Aripiprazole and Risperidone Present Comparable Long-Term Metabolic Profiles: Data From a Pragmatic Randomized Controlled Trial in Drug-Naïve First-Episode Psychosis

Objective: Aripiprazole and risperidone are 2 of the most used second-generation antipsychotics (SGAs) worldwide. Previous evidence shows a similar effect of these SGAs on weight and metabolic changes in the short term. However, a longer period is necessary for a better assessment of the SGA´s metabolic profile. We aimed to compare the long-term (1-year) metabolic profile of these 2 antipsychotics on a sample of drug-naïve first episode-psychosis (FEP) patients. Methods: A total 188 drug-naïve patients, suffering from a first episode of non-affective psychosis (FEP), were randomly assigned to treatment with either aripiprazole or risperidone. Weight and glycemic/lipid parameters were recorded at baseline and after 1-year follow-up. Results: We observed significant weight increments in both groups (9.2 kg for aripiprazole and 10.5 kg for risperidone) after 1 year of treatment. Despite this, weight and body mass index changes did not significantly differ between treatment groups (P > .05). Similarly, both treatment groups presented similar metabolic clinical impact with a comparable increase in the proportion of participants meeting criteria for metabolic disorders such as obesity or hypercholesterolemia, but not for metabolic syndrome (?9.2% vs ?4.3%) or hypertriglyceridemia (?21.9% vs ?8.0%), where aripiprazole showed worse outcomes than risperidone. Conclusion: This study shows that aripiprazole and risperidone share a similar long-term metabolic profile. After 1 year of antipsychotic treatment, drug-naïve FEP patients in both treatment groups presented a significant increase in weight and metabolic changes, leading to a greater prevalence of metabolic disorders

Aripiprazole as a Candidate Treatment of COVID-19 Identified Through Genomic Analysis

Background: Antipsychotics modulate expression of inflammatory cytokines and inducible inflammatory enzymes. Elopiprazole (a phenylpiperazine antipsychotic drug in phase 1) has been characterized as a therapeutic drug to treat SARS-CoV-2 infection in a repurposing study. We aim to investigate the potential effects of aripiprazole (an FDA approved phenylpiperazine) on COVID-19-related immunological parameters. Methods: Differential gene expression profiles of non-COVID-19 vs. COVID-19 RNA-Seq samples (CRA002390 project in GSA database) and drug-naïve patients with non-affective psychosis at baseline and after three months of aripiprazole treatment were identified. An integrative transcriptomic analyses of aripiprazole effects on differentially expressed genes in COVID-19 patients was performed. Findings: 82 out the 377 genes (21.7%) with expression significantly altered by aripiprazole have also their expression altered in COVID-19 patients and in 93.9% of these genes their expression is reverted by aripiprazole. The number of common genes with expression altered in both analyses is significantly higher than expected (Fisher?s Exact Test, two tail; p value = 3.2e-11). 11 KEGG pathways were significantly enriched with genes with altered expression both in COVID-19 patients and aripiprazole medicated non-affective psychosis patients (p adj<0.05). The most significant pathways were associated to immune responses and mechanisms of hyperinflammation-driven pathology (i.e.,?inflammatory bowel disease (IBD)? (the most significant pathway with a p adj of 0.00021), ?Th1 and Th2 cell differentiation? and ?B cell receptor signaling pathway?) that have been also associated with COVID19 clinical outcome. Interpretation: This exploratory investigation may provide further support to the notion that a protective effect is exerted by aripiprazole (phenylpiperazine) by modulating the expression of genes that have shown to be altered in COVID-19 patients. Along with many ongoing studies and clinical trials, repurposing available medications could be of use in countering SARS-CoV-2 infection, but require further studies and trials.Funding: The present study was part of a larger prospective longitudinal study, the “First Episode Psychosis Clinical Program 10” (PAFIP10) study. ClinicalTrials.gov Identifiers: NCT02200588, NCT03481465, and NCT03476473. No pharmaceutical industry or institutional sponsors participated in the study conception and design, data collection, analysis and interpretation of the results, or drafting of the manuscript. This work was supported by: SAF2016- 76046-R and SAF2013-46292-R (MINECO and FEDER) to B.C.F.Acknowledgments: We are highly indebted to the participants and their families for their cooperation in this study. We also thank IDIVAL biobank (Ines Santiuste and Jana Arozamena) for clinical samples and ́ data as well as the PAFIP members (Marga Corredera) for the data collection. We kindly thank all clinical staff at the Hospital Universitario Virgen del Rocio for support to collect clinical records and provide clinical care to COVID-19 patients. We also kindly thank Dra. Marisa Barrigon for helpful discussions regarding clinical data analysis, and Idalino Rocha for manuscript editing and formatting. This manuscript has been released as a pre-print at medRxiv. Available at: https://doi.org/ 10.1101/2020.12.05.20244590 (Crespo-Facorro et al., 2020)

Longitudinal trajectories in negative symptoms and changes in brain cortical thickness: 10-year follow-up study

Background Understanding the evolution of negative symptoms in first-episode psychosis (FEP) requires long-term longitudinal study designs that capture the progression of this condition and the associated brain changes. Aims To explore the factors underlying negative symptoms and their association with long-term abnormal brain trajectories. Method We followed up 357 people with FEP over a 10-year period. Factor analyses were conducted to explore negative symptom dimensionality. Latent growth mixture modelling (LGMM) was used to identify the latent classes. Analysis of variance (ANOVA) was conducted to investigate developmental trajectories of cortical thickness. Finally, the resulting ANOVA maps were correlated with a wide set of regional molecular profiles derived from public databases. Results Three trajectories (stable, decreasing and increasing) were found in each of the three factors (expressivity, experiential and attention) identified by the factor analyses. Patients with an increasing trajectory in the expressivity factor showed cortical thinning in caudal middle frontal, pars triangularis, rostral middle frontal and superior frontal regions from the third to the tenth year after the onset of the psychotic disorder. The F-statistic map of cortical thickness expressivity differences was associated with a receptor density map derived from positron emission tomography data. Conclusions Stable and decreasing were the most common trajectories. Additionally, cortical thickness abnormalities found at relatively late stages of FEP onset could be exploited as a biomarker of poor symptom outcome in the expressivity dimension. Finally, the brain areas with less density of receptors spatially overlap areas that discriminate the trajectories of the expressivity dimension.Funding: This work was supported by the Instituto de Salud Carlos III (PI14/00639 and PI14/00918) and Fundación Instituto de Investigación Marqués de Valdecilla (NCT0235832 and NCT02534363). M.C.-R. acknowledges funding support from the Consejería de Salud y Familias (Junta de Andalucía) 2020 grant, which covers his salary (RH-0081 2020). R.R.-G. is funded by the EMERGIA Junta de Andalucía programme (EMERGIA20_00139) and the Plan Propio of the University of Seville

Risk of suicide attempt repetition after an index attempt: A systematic review and meta-analysis

Objectives To estimate the risk of suicide attempt repetition among individuals with an index attempt. It also aims to study the role of risk factors and prevention programme in repetition. Methods This systematic review and meta-analysis was conducted in keeping with the PRISMA 2020 guidelines. Studies on attempt repetition (both cohort studies and intervention studies) were searched from inception to 2022. Results A total of 110 studies comprising 248,829 attempters was reviewed. The overall repetition rate was 0.20 (0.17, 0.22). Repetition risk linearly increased over time. A higher risk of attempt repetition was associated with female sex and index attempts in which self-cutting methods were used. Moreover, a mental disorder diagnosis was associated with an increasing repetition risk (OR = 2.02, p < .01). The delivery of a preventive programme reduced the repetition risk, OR = 0.76, p < .05; however, this effect was significant for psychotherapy interventions, OR = 0.38, p < .01. Conclusion One in five suicide attempters will engage in a new suicide attempt. An elevated repetition risk is associated with being female, more severe index methods and psychiatric disorder diagnosis. Preventive programmes, particularly psychotherapy, may contribute to reducing repetition risk and eventually save lives.This study was supported by the Instituto de Salud Carlos III-FIS research grants (PI16/00187, PI19/00236, PI19/00569, PI19/00685, PI19/00941, PI19/00954, PI19/01027, PI19/01256, PI19/01484, PI20/00229), co-funded by the European Regional Development Fund (ERDF) “A Way to Build Europe”; the Government of the Principality of Asturias (grant ref.: PCTI-2018-2022 IDI/2018/235); Secretaria d'Universitats i Recerca from the Departament d'Economia i Coneixement (ref.: 2017SGR1365 and 2017SGR134), and Generalitat de Catalunya (Government of Catalonia), CERCA Programme

Risk of suicide attempt repetition after an index attempt: A systematic review and meta-analysis

© 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).[Objectives] To estimate the risk of suicide attempt repetition among individuals with an index attempt. It also aims to study the role of risk factors and prevention programme in repetition.[Methods] This systematic review and meta-analysis was conducted in keeping with the PRISMA 2020 guidelines. Studies on attempt repetition (both cohort studies and intervention studies) were searched from inception to 2022.[Results] A total of 110 studies comprising 248,829 attempters was reviewed. The overall repetition rate was 0.20 (0.17, 0.22). Repetition risk linearly increased over time. A higher risk of attempt repetition was associated with female sex and index attempts in which self-cutting methods were used. Moreover, a mental disorder diagnosis was associated with an increasing repetition risk (OR = 2.02, p < .01). The delivery of a preventive programme reduced the repetition risk, OR = 0.76, p < .05; however, this effect was significant for psychotherapy interventions, OR = 0.38, p < .01.[Conclusion] One in five suicide attempters will engage in a new suicide attempt. An elevated repetition risk is associated with being female, more severe index methods and psychiatric disorder diagnosis. Preventive programmes, particularly psychotherapy, may contribute to reducing repetition risk and eventually save lives.This study was supported by the Instituto de Salud Carlos III-FIS research grants (PI16/00187, PI19/00236, PI19/00569, PI19/00685, PI19/00941, PI19/00954, PI19/01027, PI19/01256, PI19/01484, PI20/00229), co-funded by the European Regional Development Fund (ERDF) “A Way to Build Europe”; the Government of the Principality of Asturias (grant ref.: PCTI-2018-2022 IDI/2018/235); Secretaria d'Universitats i Recerca from the Departament d'Economia i Coneixement (ref.: 2017SGR1365 and 2017SGR134), and Generalitat de Catalunya (Government of Catalonia), CERCA Programme.Peer reviewe

Examining the immune signatures of SARS-CoV-2 infection in pregnancy and the impact on neurodevelopment: Protocol of the SIGNATURE longitudinal study.

The COVID-19 pandemic represents a valuable opportunity to carry out cohort studies that allow us to advance our knowledge on pathophysiological mechanisms of neuropsychiatric diseases. One of these opportunities is the study of the relationships between inflammation, brain development and an increased risk of suffering neuropsychiatric disorders. Based on the hypothesis that neuroinflammation during early stages of life is associated with neurodevelopmental disorders and confers a greater risk of developing neuropsychiatric disorders, we propose a cohort study of SARS-CoV-2-infected pregnant women and their newborns. The main objective of SIGNATURE project is to explore how the presence of prenatal SARS-CoV-2 infection and other non-infectious stressors generates an abnormal inflammatory activity in the newborn. The cohort of women during the COVID-19 pandemic will be psychological and biological monitored during their pregnancy, delivery, childbirth and postpartum. The biological information of the umbilical cord (foetus blood) and peripheral blood from the mother will be obtained after childbirth. These samples and the clinical characterisation of the cohort of mothers and newborns, are tremendously valuable at this time. This is a protocol report and no analyses have been conducted yet, being currently at, our study is in the recruitment process step. At the time of this publication, we have identified 1,060 SARS-CoV-2 infected mothers and all have already given birth. From the total of identified mothers, we have recruited 537 SARS-COV-2 infected women and all of them have completed the mental health assessment during pregnancy. We have collected biological samples from 119 mothers and babies. Additionally, we have recruited 390 non-infected pregnant women

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Examining the immune signatures of SARS-CoV-2 infection in pregnancy and the impact on neurodevelopment: Protocol of the SIGNATURE longitudinal study

The COVID-19 pandemic represents a valuable opportunity to carry out cohort studies that allow us to advance our knowledge on pathophysiological mechanisms of neuropsychiatric diseases. One of these opportunities is the study of the relationships between inflammation, brain development and an increased risk of suffering neuropsychiatric disorders. Based on the hypothesis that neuroinflammation during early stages of life is associated with neurodevelopmental disorders and confers a greater risk of developing neuropsychiatric disorders, we propose a cohort study of SARS-CoV-2-infected pregnant women and their newborns. The main objective of SIGNATURE project is to explore how the presence of prenatal SARS-CoV-2 infection and other non-infectious stressors generates an abnormal inflammatory activity in the newborn. The cohort of women during the COVID-19 pandemic will be psychological and biological monitored during their pregnancy, delivery, childbirth and postpartum. The biological information of the umbilical cord (foetus blood) and peripheral blood from the mother will be obtained after childbirth. These samples and the clinical characterisation of the cohort of mothers and newborns, are tremendously valuable at this time. This is a protocol report and no analyses have been conducted yet, being currently at, our study is in the recruitment process step. At the time of this publication, we have identified 1,060 SARS-CoV-2 infected mothers and all have already given birth. From the total of identified mothers, we have recruited 537 SARS-COV-2 infected women and all of them have completed the mental health assessment during pregnancy. We have collected biological samples from 119 mothers and babies. Additionally, we have recruited 390 non-infected pregnant women.This work has received support from the Fundación Alicia Koplowitz to realize the epigenetic wide association study and to the clinical assessment to the children. This work has also received public support from the Consejería de Salud y Familias para la financiación de la investigación, desarrollo e innovación (i + d + i) biomédica y en ciencias de la salud en Andalucía (CSyF 2021 - FEDER). Grant Grant number PECOVID- 0195-2020. Convocatoria financiada con Fondo Europeo de Desarrollo Regional (FEDER) al 80% dentro del Programa Operativo de Andalucía FEDER 2014-2020. Andalucía se mueve con Europa. NG-T received payment under Rio Hortega contract CM20-00015 with the Carlos III Health Institute.Peer reviewe

Metabolic syndrome in antipsychotic naïve patients with firstepisode psychosis

Antecedentes La relación entre esquizofrenia y síndrome metabólico (MetS) es ampliamente conocida y se ha atribuido principalmente a los antipsicóticos. En la última década se han publicado estudios en pacientes con trastorno psicótico que presentan alteraciones metabólicas a pesar de nunca haber tomado antipsicóticos, sin embargo, la mayoría se han centrado en la búsqueda de alteraciones metabólicas específicas sin explorar la presencia de todos los componentes de síndrome metabólico en conjunto. Métodos En una primera fase de esta tesis doctoral, se realizó una revisión sistemática y metaanálisis que incluyó estudios en pacientes con primer episodio psicótico (PEP) sin exposición previa al tratamiento antipsicótico “naïve”. En una segunda fase y una vez conocidas las limitaciones de los estudios realizados sobre este tema, se hizo un estudio transversal y después longitudinal sobre la prevalencia de síndrome metabólico en pacientes con PEP naïve y su evolución a 3 años. Para ello se utilizó el dataset del Programa de Atención a las Fases Iniciales de la Psicosis PAFIP, que es programa de referencia de psicosis a nivel nacional e internacional. Resultados En el meta-análisis se encontró que la prevalencia de síndrome metabólico en pacientes con PEP estrictamente naïve fue 13.2%. (95% CI 8.7–19.0) (n = 1009, k = 13). Además, se observó que los pacientes con PEP tienen el doble de riesgo de presentar síndrome metabólico que la población general independientemente del uso de antipsicóticos (OR 2.52, p = 0.007). Las principales fuentes de heterogeneidad fueron la disparidad de criterios usados para definir síndrome metabólico y la etnicidad. A través del estudio en una muestra representativa de pacientes naïve se hizo evidente que la prevalencia de síndrome metabólico es similar a la de los controles, sin embargo, se confirmó que los pacientes con PEP tienen más alteraciones metabólicas basales que los controles sanos. Después de analizar la prevalencia basal de síndrome metabólico en PEP, controles y el seguimiento a los 3 años, se encontró que el grupo PEP tuvo una peor evolución en comparación con el grupo control, independientemente del uso de antipsicóticos. Conclusiones Los pacientes con trastorno psicótico tienen más riesgo de síndrome metabólico y más alteraciones metabólicas que la población general. Estas alteraciones no se deben exclusivamente al uso de antipsicóticos. Hay varias causas que podrían justificar la presencia de esas alteraciones en pacientes jóvenes, una de ellas es la hipótesis de la esquizofrenia como parte de una enfermedad sistémica que tiene origen en etapas tempranas del desarrollo y que además del cerebro, compromete otros órganos. Los determinantes sociales de la salud y la exposición a factores ambientales en etapas críticas del neurodesarrollo contribuyen al aumento de riesgo de presentar trastorno psicótico y síndrome metabólico. Las mujeres con primer episodio psicótico presentan algunas alteraciones específicas y diferentes a los hombres previamente al uso de antipsicóticos. Por otra parte, es necesario tener herramientas de medida de riesgo cardiovascular validadas en población joven con primer episodio psicótico.Background The association between the psychotic disorders and metabolic syndrome (MetS) is widely knowledged and it has been mainly attributed to antipsychotics. In the last decade, studies have been published with patients who had not received pharmacological treatment and who show that the metabolic alterations could not be exclusively due to antipsychotics; however most studies on naïve patients have focused on the search for specific metabolic alterations, without exploring the presence of all MetS components together. Methods In the first step of this doctoral thesis, a systematic review and meta-analysis that included studies in patients with first psychotic episode (FEP) without prior exposure to antipsychotic treatment "naïve" was carried out. In the second step, and once the limitations of the studies carried out on this topic were known, a cross-sectional study on the prevalence of metabolic syndrome in patients with naïve FEP and then a longitudinal study about its follow-up to 3 years were carried out. For this, the dataset of the PAFIP Program for Attention to the Initial Phases of Psychosis, which is a reference program for psychosis at national and international level, was used. Results In the meta-analysis it was found that the prevalence of metabolic syndrome in patients with FEP strictly naïve was 13.2%. (95% CI 8.7–19.0) (n = 1009, k = 13). In addition, it was observed that patients with FEP have twice the risk of developing metabolic syndrome than the general population regardless of the use of antipsychotics (OR 2.52, p = 0.007). The main sources of heterogeneity were the disparity of criteria used to define metabolic syndrome and the ethnicity. Through the study of a representative sample of naïve patients it became evident that the prevalence of metabolic syndrome is similar to that of controls, however, it was confirmed that patients with FEP have more baseline metabolic alterations than healthy controls. After analyzing the baseline prevalence of metabolic syndrome in FEP, controls and follow-up at 3 years, it was found that the FEP group had a worse evolution compared to the control group, regardless of the use of antipsychotics. Conclusions Patients with FEP have a higher risk of metabolic syndrome and more metabolic disturbances than the general population. These alterations are not due exclusively to the use of antipsychotics. There are several causes that could justify the presence of these alterations in young patients, one of them is the hypothesis of schizophrenia as part of a systemic disease that originates in the early stages of development and that in addition to the brain, involves other organs. Social determinants of health and exposure to environmental factors at critical stages of neurodevelopment contribute to the increased risk of both psychotic disorder and metabolic syndrome. Women with first psychotic episode present some specific alterations more frequently than men prior to the use of antipsychotics. On the other hand, it is necessary to have cardiovascular risk measurement tools validated in young people with first psychotic episodes

Data_Sheet_1_Reelin Alterations, Behavioral Phenotypes, and Brain Anomalies in Schizophrenia: A Systematic Review of Insights From Rodent Models.pdf

Tables; Table S1. Search Strategy, Table S2. Full text of excluded articles, Table S3a. Genetic model studies, Table S3b. Environmental model studies, Table S3c Gene x environmental model studies, Quality assessment procedures S4.Reelin is an extracellular matrix glycoprotein reduced in brain regions (the prefrontal cortex and the hippocampus) of patients with schizophrenia. There are diverse rodent models of schizophrenia that mimic patient symptoms based on various causal theories; however, likely shared reelin alterations have not yet been systematically assessed in those models. A systematic review of the literature was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) model. Articles focused on psychotic disorders or schizophrenia and their relationship with reelin in rodent models were selected. Data (first author, publication year, results, both open field and prepulse inhibition test results, and type of reelin alteration) were extracted in duplicate by two independent reviewers. The 37 reviewed articles reported about various schizophrenia models and their reelin alterations, brain morphology, and behavioral defects. We conclude that reelin is an altered preclinical biomarker common to all models included, mainly prenatal or genetic models, and a key protein in schizophrenia disease, making the reelin signaling pathway in prenatal stages a target of special interest for future preclinical and clinical studies. All models presented at least one of the four described reelin alteration types. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021210568], identifier [CRD42021210568].Peer reviewe