Insulin-resistance as a modifiable pathway to cognitive dysfunction in schizophrenia: A systematic review.

BACKGROUND: Cognitive deficits are difficult to treat and negatively influence quality of life and functional outcomes of persons with schizophrenia. In the last twenty years, extensive literature demonstrated that persons with diabetes and insulin resistance (IR) also display cognitive deficits. Being type 2 diabetes (T2DM) and IR highly frequent in persons with schizophrenia, it is plausible to hypothesize that these conditions might play a role in determining dyscognition. If that is the case, acting on glucose dysmetabolism may eventually improve cognitive functioning. This review aims at: 1. evaluating the association between IR or T2DM and cognitive dysfunction in schizophrenia; 2. reviewing the evidence that pharmacological treatment of IR or T2DM may improve dyscognition in schizophrenia. METHODS: Two systematic searches were conducted in PubMed, PsycInfo, and Scopus. We followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. RESULTS: From the first search we included 17 studies, 8 on the effects of T2DM and 9 on the effects of IR-other prediabetes measures on cognition in persons with schizophrenia. From the second search we included 12 studies investigating the effect on cognition of glucose (4 studies), insulin (2 studies), metformin (2 studies), PPAR-γ agonists (2 studies), GLP-1 agonist (1 study), bromocriptine (1 study). CONCLUSIONS: T2DM was associated with worse cognitive function in persons with schizophrenia, while IR was less strongly associated with cognitive dysfunction. Evidence regarding the efficacy of glucose-lowering medications on cognition in schizophrenia is inconclusive, yet methodological issues likely contribute to explain conflicting results.

Pharmacological Treatment of Cognitive Impairment Associated With Schizophrenia: State of the Art and Future Perspectives.

Cognitive Impairment Associated with Schizophrenia (CIAS) represents one of the core dimensions of Schizophrenia Spectrum Disorders (SSD), with an important negative impact on real-world functional outcomes of people living with SSD. Treatment of CIAS represents a therapeutic goal of considerable importance, and while cognition-oriented evidence-based psychosocial interventions are available, effective pharmacological treatment could represent a game-changer in the lives of people with SSD. The present critical review reports and discusses the evidence regarding the effects of several pharmacological agents that are available in clinical practice or are under study, commenting on both current and future perspectives of CIAS treatment. In particular, the effects on CIAS of antipsychotic medications, anticholinergic medications, benzodiazepines, which are currently commonly used in the treatment of SSD, and of iclepertin, d-serine, luvadaxistat, xanomeline-trospium, ulotaront, anti-inflammatory molecules, and oxytocin, which are undergoing regulatory trials or can be considered as experimental agents, will be reported and discussed. Currently, available pharmacological agents do not appear to provide substantial benefits on CIAS, but accurate management of antipsychotic medications and avoiding treatments that can further exacerbate CIAS represent important strategies. Some molecules that are currently being investigated in Phase 2 and Phase 3 trials have provided very promising preliminary results, but more information is currently required to assess their effectiveness in real-world contexts and to provide clear recommendations regarding their use in clinical practice. The results of ongoing and future studies will reveal whether any of these molecules represents the awaited pharmacological game-changer in the treatment of CIAS.

Conceptualization and characterization of "primary" and "secondary" cognitive impairment in schizophrenia.

Cognitive impairment represents one of the core features of schizophrenia, involves both neurocognition and social cognition domains, and has a significant negative impact on real-world functioning. The present review provides a framework for the conceptualization and characterization of "primary" and "secondary" cognitive impairment in schizophrenia. In this conceptualization, primary cognitive impairment can be defined as a consequence of the neurobiological alterations that underlie psychopathological manifestations of the disorder, while secondary cognitive impairment can be defined as the results of a source issue that has a negative impact on cognitive performance. Sources of secondary cognitive impairment are frequent in people with schizophrenia and include several different factors, such as positive and negative symptoms, depressive symptoms, autistic symptoms, pharmacotherapy, substance abuse, metabolic syndrome, social deprivation, and sleep disorders. It can be hypothesized that secondary cognitive impairment may be improved by effectively resolving the source issue, while primary cognitive impairment may benefit from dedicated treatment. Further research is required to confirm this hypothesis, to better characterize the distinction between primary and secondary cognitive impairment in a clinical and in a neurobiological perspective, and to evaluate the impact of systematically assessing and treating secondary cognitive impairment.

The Relationship between Cognitive Impairment and Violent Behavior in People Living with Schizophrenia Spectrum Disorders: A Critical Review and Treatment Considerations.

Cognitive impairment is a core feature of schizophrenia spectrum disorders (SSD). Violent and aggressive behavior represents a complex issue in psychiatry, and people with SSD have been shown to be at risk of being both victims and perpetrators of violence. In this review, the complex relationship between cognitive impairment and violent behavior is explored, also considering the usefulness of treating cognitive impairment to improve violence-related outcomes. Several studies report that cognitive impairment is linked to violent behavior, but significant differences between domains and conflicting results are also present, leaving the identification of specific cognitive profiles predicting violent behavior in SSD as an important aim for future research. Evidence regarding the effectiveness of treating cognitive impairment to improve violent behavior, while heterogeneous, provides more consistent results: cognition-targeting interventions appear to provide significant benefits also in the prevention of aggression in people living with SSD, and preliminary evidence shows cognition-focused interventions targeting violent behavior improve both cognition- and violence-related outcomes. Implementing these interventions in clinical practice could be of great usefulness, particularly in forensic contexts. Physical exercise, which improves cognitive performance and psychosocial functioning in SSD, appears to reduce violent behavior in healthy individuals, but requires further studies in clinical samples.

Treatment of Cognitive Impairment Associated with Schizophrenia Spectrum Disorders: New Evidence, Challenges, and Future Perspectives.

Cognitive impairment associated with schizophrenia (CIAS) represents one of the core features of the disorder and has a significant impact on functional and rehabilitation outcomes of people living with schizophrenia spectrum disorders (SSD). The aim of this critical review is to highlight the most recent evidence on effective treatments available for CIAS, to discuss the current challenges in this field, and to present future perspectives that may help to overcome them. Concerning psychopharmacological approaches, among the most indicated strategies for the management and prevention of CIAS is to favor second-generation antipsychotic medications and avoid long-term and high-dose treatments with anticholinergic medications and benzodiazepines. Moreover, non-pharmacological approaches such as cognitive remediation and physical exercise-based programs represent evidence-based interventions in the treatment of CIAS that have shown reliable evidence of effectiveness on both cognitive and functional outcomes. These treatments, however, are still delivered to people accessing mental health services with a diagnosis of CIAS in an uneven manner, even in high-income countries. Academic and clinical partnership and collaboration, as well as advocacy from service users, families, carers, and stakeholders' organizations could help to reduce the bench to bedside gap in the treatment of CIAS. Future perspectives include the development of novel pharmacological agents that could be effective in the treatment of CIAS, the implementation of novel technologies such as telemedicine and virtual reality in the delivery of evidence-based interventions to improve accessibility and engagement, and further research in the field of non-invasive brain stimulation.

Predictors of psychosocial functioning in people diagnosed with schizophrenia spectrum disorders that committed violent offences and in those that did not: Results of the Recoviwel study.

Psychosocial functioning represents a core treatment target of Schizophrenia Spectrum Disorders (SSD), and several clinical and cognitive factors contribute to its impairment. However, determinants of psychosocial functioning in people living with SSD that committed violent offences remain to be more thoroughly explored. This study aims to separately assess and compare predictors of psychosocial functioning in people with SSD that did and that did not commit violent offences considering several clinical, cognitive and violence-related parameters. Fifty inmates convicted for violent crimes in a forensic psychiatry setting diagnosed with SSD (OP group) and fifty participants matched for age, gender, education, and diagnosis (Non-OP group) were included in the study. A higher risk of violent relapse as measured by HCR-20 clinical subscale scores (p < 0.002) and greater global clinical severity as measured by CGI-S scores (p = 0.023) emerged as individual predictors of worse psychosocial functioning, as measured by PSP scores, in the OP group. Greater global clinical severity (p < 0.001), worse performance in the processing speed domain as measured by the BACS Symbol Coding (p = 0.002) and TMT-A tests (p = 0.016) and higher levels of non-planning impulsivity as measured by BIS-11 scores (p < 0.001) emerged as individual predictors of worse psychosocial functioning in the Non-OP group. These results confirm that clinical severity impacts psychosocial functioning in all individuals diagnosed with SSD and suggest that while cognitive impairment clearly represents a determinant of worse functional outcomes in most patients, the risk of violent relapse is a specific predictor of worse psychosocial functioning in people with SSD that committed criminal offences.

Durability of Effects of Cognitive Remediation on Cognition and Psychosocial Functioning in Schizophrenia: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

OBJECTIVE: Cognitive remediation provides substantial improvements in cognitive performance and real-world functioning for people living with schizophrenia, but the durability of these benefits needs to be reassessed and better defined. The aims of this study were to provide a comprehensive assessment of the durability of the benefits of cognitive remediation for cognition and functioning in people living with schizophrenia and evaluating potential moderators of effects. METHODS: A systematic search was conducted in PubMed, Scopus, and PsycINFO, and reference lists of included articles and Google Scholar were inspected. Eligible studies were randomized clinical trials of cognitive remediation in patients diagnosed with schizophrenia spectrum disorders in which follow-up assessments were included. Screening and data extraction were performed by at least two independent reviewers. Cohen's d was used to measure outcomes. Primary outcomes were changes in cognition and functioning from baseline to conclusion of follow-up. Moderators of the durability of effects were assessed. RESULTS: Of 2,840 identified reports, 281 full texts were assessed and 130 reports on 67 studies with 5,334 participants were included. Cognitive remediation produced statistically significant positive effects that persisted at the end of follow-up in global cognition (d=0.23) and in global functioning (d=0.26). Smaller study samples and single-center studies were associated with better cognitive outcomes; longer treatment and follow-up duration, techniques for transferring cognitive gains to the real world, integration with psychiatric rehabilitation, group format of delivery, and more female participants in the sample were associated with better functional outcomes. CONCLUSIONS: Cognitive remediation provides durable improvements in cognition and functioning in schizophrenia. This finding corroborates the notion that cognitive remediation should be implemented more widely in clinical and rehabilitation practice.

Evidence-based psychosocial interventions in schizophrenia: a critical review.

PURPOSE OF REVIEW: Schizophrenia Spectrum Disorders (SSD) are severe conditions that frequently produce significant impairment in cognitive performance, social skills and psychosocial functioning. As pharmacological treatment alone often provides only limited improvements on these outcomes, several psychosocial interventions are employed in psychiatric rehabilitation practice to improve of real-world outcomes of people living with SSD: the present review aims to provide a critical overview of these treatments, focusing on those that show consistent evidence of effectiveness. RECENT FINDINGS: Several recent systematic reviews and meta-analyses have investigated in detail the acceptability, the effectiveness on several specific outcomes and moderators of response of different psychosocial interventions, and several individual studies have provided novel insight on their implementation and combination in rehabilitation practice. SUMMARY: Cognitive remediation, metacognitive training, social skills training, psychoeducation, family interventions, cognitive behavioral therapy, physical exercise and lifestyle interventions, supported employment and some other interventions can be fully considered as evidence-based treatments in SSD. Psychosocial interventions could be of particular usefulness in the context of early intervention services. Future research should focus on developing newer interventions, on better understanding the barriers and the facilitators of their implementation in clinical practice, and exploring the opportunities provided by novel technologies.

What impact can brain stimulation interventions have on borderline personality disorder?

INTRODUCTION: Borderline personality disorder (BPD) is a severe mental disorder characterized by emotion dysregulation, impulsivity, neuropsychological impairment, and interpersonal instability, presenting with multiple psychiatric comorbidities, functional disability and reduced life expectancy due suicidal behaviors. AREAS COVERED: In this perspective, the authors explore the application of noninvasive brain stimulation (NIBS) (rTMS, tDCS, and MST) in BPD individuals by considering a symptom-based approach, focusing on general BPD psychopathology, impulsivity and neuropsychological impairments, suicidality and depressive/anxious symptoms, and emotion dysregulation. EXPERT OPINION: According to a symptoms-based approach, NIBS interventions (particularly rTMS and tDCS) are promising treatment options for BPD individuals improving core symptoms such as emotional and behavioral dysregulation, neuropsychological impairments and depressive symptoms. However, the heterogeneity of stimulation protocols and of assessment tools used to detect these changes limits the possibility to provide definitive recommendations according to a symptom-based approach. To implement such armamentarium in clinical practice, future NIIBS studies should further consider a lifespan perspective due to clinical variability over time, the role of psychiatric comorbidities affecting BPD individuals and the need to combine NIBS with specialized psychotherapeutic approaches for BPD patients and with functional neuroimaging studies.

Application of cognitive remediation in the world: new experiences from two schizophrenia rehabilitation centers in Togo and Benin.

PURPOSE: People with schizophrenia in Sub-Saharan Africa often live in very difficult conditions, suffer important social isolation and usually do not receive any kind of treatment. In this context, some non-governmental initiatives have come to light, providing accommodation, food, primary healthcare, medications and, in some cases, education and rehabilitation. The aims of this study were to assess feasibility, effects, and acceptability of a Cognitive Remediation Therapy (CRT) intervention in the particular context of psychiatric rehabilitation in Togo and Benin. METHODS: Patients diagnosed with schizophrenia accessing the "Saint Camille" association rehabilitation centers in Togo and Benin during the enrollment period were allocated consecutively with a 1:1 proportion to receive a manualized CRT intervention (46 one-hour sessions over 14 weeks) or continuing Treatment As Usual (TAU). The assessment included validated measures of cognitive performance and real-world functioning and was performed at baseline and at the conclusion of treatment. RESULTS: All subjects that were invited into the study agreed to participate and completed the intervention, for a total of 36 participants. CRT produced greater improvements than TAU in processing speed, working memory, verbal memory, cognitive flexibility, and executive functions measures, with moderate to large effect sizes, in particular in processing speed and working memory domains. CONCLUSIONS: CRT represents a feasible and effective psychosocial intervention that can be implemented even in contexts with very limited resources, and could represent an important instrument to promote the rehabilitation process of people living with schizophrenia in low-income countries.

Improving depressive symptoms in patients with schizophrenia using bilateral bipolar-nonbalanced prefrontal tDCS: Results from a double-blind sham-controlled trial.

BACKGROUND: Treating depressive symptoms in patients with schizophrenia is challenging. While transcranical Dicrect Current Stimulation (tDCS) improved other core symptoms of schizophrenia, conflicting results have been obtained on depressive symptoms. Thus, we aimed to expand current evidence on tDCS efficacy to improve depressive symptoms in patients with schizophrenia. METHODS: A double-blind RCT was performed with patients randomized to 2 mA active-tDCS or sham-tDCS (15 daily sessions) with a bilateral bipolar-nonbalanced prefrontal placement (anode: left Dorsolateral prefrontal cortex; cathode: right orbitofrontal region). Clinical outcomes included variations of Calgary Depression Scale for Schizophrenia total score (CDSS) and of Depression-hopelessness and Guilty idea of reference-pathological guilt factors. Analysis of covariance was performed evaluating between-group changes over time. The presence/absence of probable clinically significant depression was determined when CDSS > 6. RESULTS: As 50 outpatients were included (both groups, n = 25), significant improvements following active-tDCS were observed for CDSS total score (p = 0.001), Depression-hopelessness (p = 0.001) and Guilty idea of reference-pathological guilt (p = 0.03). Considering patients with CDSS>6 (n = 23), compared to sham, active-tDCS significantly improved CDSS total score (p < 0.001), Depression-hopelessness (p = 0.001) but Guilty idea of reference-pathological guilt only marginally improved (p = 0.051). Considering response rates of clinically significant depression, important reductions of CDSS score were observed (78 % of the sample scored ≤6; active-tDCS, n = 23; sham-tDCS, n = 16; p = 0.017). Early wakening item did not significantly change in any group. LIMITATIONS: The study lacks a follow-up period and evaluation of tDCS effects on psychosocial functioning. CONCLUSIONS: Bilateral bipolar-nonbalanced prefrontal tDCS is a successful protocol for the treatment of depressive symptoms in patients with schizophrenia.

Psychological impact of Covid-19 pandemic in mental healthcare workers: a cross-sectional study in an Italian Department of Mental Health.

AIM: The Covid-19 pandemic is having a great impact on the lives of healthcare workers, but its psychological impact on Mental Healthcare Workers (MHWs) remains to be better explored. The aims of the present study were to assess the correlates and predictors of stress and adverse psychological effects in MHWs during the first waves of the Covid-19 pandemic. METHODS: A total of 124 MHWs (psychiatrist/psychiatry resident, nurse, psychologist/psychotherapist, psychiatric rehabilitation therapist/educator, other mental health professional) working in public facilities of the ASST Spedali Civili of Brescia, Italy, was assessed between June 28, 2020 and August 10, 2020 with an online questionnaire that included sociodemographic, professional and Covid-19 exposure information, the Impact of Event Scale - Revised and the Depression Anxiety Stress Scales 21. Multivariate linear regression models were designed to identify individual predictors of post-traumatic, depressive, anxiety and stress-symptoms. RESULTS: The professional role of nurse, having more years of professional experience and experiencing the death of a patient emerged as predictors of more severe post-traumatic symptoms. The professional role of nurse emerged as the only predictor of more severe depressive symptoms; the professional role of nurse and having more years of professional experience emerged as predictors of more severe anxiety symptoms; more years of professional experience, higher workloads, worse team relationships and experiencing the death of a loved one emerged as predictors of more severe stress symptoms. CONCLUSIONS: Alongside other stressful factors, the professional role of nurse and more years of professional experience emerged as predictors of adverse psychological events. Working as a MHW, particularly with high levels of contact with patients during the Covid-19 pandemic, may be considered strenuous work, requiring dedicated training and interventions to improve resilience. KEY WORDS: Anxiety, Covid-19, depression, mental healthcare workers, stress-related disorder, stressful life events.

The role of pharmacogenetics in the treatment of major depressive disorder: a critical review.

Pharmacological therapy represents one of the essential approaches to treatment of Major Depressive Disorder (MDD). However, currently available antidepressant medications show high rates of first-level treatment non-response, and several attempts are often required to find an effective molecule for a specific patient in clinical practice. In this context, pharmacogenetic analyses could represent a valuable tool to identify appropriate pharmacological treatment quickly and more effectively. However, the usefulness and the practical effectiveness of pharmacogenetic testing currently remains an object of scientific debate. The present narrative and critical review focuses on exploring the available evidence supporting the usefulness of pharmacogenetic testing for the treatment of MDD in clinical practice, highlighting both the points of strength and the limitations of the available studies and of currently used tests. Future research directions and suggestions to improve the quality of available evidence, as well as consideration on the potential use of pharmacogenetic tests in everyday clinical practice are also presented.

Autistic symptoms in unaffected first-degree relatives of people with schizophrenia: results from the Italian Network for Research on Psychoses multicenter study.

BACKGROUND: Autistic symptoms represent a frequent feature in schizophrenia spectrum disorders (SSD). However, the prevalence and the cognitive and functional correlates of autistic symptoms in unaffected first-degree relatives of people with SSD remain to be assessed. METHODS: A total of 342 unaffected first-degree relatives related to 247 outpatients with schizophrenia were recruited as part of the multicenter study of the Italian Network for Research on Psychoses (NIRP). Autistic features were measured with the PANSS Autism Severity Scale. Three groups of participants, defined on the presence and severity of autistic symptoms, were compared on a wide array of cognitive and functional measures. RESULTS: Of the total sample, 44.9% presented autistic symptoms; 22.8% showed moderate levels of autistic symptoms, which can be observed in the majority of people with SSD. Participants with higher levels of autistic symptoms showed worse performance on Working Memory (p = 0.014) and Social Cognition (p = 0.025) domains and in the Global Cognition composite score (p = 0.008), as well as worse on functional capacity (p = 0.001), global psychosocial functioning (p < 0.001), real-world interpersonal relationships (p < 0.001), participation in community activities (p = 0.017), and work skills (p = 0.006). CONCLUSIONS: A high prevalence of autistic symptoms was observed in first-degree relatives of people with SSD. Autistic symptoms severity showed a negative correlation with cognitive performance and functional outcomes also in this population and may represent a diagnostic and treatment target of considerable scientific and clinical interest in both patients and their first-degree relatives.

Life engagement in people living with schizophrenia: predictors and correlates of patient life engagement in a large sample of people living in the community.

BACKGROUND: Life engagement represents a holistic concept that encompasses outcomes reflecting life-fulfilment, well-being and participation in valued and meaningful activities, which is recently gaining attention and scientific interest. Despite its conceptual importance and its relevance, life engagement represents a largely unexplored domain in schizophrenia. The aims of the present study were to independently assess correlates and predictors of patient life engagement in a large and well-characterized sample of schizophrenia patients. METHODS: To assess the impact of different demographic, clinical, cognitive and functional parameters on life engagement in a large sample of patients with schizophrenia, data from the social cognition psychometric evaluation project were analyzed. RESULTS: Overall schizophrenia and depressive symptom severity, premorbid IQ, neurocognitive performance, social cognition performance both in the emotion processing and theory of mind domains, functional capacity, social skills performance and real-world functioning in different areas all emerged as correlates of patient life engagement. Greater symptom severity and greater impairment in real-world interpersonal relationships, social skills, functional capacity and work outcomes emerged as individual predictors of greater limitations in life engagement. CONCLUSIONS: Life engagement in people living with schizophrenia represents a holistic and complex construct, with several different clinical, cognitive and functional correlates. These features represent potential treatment targets to improve the clinical condition and also facilitate the process of recovery and the overall well-being of people living with schizophrenia.

Efficacy of Functional Remediation on Cognitive and Psychosocial Functioning in Patients with Bipolar Disorder: Study Protocol for a Randomized Controlled Study.

BACKGROUND: Neurocognitive impairment is a prominent characteristic of bipolar disorder (BD), linked with poor psychosocial functioning. This study's purpose is to evaluate the effectiveness of functional remediation (FR) in enhancing neurocognitive dysfunctions in a sample of remitted patients with diagnosis of BD in comparison to treatment as usual-TAU. To quantify the neurocognitive damage, the Brief Assessment of Cognition in Affective Disorders (BAC-A) will be used, and the overall psychosocial functioning will be measured with the Functioning Assessment Short Test-FAST. METHODS: The randomized, rater-blinded, controlled study will include two arms (1:1) encompassing 54 outpatients with diagnosis of BD-I and BD-II, as defined by the DSM-5 criteria. In the experimental phase, remitted patients aged 18-55 years will be involved. At the baseline, at the end of intervention and at the 6-month follow-up, patients will be evaluated using clinical scales (Young Mania Rating Scale (Y-MRS) and Hamilton Depression Rating Scale (HAM-D)). Neurocognitive measurements and psychosocial functioning will be valued, respectively, with BAC-A and FAST. DISCUSSION: The primary expected outcome is that following FR intervention, patients will exhibit improved cognitive abilities and psychosocial outcomes compared to the participants in the TAU group. It is now recognized that neurocognitive deficits are potential predictors of functional outcome in patients with BD. In recent years, there has been a growing interest in the implementation of interventions that, in addition to symptomatic remission, are also aimed at neurocognitive dysfunctions in order to achieve a recovery of psychosocial functioning.

Impact of Physical Exercise Alone or in Combination with Cognitive Remediation on Cognitive Functions in People with Schizophrenia: A Qualitative Critical Review.

Physical exercise and cognitive remediation represent the psychosocial interventions with the largest basis of evidence attesting their effectiveness in improving cognitive performance in people living with schizophrenia according to recent international guidance. The aims of this review are to provide an overview of the literature on physical exercise as a treatment for cognitive impairment in schizophrenia and of the studies that have combined physical exercise and cognitive remediation as an integrated rehabilitation intervention. Nine meta-analyses and systematic reviews on physical exercise alone and seven studies on interventions combining physical exercise and cognitive remediation are discussed. The efficacy of physical exercise in improving cognitive performance in people living with schizophrenia is well documented, but more research focused on identifying moderators of participants response and optimal modalities of delivery is required. Studies investigating the effectiveness of integrated interventions report that combining physical exercise and cognitive remediation provides superior benefits and quicker improvements compared to cognitive remediation alone, but most studies included small samples and did not explore long-term effects. While physical exercise and its combination with cognitive remediation appear to represent effective treatments for cognitive impairment in people living with schizophrenia, more evidence is currently needed to better understand how to implement these treatments in psychiatric rehabilitation practice.