delimited by symptom severity.

J Psychiatr Res 2021 Feb 22;137:48-54. Epub 2021 Feb 22.

Schizophrenia Research and Clinical Unit, Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy; School of Psychology, Vita-Salute San Raffaele University, Milan, Italy.

Background: Impairments in daily functioning characterize both autism spectrum disorder and schizophrenia. Research has shown that a subsample of schizophrenia patients presents autistic symptoms, leading to the hypothesis that their co-occurrence would be associated with a 'double dose' of deficit. A growing body of research examined this hypothesis by looking at the joint effect of autistic and positive psychotic symptoms, and yielded contrasting results, ranging from benefits to adverse effects. We hypothesized that the interactive effect of autistic and positive symptoms on functioning in schizophrenia might depend on the patients' symptom severity.

Method: In 170 schizophrenia patients, a two-step cluster analysis identified two groups of patients with different levels of autistic and positive symptom severity. Using general linear models, we examined the interactions of groups, autistic and positive symptoms on functioning.

Results: Autistic and positive symptoms were interactively associated with better functioning, but only in the symptomatically less severe patients. In contrast, autistic and positive symptoms were independently associated with worse functioning in the symptomatically more severe patients. These associations were observed above and beyond the effects of I.Q. and illness duration.

Conclusions: The findings highlight the complex role played by co-occurring autistic symptoms in schizophrenia, whose beneficial effects on functioning appear to depend on patients' psychopathological severity. Our findings may help to reconcile the seemingly contrasting results from previous studies, and to understand the heterogeneity of behavior and functional outcomes in schizophrenia. This study underscores the potential utility of routinely assessing autism in schizophrenia, in order to better formulate individualized rehabilitative programs.
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http://dx.doi.org/10.1016/j.jpsychires.2021.02.044DOI Listing
February 2021

Clozapine tolerability in Treatment Resistant Schizophrenia: exploring the role of sex.

Psychiatry Res 2021 Mar 30;297:113698. Epub 2020 Dec 30.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.

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.
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http://dx.doi.org/10.1016/j.psychres.2020.113698DOI Listing
March 2021

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

Neuropsychobiology 2021 Jan 4:1-12. Epub 2021 Jan 4.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.

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-1β (IL-1β), a key mediator of inflammatory response, is of particular interest. IL-1β 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-1β 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-1β 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-1β 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-1β 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-1β polymorphism could play a key role in mediating the complex and refined relationship between metabolic syndrome and cognitive performance.
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http://dx.doi.org/10.1159/000512082DOI Listing
January 2021

Communicative-pragmatic abilities mediate the relationship between cognition and daily functioning in schizophrenia.

Neuropsychology 2021 Jan;35(1):42-56

School of Medicine, Vita-Salute San Raffaele University.

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).
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http://dx.doi.org/10.1037/neu0000664DOI Listing
January 2021

Can IQ moderate the response to cognitive remediation in people with schizophrenia?

J Psychiatr Res 2021 Jan 4;133:38-45. Epub 2020 Dec 4.

Department of Psychology, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, SE5 8AF, UK; South London & Maudsley NHS Foundation Trust, Maudsley Hospital, London, SE5 8AZ, UK.

Background: IQ and IQ decline are considered risk factors for poor prognosis in people with a diagnosis of schizophrenia. However, it is still not clear if, at least in part, IQ and IQ decline influence long-term outcomes via a negative effect on interventions.

Aim: To identify whether current IQ, estimated premorbid IQ, or IQ decline moderate the response to cognitive remediation (CR).

Method: Individual participant data from twelve randomised controlled trials of CR were considered. Hierarchical and k-means analyses were carried out to identify different IQ clusters. The moderating effect of estimated premorbid IQ, current IQ, and different IQ clusters (preserved, deteriorated and compromised trajectories) on cognitive outcomes at post-therapy and follow-up were evaluated using multiple linear regression.

Results: Data from 984 participants (CR = 544, control = 440) with schizophrenia and schizoaffective disorders were considered. The sample had a mean current IQ of 84.16 (SD 15.61) and estimated premorbid IQ of 95.82 (SD 10.63). Current IQ moderated working memory outcomes: people with higher IQ had larger working memory gains after therapy compared to those with a lower IQ. Those with a preserved IQ had better cognitive outcomes compared to either the deteriorated or compromised IQ groups, and those with a deteriorated IQ had better outcomes compared to those in the compromised IQ group.

Conclusion: Current IQ is a significant moderator of cognitive gains after CR. These findings highlight the need to evaluate whether therapy adaptations (e.g. offering more sessions) can attenuate this effect so that those with lower IQ may derive benefit similar to those with higher IQ.
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http://dx.doi.org/10.1016/j.jpsychires.2020.12.013DOI Listing
January 2021

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

J Nerv Ment Dis 2021 01;209(1):76-81

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute.

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.
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http://dx.doi.org/10.1097/NMD.0000000000001262DOI Listing
January 2021

Neuropsychological deficits correlate with symptoms severity and cortical thickness in Borderline Personality Disorder.

J Affect Disord 2021 Jan 15;278:181-188. Epub 2020 Sep 15.

Division of Neuroscience, Psychiatry and Clinical Psychobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.

Background: Neuropsychological abnormalities have been proposed to contribute to the development and maintenance of Borderline Personality Disorder (BPD). Previous meta-analyses and reviews confirmed deficits in a broad range of cognitive domains, including attention, cognitive flexibility, memory, executive functions, planning, information processing, and visuospatial abilities, often suggested to underlie brain abnormalities. However, no study directly explored the structural neural correlates of these deficits in BPD, also accounting for the possible confounding effect of pharmacological treatments, often used as adjunctive symptom-targeted therapy in clinical setting.

Methods: In this study we compared the performance of 24 BPD patients to 24 healthy controls obtained at the neuropsychological battery "Brief Assessment and Cognition in Schizophrenia", exploring the relationship between the cognitive impairments and current symptomatology, brain grey matter volumes and cortical thickness, controlling for medications load.

Results: Data revealed deficits in verbal memory and fluency, working memory, attention and speed of information processing and psychomotor speed and coordination when medication load was not in the model. Correcting for this variable, only the impairment in psychomotor abilities remained significant. A multiple regression confirmed the effect of this neuropsychological domain on the severity of BPD symptomatology (Borderline Evaluation of Severity Over Time). In BPD, the performance at psychomotor speed and coordination was also directly associated to cortical thickness in postcentral gyrus.

Limitations: Relatively small sample size, especially for neuroimaging.

Conclusions: Our study highlighted an influence of BPD neuropsychological impairments on symptomatology, and cortical thickness, prompting the potential clinical utility of a cognitive remediation program in BPD.
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http://dx.doi.org/10.1016/j.jad.2020.09.060DOI Listing
January 2021

The role of agency in schizophrenia: A pilot study on gaze agency.

Schizophr Res 2020 Aug 28;222:465-466. Epub 2020 Jun 28.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy; School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.

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http://dx.doi.org/10.1016/j.schres.2020.06.025DOI Listing
August 2020

A leopard cannot change its spots: A novel pragmatic account of concretism in schizophrenia.

Neuropsychologia 2020 03 7;139:107332. Epub 2020 Jan 7.

School of Medicine, Vita-Salute San Raffaele University, Milan, Italy; Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Concretism is a well-known feature of schizophrenia, tracing back to the early descriptions of the disease and commonly associated with the literal interpretation of figurative expressions such as proverbs, metaphors, and idioms. However, figurative expressions are not all alike in terms of linguistic and pragmatic processes. Determining if some figurative types are more impaired than others and if the type of task affects the performance constitutes an open issue with implications for the description of the clinical profile and for treatment. We run a fine-grained assessment of figurative language comprehension by comparing 47 patients with schizophrenia and 39 controls in three figurative types (idioms, metaphors, proverbs) presented in two response formats (multiple-choice, verbal-explanation), considering also the role of cognitive and clinical variables and the impact on quality of life. Mixed-effects models analysis revealed that: i) patients performed worse than controls across figurative types and response formats, indicating a diffuse impairment; ii) there is an interplay of figurative type and response format, which makes verbal-explanation of proverbs especially challenging; iii) in patients, problems in figurative language are largely connected with formal thought disorder and global IQ. Moreover, multiple-choice of metaphors was associated with patients' quality of life. This study offers a novel account of concretism, framed in pragmatics and figurative language processing. Adopting this perspective allowed us to describe the nuances of concretism, which areas in the figurative domain are especially challenging for patients and which ones capture differences in functioning, in order to guide intervention programs and integration in society.
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http://dx.doi.org/10.1016/j.neuropsychologia.2020.107332DOI Listing
March 2020

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

Schizophr Res Cogn 2020 Mar 31;19:100164. Epub 2019 Oct 31.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.

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.
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http://dx.doi.org/10.1016/j.scog.2019.100164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890977PMC
March 2020

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

J Int Neuropsychol Soc 2020 03 11;26(3):276-285. Epub 2019 Sep 11.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, 20100, Italy.

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.
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http://dx.doi.org/10.1017/S1355617719000961DOI Listing
March 2020

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

Psychiatr Rehabil J 2020 Jun 15;43(2):140-148. Epub 2019 Aug 15.

Department of Clinical Neurosciences.

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).
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http://dx.doi.org/10.1037/prj0000379DOI Listing
June 2020

Daily Functioning in Schizophrenia: Is There Room for Anxiety?

J Nerv Ment Dis 2019 Aug;207(8):615-619

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute.

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.
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http://dx.doi.org/10.1097/NMD.0000000000001030DOI Listing
August 2019

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

Prog Neuropsychopharmacol Biol Psychiatry 2019 06 18;92:363-368. Epub 2019 Feb 18.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy; School of Medicine, Vita -Salute San Raffaele University, Milan, Italy.

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.
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http://dx.doi.org/10.1016/j.pnpbp.2019.02.009DOI Listing
June 2019

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

Front Psychiatry 2018 7;9:647. Epub 2018 Dec 7.

School of Medicine, Università Vita-Salute San Raffaele, Milan, Italy.

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.
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http://dx.doi.org/10.3389/fpsyt.2018.00647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293025PMC
December 2018

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

Schizophr Res 2018 12 29;202:106-110. Epub 2018 Jun 29.

IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.

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.
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http://dx.doi.org/10.1016/j.schres.2018.06.059DOI Listing
December 2018

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

Psychiatry Res 2019 01 6;271:446-453. Epub 2018 Dec 6.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127 Milan, Italy; School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.

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.
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http://dx.doi.org/10.1016/j.psychres.2018.12.026DOI Listing
January 2019

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

Psychiatry Res 2018 10 30;268:312-316. Epub 2018 Jul 30.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy; School of Medicine, Vita -Salute San Raffaele University, Milan, Italy.

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.
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http://dx.doi.org/10.1016/j.psychres.2018.07.039DOI Listing
October 2018

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

Neuropsychology 2018 Sep 7;32(6):746-753. Epub 2018 Jun 7.

Department of Clinical Neurosciences.

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
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http://dx.doi.org/10.1037/neu0000456DOI Listing
September 2018

Intellectual and cognitive profiles in patients affected by schizophrenia.

J Neuropsychol 2019 09 23;13(3):589-602. Epub 2018 Apr 23.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.

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.
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http://dx.doi.org/10.1111/jnp.12161DOI Listing
September 2019

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

J Int Neuropsychol Soc 2018 07 20;24(6):563-571. Epub 2018 Mar 20.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milano, Italy.

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).
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http://dx.doi.org/10.1017/S1355617718000012DOI Listing
July 2018

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

Neuropsychol Rehabil 2019 Dec 19;29(10):1611-1624. Epub 2018 Feb 19.

Department of Clinical Neurosciences, San Raffaele Scientific Institute , Milan , Italy.

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.
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http://dx.doi.org/10.1080/09602011.2018.1433048DOI Listing
December 2019

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

Psychiatry Clin Neurosci 2018 Jan 20;72(1):28-34. Epub 2017 Oct 20.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.

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.
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http://dx.doi.org/10.1111/pcn.12605DOI Listing
January 2018

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

Schizophr Res 2018 02 23;192:335-339. Epub 2017 May 23.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy; School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.

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.
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http://dx.doi.org/10.1016/j.schres.2017.05.022DOI Listing
February 2018

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

Neuropsychol Rehabil 2019 Jun 19;29(5):691-703. Epub 2017 Apr 19.

a Department of Clinical Neurosciences , San Raffaele Scientific Institute , Milan , Italy.

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.
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http://dx.doi.org/10.1080/09602011.2017.1314217DOI Listing
June 2019

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

Psychiatry Res 2017 May 9;251:118-124. Epub 2017 Feb 9.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy.

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.
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http://dx.doi.org/10.1016/j.psychres.2017.02.019DOI Listing
May 2017

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

Neuropsychology 2017 May 2;31(4):467-473. Epub 2017 Feb 2.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute.

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. (PsycINFO Database Record
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http://dx.doi.org/10.1037/neu0000347DOI Listing
May 2017

The communicative impairment as a core feature of schizophrenia: Frequency of pragmatic deficit, cognitive substrates, and relation with quality of life.

Compr Psychiatry 2016 11 26;71:106-120. Epub 2016 Aug 26.

Department of Clinical Neurosciences, IRCSS San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127, Milano, Italy; Vita Salute San Raffaele University, Via Olgettina, 58, 20132, Milano, Italy. Electronic address:

Background: Impairments in specific aspects of pragmatic competence, supporting the use of language in context, are largely documented in schizophrenia and might represent an indicator of poor outcome. Yet pragmatics is rarely included in clinical settings. This paper aims to promote a clinical consideration of pragmatics as a target of assessment and intervention. We investigated the frequency of the pragmatic deficit, its cognitive substrates, and the relation with quality of life.

Methods: Pragmatic abilities were compared in a sample of patients with schizophrenia and healthy controls based on a comprehensive pragmatic test (APACS). We assessed also for psychopathology, cognition, social cognition, and quality of life. We explored the co-occurrence of deficits in different domains, and we used multiple regressions to investigate the effect of cognition and social cognition on pragmatics, and of pragmatics on quality of life.

Results: Pragmatic abilities, especially comprehending discourse and non-literal meanings, were compromised in schizophrenia, with 77% of patients falling below cutoff. Pragmatic deficit co-occurred with cognitive or socio-cognitive deficits in approximately 30% of cases. Multiple regression analysis confirmed the interplay of cognition and social cognition in pragmatic behavior. Quality of life was predicted by symptoms and by pragmatic abilities.

Conclusions: The high frequency of impairment suggests that the pragmatic deficit is a core feature of schizophrenia, associated with quality of life. Cognitive and socio-cognitive abilities might represent necessary though not sufficient building blocks for the acquisition of pragmatic abilities throughout development. Therefore, a more precise incorporation of pragmatics in the description of the pathology is of high clinical and translational relevance.
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http://dx.doi.org/10.1016/j.comppsych.2016.08.012DOI Listing
November 2016

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

Neuropsychol Rehabil 2018 Oct 6;28(7):1131-1144. Epub 2016 Oct 6.

a Department of Clinical Neurosciences , IRCCS San Raffaele Scientific Institute , Milan , Italy.

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.
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http://dx.doi.org/10.1080/09602011.2016.1240698DOI Listing
October 2018

COMT and STH polymorphisms interaction on cognition in schizophrenia.

Neurol Sci 2015 Feb 5;36(2):215-20. Epub 2014 Oct 5.

Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy,

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.
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http://dx.doi.org/10.1007/s10072-014-1936-9DOI Listing
February 2015