Fenotipo y genotipo de los síntomas negativos en la esquizofrenia: Conceptualización, evaluación y su relación con el polimorfismo Val66Met del BDNF

[spa] Esta tesis pretende realizar una actualización de los síntomas negativos en la esquizofrenia en lo que respecta a su conceptualización, su caracterización, su evaluación y su predicción a través de marcadores genéticos y clínicos. Los objetivos de esta tesis surgieron de la necesidad, tanto en el ámbito clínico como en el de investigación, de un mejor y mayor abordaje de estos síntomas. Y es que la esquizofrenia es un trastorno en el que se ha avanzado considerablemente en lo que refiere a la mejora del tratamiento farmacológico para paliar la sintomatología positiva; sin embargo, el papel del tratamiento farmacológico y psicológico para la esfera negativa ha sido mucho más limitado, presentando escaso impacto sobre estos síntomas. Son numerosos los motivos que subyacen a esta falta de eficacia en los tratamientos existentes hasta el momento: falta de consenso en la definición de estos síntomas, así como en su evaluación; falta de conformidad en lo que respecta a los sustratos biológicos que los subyacen y los mecanismos de neurotransmisión implicados en la aparición de esta sintomatología; controversias relacionadas con la aparición y evolución de esta sintomatología a lo largo de las diferentes fases de la enfermedad, etc. En las últimas décadas se han desarrollado diversas escalas clínicas para la cuantificación y medida de esta sintomatología, pero el uso de éstas ha ido evidenciando claras limitaciones psicométricas y conceptuales. En este contexto surgieron la CAINS y la BNSS, dos escalas que demostraron características más actualizadas y óptimas en comparación con las escalas tradicionales. El primer estudio de la presente tesis doctoral se basa en la traducción y validación de la CAINS. Por otro lado, marcadores genéticos, inflamatorios, inmunológicos y neurotróficos han sido objeto de estudio con el propósito de predecir esta sintomatología y su evolución. Centrándonos en los primeros, se ha evidenciado que algunos marcadores genéticos y su interacción con el ambiente tienen un papel clave en la etiología y fisiopatología de la esquizofrenia. Sin embargo, en el caso de algunos marcadores, también se ha sugerido que pueden no tener un papel clave en la etiología per se de la enfermedad, sino que pueden actuar como posibles moduladores de la sintomatología clínica, como podría ser el caso del polimorfismo Val66Met del BDNF. Es sobre este gen en el que se focaliza el segundo estudio incluido en esta tesis. Otro factor de interés es el estudio del patrón evolutivo de la sintomatología negativa a lo largo de las diferentes fases de la enfermedad, así como los diferentes factores que puedan desempeñar un rol predictor de severidad en estos síntomas a largo plazo. El tercer estudio de esta tesis se centra en esta área. En resumen, los síntomas negativos deben considerarse claro objetivo y diana principal para una intervención temprana en personas diagnosticadas de esquizofrenia para asegurar la máxima recuperación sintomática, funcional y psicosocial. Por ello, los esfuerzos de la presente tesis doctoral se han centrado en la conceptualización, evaluación, tipificación -tanto clínica como biológica-, en la evolución y predicción de la severidad de los síntomas negativos en las primeras fases de la esquizofrenia.[eng] The present thesis aims to update the negative symptoms of schizophrenia with regard to their conceptualization, characterization, evaluation and prediction through genetic and clinical markers. The objectives of this thesis arose from the need, in the clinical as well as the research field, for a better and greater approach to this symptomatology. Schizophrenia is a disorder in which there has been considerable progress in improving pharmacological treatments to alleviate the positive symptomatology. However, the role of pharmacological and psychological treatments for the negative symptoms has been much more limited, with little impact on these symptoms. There are many reasons underlying this lack of efficacy so far: lack of consensus in the definition of these symptoms; poor consensus in their evaluation; controversies regarding the underlying biological substrates and the neurotransmission mechanisms involved in the onset of this symptomatology; and controversies related to the appearance and the evolution of this symptomatology throughout different phases of the disease. In the last decades several clinical scales have been developed for the measurement of this symptomatology, but use of these scales has shown psychometric and conceptual limitations. In this context, the CAINS and the BNSS emerged, two scales that showed more up-to-date and optimal characteristics compared to traditional scales. The first study of this doctoral thesis is based on the translation and validation of the CAINS. On the other hand, in recent years, genetic, inflammatory, immunological and neurotrophic markers have been studied in order to predict this symptomatology and its evolution. Focusing on the former, it has been shown that some genetic markers and their interaction with the environment play a key role in the etiology and / or pathophysiology of schizophrenia. However, in the case of some markers, it has also been suggested that they may not play a key role in the etiology per se of the disease, but rather act as potential modulators of clinical symptomatology, such as the Val66Met polymorphism BDNF. It is this gene that the second study included in this thesis is focused on. Another factor of interest is the study of the evolutionary pattern of the negative symptomatology throughout the different phases of the disease, as well as the different factors that may play a role in predicting a greater severity in these symptoms in the long term. The third study of this thesis focuses on this area. In summary, negative symptoms should be considered a clear and primary target for early intervention in patients diagnosed with schizophrenia to ensure maximum recovery, including symptomatic, functional and psychosocial recovery. For this reason, the efforts of this doctoral thesis have focused on the conceptualization, evaluation, classification (both clinical and biological), evolution and prediction of negative symptoms severity in the early stages of schizophrenia

Well-being in clozapine-treated schizophrenia patients: The significance of positive symptoms.

OBJECTIVES: Well-being perception is seldom explored in schizophrenia patients. Recurrent limitations, such as the questionable applicability of gold standard definitions of health and well-being, and fewer tools available to assess well-being, are pronounced in this subpopulation. This cross-sectional study sought to explore potential clinical factors that may predict subjective well-being scores in chronic schizophrenia patients (N=142) receiving clozapine treatment. METHODS: The Short Warwick-Edinburgh Mental Well-being Scale (SWEMWBS) was used to measure well-being. We correlated SWEMWBS scores and 27 clinically recognized factors, spanning socio-demographics, symptom severity scores, physical health diagnosis, clozapine side effects, habits and prescribed medication. Factors with a p<0.2 correlation were included as a predictors in a linear regression model. RESULTS: Ten factors were included in the linear regression model, however only positive symptom severity was a significant predictor of SWEMWBS score (p<0.0001). CONCLUSIONS: We suggest that greater levels of clinical attention given to positive symptoms compared with other symptoms and aspects of well-being, during biomedical treatment for chronic schizophrenia, may partially explain the finding that only positive symptoms significantly predicted patient perceptions of low well-being.While not directly funding this study, the authors of this work are supported by the Australian Postgraduate Award (J.B., APA 1183a/2010) and Government of Catalonia with the Secretaria d‟Universitats i Recerca del Departament d‟Economia i Coneixement (G.M., 2014SGR441), the grant FIDGR-2013 Contract of the Agència de Gestió d‟Ajuts Universitaris i de Recerca (G.M., AGAUR, 2015 FI_B2 00100) and a 2009 Young Investigator Award (NARSAD) (E.F-E., RG53588). This study used data extracted from the Clinical and Research Database for Persistent Schizophrenia, partially funded by the UK-National Institute for Health Research - Biomedical Research Center Cambridge. We also thank service users and Clozapine Clinic staff for their participation and support.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.comppsych.2016.04.00

Búsqueda De Nuevos Biomarcadores De La Cognición En Esquizofrenia

ResumenLa búsqueda de biomarcadores en la cognición ha centrado una gran parte de las investigaciones en pacientes con esquizofrenia. La literatura científica es heterogénea y son escasos los estudios disponibles que permitan establecer un modelo integrador de la etiopatogenia y respuesta terapéutica basada en estos marcadores. En el presente trabajo nos proponemos revisar tres aspectos fundamentales correlacionados con el rendimiento cognitivo: 1) la relación entre cognición e inflamación en esquizofrenia, 2) el papel de la prolactina en la cognición, y 3) la asociación entre cognición y factores neurotróficos, en particular el BDNF.Numerosos estudios apoyan la asociación de diversos marcadores inflamatorios con el estado cognitivo en esquizofrenia. El desarrollo de terapias eficaces en el rendimiento cognitivo se ha centrado en las últimas décadas en la búsqueda de fármacos inmunomoduladores o antiinflamatorios. Por otro lado, se ha demostrado la implicación de la prolactina y su función en la cognición y transición a la psicosis, así como en el pronóstico y diagnóstico de la esquizofrenia con independencia del tratamiento antipsicótico. En cuanto a factores neurotróficos, un estudio reciente correlaciona los niveles de BDNF con la mejoría cognitiva en pacientes diagnosticados de esquizofrenia tratados con rehabilitación cognitiva. Concluimos que, a pesar de la diversidad de biomarcadores asociados con el estado cognitivo en esquizofrenia, el BDNF es el biomarcador que acumula mayor evidencia en la literatura científica actual

Obstetric Phenotypes in the Heterogeneity of Schizophrenia.

Schizophrenia is a complex mental disorder with genetic and environmental components. Obstetric complications (OCs) are one of the most common environmental risk factors described. However, despite being different in timing and outcome, OCs are usually described as a homogeneous entity. In the present study, we evaluate the presence of different patterns of OCs evaluated with the Lewis-Murray Scale in chronic schizophrenia patients (n = 101) and their association with a crude marker of the intrauterine environment such as weight at birth.OCs related with abnormal fetal growth (p < 0.001) and OCs during gestation (p = 0.003) were associated with lower birth weight. However, difficulties in delivery, complications in pregnancy, and OCs all together (as a set) were not associated with weight at birth.Our results infer that OCs cannot be taken as a homogeneous group. Different patterns of OCs result in different birth weights, which is associated with specific metabolic, cognitive, and brain structure outcomes.This work was supported by the Government of Catalonia, Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement (2014SGR441), with the grants FI-DGR-2013 Contract of the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) (2015 FI_B2 00100) and from Fundació Bosch Gimpera (FBG) within the RETOS COLABORACIÓN 2015, funded by the Spanish Ministry of Economic Affairs and Competitiveness (RTC-2015-3440-1) to G. Mezquida. Dr. Bernardo has been supported by research funding from the Spanish Ministry of Health, the Spanish Ministry of Science and Education, the Spanish Ministry of Economic Affairs and Competitiveness, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), by Secretaria d'Universitat i Recerca del Departament d'Economia I Coneixement (2014SGR441), Foundation European Group for Research In Schizophrenia (EGRIS), and the 7th Framework Program of the European Union. Dr. Garcia-Rizo is supported by the PI14/00753 project, integrated into the State Plan of Scientific and Technical Research and Innovation 2013–2016 and co-financed by the ISCIII-General Evaluation Branch and the European Regional Development Fund (ERDF). Dr. Bobes is supported by the Spanish Ministry of Health, the Spanish Ministry of Science and Education, the Spanish Ministry of Economic Affairs and Competitiveness and CIBERSAM. Dr. Paz-Portilla has been also supported by the European Commission, ISCIII-General Evaluation Branch and CIBERSAM. Dr. Savulich is funded by a grant from Eton College and theWallitt Foundation. Dr. Fernanez-Egea is supported, in part, by the NIRH-Biomedical Research Center, Cambridge

Inverse association between negative symptoms and body mass index in chronic schizophrenia

BACKGROUND: We investigated whether negative symptoms, such as poor motivation or anhedonia, were associated with higher body mass index (BMI) in stable patients with schizophrenia chronically treated with antipsychotic medication. METHODS: 62 olanzapine- or clozapine-treated patients with illness duration of at least four years were selected from an international multicenter study on the characterization of negative symptoms. All participants completed the Brief Negative Symptom Scale (BNSS) and the Positive and Negative Syndrome Scale (PANSS). Bivariate correlations between BMI and negative symptoms (BNSS) were explored, as well as multiple regression analyses. We further explored the association of two principal component factors of the BNSS and BMI. Subsidiary analyses re-modeled the above using the negative symptoms subscale of the PANSS and the EMSLEY factor for negative symptoms for convergent validity. RESULTS: Lower negative symptoms (BNSS score) were associated with higher BMI (r=-0.31; p=0.015). A multiple regression analysis showed that negative symptoms (BNSS score) and age were significant predictors of BMI (p=0.037). This was mostly driven by the motivation/pleasure factor of the BNSS. Within this second factor, BMI was negatively associated with anhedonia (r=-0.254; p=0.046) and asociality (r=-0.253; p=0.048), but not avolition (r=-0.169; p=0.188). EMSLEY score was positively associated with BNSS (r=0.873, p<0.001), but negatively associated with BMI (r=-0.308; p=0.015). The association between PANSS and BMI did not reach significance (r=-224, p=0.080). CONCLUSIONS: We conclude that lower negative symptoms were associated with higher BMI (assessed using both the BNSS and EMSLEY) in chronic stable schizophrenia patients, mostly due to lower anhedonia and asociality levels

Combining MRI and clinical data to detect high relapse risk after the first episode of psychosis.

Detecting patients at high relapse risk after the first episode of psychosis (HRR-FEP) could help the clinician adjust the preventive treatment. To develop a tool to detect patients at HRR using their baseline clinical and structural MRI, we followed 227 patients with FEP for 18-24 months and applied MRIPredict. We previously optimized the MRI-based machine-learning parameters (combining unmodulated and modulated gray and white matter and using voxel-based ensemble) in two independent datasets. Patients estimated to be at HRR-FEP showed a substantially increased risk of relapse (hazard ratio=4.58, P<0.05). Accuracy was poorer when we only used clinical or MRI data. We thus show the potential of combining clinical and MRI data to detect which individuals are more likely to relapse, who may benefit from increased frequency of visits, and which are unlikely, who may be currently receiving unnecessary prophylactic treatments. We also provide an updated version of the MRIPredict software.We would also like to thank the Instituto de Salud Carlos III, the Spanish Ministry of Science, Innovation, and Universities, the European Regional Development Fund (ERDF/FEDER), European Social Fund, “Investing in your future”, “A way of making Europe” (projects: PI08/0208, PI11/00325, PI14/00292, PI14/00612, PI14/01148, PI14/01151, PI17/00481, PI17/01997, PI18/01055, PI19/00394, PI19/00766, PI20/00721, PI20/01342, and PI21/00713; contracts: CP14/00041, JR19/00024, CPII19/00009, and CD20/00177); CERCA Program; Catalan Government, the Secretariat of Universities and Research of the Department of Enterprise and Knowledge (2017SGR01271, 2017SGR1355, and 2017SGR1365); Institut de Neurociències, Universitat de Barcelona; Madrid Regional Government (B2017/BMD-3740 AGES-CM-2); the University of the Basque Country (2019 321218ELCY GIC18/107); the Basque Government (2017111104); European Union Structural Funds, European Union Seventh Framework Program, European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement No 115916, Project PRISM, and grant agreement No 777394, Project AIMS-2-TRIALS), Fundación Familia Alonso, Fundación Alicia Koplowitz and Fundación Mutua Madrileña. The funding organizations played no role in the study design, data collection, analysis, or manuscript approval

Self-reported neurocognitive symptoms during COVID-19 lockdown and its associated factors in a sample of psychiatric patients. Results from the BRIS-MHC study

Lockdown caused by COVID-19 pandemic has a negative impact on mental health. The aim was to assess self-reported neurocognitive symptoms during the lockdown and identify associated vulnerable and protective factors in a sample of psychiatric patients in a Spanish population.These results are part of the Barcelona ResIlience Survey for Mental Health COVID-19 (BRISMHC) project. Neurocognitive symptoms were assessed through an online survey considering the five items that represented self-reported neurocognitive complaints. We split the sample into two groups based on the severity of the self-reported neurocognitive complaints: intact cognitive function/mild cognitive impairment (CI-) and moderate/severe cognitive impairment (CI+). Univariate analyses were used to compare both groups in terms of sociodemographic and clinical variables. Multiple logistic regression models were carried out to identify clinical variables and coping strategies associated with neurocognitive symptoms. 198 patients with different psychiatric diagnoses were included in this study. One hundred seventeen patients were classified in the CI- group and 81 in the CI+ group. Depressive symptoms and negative psychotic-like symptoms were vulnerable factors for neurocognitive impairment. Coping strategies of performing physical activity, carrying out relaxing activities and maintaining a routine were protective factors against cognitive impairment. Lockdown situation negatively impact on neurocognitive function. Psychopathological symptoms and coping strategies were associated with neurocognitive symptoms during lockdown in subjects with psychiatric illness. The early treatment of psychopathological symptoms in psychiatric patients and promoting coping strategies during lockdown should be considered an intervention strategy against cognitive impairment

Cortical thinning over two years after first-episode psychosis depends on age of onset.

[EN] First-episode psychosis (FEP) patients show structural brain abnormalities at the first episode. Whether the cortical changes that follow a FEP are progressive and whether age at onset modulates these changes remains unclear. This is a multicenter MRI study in a deeply phenotyped sample of 74 FEP patients with a wide age range at onset (15-35 years) and 64 neurotypical healthy controls (HC). All participants underwent two MRI scans with a 2-year follow-up interval. We computed the longitudinal percentage of change (PC) for cortical thickness (CT), surface area (CSA) and volume (CV) for frontal, temporal, parietal and occipital lobes. We used general linear models to assess group differences in PC as a function of age at FEP. We conducted post-hoc analyses for metrics where PC differed as a function of age at onset. We found a significant age-by-diagnosis interaction effect for PC of temporal lobe CT (d=0.54; p=002). In a post-hoc-analysis, adolescent-onset (≤19y) FEP showed more severe longitudinal cortical thinning in the temporal lobe than adolescent HC. We did not find this difference in adult-onset FEP compared to adult HC. Our study suggests that, in individuals with psychosis, CT changes that follow the FEP are dependent on the age at first episode, with those with an earlier onset showing more pronounced cortical thinning in the temporal lobe.We are extremely grateful to all subjects who took part in this study. This work was supported by CIBERSAM; Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (PI081203, PI08/0208; PI11/00325; PI1101686, PI14/00612, PI17/01997, PI20/01342), co‐financed by the ERDF from the European Commission “A way of making Europe”, European Union Seventh Framework Program (FP7- HEALTH-2013-2.2.1-2-603196 [Project PSYSCAN]), EU H2020 (IMI‐2 Joint Undertaking under grant agreements 115916 (project PRISM) and 777394 (project AIMS‐2‐TRIALS)), Madrid Regional Government (S2017/BMD‐3740, and AGES-CM-2-CM) and European Union Structural Funds; Fundación Familia Alonso, Fundacion Mutua Madrileña, and Fundación Alicia Koplowitz

Obstetric complications and genetic risk for schizophrenia: Differential role of antenatal and perinatal events in first episode psychosis

Background: Obstetric complications (OCs) are key contributors to psychosis risk. However, it is unclear whether they increase psychosis vulnerability independently of genetic risk, in interaction with it, or are a manifestation of psychosis proneness. We examined the role of distinct types of OCs in terms of psychosis risk and tested whether they interact differently with genetic vulnerability, whilst accounting for other known environmental risk factors. Study Design: 405 participants (219 first episode psychosis patients and 186 healthy volunteers) underwent a comprehensive assessment of OCs, measured using the Lewis-Murray scale and divided into complications of pregnancy, abnormalities of foetal growth and development, and complications of delivery. Participants were compared in terms of history of OCs, polygenic risk score for schizophrenia (PRS-SZ) and interactions between these. Results: Both complications of pregnancy and abnormalities of foetal growth were significantly associated with case–control status (p = 0.02 and 0.03, respectively), whereas complications of delivery were not. PRS-SZ showed a significant association with psychosis (p = 0.04), but there were no significant interactions between genetic risk for schizophrenia and OCs, either when these were considered globally or separated based on their timeframe. Conclusions: We observed no significant interaction between genetic and obstetric vulnerability, yet distinct types of OCs may have a different impact on psychosis risk, based on their nature and timeframe. Examining their differential role might clarify their relative contributions to this risk

Link between cognitive polygenic risk scores and clinical progression after a first-psychotic episode

Background Clinical intervention in early stages of psychotic disorders is crucial for the prevention of severe symptomatology trajectories and poor outcomes. Genetic variability is studied as a promising modulator of prognosis, thus novel approaches considering the polygenic nature of these complex phenotypes are required to unravel the mechanisms underlying the early progression of the disorder. Methods The sample comprised of 233 first-episode psychosis (FEP) subjects with clinical and cognitive data assessed periodically for a 2-year period and 150 matched controls. Polygenic risk scores (PRSs) for schizophrenia, bipolar disorder, depression, education attainment and cognitive performance were used to assess the genetic risk of FEP and to characterize their association with premorbid, baseline and progression of clinical and cognitive status. Results Schizophrenia, bipolar disorder and cognitive performance PRSs were associated with an increased risk of FEP [false discovery rate (FDR) ⩽ 0.027]. In FEP patients, increased cognitive PRSs were found for FEP patients with more cognitive reserve (FDR ⩽ 0.037). PRSs reflecting a genetic liability for improved cognition were associated with a better course of symptoms, functionality and working memory (FDR ⩽ 0.039). Moreover, the PRS of depression was associated with a worse trajectory of the executive function and the general cognitive status (FDR ⩽ 0.001). Conclusions Our study provides novel evidence of the polygenic bases of psychosis and its clinical manifestation in its first stage. The consistent effect of cognitive PRSs on the early clinical progression suggests that the mechanisms underlying the psychotic episode and its severity could be partially independent