The kynurenine pathway in treatment-resistant schizophrenia at the crossroads between pathophysiology and pharmacotherapy.

Two cardinal elements in the complex and multifaceted pathophysiology of schizophrenia (SCZ) are neuroinflammation and dysregulation of glutamatergic neurotransmission, with the latter being especially involved in treatment-resistant schizophrenia (TRS). Interestingly, the Kynurenine (KYN) pathway (KP) is at the crossroad between them, constituting a potential causal link and a therapeutic target. Although there is preclinical and clinical evidence indicating a dysregulation of KP associated with the clinical phenotype of SCZ, clinical studies investigating the possible relationship between changes in biomarkers of the KP and response to pharmacotherapy are still limited. Therefore, we have studied possible differences in the circulating levels of biomarkers of the metabolism of tryptophan along the KP in 43 responders to first-line treatments (FLR) and 32 TRS patients treated with clozapine, and their possible associations with psychopathology in the two subgroups. Plasma levels of KYN were significantly higher in TRS patients than in FLR patients, indicating a greater activation of KP. Furthermore, the levels of quinolinic (NMDA receptor agonist) and kynurenic acid (NMDA negative allosteric modulator) showed a negative and a positive correlation with several dimensions and the overall symptomatology in the whole sample and in FLR, but not in TRS, suggesting a putative modulating effect of clozapine elicited through the NMDA receptors. Despite the cross-sectional design of the study that prevents us from demonstrating causation, these findings show a significant relationship among circulating KP biomarkers, psychopathology, and response to pharmacotherapy in SCZ. Therefore, plasma KP biomarkers should be further investigated for developing personalized medicine approaches in SCZ.

Improving outcome of treatment-resistant schizophrenia: effects of cognitive remediation therapy.

Treatment-Resistant Schizophrenia (TRS) represents a main clinical issue, associated with worse psychopathological outcomes, a more disrupted neurobiological substrate, and poorer neurocognitive performance across several domains, especially in verbal abilities. If cognitive impairment is a major determinant of patients' functional outcomes and quality of life, targeting cognitive dysfunction becomes even more crucial in TRS patients in order to minimize cognitive and functional deterioration. However, although Cognitive Remediation Therapy (CRT) represents the best available tool to treat cognitive dysfunction in schizophrenia, specific evidence of its efficacy in TRS is lacking. Based on these premises, our study aimed at investigating possible differences in CRT outcomes in a sample of 150 patients with schizophrenia, stratified according to antipsychotic response (TRS vs. non-TRS). Subjects were assessed for neurocognition through Brief Assessment of Cognition in Schizophrenia (BACS) and the Wisconsin Card Sorting Test (WCST) at baseline and after CRT. As expected, we observed greater baseline impairment among TRS patients in BACS-Verbal Memory and WCST-Executive Functions. Repeated measures ANCOVAs showed significant within-group pre-/post-CRT differences in the above-mentioned domains, both among non-TRS and TRS subjects. However, after CRT, no differences were observed between groups. This is the first study to indicate that CRT represents a highly valuable resource for TRS patients, since it may be able to fill the cognitive gap between treatment response groups. Our finding further highlights the importance of early implementation of CRT in addition to pharmacotherapy to reduce the cognitive and functional burden associated with the disease, especially for TRS patients.

Importance of the dysregulation of the kynurenine pathway on cognition in schizophrenia: a systematic review of clinical studies.

Schizophrenia is a chronic psychotic disease burdened by cognitive deficits which hamper daily functioning causing disability and costs for society. Biological determinants underlying cognitive impairment are only partially understood and there are no convincing pharmacological targets able to improve cognitive outcome. Mounting evidence has shown the involvement of the kynurenine pathway in the pathophysiology of schizophrenia, also concerning cognitive symptoms. Therefore, the action of specific metabolites of kynurenine could affects cognition in schizophrenia. To evaluate the impact of the metabolites of kynurenine pathway on cognitive functions in schizophrenia spectrum disorders, with a focus on the modulating role of gender, to identify predictors of cognitive functioning and hypothetical pharmacological targets able to resize disability by improving cognition, thus functioning and quality of life. A systematic review was performed in PubMed/MEDLINE and Embase according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. All studies measuring the direct impact of kynurenine metabolites on cognitive performances in living individuals with schizophrenia spectrum disorders were included in the review. Six studies were included. The activation of the kynurenine pathway resulted associated with greater cognitive deficits in patients with schizophrenia and both elevations and reduction of metabolites seemed able to affect cognitive outcome. No modulating role of sex emerged. This systematic review provides evidence that the activation of the kynurenine pathway affects cognition in patients with schizophrenia and highlights this pathway as a possible future target for developing novel drugs toward this still unmet clinical need. However, evidence is still limited and future studies are needed to further clarify the relationship between kynurenine pathway and cognition in schizophrenia.

Schizophrenia and psychedelic state: Dysconnection versus hyper-connection. A perspective on two different models of psychosis stemming from dysfunctional integration processes.

Psychotic symptoms are a cross-sectional dimension affecting multiple diagnostic categories, despite schizophrenia represents the prototype of psychoses. Initially, dopamine was considered the most involved molecule in the neurobiology of schizophrenia. Over the next years, several biological factors were added to the discussion helping to constitute the concept of schizophrenia as a disease marked by a deficit of functional integration, contributing to the formulation of the Dysconnection Hypothesis in 1995. Nowadays the notion of dysconnection persists in the conceptualization of schizophrenia enriched by neuroimaging findings which corroborate the hypothesis. At the same time, in recent years, psychedelics received a lot of attention by the scientific community and astonishing findings emerged about the rearrangement of brain networks under the effect of these compounds. Specifically, a global decrease in functional connectivity was found, highlighting the disintegration of preserved and functional circuits and an increase of overall connectivity in the brain. The aim of this paper is to compare the biological bases of dysconnection in schizophrenia with the alterations of neuronal cyto-architecture induced by psychedelics and the consequent state of cerebral hyper-connection. These two models of psychosis, despite diametrically opposed, imply a substantial deficit of integration of neural signaling reached through two opposite paths.

Deconstructing heterogeneity in schizophrenia through language: a semi-automated linguistic analysis and data-driven clustering approach.

Previous works highlighted the relevance of automated language analysis for predicting diagnosis in schizophrenia, but a deeper language-based data-driven investigation of the clinical heterogeneity through the illness course has been generally neglected. Here we used a semiautomated multidimensional linguistic analysis innovatively combined with a machine-driven clustering technique to characterize the speech of 67 individuals with schizophrenia. Clusters were then compared for psychopathological, cognitive, and functional characteristics. We identified two subgroups with distinctive linguistic profiles: one with higher fluency, lower lexical variety but greater use of psychological lexicon; the other with reduced fluency, greater lexical variety but reduced psychological lexicon. The former cluster was associated with lower symptoms and better quality of life, pointing to the existence of specific language profiles, which also show clinically meaningful differences. These findings highlight the importance of considering language disturbances in schizophrenia as multifaceted and approaching them in automated and data-driven ways.

It is time to address language disorders in schizophrenia: A RCT on the efficacy of a novel training targeting the pragmatics of communication (PragmaCom).

INTRODUCTION: Language and communication disruptions in schizophrenia are at the center of a large body of investigation. Yet, the remediation of such disruptions is still in its infancy. Here we targeted what is known to be one of the most damaged language domains in schizophrenia, namely pragmatics, by conducting a pragmatics-centered intervention with a randomized controlled trial design and assessing also durability and generalization. To the best of our knowledge, this is the first study with these characteristics. METHODS: Inspired by the Gricean account of natural language use, we tailored a novel treatment addressing the pragmatics of communication (PragmaCom) and we tested its efficacy in a sample of individuals with schizophrenia randomized to the experimental group or to an active control group. The primary outcome with respect to the efficacy of the PragmaCom was measured by changes in pragmatic abilities (as evaluated with the global score of the Assessment of Pragmatic Abilities and Cognitive Substrates test) from baseline to 12 weeks and at 3-month follow-up. The secondary outcome was measured by changes in metaphor comprehension, abstract thinking, and global functioning from baseline to 12 weeks and at 3-month follow-up. RESULTS: Relative to the control group, at post-test the PragmaCom group showed greater and enduring improvement in global pragmatic skills and in metaphor comprehension. At follow-up, these improvements persisted and the PragmaCom exerted beneficial effects also on functioning. CONCLUSIONS: Despite the limited sample size, we believe that these findings offer initial yet encouraging evidence of the possibility to improve pragmatic skills with a theoretically grounded approach and to obtain durable and clinically relevant benefits. We argue that it is time that therapeutic efforts embrace communicative dysfunctions in order to improve illness outcome.

Get up! Functional mobility and metabolic syndrome in chronic schizophrenia: Effects on cognition and quality of life.

Low mobility and poor physical health, especially metabolic syndrome, are frequently reported in patients with schizophrenia and tend to increase with age. Recent evidence suggests that metabolic syndrome may affect cognition and quality of life, while the role functional mobility is still less addressed and their interplay needs to be further explored. This study aims to analyze the effects of functional mobility on cognitive performance, symptoms and quality of life, taking into account age and also modeling it relationship with metabolic syndrome in a sample of 103 adults with chronic schizophrenia. Data were analyzed by means of Pearson's correlations, forward stepwise regressions and mediation models. Results showed that poorer functional mobility is associated with metabolic syndrome and related to more severe negative symptoms, worse cognitive abilities and more disrupted quality of life. Moreover, functional mobility proved to be a significant predictor of cognitive abilities and quality of life, even when other influencing factors were taken into account and independently of age. Finally, analyses showed that functional mobility mediates the effect of metabolic syndrome on both cognition and quality of life. Taken together, these results suggest that functional mobility and metabolic syndrome may represent relevant aspects that further contribute to the evolution of cognitive deficits through all stages of the disease, with also impact on quality of life. In this perspective, the assessment of functional mobility, a non-invasive and quickly performed test may be worth to be implemented in clinical practice, with important implications for treatment and monitoring.

Longitudinal course of cognition in schizophrenia: Does treatment resistance play a role?

Treatment-resistant schizophrenia (TRS) represents a main clinical issue, associated with worse functional outcome and higher healthcare costs. Clozapine is the most effective antipsychotic for TRS, although 40% of resistant patients, defined as ultra-treatment resistant (UTR), are clozapine-refractory. Previous literature suggests that TRS is characterized by worse cognitive functioning and a more disrupted neurobiological substrate, but only few studies focused on UTR schizophrenia. Moreover, despite this evidence and the central role of cognition, to date no study has investigated long-term cognitive outcome in TRS. Based on these premises, this study aims to analyze cross-sectional and long-term cognitive functioning of patients with schizophrenia, stratified according to antipsychotic response: first-line responders (FLRs), clozapine responders (CRs) and UTRs. We analyzed cross-sectional and retrospective cognitive evaluations of 93 patients with schizophrenia (32 FLRs, 42 CRs, 19 UTRs) over a mean follow-up period of 9 years, also taking into account possible influencing factors such as clinical severity and antipsychotic load. Analyses showed that UTR is associated with overall impaired cognitive functioning and represents the main predictor of long-term cognitive decline. We observed no significant differences between FLR and CR patients, which showed moderate cognitive improvement over time. This is the first study to report an association of treatment resistance with longitudinal cognitive course in schizophrenia, indicating that UTR is correlated with cognitive decline over time. This decline may either be a consequence of the persistence of psychotic symptoms or depend on a distinct and more disrupted neurobiological substrate affecting both cognition and antipsychotic response.

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.

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

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).

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

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-1ß (IL-1ß), a key mediator of inflammatory response, is of particular interest. IL-1ß 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-1ß 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-1ß 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-1ß 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-1ß 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-1ß polymorphism could play a key role in mediating the complex and refined relationship between metabolic syndrome and cognitive performance.