Targeting anxiety to improve quality of life in patients with schizophrenia.

BACKGROUND: Several studies suggested that anxiety can significantly affect the outcome of schizophrenia. Despite this evidence, non-pharmacological interventions targeting anxiety are still heterogenous. This study aims to test the efficacy of a novel training specifically designed to target anxiety in patients with schizophrenia. Innovatively, this training, beyond psychoeducation and problem solving, also targets Theory of Mind, as it provides coping strategies. METHOD: Twenty-seven outpatients with schizophrenia received a novel rehabilitative training targeting anxiety (Anxiety Management Group [AMG]) combined with a Computer-Assisted Cognitive Remediation (CACR), and twenty received CACR plus a control intervention (Control Newspaper discussion Group [CNG]). All patients were assessed at baseline and after treatment for quality of life, neurocognition and anxiety. RESULTS: After training, patients treated with AMG+CACR showed significantly greater improvements on anxiety. A significant increase in quality of life was observed only for AMG+CACR group. Moreover, the participants' appraisal showed a significant difference between treatment groups with higher ratings among patients who received the AMG+CACR. CONCLUSIONS: This study thus suggests feasibility and efficacy of the proposed intervention, that could be implemented in rehabilitative programs for patients with schizophrenia with potential benefits also on disease course and outcome.

Cognitive remediation and functional improvement in schizophrenia: Is it a matter of size?

BACKGROUND: Cognitive Remediation represents the best available tool to treat cognitive deficits in schizophrenia and evidence suggests an effect also on global functioning. However, the relationship between cognitive and functional improvement is not yet fully elucidated: do cognitive changes need to be of a definite size and/or encompass a certain number of domains in order to impact on daily functioning? This study aims to explore the role of cognitive improvement, evaluated both quantitatively and qualitatively through the use of Italian equivalent scores, on the daily functioning of patients. As secondary goal, the influence of demographic, clinical and neuropsychological variables on functional outcome was also systematically investigated. METHODS: One hundred subjects with a diagnosis of schizophrenia underwent 36 sessions of Cognitive Remediation and were evaluated at baseline and after the training with the Brief Assessment of Cognition in Schizophrenia and the Quality of Life Scale. RESULTS: A total of 70% of patients improved in at least one cognitive domain and over 50% obtained a normalized score. Among the clinical and neurocognitive factors examined, the only significant predictor of quality of life's improvement was the proportion of cognitive functions that reached an equivalent score of "normal". CONCLUSIONS: This study suggests that improvements in daily functioning depend on the achievement of a cognitive profile as much as possible "normal", harmonious and balanced, supporting the idea that a qualitative leap in cognition is needed in order to gain an advantage in real life activities.

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.

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.

Abnormal cortico-limbic connectivity during emotional processing correlates with symptom severity in schizophrenia.

BACKGROUND: Impaired emotional processing is a core feature of schizophrenia (SZ). Consistent findings suggested that abnormal emotional processing in SZ could be paralleled by a disrupted functional and structural integrity within the fronto-limbic circuitry. The effective connectivity of emotional circuitry in SZ has never been explored in terms of causal relationship between brain regions. We used functional magnetic resonance imaging and Dynamic Causal Modeling (DCM) to characterize effective connectivity during implicit processing of affective stimuli in SZ. METHODS: We performed DCM to model connectivity between amygdala (Amy), dorsolateral prefrontal cortex (DLPFC), ventral prefrontal cortex (VPFC), fusiform gyrus (FG) and visual cortex (VC) in 25 patients with SZ and 29 HC. Bayesian Model Selection and average were performed to determine the optimal structural model and its parameters. RESULTS: Analyses revealed that patients with SZ are characterized by a significant reduced top-down endogenous connectivity from DLPFC to Amy, an increased connectivity from Amy to VPFC and a decreased driving input to Amy of affective stimuli compared to HC. Furthermore, DLPFC to Amy connection in patients significantly influenced the severity of psychopathology as rated on Positive and Negative Syndrome Scale. CONCLUSIONS: Results suggest a functional disconnection in brain network that contributes to the symptomatic outcome of the disorder. Our findings support the study of effective connectivity within cortico-limbic structures as a marker of severity and treatment efficacy in SZ.

Effect of glutamate transporter EAAT2 gene variants and gray matter deficits on working memory in schizophrenia.

Glutamate is the major excitatory neurotransmitter in the brain, with up to 40% of all synapses being glutamatergic. An altered glutamatergic transmission could play a critical role in working memory deficts observed in schizophrenia and could underline progressive changes such as grey matter loss throughout the brain. The aim of the study was to investigate if gray matter volume and working memory could be modulated by a genetic polymorphism related to glutamatergic function. Fifty schizophrenia patients underwent magnetic resonance and working memory testing outside of the scanner and were genotyped for rs4354668 EAAT2 polymorphism. Carriers of the G allele had lower gray matter volumes than T/T homozygote and worse working memory performance. Poor working memory performance was associated with gray matter reduction. Differences between the three genotypes are more relevant among patients showing poor performance at the 2-back task. Since glutamate abnormalities are known to be involved in excitotoxic processes, the decrease in cortical thickness observed in schizophrenia patients could be linked to an excess of extracellular glutamate. The differential effect of EAAT2 observed between good and poor performers suggests that the effect of EEAT2 on gray matter might reveal in the presence of a pathological process affecting gray matter.

Factors involved in the level of functioning of patients with schizophrenia according to latent variable modeling.

PURPOSE: This study aimed at using latent variable modelling to explore the significantly contributing variables to functioning in schizophrenia patients. METHODS: The study cohort comprised 296 schizophrenia patients evaluated once for demographic characteristics, functioning (FROGS, SWN-K, QLS) and symptomatology (Positive and Negative Syndrome Scale [PANSS]). First exploratory multivariate analyses were conducted and then a model with functioning as a latent variable was proposed and tested with the data. RESULTS: Symptomatology as negative, cognitive and excitation factor are significant predictors of functioning assessed through FROGS (P<0.0001), SWN-K and QLS (P<0.001). The model was constructed with functioning defined as a latent variable, indicators are subscores on FROGS, SWN-K, QLS and exogenous variable included symptomatology, Duration of Untreated Psychosis (DUP) and educational level. CONCLUSION: Using the five clinical dimensions of the PANSS, (Positive, Negative, Cognitive, Anxiety/Depression and Excitation) the negative and cognitive dimensions are highly correlated via the latent variable to the three dimensions of functioning evaluated by the FROGS: "daily life", "social functioning" and "treatment" and the QLS subscores (interpersonnal, common object, instrumental role). Educationnal level is positively linked to functioning but not DUP. The model emphasizes the need for treatment strategies that have an effect on cognitive-factors, to improve functioning in schizophrenia.

A functional comparison of patients with schizophrenia between the North and South of Europe.

INTRODUCTION: The main objective of this study was to compare clinical and functional outcomes of patients with schizophrenia in Italy and Sweden with a special focus on daily functioning performance and real life milestones. Also, to study if outcome is to be regarded as a consequence of premorbid function, the level of symptom control and functional capacity or if other influences, such as cultural differences, must parallel be considered. METHOD: Ninety-five patients from three centres, Milan and Naples in Italy and Trollhattan in Sweden were investigated. The Positive and Negative Syndrome Scale and the UCSD Performance-Based Skills Assessment - Brief version were used together with patients' school history and their status of accommodation and occupation. RESULTS: Patients in Trollhattan were more likely to live independently and patients in Naples to have a work or take part in education. Differences in symptoms and the performance test were present but subtle. DISCUSSION: Differences in real life milestones were not explained by corresponding differences in symptoms, premorbid function or the performance-based test. It is therefore not appropriate only to present functional outcome as an expression of how successful treatment has been.

Emotional reactivity in chronic schizophrenia: structural and functional brain correlates and the influence of adverse childhood experiences.

BACKGROUND: Despite behavioural signs of flattened affect, patients affected by schizophrenia show enhanced sensitivity to negative stimuli. The current literature concerning neural circuitry for emotions supports dysregulations of cortico-limbic networks, but gives contrasting results. Adverse childhood experiences (ACEs) could persistently influence emotional regulation and neural correlates of response to emotional stimuli in healthy humans. This study evaluated the effect of ACEs and chronic undifferentiated schizophrenia on neural responses to emotional stimuli (negative facial expression). METHOD: Brain blood-oxygen-level-dependent functional magnetic resonance imaging neural responses to a face-matching paradigm, and regional grey matter (GM) volumes were studied at 3.0 T in the amygdala, hippocampus, anterior cingulated cortex (ACC) and prefrontal cortex (PFC). The severity of ACEs was assessed. Participants included 20 consecutively admitted in-patients affected by chronic undifferentiated schizophrenia, and 20 unrelated healthy volunteers from the general population. RESULTS: Patients reported higher ACEs than controls. Worse ACEs proportionally led to decreasing responses in the amygdala and hippocampus, and to increasing responses in the PFC and ACC in all participants. Patients showed higher activations in the amygdala and hippocampus, and lower activations in the PFC and ACC. Higher ACEs were associated with higher GM volumes in the PFC and ACC, and schizophrenia was associated with GM reduction in all studied regions. CONCLUSIONS: Structural and functional brain correlates of emotional reactivity are influenced by both current chronic undifferentiated schizophrenia and the severity of past ACEs.

Management of physical health in patients with schizophrenia: international insights.

This international meeting discussed the management of physical health in patients with schizophrenia in several countries including France, Spain, Germany, the UK and Italy. Physical health parameters, including weight, blood pressure, blood glucose, lipids and standard biochemical assessments are measured in many patients at the first hospital consultation. These reveal physical disorders such as obesity, hypertension, dyslipidaemia, the metabolic syndrome, substance abuse, cardiovascular disease, extrapyramidal symptoms, sexual dysfunction and diabetes in substantial proportions of patients. Psychiatrists consider switching antipsychotic therapy if excessive sedation, extrapyramidal symptoms, unacceptable weight gain, hyperglycaemia or dyslipidaemia occur. In general, switching is more likely to be considered for symptomatic adverse events than for laboratory abnormalities. Switching is discouraged by limited knowledge of protocols, the absence of guidelines and fears of relapse or reduced treatment adherence. The physical health of patients with schizophrenia receives much less attention in the community setting than in the hospital setting. Improved guidelines, protocols, resources and support are needed to improve the physical health of patients in the community.

Computer-aided neurocognitive remediation in schizophrenia: durability of rehabilitation outcomes in a follow-up study.

Cognitive deficits in patients with schizophrenia constitute a limiting factor to the chances of rehabilitation of daily living abilities, like personal and relational autonomy and working ability. Cognitive Remediation Therapy (CRT) is a rehabilitative technique that aims at the recovery of single cognitive functions through the execution of massive exercises of impaired cognitive domains. This study aims to establish if the results achieved through an intensive deficit-specific neurocognitive treatment of three months duration, were maintained over time. The sample consists in 100 patients diagnosed with schizophrenia according to the criteria of DSM IV. Patients were assessed on cognitive and daily functioning at baseline, after 3 months of either CRT or placebo training added to their standard rehabilitation treatment, at 6 month and 12-month follow-up. Results showed significant changes that were maintained at follow-up for executive function, attention and psychomotor coordination. Moreover the significant improvement in daily functioning was maintained at 6 and 12-month follow-up. In conclusion improvements in cognitive functions and daily functioning achieved through the association of CRT and standard rehabilitation treatment persist over time after the conclusion of the training period.

Temporal lobe grey matter volume in schizophrenia is associated with a genetic polymorphism influencing glycogen synthase kinase 3-ß activity.

At the crossroad of multiple pathways regulating trophism and metabolism, glycogen synthase kinase (GSK)3 is considered a key factor in influencing the susceptibility of neurons to harmful stimuli (neuronal resilience) and is a target for several psychiatric drugs that directly inhibit it or increase its inhibitory phosphorylation. Inhibition of GSK3 prevents apoptosis and could protect against the neuropathological processes associated with psychiatric disorders. A GSK3-beta promoter single-nucleotide polymorphism (rs334558) influences transcriptional strength, and the less active form was associated with less detrimental clinical features of mood disorders. Here we studied the effect of rs334558 on grey matter volumes (voxel-based morphometry) of 57 patients affected by chronic schizophrenia. Carriers of the less active C allele variant showed significantly higher brain volumes in an area encompassing posterior regions of right middle and superior temporal gyrus, within the boundaries of Brodmann area 21. The temporal lobe is the brain parenchymal region with the most consistently documented morphometric abnormalities in schizophrenia, and neuropathological processes in these regions develop soon at the beginning of the illness. These results support the interest for GSK3-beta as a factor affecting neuropathology in major behavioural disorders, such as schizophrenia, and thus as a possible target for treatment.

'Theory' of mind impairment in patients affected by schizophrenia and in their parents.

"Theory of mind" (ToM) is the ability to judge the mental states of the self and others. It is currently considered as a part of the broader concept of social cognition, known to influence the social behaviour of patients affected by schizophrenia. Recently it has been hypothesized that the impairment of ToM is a trait that can be detected both in patients with schizophrenia and in non-psychotic relatives of patients, but it still not clear what the contribution of the familial patterns of cognitive impairment is. The aim of this study is to assess parental impairments of ToM performance considering the effects of the neurocognitive abilities known to be impaired in their first-degree relatives and to influence ToM in schizophrenic patients. Patients, their parents and control trios were assessed with the Wisconsin Card Sorting Test (WCST), the Symbol Coding Task and the ToM Picture Sequencing Task. The ANCOVA analysis on 47 trios including a schizophrenic offspring and 47 healthy trios showed a statistically significant poorer performance of patients and their parents in comparison to control trios at Symbol Coding Task and ToM task. Moreover a regression analysis showed that the neuropsychological abilities tested were significant predictors of ToM performance only in patients. Results confirm a ToM impairment among parents of patients with schizophrenia that is not directly correlated to other aspects of neurocognitive functioning.

Standardized remission criteria in schizophrenia.

OBJECTIVE: Recent work has focussed on schizophrenia as a 'deficit' state but little attention has been paid to defining illness plasticity in terms of symptomatic remission. METHOD: A qualitative review of a recently proposed concept of remission [N.C. Andreasen, W.T. Carpenter Jr, J.M. Kane, R.A. Lasser, S.R. Marder, D.R. Weinberger (2005) Am J Psychiatry 162: 441] is presented. RESULTS: The proposed definition of remission is conceptually viable, and can be easily implemented in clinical trials and clinical practice. Its increasing acceptance may reset expectations of treatment to a higher level, improve documentation of clinical status and facilitate dialogue on treatment expectations. The availability of validated outcome measures based on remission will enhance the conduct and reporting of clinical investigations, and could facilitate the design and interpretation of new studies on cognition and functional outcomes. While useful as a concept, it is important to consider that remission is distinct from recovery. CONCLUSION: The introduction of standardized remission criteria may offer significant opportunities for clinical practice, health services research and clinical trials.

Helicobacter pylori impairs iron absorption in infected individuals.

BACKGROUND: Infection with Helicobacter pylori is recognised as a major risk factor for chronic gastritis, peptic ulcer disease and gastric cancer. The association between H. pylori infection and iron deficiency anaemia has been established. Multiple mechanisms have been advocated to explain the relationship between H. pylori and iron status and their association might reduce iron deposit. AIM: Aim of this study was to investigate whether H. pylori infection affects iron absorption. METHODS: The study was designed on a prospective basis. Fifty-five subjects underwent upper gastrointestinal endoscopy and biopsy to investigate the presence of H. pylori and, when this was positive, also search of serum anti-CagA was performed. Tests included an oral iron absorption test with the administration of 1 mg/kg of Fe2+. Iron levels were measured before and 2 h after iron administration (delta iron). H. pylori-positive subjects were administered antibiotic therapy for 1 week and, 2 months later, the oral iron absorption test was repeated and urea-breath test was first performed. RESULTS: H. pylori-positive subjects had lower serum level of ferritin and lower delta iron compared to H. pylori-negative subjects. That difference is significant in anaemic women and is independent of the presence of serum anti-CagA antibodies. After H. pylori eradication iron absorption test was similar to those of non-infected subjects. CONCLUSION: H. pylori infection impairs iron uptake. That mechanism, together with others, may contribute to the depletion of iron in infected patients.

Citalopram concentrations and response in obsessive-compulsive disorder. Preliminary results.

OBJECTIVE: Citalopram, a highly potent SSRI, is effective in the treatment of depressive disorders and obsessive-compulsive disorder (OCD); however, very few studies have reported concentration-effect relationships for SSRIs. The aim of this study was to investigate the relationship between citalopram concentrations and clinical response in patients with OCD. METHODS AND STUDY DESIGN: Fifteen patients (aged 18-65 years) with a DSM-IV diagnosis of OCD were included in this open-label, single-blind study. Citalopram was started at a dosage of 20 mg/day; the dosage was increased to a maximum of 60 mg/day by the third week, on the basis of clinical need and tolerability. The dosage then remained unchanged until the end of the 10-week study. Clinical assessments were made at baseline, weekly for the first four weeks and then at weeks 6, 8 and 10. The assessment scales used were the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Clinical Global Impression Scale (CGI) and the Hamilton Depression Rating Scale (HDRS). Plasma citalopram concentrations were determined using a high performance liquid chromatography method after solid phase extraction. RESULTS: One patient was withdrawn from the study because of poor compliance. Of the 14 patients who completed the study, nine did not meet the treatment response criterion of an improvement of >25% from the baseline total Y-BOCS score and a score of < or =3 for the global improvement item of the CGI (these patients were termed non-responders), while five did (responders). There were no differences in the main demographic and baseline clinical variables between responders and non-responders. Steady-state citalopram concentrations were similar in the two groups, suggesting that the anti-obsessional effects of citalopram were not related to pharmacokinetic differences between responders and non-responders. There was no linear relationship between steady-state citalopram concentrations and response. The citalopram concentrations and Y-BOCS scores of individual responders obtained at baseline and various study timepoints showed a sigmoid relationship when analysed using the E(max) (maximum change in Y-BOCS score) model, with a mean EC(50) value (drug concentration that elicits 50% of the E(max)) of 152 microg/L, whereas a similar analysis of the non-responders generated a flat line. CONCLUSION: The results of this preliminary study suggest that plasma citalopram concentrations may be related to the clinical response in responders, but do not seem to account for the lack of clinical effect in non-responders. These data, as well as the usefulness of the model in relating plasma concentrations to response, even after repeated administration, need to be validated by further investigations.

Gene silencing by S-adenosylmethionine in muscle differentiation.

A well-characterised experimental system, the myogenin gene in C2C12 muscle cell culture, was chosen to better understand the methylation mechanism underlying the regulation of gene expression. We already demonstrated that demethylation dynamics of a specific CpG site in the 5'-flanking region of myogenin well correlates with gene expression and terminal differentiation. Here we demonstrate that S-adenosylmethionine-sulphate-p-toluenesulphonate (SAM) inhibits myogenin expression and myoblast differentiation by delaying the demethylation of specific CpG in differentiating myoblasts. These results suggest new perspectives in methylation mechanisms and the use of SAM in the partial silencing of gene expression, as it could be required in disease treatment.

Increased risk of surgery in undiagnosed celiac disease.

The diagnosis of celiac disease patients may be delayed by misdiagnosis. Our aim was to evaluate in celiac patients the prevalence of surgery before diagnosis. Two hundred forty-four adult celiac patients and 232 controls were retrospectively investigated for surgery before diagnosis of celiac disease. The prevalence of surgery was increased in celiac patients versus controls (P = 0.001). Frequency of appendectomy (P = 0.0001), tonsillectomy (P = 0.009), and hernia repair (P = 0.05) were increased in celiac patients versus controls. Appendectomy was related to anemia (P = 0.006) and abdominal pain (P = 0.005); tonsillectomy was related to diarrhea (P = 0.02) and weight loss (P = 0,04). Appendectomy was elective in 73% of celiac patients and in 46% of controls. Cosmetic surgery was increased in celiac patients versus controls (P = 0.058). In conclusions, surgery before celiac disease diagnosis is increased in celiac patients compared to controls, as a result of doctors' misdiagnosis and/or poor health status, which increases the demand for medical intervention. The frequency of cosmetic surgery in celiac patients may berelated to impaired psychological profile of patients.