No Sex-based Differences in Self-reported Empathy between Patients with Schizophrenia and Control Subjects.

BACKGROUND: Schizophrenia, one of the most disabling disorders worldwide, is characterized by impaired empathy, which appears to be more common in women. METHODS: This study aimed to compare empathy levels between control subjects and patients with schizophrenia by sex. We compared sixty-two patients with schizophrenia and 166 control subjects. All participants completed the Empathy Quotient (EQ) questionnaire. A multivariate analysis of variance model was performed with the EQ as the outcome criterion, and group and sex as fixed factors to test for interaction effects. RESULTS: Overall, patients obtained lower scores in the cognitive, emotional reactivity and social skills domains of empathy (p < 0.001). No differences between men and women were found and no interaction effect was identified between sex and group (schizophrenia vs. control) (p > 0.05). CONCLUSION: This study adds to the evidence on differences in social cognition between people with and without a mental illness such as schizophrenia. It also identifies the absence of sex differences between men and women, observed in both the group of patients and control subjects, which warrants further exploration.

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.

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.

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.

Neurolipidomics in schizophrenia: A not so well-oiled machine.

Most patients with schizophrenia (SCZ) do not exhibit violent behaviors and are more likely to be victims rather than perpetrators of violent acts. However, a subgroup of forensic detainees with SCZ exhibit tendencies to engage in criminal violations. Although numerous models have been proposed, ranging from substance use, serotonin transporter gene, and cognitive dysfunction, the molecular underpinnings of violence in SCZ patients remains elusive. Lithium and clozapine have established anti-aggression properties and recent studies have linked low cholesterol levels and ultraviolet (UV) radiation with human aggression, while vitamin D3 reduces violent behaviors. A recent study found that vitamin D3, omega-3 fatty acids, magnesium, and zinc lower aggression in forensic population. In this review article, we take a closer look at aryl hydrocarbon receptor (AhR) and the dysfunctional lipidome in neuronal membranes, with emphasis on cholesterol and vitamin D3 depletion, as sources of aggressive behavior. We also discuss modalities to increase the fluidity of neuronal double layer via membrane lipid replacement (MLR) and natural or synthetic compounds. This article is part of the Special Issue on "Personality Disorders".

Transitional discharge interventions for people with schizophrenia.

BACKGROUND: Schizophrenia is a chronic mental illness characterized by delusions, hallucinations, and important functional and social disability. Interventions labeled as 'transitional' add to care plans made during the hospital stay in preparation for discharge. They also include interventions developed after discharge to support people with serious mental illness as they make the transition from the hospital to the community. Transitional discharge interventions may anticipate the future needs of the patient after discharge by co-ordinating the different levels of the health system that can effectively guarantee continuity of care in the community. This occurs through the provision of therapeutic relationships which give a safety net throughout the discharge and community reintegration processes to improve the general condition of users, level of functioning, use of health resources, and satisfaction with care. OBJECTIVES: To assess the effects of transitional discharge interventions for people with schizophrenia. SEARCH METHODS: On 7 December 2022, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on CENTRAL, MEDLINE, Embase, PubMed, CINAHL, ClinicalTrials.gov, ISRCTN, PsycINFO, and WHO ICTRP. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating the effects of transitional discharge interventions in people with schizophrenia and schizophrenia-related disorders. Eligible interventions included three key elements: predischarge planning, co-ordination of care and follow-up, and postdischarge support. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Outcomes of this review included global state (relapse), service use (hospitalization), general functioning, satisfaction with care, adverse effects/events, quality of life, and direct costs. For binary outcomes, we calculated risk ratios (RRs) and their 95% confidence intervals (CIs). For continuous outcomes, we calculated the mean difference (MD) or standardized mean difference (SMD) and their 95% CIs. We used GRADE to assess certainty of evidence. MAIN RESULTS: We found 12 studies with 1748 participants comparing transitional discharge interventions to usual care. All were parallel-group RCTs. No studies assessed global state (relapse) or reported data about adverse events/effects. All studies had a high risk of bias, mainly due to serious concerns about allocation concealment, deviations from intended interventions, measurement of the outcomes, and missing outcome data. Transitional discharge interventions may make little to no difference in service use (hospitalization) at short- and long-term follow-ups, but the evidence is very uncertain (RR 1.18, 95% CI 0.55 to 2.50; I2 = 54%; 4 studies, 462 participants; very low-certainty evidence). Transitional discharge intervention may increase the levels of functioning after discharge (clinically important change in general functioning) (SMD 0.95, 95% CI -0.06 to 1.97; I² = 95%; 4 studies, 437 participants; very low-certainty evidence) and may increase the proportion of participants who are satisfied with the intervention (clinically important change in satisfaction) (RR 1.96, 95% CI 1.37 to 2.80; 1 study, 76 participants; very low-certainty evidence), but for both outcomes the evidence is very uncertain. Transitional discharge intervention may make little to no difference in quality of life compared to treatment as usual (SMD 0.24, 95% CI -0.30 to 0.78; I² = 90%; 4 studies, 748 participants; very low-certainty evidence), but we are very uncertain. For direct costs, one study with 124 participants did not report full details and thus the results were inconclusive. AUTHORS' CONCLUSIONS: There is currently no clear evidence for or against implementing transitional discharge interventions for people with schizophrenia. Transitional discharge interventions may improve patient satisfaction and functionality, but this evidence is also very uncertain. For future research, it is important to improve the quality of the conduct and reporting of these trials, including using validated tools for measuring their outcomes.

Factors Associated with Readmission within 30 Days of Hospital Discharge of Psychiatric Patients: Case-Control Study.

BACKGROUND: Readmission, defined as any admission after discharge from the same hospital, has negative implications for health outcomes. This study aims to identify the sociodemographic and clinical factors associated with hospital readmission among psychiatric patients. METHODOLOGY: This case-control study analyzed 202 clinical records of patients admitted to a psychiatric hospital between 2019-2021. The sample was selected using simple random sampling. Qualitative variables were presented using frequencies, percentages, and chi-square tests for association. Quantitative variables were described using central tendency measures and dispersion of data, investigated with the Kolmogorov-Smirnov test, Student's t-test or Wilcoxon test as appropriate. Regression analysis was conducted to determine factors linked to readmission. p < 0.05 was considered. RESULTS: Women accounted for a higher readmission rate (59%). Patients diagnosed with schizophrenia had a higher readmission rate (63%), experienced longer transfer times to the hospital during readmissions, and had shorter hospital stays. Polypharmacy and pharmacological interactions were associated with readmission. Olanzapine treatment was identified as a risk factor for readmission (ExpB = 3.203, 95% CI 1.405-7.306, p = 0.006). CONCLUSIONS: The findings suggest avoiding polypharmacy and medications with high side effect profiles to reduce readmissions. This study offers valuable insights for clinical decision-making from admission to discharge planning, aiming to enhance the quality of care.

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.

Outpatient prescription of clozapine in Colombia: factors related to the use of doses lower than 100 mg/day / Prescripción ambulatoria de clozapina en Colombia: factores relacionados con el uso de dosis inferiores a 100 mg/día.

Although commonly used in clinical practice, scientific literature about clozapine prescription patterns in Colombia is scarce. A cross-sectional observational study was conducted in an outpatient clinic in Bogotá, Colombia. Between 2016 and 2018, clozapine was prescribed to 2603 patients, mainly for Schizophrenia Spectrum Disorders and Bipolar and Depressive Disorders, at a median dose of 100mg/day. After controlling for other variables, older age was the only variable that explained the use of doses lower than 100mg/day. Clozapine was not only used for Treatment-Resistant Schizophrenia, and further studies are needed to explain these differences.

Aunque se utiliza comúnmente en la práctica clínica, la literatura científica sobre los patrones de prescripción de clozapina en Colombia es escasa. Se realizó un estudio observacional transversal en el servicio ambulatorio de una clínica de referencia en Bogotá, Colombia. Entre 2016 y 2018, se recetó clozapina a 2603 pacientes, principalmente para esquizofrenia y trastornos relacionados, trastorno afectivo bipolar y trastornos depresivos, a una dosis media de 100 mg/día. Después de controlar otras variables, la edad avanzada fue la única variable que explicó el uso de dosis inferiores a 100 mg/día. La clozapina no se utilizó sólo para la esquizofrenia resistente al tratamiento, y se necesitan estudios adicionales para explicar estas diferencias.

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.

Cannabidiol as an antipsychotic drug.

Cannabidiol (CBD) is a major phytocannabinoid in the Cannabis sativa plant. In contrast to Δ9-tetrahydrocannabinol (THC), CBD does not produce the typical psychotomimetic effects of the plant. In addition, CBD has attracted increased interest due to its potential therapeutic effects in various psychiatric disorders, including schizophrenia. Several studies have proposed that CBD has pharmacological properties similar to atypical antipsychotics. Despite accumulating evidence supporting the antipsychotic potential of CBD, the mechanisms of action in which this phytocannabinoid produces antipsychotic effects are still not fully elucidated. Here, we focused on the antipsychotic properties of CBD indicated by a series of preclinical and clinical studies and the evidence currently available about its possible mechanisms. Findings from preclinical studies suggest that CBD effects may depend on the animal model (pharmacological, neurodevelopmental, or genetic models for schizophrenia), dose, treatment schedule (acute vs. repeated) and route of administration (intraperitoneal vs local injection into specific brain regions). Clinical studies suggest a potential role for CBD in the treatment of psychotic disorders. However, future studies with more robust sample sizes are needed to confirm these positive findings. Overall, although more studies are needed, current evidence indicates that CBD may be a promising therapeutic option for the treatment of schizophrenia.

Effects of different indications on electroconvulsive therapy.

OBJECTIVE: The objective of the study is to evaluate how electroconvulsive therapy (ECT) affects treatment-resistant depression, bipolar and schizophrenic patient groups, and suicide attempt histories and to evaluate the relationship between treatment variables and patient outcomes. METHOD: In a retrospective cohort study at the inpatient psychiatry clinic of Çam and Sakura City Hospital between January, 2021, and February, 2023, 103 patients receiving ECT were analyzed. They were categorized into two groups according to indications that suicide risk (n = 76) and resistance to pharmacotherapy (n = 27). RESULTS: The analysis revealed no significant age (p = 0.374) or gender (p = 0.304) differences between groups. However, significant differences emerged in diagnostic distribution (p = 0.027), with the suicide risk group receiving more ECT sessions (13.6 ± 11.2, p = 0.025) and experiencing longer total seizure times (427 ± 325 s, p = 0.023) compared to the treatment-resistant group (8.5 ± 4.7 sessions and 279 ± 115 s, respectively). CONCLUSIONS: ECT's therapeutic application does not differ from demographic variables but is influenced by clinical diagnosis, with suicide risk patients receiving more intensive treatment. These findings highlight the necessity of individualized ECT protocols and suggest that diagnostic considerations are critical in optimizing ECT treatment strategies. Despite its retrospective design, the study underscores the importance of personalized ECT regimens and calls for further prospective research to validate these findings.

OBJETIVO: Evaluar cómo la terapia electroconvulsiva afecta a grupos de pacientes con depresión resistente al tratamiento, trastorno bipolar, esquizofrenia y antecedentes de intentos suicidio, y evaluar la relación entre variables de tratamiento y resultados. MÉTODO: En una cohorte retrospectiva en la clínica de psiquiatría para pacientes internados del Çam and Sakura City Hospital, entre el 01/2021 y el 03/2023, se analizaron 103 pacientes que recibieron terapia electroconvulsiva. Estos se clasificaron en dos grupos según los indicios de riesgo de suicidio (n = 76) y de resistencia a la farmacoterapia (n = 27). RESULTADOS: El análisis no mostró diferencias significativas en cuanto a edad (p = 0.374) y sexo (p = 0.304) entre los grupos. Sin embargo, hubo diferencias significativas en la distribución diagnóstica (p = 0.027), con el grupo de riesgo de suicidio recibiendo más sesiones de terapia electroconvulsiva (13.6 ± 11.2; p = 0.025) y experimentando tiempos totales de convulsión más largos (427 ± 325 segundos; p = 0.023) en comparación con el grupo resistente al tratamiento (8.5 ± 4.7 sesiones y 279 ± 115 segundos, respectivamente). CONCLUSIONES: La aplicación terapéutica de la terapia electroconvulsiva no difiere según las variables demográficas, pero sí se ve influenciada por el diagnóstico clínico, recibiendo los pacientes de riesgo de suicidio un tratamiento más intensivo.

Effectiveness of AstraZeneca vaccine against SARS-CoV-2 (ChAdox1-S) in reducing in-hospital mortality in individuals with COVID-19 and schizophrenia: A retrospective cohort study.

ChAdOx1-S is a viral vector vaccine developed by AstraZeneca. We aimed to assess the effectiveness of 1 and 2 doses of the ChAdOx1-S vaccine in reducing COVID-19-related in-hospital mortality in individuals with schizophrenia. This is a retrospective cohort study using a nationwide hospital database in Brazil. Individuals diagnosed with COVID-19 and schizophrenia were included in the study. The exposures were 0, 1, and 2 doses of ChAdOx1-S. The outcome of mortality was measured in hazard ratios (HR), calculated using multivariable Cox regression models. The study included 1,929 positive cases of COVID-19 in schizophrenia patients. After adjusting for age, socioeconomic factors, and comorbidities, we observed a significant 55% decrease in the hazard of mortality in the 2-dose vaccination group (HR 0.45, 95% CI: 0.310-0.652) compared to the unvaccinated. Surprisingly, our results did not show any significant reduction in the hazard of mortality in the 1 dose vaccination group (HR 1.278, 95% CI: 0.910-1.795). The effectiveness of two doses of ChAdOx1-S in individuals with schizophrenia aligns with findings from studies on the general population. That one dose was insignificant. Overall, these findings are important for informing public health decisions - prioritizing individuals with schizophrenia for vaccinations and managing acceptance of vaccines.

Is the antidepressant effect of ketamine separate from its psychotomimetic effect? A review of rodent models.

Ketamine is an NMDA (N-methyl-d-aspartate) glutamate receptor antagonist, which has a myriad of dose-dependent pharmacological and behavioral effects, including anesthetic, sedative, amnestic, analgesic, and anti-inflammatory properties. Intriguingly, ketamine at subanesthetic doses displays a relevant profile both in mimicking symptoms of schizophrenia and also as the first fast-acting treatment for depression. Here, we present an overview of the state-of-the-art knowledge about ketamine as an antidepressant as well as a pharmacological model of schizophrenia in animal models and human participants. Ketamine's dual effect appears to arise from its mechanism of action involving NMDA receptors, with both immediate and downstream consequences being triggered as a result. Finally, we discuss the feasibility of a unified approach linking the glutamatergic hypothesis of schizophrenia to the promising preclinical and clinical success of ketamine in the treatment of refractory depression.

Influence of antipsychotic drugs on microRNA expression in schizophrenia patients - A systematic review.

Schizophrenia (SCZ) is a severe psychiatric disorder with unclear pathophysiology. Moreover, there is no specific biological marker to help clinicians to define a diagnosis, and medication is decided according to the psychiatrist's experience. In this scenario, microRNAs (miRNAs), which are small noncoding RNA molecules that regulate several genes, emerge as potential peripheral biomarkers to help not only the evaluation of the disease state but also the treatment response. Here, we systematically reviewed indexed literature and evaluated follow-up studies investigating the changes in miRNA expression due to antipsychotic treatment. We also assessed target genes and performed pathway enrichment analysis of miRNAs listed in this systematic review. A total of 11 studies were selected according to research criteria, and we observed that 28 miRNAs play a relevant role in schizophrenia pathogenesis or response to antipsychotic treatment, seven of those of extreme interest as possible biomarkers either for condition or treatment. Predicted targets of the miRNAs reviewed here were previously associated with schizophrenia in genome-wide studies, and pathway analysis showed enrichment for genes related to neural processes. With this review, we expect to highlight the importance of miRNAs in schizophrenia pathogenesis and its treatment and point out interesting miRNAs to future studies.

Long-term Environmental Enrichment Normalizes Schizophrenia-like Abnormalities and Promotes Hippocampal Slc6a4 Promoter Demethylation in Mice Submitted to a Two-hit Model.

Here, we explored the impact of prolonged environmental enrichment (EE) on behavioral, neurochemical, and epigenetic changes in the serotonin transporter gene in mice subjected to a two-hit schizophrenia model. The methodology involved administering the viral mimetic PolyI:C to neonatal Swiss mice as a first hit during postnatal days (PND) 5-7, or a sterile saline solution as a control. At PND21, mice were randomly assigned either to standard environment (SE) or EE housing conditions. Between PND35-44, the PolyI:C-treated group was submitted to various unpredictable stressors, constituting the second hit. Behavioral assessments were conducted on PND70, immediately after the final EE exposure. Following the completion of behavioral assessments, we evaluated the expression of proteins in the hippocampus that are indicative of microglial activation, such as Iba-1, as well as related to neurogenesis, including doublecortin (Dcx). We also performed methylation analysis on the serotonin transporter gene (Slc6a4) to investigate alterations in serotonin signaling. The findings revealed that EE for 50 days mitigated sensorimotor gating deficits and working memory impairments in two-hit mice and enhanced their locomotor and exploratory behaviors. EE also normalized the overexpression of hippocampal Iba-1 and increased the expression of hippocampal Dcx. Additionally, we observed hippocampal demethylation of the Slc6a4 gene in the EE-exposed two-hit group, indicating epigenetic reprogramming. These results contribute to the growing body of evidence supporting the protective effects of long-term EE in counteracting behavioral disruptions caused by the two-hit schizophrenia model, pointing to enhanced neurogenesis, diminished microglial activation, and epigenetic modifications of serotonergic pathways as underlying mechanisms.

GAPi: A description of the initiative for early psychosis intervention in Latin America and the short- to medium-term outcomes in early psychosis patients.

INTRODUCTION: Schizophrenia is a debilitating disorder that affects a significant proportion of the population and leads to impaired functionality and long-term challenges. The first episode of psychosis (FEP) is a critical intervention stage for improving long-term outcomes. The GAPi program was established in São Paulo, Brazil to provide early intervention services and evaluate biomarkers in individuals with FEP. This article delineates the objectives of the GAPi program, detailing its innovative research protocol, examining the clinical outcomes achieved, and discussing the operational challenges encountered during its initial decade of operation. METHODS: The study comprised a prospective cohort of antipsychotic-naïve individuals with first-episode psychosis aged between 16 and 35 years. Participants were recruited from a public psychiatric facility in São Paulo. Emphasizing the initiative's commitment to early intervention, clinical assessments were systematically conducted at baseline and at two months, one year, two years, and five years of treatment to capture both short- and medium-term outcomes. Various assessment tools were utilized, including structured interviews, symptom scales, the Addiction Severity Index, and functional assessments. RESULTS: A total of 232 patients were enrolled in the cohort. Among them, 65.95 % completed the 2-month follow-up. Most patients presented with schizophrenia spectrum disorders, followed by bipolar disorder and major depressive disorder with psychotic features. Treatment response rates and remission rates were evaluated at different time points, with promising outcomes observed. The program also assessed socio-demographic factors, substance use, family history, and genetic and biomarker profiles, providing valuable data for research. DISCUSSION: The GAPi program has emerged as the largest ongoing cohort of antipsychotic-naïve first-episode psychosis in Latin America, contributing to the understanding of early psychosis in low- and middle-income countries. Despite operational challenges, the program has demonstrated efficacy in reducing the duration of untreated psychosis and in improving clinical outcomes. A multidisciplinary approach, including pharmacological treatment, psychosocial interventions, and family involvement, has been instrumental in enhancing treatment adherence and long-term prognosis. CONCLUSION: The GAPi program represents a valuable model for early intervention in first-episode psychosis and provides insights into the pathophysiology, treatment, and long-term outcomes of individuals with schizophrenia and related disorders. Continued research and resource allocation are essential for addressing operational challenges and expanding early intervention services in low- and middle-income countries.