Browsing by Author "Nachar, Ruben"
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Publication Differences of affective and non-affective psychoses in early intervention services from Latin America(2022) Cerqueira, Raphael; Ziebold, Carolina; Cavalcante, Daniel; Oliveira, Giovany; Vásquez, Javiera; Undurraga, Juan; González, Alfonso; Nachar, Ruben; López, Carlos; Noto, Cristiano; Crossley, Nicolas; Gadelha, AryBackground: Psychosis presentation can be affected by genetic and environmental factors. Differentiating between affective and non-affective psychosis (A-FEP and NA-FEP, respectively) may influence treatment decisions and clinical outcomes. The objective of this paper is to examine differences between patients with A-FEP or NA-FEP in a Latin American sample. Methods: Patients from two cohorts of patients with a FEP recruited from Brazil and Chile. Subjects included were aged between 15 and 30 years, with an A-FEP or NA-FEP (schizophrenia-spectrum disorders) according to DSM-IV-TR. Sociodemographic data, duration of untreated psychosis and psychotic/mood symptoms were assessed. Generalized estimating equation models were used to assess clinical changes between baseline-follow-up according to diagnosis status. Results: A total of 265 subjects were included. Most of the subjects were male (70.9 %), mean age was 21.36 years. A-FEP and NA-FEP groups were similar in almost all sociodemographic variables, but A-FEP patients had a higher probability of being female. At baseline, the A-FEP group had more manic symptoms and a steeper reduction in manic symptoms scores during the follow- up. The NA-FEP group had more negative symptoms at baseline and a higher improvement during follow-up. All domains of The Positive and Negative Syndrome Scale improved for both groups. No difference for DUP and depression z-scores at baseline and follow-up. Limitations: The sample was recruited at tertiary hospitals, which may bias the sample towards more severe cases. Conclusions: This is the largest cohort comparing A-FEP and NA-FEP in Latin America. We found that features in FEP patients could be used to improve diagnosis and support treatment decisions.Publication Dysconnectivity in Schizophrenia Revisited: Abnormal Temporal Organization of Dynamic Functional Connectivity in Patients With a First Episode of Psychosis(2022) Ramírez, Juan; Tepper, Ángeles; Alliende, Luz; Mena, Carlos; Castañeda, Carmen; Iruretagoyena, Bárbara; Nachar, Ruben; Reyes, Francisco; León, Pablo; Mora, Ricardo; Ossandon, Tomas; González, Alfonso; Undurraga, Juan; De la Fuente, Camilo; Crossley, NicolasBackground and hypothesis: Abnormal functional connectivity between brain regions is a consistent finding in schizophrenia, including functional magnetic resonance imaging (fMRI) studies. Recent studies have highlighted that connectivity changes in time in healthy subjects. We here examined the temporal changes in functional connectivity in patients with a first episode of psychosis (FEP). Specifically, we analyzed the temporal order in which whole-brain organization states were visited. Study design: Two case-control studies, including in each sample a subgroup scanned a second time after treatment. Chilean sample included 79 patients with a FEP and 83 healthy controls. Mexican sample included 21 antipsychotic-naïve FEP patients and 15 healthy controls. Characteristics of the temporal trajectories between whole-brain functional connectivity meta-states were examined via resting-state functional MRI using elements of network science. We compared the cohorts of cases and controls and explored their differences as well as potential associations with symptoms, cognition, and antipsychotic medication doses. Study results: We found that the temporal sequence in which patients' brain dynamics visited the different states was more redundant and segregated. Patients were less flexible than controls in changing their network in time from different configurations, and explored the whole landscape of possible states in a less efficient way. These changes were related to the dose of antipsychotics the patients were receiving. We replicated the relationship with antipsychotic medication in the antipsychotic-naïve FEP sample scanned before and after treatment. Conclusions: We conclude that psychosis is related to a temporal disorganization of the brain's dynamic functional connectivity, and this is associated with antipsychotic medication use.Item Functional Dysconnectivity in Ventral Striatocortical Systems in 22q11.2 Deletion Syndrome(2022) Tepper, Ángeles; Cuiza, Analía; Alliende, Luz; Mena, Carlos; Ramirez, Juan; Iruretagoyena, Bárbara; Ornstein, Claudia; Fritsch, Rosemarie; Nachar, Ruben; González, Alfonso; Undurraga, Juan; Cruz, Juan; Nachar, Ruben; González, Alfonso; Undurraga, Juan; Cruz, Juan; Tejos, Cristian; Fornito, Alex; Repetto, Gabriela; Crossley, Nicolás22q11.2 deletion syndrome (22q11.2DS) is a genetic neurodevelopmental disorder that represents one of the greatest known risk factors for psychosis. Previous studies in psychotic subjects without the deletion have identified a dopaminergic dysfunction in striatal regions, and dysconnectivity of striatocortical systems, as an important mechanism in the emergence of psychosis. Here, we used resting-state functional MRI to examine striatocortical functional connectivity in 22q11.2DS patients. We used a 2 × 2 factorial design including 125 subjects (55 healthy controls, 28 22q11.2DS patients without a history of psychosis, 10 22q11.2DS patients with a history of psychosis, and 32 subjects with a history of psychosis without the deletion), allowing us to identify network effects related to the deletion and to the presence of psychosis. In line with previous results from psychotic patients without 22q11.2DS, we found that there was a dorsal to ventral gradient of hypo- to hyperstriatocortical connectivity related to psychosis across both patient groups. The 22q11.2DS was additionally associated with abnormal functional connectivity in ventral striatocortical networks, with no significant differences identified in the dorsal system. Abnormalities in the ventral striatocortical system observed in these individuals with high genetic risk to psychosis may thus reflect a marker of illness risk.Item Intervención Temprana en Psicosis, una perspectiva clínica(2021) Undurraga, Juan; Gaspar, Pablo; Nachar, Ruben; Díaz, Camila; Rivera, Guillermo; Noto, CristianoIdentificar a aquellas personas que tienen un mayor riesgo para desarrollar trastornos psiquiátricos severos e intervenir precozmente para evitar el desarrollo de éstos o mejorar su pronóstico en el largo plazo, ha sido el motor principal de los programas de intervención temprana. Hoy sabemos que existen estrategias de intervención sistematizadas que permiten disminuir la transición a psicosis en esta población. Asimismo, sabemos que las intervenciones clínicas en los primeros años desde el inicio de los síntomas, mejoran la respuesta al tratamiento y el pronóstico funcional en el largo plazo de nuestros pacientes. Sin embargo, estas intervenciones son complejas y requieren de grupos interdisciplinarios con un enfoque flexible, para dar respuestas apropiadas a cada etapa de la enfermedad, que incluyan a los pacientes, familiares y a la comunidad. Esta revisión narrativa tiene como objetivo revisar el conocimiento actual sobre la intervención temprana desde una perspectiva clínica y proponer un acercamiento contingente y progresivo en la población de alto riesgo y psicosis temprana.Publication Intra and inter-individual variability in functional connectomes of patients with First Episode of Psychosis(2023) Tepper, Angeles; Vásquez Núñez, Javiera; Ramirez-Mahaluf, Juan Pablo; Aguirre, Juan Manuel; Barbagelata, Daniella; Maldonado, Elisa; Díaz Dellarossa, Camila; Nachar, Ruben; González-Valderrama, Alfonso; Undurraga, Juan; Goñi, Joaquín; Crossley, NicolásPatients with Schizophrenia may show different clinical presentations, not only regarding inter-individual comparisons but also in one specific subject over time. In fMRI studies, functional connectomes have been shown to carry valuable individual level information, which can be associated with cognitive and behavioral variables. Moreover, functional connectomes have been used to identify subjects within a group, as if they were fingerprints. For the particular case of Schizophrenia, it has been shown that there is reduced connectome stability as well as higher inter-individual variability. Here, we studied inter and intra-individual heterogeneity by exploring functional connectomes’ variability and related it with clinical variables (PANSS Total scores and antipsychotic’s doses). Our sample consisted of 30 patients with First Episode of Psychosis and 32 Healthy Controls, with a test–retest approach of two resting-state fMRI scanning sessions. In our patients’ group, we found increased deviation from healthy functional connectomes and increased intragroup inter-subject variability, which was positively correlated to symptoms’ levels in six subnetworks (visual, somatomotor, dorsal attention, ventral attention, frontoparietal and DMN). Moreover, changes in symptom severity were positively related to changes in deviation from healthy functional connectomes. Regarding intra-subject variability, we were unable to replicate previous findings of reduced connectome stability (i.e., increased intra-subject variability), but we found a trend suggesting that result. Our findings highlight the relevance of variability characterization in Schizophrenia, and they can be related to evidence of Schizophrenia patients having a noisy functional connectome.Item Predictors of clozapine discontinuation at 2 years in treatment-resistant schizophrenia(2021) Iruretagoyena, Bárbara; Castañeda, Carmen Paz; Mena, Cristian; Diaz, Camila; Nachar, Ruben; Ramirez, Juan Pablo; González, Alfonso; Undurraga, JuanIntroduction: Little is known about predictors of clinical response to clozapine treatment in treatment-resistant psychosis. Most published cohorts are small, providing inconsistent results. We aimed to identify baseline clinical predictors of future clinical response in patients who initiate clozapine treatment, mainly focusing on the effect of age, duration of illness, baseline clinical symptoms and homelessness. Methodology: Retrospective cohort of patients with treatment-resistant schizophrenia, aged between 15 and 60 years, that initiated clozapine between 2014 and 2017. Sociodemographic characteristics, years from illness diagnosis, and clinical presentation before the initiation of clozapine were collected and analyzed. All-cause discontinuation at two years follow-up was used as the primary measure of clozapine response. Results: 261 patients were included with a median age at illness diagnosis of 23 years old (IQR 19-29) and a median age at clozapine initiation of 25 (IQR: 21-33). 72.33% (183/253) continued clozapine after two years follow-up. Being homeless was associated to higher clozapine non-adherence, with an OR of 2.78 (95%CI 1.051-7.38) (p = 0.039, controlled by gender). Older age at clozapine initiation and longer delay from first schizophrenia diagnosis to clozapine initiation were also associated with higher clozapine non-adherence, with each year increasing the odds of discontinuation by 1.043 (95%CI 1.02-1.07; p = 0.001) and OR 1.092 (95%CI 1.01-1.18;p = 0.032) respectively. Conclusion: Starting clozapine in younger patients or shortly after schizophrenia diagnosis were associated with better adherence.Publication Quantitative Susceptibility Mapping MRI in Deep-Brain Nuclei in First-Episode Psychosis(2023) García Saborit, Marisleydis; Jara, Alejandro; Muñoz, Néstor; Milovic, Carlos; Tepper, Angeles; Alliende, Luz María; Mena, Carlos; Iruretagoyena, Bárbara; Ramírez-Mahaluf, Juan Pablo; Díaz, Camila; Nachar, Ruben; Castañeda, Carmen Paz; González, Alfonso; Undurraga, Juan; Crossley, Nicolás; Tejos, CristianBackground: Psychosis is related to neurochemical changes in deep-brain nuclei, particularly suggesting dopamine dysfunctions. We used an magnetic resonance imaging-based technique called quantitative susceptibility mapping (QSM) to study these regions in psychosis. QSM quantifies magnetic susceptibility in the brain, which is associated with iron concentrations. Since iron is a cofactor in dopamine pathways and co-localizes with inhibitory neurons, differences in QSM could reflect changes in these processes. Methods: We scanned 83 patients with first-episode psychosis and 64 healthy subjects. We reassessed 22 patients and 21 control subjects after 3 months. Mean susceptibility was measured in 6 deep-brain nuclei. Using linear mixed models, we analyzed the effect of case-control differences, region, age, gender, volume, framewise displacement (FD), treatment duration, dose, laterality, session, and psychotic symptoms on QSM. Results: Patients showed a significant susceptibility reduction in the putamen and globus pallidus externa (GPe). Patients also showed a significant R2* reduction in GPe. Age, gender, FD, session, group, and region are significant predictor variables for QSM. Dose, treatment duration, and volume were not predictor variables of QSM. Conclusions: Reduction in QSM and R2* suggests a decreased iron concentration in the GPe of patients. Susceptibility reduction in putamen cannot be associated with iron changes. Since changes observed in putamen and GPe were not associated with symptoms, dose, and treatment duration, we hypothesize that susceptibility may be a trait marker rather than a state marker, but this must be verified with long-term studies.Item Structural brain abnormalities in schizophrenia in adverse environments: examining the effect of poverty and violence in six Latin American cities(2021) Crossley, Nicolas; Zugman, Andre; Reyes, Francisco; Czepielewski, Leticia; Castro, Mariana; Diaz, Ana; Pineda, Julian; Reckziegel, Ramiro; Gadelha, Ary; Jackowski, Andrea; Noto, Cristiano; Alliende, Luz; Iruretagoyena, Bárbara; Ossandon, Tomas; Ramírez, Juan; Castañeda, Carmen; González, Alfonso; Nachar, Ruben; León, Pablo; Undurraga, Juan; De la Fuente, Camilo; Bressan, Rodrigo; ANDES NetworkBackground: Social and environmental factors such as poverty or violence modulate the risk and course of schizophrenia. However, how they affect the brain in patients with psychosis remains unclear. Aims: We studied how environmental factors are related to brain structure in patients with schizophrenia and controls in Latin America, where these factors are large and unequally distributed. Method: This is a multicentre study of magnetic resonance imaging in patients with schizophrenia and controls from six Latin American cities. Total and voxel-level grey matter volumes, and their relationship with neighbourhood characteristics such as average income and homicide rates, were analysed with a general linear model. Results: A total of 334 patients with schizophrenia and 262 controls were included. Income was differentially related to total grey matter volume in both groups (P = 0.006). Controls showed a positive correlation between total grey matter volume and income (R = 0.14, P = 0.02). Surprisingly, this relationship was not present in patients with schizophrenia (R = -0.076, P = 0.17). Voxel-level analysis confirmed that this interaction was widespread across the cortex. After adjusting for global brain changes, income was positively related to prefrontal cortex volumes only in controls. Conversely, the hippocampus in patients with schizophrenia, but not in controls, was relatively larger in affluent environments. There was no significant correlation between environmental violence and brain structure. Conclusions: Our results highlight the interplay between environment, particularly poverty, and individual characteristics in psychosis. This is particularly important for harsh environments such as low- and middle-income countries, where potentially less brain vulnerability (less grey matter loss) is sufficient to become unwell in adverse (poor) environments.