Plasma β-III tubulin, neurofilament light chain and glial fibrillary acidic protein are associated with neurodegeneration and progression in schizophrenia

Schizophrenia is a progressive disorder characterized by multiple psychotic relapses. After every relapse, patients may not fully recover, and this may lead to a progressive loss of functionality. Pharmacological treatment represents a key factor to minimize the biological, psychological and psychosocial impact of the disorder. The number of relapses and the duration of psychotic episodes induce a potential neuronal damage and subsequently, neurodegenerative processes. Thus, a comparative study was performed, including forty healthy controls and forty-two SZ patients divided into first-episode psychosis (FEP) and chronic SZ (CSZ) subgroups, where the CSZ sub group was subdivided by antipsychotic treatment. In order to measure the potential neuronal damage, plasma levels of β-III tubulin, neurofilament light chain (Nf-L), and glial fibrillary acidic protein (GFAP) were performed. The results revealed that the levels of these proteins were increased in the SZ group compared to the control group (P < 0.05). Moreover, multiple comparison analysis showed highly significant levels of β-III tubulin (P = 0.0002), Nf-L (P = 0.0403) and GFAP (P < 0.015) in the subgroup of CSZ clozapine-treated. In conclusion, β-III tubulin, Nf-L and GFAP proteins may be potential biomarkers of neurodegeneration and progression in SZFundação para a Ciência e a Tecnologia | Ref. SFRH/BD/135623/20Instituto de Salud Carlos III | Ref. P16/00405Ministerio de Sanidad, Igualdad y Política Social | Ref. 2017I054Agencia del Conocimiento en Salud | Ref. PRIS2-17Xunta de Galicia | Ref. IN607C-2017/02Xunta de Galicia | Ref. IN607B 2018/1

Human breast milk microRNAs, potential players in the regulation of nervous system

Human milk is the biological fluid with the highest exosome amount and is rich in microRNAs (miRNAs). These are key regulators of gene expression networks in both normal physiologic and disease contexts, miRNAs can influence many biological processes and have also shown promise as biomarkers for disease. One of the key aspects in the regeneration of the nervous system is that there are practically no molecules that can be used as potential drugs. In the first weeks of lactation, we know that human breast milk must contain the mechanisms to transmit molecular and biological information for brain development. For this reason, our objective is to identify new modulators of the nervous system that can be used to investigate neurodevelopmental functions based on miRNAs. To do this, we collected human breast milk samples according to the time of delivery and milk states: mature milk and colostrum at term; moderate and very preterm mature milk and colostrum; and late preterm mature milk. We extracted exosomes and miRNAs and realized the miRNA functional assays and target prediction. Our results demonstrate that miRNAs are abundant in human milk and likely play significant roles in neurodevelopment and normal function. We found 132 different miRNAs were identified across all samples. Sixty-nine miRNAs had significant differential expression after paired group comparison. These miRNAs are implicated in gene regulation of dopaminergic/glutamatergic synapses and neurotransmitter secretion and are related to the biological process that regulates neuron projection morphogenesis and synaptic vesicle transport. We observed differences according to the delivery time and with less clarity according to the milk type. Our data demonstrate that miRNAs are abundant in human milk and likely play significant roles in neurodevelopment and normal function.Sociedad de Pediatría Gallega | Ref. BecaSOPEGA2016Axencia Galega de Innovación | Ref. IN607B-2018/17Axencia Galega de Innovación | Ref. PI20/00937Axencia Galega de Innovación | Ref. IN606A-2019/02

Comprehensive dissection of prevalence rates, sex differences, and blood level-dependencies of clozapine-associated adverse drug reactions

Clozapine is often underused due to concerns about adverse drug reactions (ADRs) but studies into their prevalences are inconclusive. We therefore comprehensively examined prevalences of clozapineassociated ADRs in individuals with schizophrenia and demographic and clinical factors associated with their occurrence. Data from a multi-center study (n=698 participants) were collected. The mean number of ADRs during clozapine treatment was 4.8, with 2.4% of participants reporting no ADRs. The most common ADRs were hypersalivation (74.6%), weight gain (69.3%), and increased sleep necessity (65.9%), all of which were more common in younger participants. Participants with lower BMI prior to treatment were more likely to experience significant weight gain (>10%). Constipation occurred more frequently with higher clozapine blood levels and doses. There were no differences in ADR prevalence rates between participants receiving clozapine monotherapy and polytherapy. These findings emphasize the high prevalence of clozapine-associated ADRs and highlight several demographic and clinical factors contributing to their occurrence. By understanding these factors, clinicians can better anticipate and manage clozapine-associated ADRs, leading to improved treatment outcomes and patient well-being

Búsqueda de Biomarcadores Periféricos en Trastorno Depresivo Mayor

La búsqueda de biomarcadores de trastornos afectivos como la depresión mayor que puedan ser trasladados a la clínica está adquiriendo cada vez mayor importancia. En este trabajo estudiamos en primer lugar la alteración en la agrupación del transportador de serotonina (SERT) en linfocitos sanguíneos de ratones heterocigotos reeler (que presentan una disminución de reelina de un 50%), donde se observa un aumento en el número y tamaño de los agrupamientos de SERT. Posteriormente, analizamos las alteraciones de SERT y 5-HT2A en linfocitos de pacientes con depresión mayor (donde se ha mostrado una disminución de reelina en muestras postmortem) y observamos que en pacientes naïve existen alteraciones especificas en tamaño y numero de agrupamientos de SERT y 5-HT2A, que permiten diferenciar dos subtipos de pacientes naïve (D-I y D-II). Los dos subtipos mostraron puntuaciones clínicas (escala de Hamilton y escala de evaluación de la anhedonia) similares antes del tratamiento, sin embargo, tras el tratamiento farmacológico los pacientes D-II presentaron una mejoría clínica significativamente mayor que en el grupo D-I, y un incremento en el número medio de agrupamientos de SERT y una disminución del número de 5-HT2A (parámetros que no se observan alterados por el tratamiento farmacológico en el grupo D-I). Se concluye que el análisis de agrupamientos de SERT y 5-HT2A en linfocitos podría representar un biomarcador de eficacia terapéutica en depresión mayor, aunque entendemos que la validación de estos biomarcadores debiera realizarse en estudios que incluyan un tamaño de muestra mayor y un ensayo clínico controlado

A systematic review of efficacy, safety, and tolerability of duloxetine

Fundação para a Ciência e Tecnologia | Ref. SFRH/BD/135623/2018Instituto de Salud Carlos III | Ref. P16/0040

Proteomics in Schizophrenia: A Gateway to Discover Potential Biomarkers of Psychoneuroimmune Pathways

Schizophrenia is a severe and disabling psychiatric disorder with a complex and multifactorial etiology. The lack of consensus regarding the multifaceted dysfunction of this ailment has increased the need to explore new research lines. This research makes use of proteomics data to discover possible analytes associated with psychoneuroimmune signaling pathways in schizophrenia. Thus, we analyze plasma of 45 patients [10 patients with first-episode schizophrenia (FES) and 35 patients with chronic schizophrenia] and 43 healthy subjects by label-free liquid chromatography–tandem mass spectrometry. The analysis revealed a significant reduction in the levels of glia maturation factor beta (GMF- β), the brain-derived neurotrophic factor (BDNF), and the 115-kDa isoform of the Rab3 GTPase-activating protein catalytic subunit (RAB3GAP1) in patients with schizophrenia as compared to healthy volunteers. In conclusion, GMF-β, BDNF, and 115-kDa isoform of RAB3GAP1 showed significantly reduced levels in plasma of patients with schizophrenia, thus making them potential biomarkers in schizophrenia.This work was financially backed by the Foundation for Science and Technology (FCT, Fundação para a Ciência e Tecnologia) within the framework of grant SFRH/BD/135623/2018 awarded to Daniela Rodrigues- Amorim, and another grant of Fundación Tatiana Pérez de Guzmanel Bueno provided to Carlos Spuch. Our research was further supported by the Carlos III Health Institute (ISCIII, Instituto Carlos III) through grant P16/00405 and co-funding awarded by the Spanish Foundation of Rare Diseases (FEDER, Fundación Española de Enfermedades Raras) to José Manuel OlivaresS

MiRNA Differences Related to Treatment-Resistant Schizophrenia

Schizophrenia (SZ) is a serious mental disorder that is typically treated with antipsychotic medication. Treatment-resistant schizophrenia (TRS) is the condition where symptoms remain after pharmacological intervention, resulting in long-lasting functional and social impairments. As the identification and treatment of a TRS patient requires previous failed treatments, early mechanisms of detection are needed in order to quicken the access to effective therapy, as well as improve treatment adherence. In this study, we aim to find a microRNA (miRNA) signature for TRS, as well as to shed some light on the molecular pathways potentially involved in this severe condition. To do this, we compared the blood miRNAs of schizophrenia patients that respond to medication and TRS patients, thus obtaining a 16-miRNA TRS profile. Then, we assessed the ability of this signature to separate responders and TRS patients using hierarchical clustering, observing that most of them are grouped correctly (~70% accuracy). We also conducted a network, pathway analysis, and bibliography search to spot molecular pathways potentially altered in TRS. We found that the response to stress seems to be a key factor in TRS and that proteins p53, SIRT1, MDM2, and TRIM28 could be the potential mediators of such responses. Finally, we suggest a molecular pathway potentially regulated by the miRNAs of the TRS profile

The neurobiological hypothesis of neurotrophins in the pathophysiology of schizophrenia: A meta-analysis

Schizophrenia is associated with patterns of aberrant neurobiological circuitry. The disease complexity is mirrored by multiple biological interactions known to contribute to the disease pathology. One potential contributor is the family of neurotrophins which are proteins involved in multiple functional processes in the nervous system, with crucial roles in neurodevelopment, synaptogenesis and neuroplasticity. With these roles in mind, abnormal neurotrophin profiles have been hypothesized to contribute to the pathology of schizophrenia.CS is supported by the Fundación Tatiana Pérez de Guzman el Bueno and Rede Galega de Investigación en DemenciasIN607C-2017/02, GAIN, Xunta de Galicia, JMO is supported by ISCIIIP16/00405, RCAB is funded by FEDER, a Ramón& Cajal grant (RYC-2014-15246) and the Galicia Innovation Agency - GAIN grant (IN607D-2016/003)info:eu-repo/semantics/publishedVersio

The role of the second extracellular loop of norepinephrine transporter, neurotrophin-3 and tropomyosin receptor kinase C in T cells: a peripheral biomarker in the etiology of schizophrenia

The neurobiology of schizophrenia is multifactorial, comprising the dysregulation of several biochemical pathways and molecules. This research proposes a peripheral biomarker for schizophrenia that involves the second extracellular loop of norepinephrine transporter (NEText), the tropomyosin receptor kinase C (TrkC), and the neurotrophin-3 (NT-3) in T cells. The study of NEText, NT-3, and TrkC was performed in T cells and plasma extracted from peripheral blood of 54 patients with schizophrenia and 54 healthy controls. Levels of NT-3, TrkC, and NET were significantly lower in plasma and T cells of patients compared to healthy controls. Co-immunoprecipitation (co-IPs) showed protein interactions with Co-IP NEText–NT-3 and Co-IP NEText–TrkC. Computational modelling of protein–peptide docking by CABS-dock provided a medium–high accuracy model for NT-3–NEText (4.6935 Å) and TrkC–NEText (2.1365 Å). In summary, immunocomplexes reached statistical relevance in the T cells of the control group contrary to the results obtained with schizophrenia. The reduced expression of NT-3, TrkC, and NET, and the lack of molecular complexes in T cells of patients with schizophrenia may lead to a peripheral dysregulation of intracellular signaling pathways and an abnormal reuptake of norepinephrine (NE) by NET. This peripheral molecular biomarker underlying schizophrenia reinforces the role of neurotrophins, and noradrenergic and immune systems in the pathophysiology of schizophrenia.Fundação para a Ciência e a Tecnologia | Ref. SFRH/BD/135623/2018Instituto de Salud Carlos III | Ref. P16/00405Instituto de Salud Carlos III | Ref. PI20/00937Axencia Galega de Innovación | Ref. IN607B 2018/1