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.

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.

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.

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.

External validation of the five domains of negative symptoms: Focus on cognition, functional capacity, and real-world functioning.

BACKGROUND: The conceptualization of negative symptoms (NS) in schizophrenia is still controversial. Recent confirmatory factor-analytic studies suggested that the bi-dimensional model (motivational deficit [MAP] and expressive deficit [EXP]) may not capture the complexity of NS structure, which could be better defined by a five-factor (five NS domains) or a hierarchical model (five NS domains as first-order factors, and MAP and EXP, as second-order factors). A validation of these models is needed to define the structure of NS. To evaluate the validity and temporal stability of the five-factor or the hierarchical structure of the brief negative symptom scale (BNSS) in individuals with schizophrenia (SCZ), exploring associations between these models with cognition, social cognition, functional capacity, and functioning at baseline and at 4 years follow-up. METHODS: Clinical variables were assessed using state-of-the-art tools in 612 SCZ at two-time points. The validity of the five-factor and the hierarchical models was analyzed through structural equation models. RESULTS: The two models had both a good fit and showed a similar pattern of associations with external validators at the two-time points, with minor variations. The five-factor solution had a slightly better fit. The associations with external validators favored the five-factor structure. CONCLUSIONS: Our findings suggest that both five-factor and hierarchical models provide a valid conceptualization of NS in relation to external variables and that five-factor solution provides the best balance between parsimony and granularity to summarize the BNSS structure. This finding has important implications for the study of pathophysiological mechanisms and the development of new treatments.