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

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

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

Resilience and mental health during the COVID-19 pandemic

Background: Resilience is a process that allows recovery from or adaptation to adversities. The aim of this study was to evaluate state resilience during the COVID-19 pandemic in psychiatric patients (PP), unaffected relatives (UR) and community controls (CC). Methods: This study is part of the Barcelona ResIlience Survey for Mental Health COVID-19 (BRIS-MHC) project. Logistic regression models were performed to identify mental health outcomes associated with bad state resilience and predictors of good state resilience. The association between state resilience and specific affective temperaments as well as their influence on the association between depressive symptoms and state resilience were verified. Results: The study recruited 898 participants that took part in the survey. The presence of depressive symptoms was a predictor of bad state resilience in PP (β=0.110, OR=1.117, p=0.028). No specific mental health outcome was associated with bad state resilience in UR and CC. Predictors of good state resilience in PP were having pursued hobbies/conducted home tasks (β=1.261, OR=3.528, p=0.044) and level of organization in the family (β=0.986, OR=2.682, p=0.008). Having a controlling family was inversely associated with good state resilience in CC (β=-1.004, OR=0.367, p=0.012). The association between bad state resilience and depressive symptoms was partially mediated by affective temperaments. Limitations: Participants self-reported their psychiatric diagnoses, their relatives' diagnoses or the absence of a psychiatric disorder, as well as their psychiatric symptoms. Conclusions: Enhancing resilience and coping strategies in the face of the COVID-19 pandemic might have important implications in terms of mental health outcomes

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

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 (≤19 y) 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

The effect of early life events on glucose levels in first-episode psychosis

First episode of psychosis (FEP) patients display a wide variety of metabolic disturbances at onset, which might underlie these patients' increased morbidity and early mortality. Glycemic abnormalities have been previously related to pharmacological agents; however, recent research highlights the impact of early life events. Birth weight (BW), an indirect marker of the fetal environment, has been related to glucose abnormalities in the general population over time. We aim to evaluate if BW correlates with glucose values in a sample of FEP patients treated with different antipsychotics. Two hundred and thirty-six patients were included and evaluated for clinical and metabolic variables at baseline and at 2, 6, 12, and 24 months of follow-up. Pearson correlations and linear mixed model analysis were conducted to analyze the data. Antipsychotic treatment was grouped due to its metabolic risk profile. In our sample of FEP patients, BW was negatively correlated with glucose values at 24 months of follow-up [r=-0.167, p=0.037]. BW showed a trend towards significance in the association with glucose values over the 24-month period (F=3.22; p=0.073) despite other confounders such as age, time, sex, body mass index, antipsychotic type, and chlorpromazine dosage. This finding suggests that BW is involved in the evolution of glucose values over time in a cohort of patients with an FEP, independently of the type of pharmacological agent used in treatment. Our results highlight the importance of early life events in the later metabolic outcome of patients

The effect of family environment and psychiatric family history on psychosocial functioning in first-episode psychosis at baseline and after 2 years

Abstract The aim of the present study was to evaluate the contribution of family environment styles and psychiatric family history on functioning of patients presenting first-episode psychosis (FEP). Patients with FEP and healthy controls (HC) were assessed at baseline and after 2 years. The Functional Assessment Short Test (FAST) was used to assess functional outcome and the Family Environment Scale (FES) to evaluate family environment. Linear regressions evaluated the effect that family environment exerts on functioning at baseline and at 2-year follow-up, when FEP patients were diagnosed according to non-affective (NA-PSYCH) or affective psychoses (APSYCH). The influence of a positive parents' psychiatric history on functioning was evaluated through one-way between-groups analysis of covariance (ANCOVA) models, after controlling for family environmental styles. At baseline, FEP patients presented moderate functioning impairment, significantly worse than HC (28.65±16.17 versus 3.25±7.92; p<0.001, g = 1.91). At 2-year follow-up, the functioning of NA-PSYCH patients was significantly worse than in A-PSYCH (19.92±14.83 versus 12.46±14.86; p = 0.020, g = 0.50). No specific family environment style was associated with functioning in FEP patients and HC. On the contrary, a positive psychiatric father's history influenced functioning of FEP patients. After 2 years, worse functioning in NA-PSYCH patients was associated with lower rates of active-recreational and achievement orientated family environment and with higher rates of moral-religious emphasis and control. In A-PSYCH, worse functioning was associated with higher rates of conflict in the family. Both family environment and psychiatric history influence psychosocial functioning, with important implications for early interventions, that should involve both patients and caregivers

A longitudinal study of gene expression in first-episode schizophrenia; exploring relapse mechanisms by co-expression analysis in peripheral blood.

Little is known about the pathophysiological mechanisms of relapse in first-episode schizophrenia, which limits the study of potential biomarkers. To explore relapse mechanisms and identify potential biomarkers for relapse prediction, we analyzed gene expression in peripheral blood in a cohort of first-episode schizophrenia patients with less than 5 years of evolution who had been evaluated over a 3-year follow-up period. A total of 91 participants of the 2EPs project formed the sample for baseline gene expression analysis. Of these, 67 provided biological samples at follow-up (36 after 3 years and 31 at relapse). Gene expression was assessed using the Clariom S Human Array. Weighted gene co-expression network analysis was applied to identify modules of co-expressed genes and to analyze their preservation after 3 years of follow-up or at relapse. Among the 25 modules identified, one module was semi-conserved at relapse (DarkTurquoise) and was enriched with risk genes for schizophrenia, showing a dysregulation of the TCF4 gene network in the module. Two modules were semi-conserved both at relapse and after 3 years of follow-up (DarkRed and DarkGrey) and were found to be biologically associated with protein modification and protein location processes. Higher expression of DarkRed genes was associated with higher risk of suffering a relapse and early appearance of relapse (p = 0.045). Our findings suggest that a dysregulation of the TCF4 network could be an important step in the biological process that leads to relapse and suggest that genes related to the ubiquitin proteosome system could be potential biomarkers of relapse

Cognitive clusters in first-episode psychosis

Impairments in a broad range of cognitive domains have been consistently reported in some individuals with first-episode psychosis (FEP). Cognitive deficits can be observed during the prodromal stage. However, the course of cognitive deficits is still unclear. The aim of this study was to identify cognitive subgroups over time and to compare their sociodemographic, clinical and functional profiles. A total of 114 patients with Schizophrenia Spectrum Disorders were included in the present study. We assessed subjects through psychiatric scales and eight neuropsychological tests at baseline and at two-year follow-up visit. We performed the Partition Around Medoids algorithm with all cognitive variables. Furthermore, we performed a logistic regression to identify the predictors related to the different cognitive clusters at follow-up. Two distinct subgroups were found: the first cluster characterized by cognitive impairment and a second cluster had relatively intact cognition in comparison with norms. Up to 54.7% of patients with cognitive deficits at baseline tended to improve during the first two years of treatment. Patients with intact cognition at follow-up had a higher socioeconomic status, later age of onset, lower negative symptoms and a higher cognitive reserve (CR) at baseline. CR and age of onset were the baseline variables that predicted cognitive impairment. This research allows us to obtain a better understanding of the heterogeneous profile of psychotic disorders. Identifying the characteristics of patients who wil

The role of cognitive reserve and clinical symptoms in the association between genetic liability for educational attainment and functioning in first-episode psychosis: a mediation analysis

Background: Polygenic risk scores for educational attainment (PRSEA), cognitive reserve (CR), and clinical symptoms are associated with psychosocial functioning in first-episode psychosis (FEP). Nevertheless, the mechanisms underlying their complex interaction is yet to be explored. This study aimed to assess the mediating role of CR and clinical symptoms, both negative (NS) and positive (PS), on the interrelationship between PRSEA and functionality, one year after a FEP.Methods: A total of 162 FEP patients underwent clinical, functional, and genetic assessments. Using genome-wide association study (GWAS) summary results, PRSEA were constructed for each individual. Two mediation models were explored. The parallel mediation model explored the relationship of PRSEA with functionality through CR and clinical symptoms, NS, and PS. The serial mediation model tested a causal chain of the three mediators: CR, NS and PS. Mediation analysis was performed using the PROCESS function V.4.1 in SPSS V.22.Results: A serial mediation model revealed a causal chain for PRSEA > CR > NS > Functionality (β=-0.35, 95%CI [-0.85, -0.04], pConclusions: Both CR and NS mediate the relationship between PRSEA and functionality at one-year follow-up, using serial mediation analysis. This may be relevant for prevention and personalized early intervention to reduce illness impact and improve functional outcomes in FEP patients.</p