Advances in the understanding of the pathophysiology of schizophrenia and bipolar disorder through induced pluripotent stem cell models.

The pathophysiology of schizophrenia and bipolar disorder involves a complex interaction between genetic and environmental factors that begins in the early stages of neurodevelopment. Recent advancements in the field of induced pluripotent stem cells (iPSCs) offer a promising tool for understanding the neurobiological alterations involved in these disorders and, potentially, for developing new treatment options. In this review, we summarize the results of iPSC-based research on schizophrenia and bipolar disorder, showing disturbances in neurodevelopmental processes, imbalance in glutamatergic-GABAergic transmission and neuromorphological alterations. The limitations of the reviewed literature are also highlighted, particularly the methodological heterogeneity of the studies, the limited number of studies developing iPSC models of both diseases simultaneously, and the lack of in-depth clinical characterization of the included samples. Further studies are needed to advance knowledge on the common and disease-specific pathophysiological features of schizophrenia and bipolar disorder and to promote the development of new treatment options.

Insight in cognitive impairment assessed with the Cognitive Assessment Interview in a large sample of patients with schizophrenia.

The Cognitive Assessment Interview (CAI) is an interview-based scale measuring cognitive impairment and its impact on functioning in subjects with schizophrenia (SCZ). The present study aimed at assessing, in a large sample of SCZ (n = 601), the agreement between patients and their informants on CAI ratings, to explore patients' insight in their cognitive deficits and its relationships with clinical and functional indices. Agreement between patient- and informant-based ratings was assessed by the Gwet's agreement coefficient. Predictors of insight in cognitive deficits were explored by stepwise multiple regression analyses. Patients reported lower severity of cognitive impairment vs. informants. A substantial to almost perfect agreement was observed between patients' and informants' ratings. Lower insight in cognitive deficits was associated to greater severity of neurocognitive impairment and positive symptoms, lower severity of depressive symptoms, and older age. Worse real-life functioning was associated to lower insight in cognitive deficit, worse neurocognitive performance, and worse functional capacity. Our findings indicate that the CAI is a valid co-primary measure with the interview to patients providing a reliable assessment of their cognitive deficits. In the absence of informants with good knowledge of the subject, the interview to the patient may represent a valid alternative.

Long-term effect of epoetin alfa on clinical and biochemical markers in friedreich ataxia.

BACKGROUND: Friedreich ataxia is an autosomal recessive disease with no available therapy. Clinical trials with erythropoietin in Friedreich ataxia patients have yielded conflicting results, and the long-term effect of the drug remains unknown. METHODS: We designed a double-blind, placebo-controlled, multicenter trial to test the efficacy of epoetin alfa on 56 patients with Friedreich ataxia. The primary endpoint of the study was the effect of epoetin alfa on peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test. Secondary endpoints were frataxin levels in peripheral blood mononuclear cells, improvement in echocardiography findings, vascular reactivity, neurological progression, upper limb dexterity, safety, and quality of life. Epoetin alfa or placebo (1:1 ratio) was administered subcutaneously at a dose of 1200 IU/Kg of body weight every 12 weeks for 48 weeks. RESULTS: A total of 56 patients were randomized; 27 completed the study in the active treatment group, and 26 completed the study in the placebo group[KG1]. VO2 max was not modified after treatment (0.01 [-0.04 to 0.05]; P = .749), as well as most of the secondary endpoint measures, including frataxin. The 9-hole peg test showed a significant amelioration in the treatment group (-17.24 sec. [-31.5 to -3.0]; P = .018). The treatment was safe and well tolerated. CONCLUSIONS: Although results are not in favor of an effect of epoetin alfa in Friedreich ataxia, this is the largest trial testing its effect. It is still possible that epoetin alfa may show some symptomatic effect on upper-limb performance. This study provides class I evidence that erythropoietin does not ameliorate VO2 max in patients with Friedreich ataxia. © 2016 International Parkinson and Movement Disorder Society.

Combining transcranial magnetic stimulation with training to improve social cognition impairment in schizophrenia: a pilot randomized controlled trial.

Schizophrenia is a severe, chronic mental disorder that profoundly impacts patients' everyday lives. The illness's core features include positive and negative symptoms and cognitive impairments. In particular, deficits in the social cognition domain showed a tighter connection to patients' everyday functioning than the other symptoms. Social remediation interventions have been developed, providing heterogeneous results considering the possibility of generalizing the acquired improvements in patients' daily activities. In this pilot randomized controlled trial, we investigated the feasibility of combining fifteen daily cognitive and social training sessions with non-invasive brain stimulation to boost the effectiveness of the two interventions. We delivered intermittent theta burst stimulation (iTBS) over the left dorsolateral prefrontal cortex (DLPFC). Twenty-one patients were randomized into four groups, varying for the assigned stimulation condition (real vs. sham iTBS) and the type of cognitive intervention (training vs. no training). Clinical symptoms and social cognition tests were administered at five time points, i.e., before and after the treatment, and at three follow-ups at one, three, and six months after the treatments' end. Preliminary data show a trend in improving the competence in managing emotion in participants performing the training. Conversely, no differences were found in pre and post-treatment scores for emotion recognition, theory of mind, and attribution of intentions scores. The iTBS intervention did not induce additional effects on individuals' performance. The methodological approach's novelty and limitations of the present study are discussed.

Research evidence on the management of the cognitive impairment component of the post-COVID condition: a qualitative systematic review.

BACKGROUND: Cognitive impairment (CI) is one of the most prevalent and burdensome consequences of COVID-19 infection, which can persist up to months or even years after remission of the infection. Current guidelines on post-COVID CI are based on available knowledge on treatments used for improving CI in other conditions. The current review aims to provide an updated overview of the existing evidence on the efficacy of treatments for post-COVID CI. METHODS: A systematic literature search was conducted for studies published up to December 2023 using three databases (PubMed-Scopus-ProQuest). Controlled and noncontrolled trials, cohort studies, case series, and reports testing interventions on subjects with CI following COVID-19 infection were included. RESULTS: After screening 7790 articles, 29 studies were included. Multidisciplinary approaches, particularly those combining cognitive remediation interventions, physical exercise, and dietary and sleep support, may improve CI and address the different needs of individuals with post-COVID-19 condition. Cognitive remediation interventions can provide a safe, cost-effective option and may be tailored to deficits in specific cognitive domains. Noninvasive brain stimulation techniques and hyperbaric oxygen therapy showed mixed and preliminary results. Evidence for other interventions, including pharmacological ones, remains sparse. Challenges in interpreting existing evidence include heterogeneity in study designs, assessment tools, and recruitment criteria; lack of long-term follow-up; and under-characterization of samples in relation to confounding factors. CONCLUSIONS: Further research, grounded on shared definitions of the post-COVID condition and on the accurate assessment of COVID-related CI, in well-defined study samples and with longer follow-ups, is crucial to address this significant unmet need.

Illness-related variables and abnormalities of resting-state brain activity in schizophrenia.

Background: The development of neuroimaging biomarkers in patients with schizophrenia (SCZ) requires a refined clinical characterization. A limitation of the neuroimaging literature is the partial uptake of progress in characterizing disease-related features, particularly negative symptoms (NS) and cognitive impairment (CI). In the present study, we assessed NS and CI using up-to-date instruments and investigated the associations of abnormalities in brain resting-state (rs)-activity with disease-related features. Methods: Sixty-two community-dwelling SCZ subjects participated in the study. Multiple regression analyses were performed with the rs-activity of nine regions of interest as dependent variables and disease-related features as explanatory variables. Results: Attention/vigilance deficits were negatively associated with dorsal anterior cingulate rs-activity and, together with depression, were positively associated with right dorsolateral prefrontal cortex rs-activity. These deficits and impairment of Reasoning/problem-solving, together with conceptual disorganization, were associated with right inferior parietal lobule and temporal parietal junction rs-activity. Independent of other features, the NS Expressive Deficit domain was associated with the left ventral caudate, while the Motivational Deficit was associated with the dorsal caudate rs-activity. Conclusion: Neurocognitive deficits and the two negative symptom domains are associated with different neural markers. Replications of these findings could foster the identification of clinically actionable biomarkers of poor functional outcomes.

Cognitive impairment after recovery from COVID-19: Frequency, profile, and relationships with clinical and laboratory indices.

Cognitive impairment (CI) is regarded as a remarkable burden in COVID-19 survivors. Its prevalence and profile, and relationships with the disease clinical and laboratory indices, remain unclear. The present study investigated, in a large sample of patients recovered from COVID-19, the frequency of CI with both a face-to-face screening tool and comprehensive test battery (MCCB). The study also evaluated the profile of CI and its relationships with COVID-19 clinical and laboratory indices and with psychopathological features. Out of 1344 subjects assessed for eligibility, 736 completed the screening phase 11 months after the COVID-19 infection; 402 participated in the baseline phase and completed an in depth cognitive, clinical and laboratory assessment about one month later. More than one third of the screened subjects presented a CI (COG+); it was associated to age, education, male gender, COVID-19 severity, and presence of anosmia, dyspnea at rest and exertional dyspnea during the acute phase. COG+ subjects showed a higher severity of depression, anxiety and post-traumatic distress, and worse global functioning, than subjects without CI. The MCCB showed that 45% of the subjects had a CI involving attention, working memory, verbal learning, visual learning, and reasoning and problem solving. Finally, neurocognitive functioning was inversely correlated with LDH blood levels, a potential biomarker of disease severity. According to our findings, cognitive functioning should be routinely and periodically assessed in COVID-19 patients, especially in older subjects, who experienced more severe COVID-19 symptoms. In case of persisting dysfunctions cognitive training programs should be considered as treatment strategies.

Genetic determinants of coping, resilience and self-esteem in schizophrenia suggest a primary role for social factors and hippocampal neurogenesis.

Schizophrenia is a severe psychiatric disorder, associated with a reduction in life expectancy of 15-20 years. Available treatments are at least partially effective in most affected individuals, and personal resources such as resilience (successful adaptation despite adversity) and coping abilities (strategies used to deal with stressful or threatening situations), are important determinants of disease outcomes and long-term sustained recovery. Published findings support the existence of a genetic background underlying resilience and coping, with variable heritability estimates. However, genome-wide analyses concerning the genetic determinants of these personal resources, especially in the context of schizophrenia, are lacking. Here, we performed a genome-wide association study coupled with accessory analyses to investigate potential genetic determinants of resilience, coping and self-esteem in 490 schizophrenia patients. Results revealed a complex genetic background partly overlapping with that of neuroticism, worry and schizophrenia itself and support the importance of social aspects in shapingthese psychological constructs. Hippocampal neurogenesis and lipid metabolism appear to be potentially relevant biological underpinnings, and specific miRNAs such as miR-124 and miR-137 may warrant further studies as potential biomarkers. In conclusion, this study represents an important first step in the identification of genetic and biological correlates shaping resilience, coping resources and self-esteem in schizophrenia.

Correlations between Negative Symptoms and Cognitive Deficits in Individuals at First Psychotic Episode or at High Risk of Psychosis: A Systematic Review.

The present review aims to identify correlations between negative symptoms (NS) and deficits in neurocognition and social cognition in subjects with first-episode psychosis (FEP) and at-high-risk populations (HR). A systematic search of the literature published between 1 January 2005 and 31 December 2022 was conducted on PubMed, Scopus, and PsycInfo. Out of the 4599 records identified, a total of 32 studies met our inclusion/exclusion criteria. Data on a total of 3086 FEP and 1732 HR were collected. The available evidence shows that NS correlate with executive functioning and theory of mind deficits in FEP subjects, and with deficits in the processing speed, attention and vigilance, and working memory in HR subjects. Visual learning and memory do not correlate with NS in either FEP or HR subjects. More inconsistent findings were retrieved in relation to other cognitive domains in both samples. The available evidence is limited by sample and methodological heterogeneity across studies and was rated as poor or average quality for the majority of included studies in both FEP and CHR populations. Further research based on shared definitions of first-episode psychosis and at-risk states, as well as on more recent conceptualizations of negative symptoms and cognitive impairment, is highly needed.

The structure stability of negative symptoms: longitudinal network analysis of the Brief Negative Symptom Scale in people with schizophrenia.

BACKGROUND: The structure of negative symptoms of schizophrenia is still a matter of controversy. Although a two-dimensional model (comprising the expressive deficit dimension and the motivation and pleasure dimension) has gained a large consensus, it has been questioned by recent investigations. AIMS: To investigate the latent structure of negative symptoms and its stability over time in people with schizophrenia using network analysis. METHOD: Negative symptoms were assessed in 612 people with schizophrenia using the Brief Negative Symptom Scale (BNSS) at baseline and at 4-year follow-up. A network invariance analysis was conducted to investigate changes in the network structure and strength of connections between the two time points. RESULTS: The network analysis carried out at baseline and follow-up, supported by community detection analysis, indicated that the BNSS's items aggregate to form four or five distinct domains (avolition/asociality, anhedonia, blunted affect and alogia). The network invariance test indicated that the network structure remained unchanged over time (network invariance test score 0.13; P = 0.169), although its overall strength decreased (6.28 at baseline, 5.79 at follow-up; global strength invariance test score 0.48; P = 0.016). CONCLUSIONS: The results lend support to a four- or five-factor model of negative symptoms and indicate overall stability over time. These data have implications for the study of pathophysiological mechanisms and the development of targeted treatments for negative symptoms.