Extracellular vesicles in neurodegenerative, mental, and other neurological disorders: Perspectives into mechanisms, biomarker potential, and therapeutic implications.

Extracellular vesicles (EVs) are produced, secreted, and targeted by most human cells, including cells that compose nervous system tissues. EVs carry several types of biomolecules, such as lipids, proteins and microRNA, and can function as signaling agents in physiological and pathological processes. In this chapter, we will focus on EVs and their cargo secreted by brain cells, especially neurons and glia, and how these aspects are affected in pathological conditions. The chapter covers neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, as well as several psychiatric disorders, namely schizophrenia, autism spectrum disorder and major depressive disorder. This chapter also addresses other types of neurological dysfunctions, epilepsy and traumatic brain injury. EVs can cross the blood brain barrier, and thus brain EVs may be detected in more accessible peripheral tissue, such as circulating blood. Alterations in EV composition and contents can therefore impart valuable clues into the molecular etiology of these disorders, and serve biomarkers regarding disease prevalence, progression and treatment. EVs can also be used to carry drugs and biomolecules into brain tissue, considered as a promising drug delivery agent for neurological diseases. Therefore, although this area of research is still in its early development, it offers great potential in further elucidating and in treating neurological disorders.

Assessing Patient Satisfaction With Metacognitive Training (MCT) for Psychosis: A Systematic Review of Randomized Clinical Trials.

OBJECTIVES: Metacognitive training (MCT) for psychosis is a group intervention that combines cognitive-behavioural therapy and psychoeducation. It has proven efficacy in reducing psychotic symptoms and correcting cognitive biases implicated in the development and maintenance of psychotic symptoms. However, other outcomes, such as patient satisfaction with the intervention, have not been well studied despite their importance for adherence and overall success. A systematic review of randomized clinical trials was conducted to assess satisfaction with MCT among adults with psychotic spectrum disorders. METHODS: The search was conducted in Ovid Embase, Ovid MEDLINE, PsycINFO and Cochrane Central Register of Controlled Trials (CENTRAL). PRISMA guidelines and the Cochrane Risk of Bias Tool were followed, and certainty of evidence was ascertained using the Grading of Recommendations Assessment, Development and Evaluation framework. The study is registered with PROSPERO (CRD42023418097). RESULTS: Patient satisfaction was considered the primary outcome in 3 of the 10 studies reviewed. Four studies compared MCT with other psychosocial interventions (a newspaper discussion group, cognitive remediation and supportive therapy), two of which found significantly higher satisfaction with MCT. A high percentage of all patients found MCT comprehensible and considered it an important part of their treatment; they would recommend the training to others and found the group setting advantageous. Most participants expressed high subjective satisfaction or acceptance of MCT. CONCLUSIONS: The authors found evidence that MCT may be associated with high levels of satisfaction in clinical trials whose main objective is to assess patient satisfaction, but more research is needed to consolidate the findings, especially for the extended version of MCT.

The relationship between alcohol bingeing in the gestational period of wistar rats and the development of schizophrenia in the offspring adult life.

The incidence of schizophrenia in young adulthood may be associated with intrauterine factors, such as gestational alcohol consumption. This study investigated the relationship between a single high dose of alcohol during pregnancy in Wistar rats and the development of schizophrenia in the adult life of the offspring. On the 11th day of gestation, pregnant rats received either water or alcohol via intragastric gavage. Male and female offspring were subjected to behavioral tests at 30 days of age according to the maternal group. At 60 days of age, offspring received intraperitoneal injections of ketamine (ket) or saline (SAL). After the final ketamine administration, the adult offspring underwent behavioral tests, and their brain structures were removed for biochemical analysis. Alcohol binge drinking during pregnancy induces hyperlocomotion in both young female and male offspring, with males of alcohol-exposed mothers showing reduced social interactions. In adult offspring, ketamine induced hyperlocomotion; however, only females in the alcohol + ket group exhibited increased locomotor activity, and a decrease in the time to first contact was observed in the alcohol group. Cognitive impairment was exclusively observed in male animals in the alcohol group. Increased serotonin and dopamine levels were observed in male rats in the alcohol + ket group. Biochemical alterations indicate the effects of intrauterine alcohol exposure associated with ketamine in adult animals. These behavioral and biochemical changes suggest that the impact of prenatal stressors such as alcohol persists throughout the animals' lives and may be exacerbated by a second stressor in adulthood, such as ketamine.

Corrigendum: Global research in schizophrenia and serotonin: a bibliometric analysis.

[This corrects the article DOI: 10.3389/fpsyt.2024.1436906.].

Circulating Cell-Free Mitochondrial DNA in Plasma of Individuals with Schizophrenia and Cognitive Deficit in Mexican Population.

Purpose: Cognitive domains are affected in patients with schizophrenia. Mitochondrial dysfunction has been proposed as a possible origin of these symptoms. Cell-free mitochondrial DNA (cf-mtDNA) is an indicator of cellular stress, and it can be identified in individuals with age-associated disorders, this study aimed to explore the presence of cf-mtDNA in plasma of schizophrenia patients and its association with cognitive deficit. Patients and Methods: Ninety-nine subjects were clinically evaluated; the case group included 60 patients diagnosed with schizophrenia and 39 randomly-individuals without psychiatric disorders were included in the comparison group. Cognitive status (MoCA scale) and cell-free mtDNA in blood plasma were assessed and quantified in both groups. Results: From the original sample, cf-mtDNA was identified in 43 subjects, 40 patients with schizophrenia and 3 controls (Χ2 = 31.10, p-value < 0.0001). Thirty-nine out of forty patients with schizophrenia had a cognitive deficit. Conclusion: According to our findings, cognitive impairment and presence of cf-mtDNA were related in subjects with schizophrenia. Thus, while the cognitive deficit might reflect an accelerated aging process, the cf-mtDNA plays a role as a potential biomarker in this mechanism.

Parenthood and All-cause Mortality in Older Adults with Schizophrenia: A Multicenter 5-Year Prospective Study.

OBJECTIVE: The large body of literature examining the association between parenthood and mortality in the general population contrasts with a lack of studies among older adults with schizophrenia. Identifying potential protective factors of premature death in this population is important to help guide prevention measures. Here, we examined whether all-cause and cause-specific mortality rates significantly differ between older adults with schizophrenia with and without children, during a 5-year follow-up. METHODS: We used data from a 5-year prospective multicenter sample of older adults with an ICD-10 diagnosis of schizophrenia (aged 55 years or more) recruited in France. We performed a forward stepwise logistic regression to examine the association between parenthood and all-cause mortality, including only those independent variables that best explain outcome. RESULTS: Of 323 older adults with schizophrenia, 133 (41.2%) had children (mean age=67.0, SD=6.1), whereas 190 were without children (mean age=67.2, SD=6.6). Following adjustments, parenthood was significantly associated with lower all-cause mortality compared to patients without children in this population (21.1% (n=28) versus 35.8% (n=68); AOR=0.50; 95%CI=0.27-0.94; p=0.032), without significant sex differences in this association. CONCLUSIONS: Parenthood could be protective against mortality among older patients with schizophrenia who live in France. Further research is needed to understand the specific mechanisms underlying this association.

Feuerstein Instrumental Enrichment Program for People With Schizophrenia After the First Episode of Psychosis: Protocol for an Open-Label Intervention Study.

BACKGROUND: Schizophrenia is a disorder associated with neurocognitive deficits that adversely affect daily functioning and impose an economic burden. Cognitive rehabilitation interventions, particularly during the early phases of illness, have been shown to improve cognition, functionality, and quality of life. The Feuerstein Instrumental Enrichment (FIE) program, based on the Mediated Learning Experience and the Structural Cognitive Modifiability theory, has been applied in various disorders, but its applicability in schizophrenia has not yet been clarified. OBJECTIVE: This study aims to investigate the effects of the FIE program on the functionality of patients with first-episode schizophrenia. METHODS: In total, 17 patients will be recruited for an open-label intervention consisting of twice-weekly sessions for 10 weeks. The primary outcome measure will be changes in the Goal Achievement Scale score. Maze task performance from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery will serve as a secondary outcome measure. At the same time, changes in Positive and Negative Syndrome Scale scores and other MATRICS domains will be analyzed as exploratory outcomes. Assessments will be administered before and after the intervention, with a follow-up period of 6 months. RESULTS: This trial was preregistered in The Brazilian Registry of Clinical Trials (RBR-4gzhy4s). By February 2024, 11 participants were enrolled in the training. Recruitment is expected to be completed by May 2024. Data analysis will be conducted between May and September 2024. The results are expected to be published in January 2025. CONCLUSIONS: This study may establish a protocol for the FIE program that uses mediation techniques for individuals in the early stages of schizophrenia. The results will add to the knowledge about strategies to promote cognitive skills and functional impairment in daily life. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57031.

On Metacognition: Overconfidence in Word Recall Prediction and Its Association with Psychotic Symptoms in Patients with Schizophrenia.

A two-factor account has been proposed as an explanatory model for the formation and maintenance of delusions. The first factor refers to a neurocognitive process leading to a significant change in subjective experience; the second factor has been regarded as a failure in hypothesis evaluation characterized by an impairment in metacognitive ability. This study was focused on the assessment of metacognition in patients with schizophrenia. The aims of the study were to measure the overconfidence in metacognitive judgments through the prediction of word list recall and to analyze the correlation between basic neurocognition (memory and executive function) and metacognition through a metamemory test and the severity of psychotic symptoms. METHOD: Fifty-one participants with a diagnosis of schizophrenia were evaluated. The Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of psychiatric symptoms, and the subtest of metamemory included in the Executive Functions and Frontal Lobe-2 battery (BANFE-2) was used to evaluate overconfidence and underestimation errors, intrusion and perseverative response, total volume of recall, and Brief Functioning Assessment Scale (FAST) for social functioning. RESULTS: The strongest correlation is observed between overconfidence errors and the positive factor of the PANSS (r = 0.774, p < 0.001). For the enter model in the multiple linear regression (r = 0.78, r2 = 0.61; F = 24.57, p < 0.001), the only significant predictor was overconfidence errors. CONCLUSION: Our results highlight the relevance of a metacognitive bias of overconfidence, strongly correlated with psychotic symptoms, and support the hypothesis that metacognitive defects contribute to the failure to reject contradictory evidence. From our perspective, these findings align with current mechanistic models of schizophrenia that focus on the role of the prefrontal cortex.

Physiology, Pathophysiology and Clinical Relevance of D-Amino Acids Dynamics: From Neurochemistry to Pharmacotherapy.

Over three decades ago, two independent groups of investigators identified free D-aspartic and later D-serine in specific brain nuclei and endocrine glands. This finding revealed a novel, non-proteinogenic role of these molecules. Moreover, the finding that aged proteins from the human eye crystallin, teeth, bone, blood vessels or the brain incorporate D-aspartic acids to specific primary protein sequences fostered the hypothesis that aging might be related to D-amino acid isomerization of body proteins. The experimental confirmation that schizophrenia and neurodegenerative diseases modify plasma free D-amino acids or tissue levelsnurtured the opportunity of using D-amino acids as therapeutic agents for several disease treatments, a strategy that prompted the successful current application of D-amino acids to human medicine.

Introducing a New Severity Specifier for Schizophrenia: Conceptual Framework and Clinical Implications.

Schizophrenia patients represent a heterogeneous group in clinical presentation and severity. Although severity has been operationalized in different ways, mostly on a gradient between symptom severity and functional impairment, such approaches are limited in capturing real-world functioning. We suggest adopting the severity model proposed by DSM-5 for autism spectrum disorders. The model defines three levels of severity, based on the support required, directly addressing two barriers from previous models: real-world functioning and ease of implementation. Our adapted model includes three new features: First, this severity specifier is global, rather than for each symptom domain. Second, the centrality of occupational functioning is emphasized to define the level of support. Third, we propose a one-month timeframe for severity appraisal, standardizing the assessment process. Considering practical utility, we indicate how severity assessment can guide clinical practice towards rehabilitation. Additionally, we outlined operational definitions for severity and functioning in schizophrenia, aligned with the premises of our model. Finally, we acknowledge potential limitations, the most relevant being the need for empirical validation. The model is presented to foster discussion. Additional studies will follow to investigate inter-rater reliability and convergent validation with standard measures of symptom and functioning severity.

Directed brain interactions over time: A resting-state EEG comparison between schizophrenia and healthy individuals.

Understanding the neurophysiological mechanisms of schizophrenia (SZ) is one of the challenges of neuroscience. Many anatomical and functional studies have pointed to problems in brain connectivity in SZ individuals. However, little is known about the relationships between specific brain regions and impairments in brain connectivity in SZ individuals. Herein we propose a new approach using time-varying graphs and the motif synchronization method to build dynamic brain functional networks (BFNs). Dynamic BFNs were constructed from resting-state electroencephalography (rs-EEG) of 14 schizophrenia (SZ) individuals and 14 healthy controls (HCs). BFNs were evaluated based on the percentage of synchronization importance between a pair of regions (considering external and internal interactions) over time. We found differences in the directed interaction between brain regions in SZ individuals compared to the control group. Our method revealed low bilaterally directed interactions between the temporal lobes in SZ individuals compared to HCs, indicating a potential link between altered brain connectivity and the characteristic symptoms of schizophrenia. From a clinical perspective, these results shed light on developing new therapeutic approaches targeting these specific neural interactions that are altered in individuals with SZ. This knowledge allows the application of better interventions focused on restoring or compensating for interrupted connectivity patterns.

Global research in schizophrenia and serotonin: a bibliometric analysis.

Background: Schizophrenia is a chronic mental illness that affects millions of individuals worldwide. The etiological origin of schizophrenia is heterogeneous, but it has been shown to be associated with dysfunction in serotonin activity, serotonin receptors, and serotonin metabolism in the brain. Bibliometric analysis is a tool used to scrutinise and analyse research activities and evidence in a specific research area. No existing bibliometric analyses have considered both serotonin and schizophrenia. Methods: We conducted a bibliometric analysis including 12,027 studies related to the schizophrenia-serotonin link published from the inception of the study to 2023 and available in the Scopus database. We used VOSviewer software to identify global trends, analyse the author and editors keywords, the most cited articles and author, as well as the most productive institutes and journals publishing research on schizophrenia-serotonin link. Results: Most publications related to the link between schizophrenia and serotonin are focused on adult humans and examine topics such as antipsychotic agents, depression, and serotonin uptake inhibitors. The Journal of Clinical Psychiatry has published the most papers on the schizophrenia-serotonin relationship. Among nations, the United States is the leader in publications. King's College London is the institution with the highest number of publications, and H. Y. Meltzer is the most influential author. Growing trends in schizophrenia-serotonin research are personalised medicine, alternative medicine, transcranial magnetic stimulation, artificial intelligence, nervous system inflammation, brain-gut axis, and the gut microbiome. Conclusion: Since 1950, there have been several fluctuations in the number of published studies related to schizophrenia and serotonin. We believe that the development of novel medications and treatments for schizophrenia will be increased in the future, as well as research into genetic risks, psychological factors, and cranial neuroimaging components. Future schizophrenia and serotonin research is likely to focus on personalised medicine, alternative therapies, novel pathogenesis of schizophrenia, and the use of emerging technologies such as artificial intelligence.

Exercise and Schizophrenia.

Schizophrenia is a complex mental disorder that affects millions of people worldwide and has a profound impact on various aspects of life, including physical activity. The relationship between schizophrenia and physical activity is an area of growing interest in medical and health research from a physical, mental, and psychosocial health perspective. Physical activity and structured exercise have been identified as promising interventions to improve physical and psychological health outcomes of people living with schizophrenia. This chapter provides a brief overview that explores various aspects of the relationship between physical activity, exercise, and schizophrenia. The impact of schizophrenia on human movement is discussed, along with an overview of physical activity and cardiorespiratory fitness levels in adults with schizophrenia. Additionally, the influence of exercise interventions on physical and psychological outcomes will be discussed, along with current physical activity recommendations for those living with schizophrenia.

Degradation of Perineuronal Nets in the Ventral Hippocampus of Adult Rats Recreates an Adolescent-Like Phenotype of Stress Susceptibility.

Background: Psychiatric disorders often emerge during late adolescence/early adulthood, a period with increased susceptibility to socioenvironmental factors that coincides with incomplete parvalbumin interneuron (PVI) development. Stress during this period causes functional loss of PVIs in the ventral hippocampus (vHip), which has been associated with dopamine system overdrive. This vulnerability persists until the appearance of perineuronal nets (PNNs) around PVIs. We assessed the long-lasting effects of adolescent or adult stress on behavior, ventral tegmental area dopamine neuron activity, and the number of PVIs and their associated PNNs in the vHip. Additionally, we tested whether PNN removal in the vHip of adult rats, proposed to reset PVIs to a juvenile-like state, would recreate an adolescent-like phenotype of stress susceptibility. Methods: Male rats underwent a 10-day stress protocol during adolescence or adulthood. Three to 4 weeks poststress, we evaluated behaviors related to anxiety, sociability, and cognition, ventral tegmental area dopamine neuron activity, and the number of PV+ and PNN+ cells in the vHip. Furthermore, adult animals received intra-vHip infusion of ChABC (chondroitinase ABC) to degrade PNNs before undergoing stress. Results: Unlike adult stress, adolescent stress induced anxiety responses, reduced sociability, cognitive deficits, ventral tegmental area dopamine system overdrive, and decreased PV+ and PNN+ cells in the vHip. However, intra-vHip ChABC infusion caused the adult stress to produce changes similar to the ones observed after adolescent stress. Conclusions: Our findings underscore adolescence as a period of heightened vulnerability to the long-lasting impact of stress and highlight the protective role of PNNs against stress-induced damage in PVIs.

In this work, we aimed to go deeper into understanding perineuronal nets (PNNs), a specialized extracellular matrix that evolves and protects inhibitory neurons in the brain, specifically parvalbumin-positive interneurons (PVIs). PVIs are essential in regulating brain activity. PNNs only reach maturity in adulthood, which leaves these interneurons unprotected during early life. To investigate this vulnerability, we conducted experiments in which we exposed adolescent and adult animals to a stress protocol. We observed that adolescent animals exhibited a higher susceptibility to developing changes associated with psychiatric disorders later in life. This susceptibility may stem from the absence of PNN protection around their PVIs. To explore this possibility further, we administered an enzyme into a specific brain region, the ventral hippocampus, of adult animals to selectively remove PNNs and induce an adolescent-like state. When subjected to stress, these animals displayed abnormalities similar to those observed in animals stressed during adolescence. Our findings have significant implications, suggesting that the presence of PNN protection around PVIs may be critical for mitigating stress-related psychiatric disorders.

Short and Long-term Effects of Cognitive Behavioral Therapy on Sleep Problems and Psychotic Symptoms in Patients with Psychotic Disorders: A Meta-Analysis Study.

OBJECTIVE: Sleep problems are common in patients with psychotic disorders, especially schizophrenia. Although pharmacological methods are at the forefront of treatment, this method has some drawbacks. Cognitive behavioral therapy for insomnia (CBT-I) is an option for the treatment of individuals with insomnia. In recent years, there has been an increasing interest in its use in patients with psychotic disorders. This meta-analysis aims to evaluate the effectiveness of CBT-I on sleep problems in patients with psychotic disorders. METHODS: A systematic search was conducted using PubMed, Scopus, and EBSCO (MEDLINE) databases to identify relevant studies. The study included RCTs and uncontrolled studies that focused on participants diagnosed with schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorders not otherwise specified, bipolar disorders, or unipolar depression with psychotic features, who had sleep problems for at least one month, and who were receiving treatment. The initial search yielded 246 studies, and eight studies were selected for the meta-analysis after screening and applying inclusion and exclusion criteria.The statistical analysis was conducted using the R software. RESULTS: CBT-I significantly ameliorates insomnia and sleep quality in patients with psychotic disorders during short and long-term periods. In addition to this, CBT-I leads to a significant improvement in psychotic symptoms in the short-term period and contributes significantly to the improvement in mental well-being in both short and long-term periods. CONCLUSIONS: CBT-I is an effective and valuable method for sleep problems in patients with psychotic disorders and its use is recommended to be widespread.

Women with Schizophrenia: Beyond Psychosis.

Although women with schizophrenia face significant lifelong challenges due to their diagnosis and sex-related issues, those challenges are seldom taken into consideration in their medical treatment and general care. In order to report the needs and desires of a group of women with schizophrenia, we conducted a series of semistructured interviews with nine women diagnosed with schizophrenia and attending outpatient clinics at the Hospital Del Salvador in Valparaíso. Our qualitative study followed a phenomenological design. Using ATLAS.ti software, we performed a content analysis of the interview transcripts, developed a coding frame for each major topic addressed in the interviews, and triangulated the results. Despite presenting with psychotic symptoms, some women received different diagnoses. Although acknowledging the benefits of medication, women also reported concerns about weight gain and body image. All women reported experiences with stigma and self-stigma related to the diagnosis of schizophrenia, and most had experienced childhood trauma, including sexual abuse, parental violence, and/or bullying. Young women with schizophrenia also feared that if they become mothers, then their children might also have schizophrenia and/or that they would be unable to adequately care for them. Women with schizophrenia have different experiences and play different roles in society beyond their psychoses, an understanding that should integrated into more personalized treatments for schizophrenia that consider individual characteristics and needs.

Characteristics of hallucinations in borderline personality disorder. Similarities and differences with schizophrenia and bipolar disorder / Características de las alucinaciones en el trastorno límite de la personalidad. Similitudes y diferencias con la esquizofrenia y el trastorno bipolar.

Psychosis can be considered a dimension that in its most severe extreme can be expressed with alterations in sensory perception, mainly hallucinations. Their presence is a fact that is frequently observed in severe psychiatric pathologies such as schizophrenia (EZQ) and bipolar disorder (BD) where they can be markers of severity. However, sensory-perceptual disturbances are not pathognomonic of these disorders, nor do they signal any of these illnesses as an isolated event. Such symptomatology can be described in a variety of situations both within and outside psychopathology. In this sense, proposing a direct line between hallucinations and diseases such as CZS or TB disregards their occurrence in other pathologies, as is the case of Borderline Personality Disorder (BPD). It is feasible that we may find the expression of pseudo hallucinations or hallucinations in patients with this disorder and their presence may have etiological, clinical and therapeutic connotations that should be reviewed and taken into account in our clinical practice.

La psicosis puede ser considerada una dimensión que en su extremo de mayor gravedad puede expresarse con alteraciones en la sensopercepción, principalmente alucinaciones. Su presencia es un hecho que se constata con frecuencia en patologías psiquiátricas severas como la esquizofrenia (EZQ) y el trastorno bipolar (TB) donde pueden ser marcadores de gravedad. No obstante, las alteraciones sensoperceptivas no son patognomónicas de estos trastornos ni señalan ninguna de estas enfermedades como un hecho aislado. Dicha sintomatología puede ser descripta en diversas situaciones dentro y fuera de la psicopatología. En este sentido, proponer una línea directa entre las alucinaciones con enfermedades tales como la EZQ o el TB desestima su ocurrencia en otras patologías, como es el caso del Trastorno límite de la personalidad (TLP). Es factible que constatemos la expresión de alucinaciones en pacientes con este trastorno y su presencia puede tener connotaciones etiológicas, clínicas y terapéuticas que deben ser revisadas para tener en cuenta en nuestra práctica clínica.

Increased COVID-19 mortality in patients with schizophrenia: A retrospective study in Brazil.

The risk that COVID-19 poses for mortality risk in individuals with schizophrenia in low- and middle-income countries has only been the subject of a few studies. In this retrospective study, we examined the standardized mortality ratio (SMR), by age group and sex, in a cohort of patients diagnosed with schizophrenia (n = 20,417), with second-generation antipsychotics, in a South Brazilian State database (Paraná-Brazil). We performed a linkage with the Brazilian Mortality Information System database between 2020 and 2021. We also assessed in a logistic regression how clozapine could affect COVID-19 mortality controlling by sex, age, and presence of obesity. A secondary analysis was to compare mortality with SMR due to COVID-19 in individuals with and without obesity. Compared to the State population (8,850,682 individuals), those with schizophrenia had more than two times greater risk of dying from COVID-19 (SMR = 2.21, 95 % CI: 1.90-2.55). Between the ages of 16 and 29, their risk is more than ten times higher than the state population (SMR = 10.18, 95 % CI: 4.73-19.33). Obesity showed an almost twofold risk of dying from COVID-19 in the patient's group (OR = 1.89, 95 % CI: 1.39-2.57). Clozapine was not found as a protector or a risk factor for COVID-19 mortality. In Brazil, a middle-income nation, people with schizophrenia are more likely to die prematurely from COVID-19. The burden of schizophrenia is higher in younger and in patients with obesity.

Comparative effectiveness of clozapine and non-clozapine atypical antipsychotics provided by the Brazilian National Health System in adults with schizophrenia.

Introduction: Currently, 21 million people live with the disease, mostly in low to middle-income countries. We aimed to assess the survival of patients with schizophrenia using clozapine compared with non-clozapine atypical antipsychotics provided by the Brazilian National Health System using real-world data. Materials and methods: This is an open retrospective cohort study of patients diagnosed with schizophrenia to whom atypical antipsychotics were dispensed by the Brazilian National Health System between 2000 and 2015, based on deterministic-probabilistic pairing of administrative data records. The Kaplan-Meier method was used to estimate the cumulative probability of survival and the Cox proportional hazards model was adjusted to assess the risk factors for survival via the hazard ratio (HR). Result: Participants were 375,352 adults with schizophrenia, with an overall survival rate of 76.0% (95%CI 75.0-76.0) at the end of the cohort. Multivariate analysis indicated a greater risk of death for men (HR=1.30; 95%CI 1.27-1.32), older adults (HR=17.05; 95%CI 16.52-17.60), and in the Southeast region of Brazil (HR=1.20; 95%CI 1.17-1.23). Patients who used non-clozapine atypical antipsychotics had a 21% greater risk of death when compared to those taking clozapine (HR=1.21; 95%CI 1.14-1.29). Additionally, a history of hospitalization for pneumonia (HR=2.17; 95%CI 2.11-2.23) was the main clinical variable associated with increased risk of death, followed by hospitalization for lung cancer (HR=1.82; 95%CI 1.58-2.08), cardiovascular diseases (HR=1.44; 95%CI 1.40-1.49) and any type of neoplasia (HR=1.29; 95%CI 1.19-1.40). Discussion: This is the first published Brazilian cohort study that evaluated survival in people with schizophrenia, highlighting the impact of atypical antipsychotics. In this real-world analysis, the use of clozapine had a protective effect on survival when compared to olanzapine, risperidone, quetiapine, and ziprasidone.

Molecular overlaps of neurological manifestations of COVID-19 and schizophrenia from a proteomic perspective.

COVID-19, a complex multisystem disorder affecting the central nervous system, can also have psychiatric sequelae. In addition, clinical evidence indicates that a diagnosis of a schizophrenia spectrum disorder is a risk factor for mortality in patients with COVID-19. In this study, we aimed to explore brain-specific molecular aspects of COVID-19 by using a proteomic approach. We analyzed the brain proteome of fatal COVID-19 cases and compared it with differentially regulated proteins found in postmortem schizophrenia brains. The COVID-19 proteomic dataset revealed a strong enrichment of proteins expressed by glial and neuronal cells and processes related to diseases with a psychiatric and neurodegenerative component. Specifically, the COVID-19 brain proteome enriches processes that are hallmark features of schizophrenia. Furthermore, we identified shared and distinct molecular pathways affected in both conditions. We found that brain ageing processes are likely present in both COVID-19 and schizophrenia, albeit possibly driven by distinct processes. In addition, alterations in brain cell metabolism were observed, with schizophrenia primarily impacting amino acid metabolism and COVID-19 predominantly affecting carbohydrate metabolism. The enrichment of metabolic pathways associated with astrocytic components in both conditions suggests the involvement of this cell type in the pathogenesis. Both COVID-19 and schizophrenia influenced neurotransmitter systems, but with distinct impacts. Future studies exploring the underlying mechanisms linking brain ageing and metabolic dysregulation may provide valuable insights into the complex pathophysiology of these conditions and the increased vulnerability of schizophrenia patients to severe outcomes.