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

Clozapine is the only evidence-based drug indicated for Treatment Resistant Schizophrenia but it is largely underprescribed, partially due to its life-threatening adverse effects (AEs). However, clozapine treatment is burdened by other common AEs as constipation, hypersalivation, postural hypotension, tachycardia and metabolic abnormalities. Few studies have investigated sex-related differences in clozapine's tolerability, reporting women to experience more frequently weight gain, hyperglycemia and constipation, while men hypertension and dyslipidemia. Based on these premises, we investigated clinical, psychopathological and metabolic sex-related differences among 147 treatment-resistant patients treated with clozapine, with a specific focus on non-life-threatening AEs. We observed significant higher prevalence of tachycardia in men, and of orthostatic hypotension and constipation in women. Concerning metabolic alterations, we observed significant lower levels of HDL-cholesterol and higher prevalence of hypertriglyceridemia among men, whereas females showed higher prevalence of abdominal obesity. Consistently with previous studies, our data confirm the presence of sex-related differences in clozapine tolerability, with a main effect of sex especially for tachycardia, postural hypotension and constipation. Although non-life-threatening, these common AEs significantly affect patients' quality of life, undermine compliance and cause treatment discontinuation. A better understanding of this topic could contribute to tailor therapeutic approaches, thus improving tolerability, compliance and clinical stability.

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

Premorbid adjustment has been associated with several outcomes in schizophrenia and has been proposed as an index of cognitive reserve. This study aims to comprehensively analyse the relation between premorbid adjustment and clinical, neurocognitive, socio-cognitive and functional assessments, as well as to investigate the effect of premorbid adjustment on cognitive improvements after a cognitive remediation therapy protocol. Seventy-nine clinically stabilised outpatients with schizophrenia underwent a combined intervention consisting of cognitive remediation therapy added to standard rehabilitation therapy. All patients were assessed at baseline for psychopathology, premorbid adjustment, intellectual level, cognition and functioning. Cognitive evaluations were also repeated after the intervention. At baseline, significant correlations were observed between premorbid adjustment and working memory. The global cognitive improvement after treatment was significantly predicted by age and premorbid adjustment. This study confirms the association between premorbid adjustment and cognitive impairment and is the first to highlight the possible role of premorbid adjustment on the capacity to recover from cognitive deficits through a cognitive remediation therapy protocol. The data suggest that cognitive remediation may be particularly effective for people in the early course and that the assessment of premorbid adjustment could be of value to design individualised interventions.

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

In schizophrenia employment rate is dramatically low, also among patients receiving job support interventions. Recent studies showed a direct relationship between neurocognitive deficits and work functioning, as well as proving the benefits of combined neurocognitive and work interventions. Current evidence also supports a role of Theory of Mind (ToM), on work functioning. However, the effect of integrated rehabilitation programmes including a social cognitive training on job outcome is still less explored. The aim of this pilot study is to investigate the relationship between work competence and clinical factors, neurocognitive and ToM abilities, as well as to explore the effect of neurocognitive and ToM treatments combined with work therapy. Thirty-seven outpatients with schizophrenia were assigned to either a Computer-assisted Cognitive Remediation (CACR) plus work therapy group (WTG) or to CACR and WTG added to ToM Intervention, both followed by a job support programme. All patients were assessed for psychopathology, neurocognition, ToM and work functioning. Work outcome was significantly predicted by age at onset, neurocognitive abilities and the degree of ToM improvement after the specific intervention. This study provides preliminary insight on predictors of work competence in schizophrenia, highlighting the importance of ToM abilities.

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.

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

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.

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. (PsycINFO Database Record

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).

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

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.

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

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

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. (PsycINFO Database Record