RESUMEN
Schizophrenia is a complex mental disorder with a genetic component. The GRIK gene family encodes ionotropic glutamate receptors of the kainate subtype, which are considered candidate genes for schizophrenia. We screened for rare and pathogenic mutations in the protein-coding sequences of the GRIK gene family in 516 unrelated patients with schizophrenia using the ion semiconductor sequencing method. We identified 44 protein-altered variants, and in silico analysis indicated that 36 of these mutations were rare and damaging or pathological based on putative protein function. Notably, we identified four truncating mutations, including two frameshift deletion mutations (GRIK1p.Phe24fs and GRIK1p.Thr882fs) and two nonsense mutations (GRIK2p.Arg300Ter and GRIK4p.Gln342Ter) in four unrelated patients with schizophrenia. They exhibited minor allele frequencies of less than 0.01% and were absent in 1517 healthy controls from Taiwan Biobank. Functional analysis identified these four truncating mutants as loss-of-function (LoF) mutants in HEK-293 cells. We also showed that three mutations (GRIK1p.Phe24fs, GRIK1p.Thr882fs, and GRIK2p.Arg300Ter) weakened the interaction with the PSD95 protein. The results suggest that the GRIK gene family harbors ultrarare LoF mutations in some patients with schizophrenia. The identification of proteins that interact with the kainate receptors will be essential to determine kainate receptor-mediated signaling in the brain.
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Given the frequent concomitance between depression and gastroesophageal reflux disease (GERD), it is important to evaluate the change of depression in patients with GERD, especially considering the presence of esophageal mucosal breaks (MB). This study aimed to examine the change in the levels of depression in patients with GERD during proton-pump inhibitors (PPI) therapy. We designed a prospective cohort study to explore the profile of the alteration in depression with respect to the impact of esophageal MB. This study recruited 172 eligible patients with GERD between February 2016 and May 2018. The change in depression was defined as the difference between the respective Taiwanese Depression Questionnaire (TDQ) scores obtained at baseline and after PPI therapy. Multivariate linear regression models were used to estimate the factors associated with the change in depression. The results revealed statistically significant improvements in the TDQ score (mean score: baseline = 13.2, after PPI therapy = 10.9, p < 0.01, Cohen's d = 0.30) during PPI therapy for GERD. Moreover, the MB was an independent variable associated with changes in the TDQ score [B = 3.31, 95% confidence interval (CI): (1.12, 5.51), p < 0.01] and the improvement in depression [odds ratio = 0.38, 95% CI: (0.17, 0.86), p = 0.02]. Our findings revealed that depressive symptoms improved slightly following PPI therapy. Moreover, MB was an unfavorable prognostic factor for the improvement in depression.
Asunto(s)
Reflujo Gastroesofágico , Inhibidores de la Bomba de Protones , Depresión/tratamiento farmacológico , Depresión/epidemiología , Reflujo Gastroesofágico/tratamiento farmacológico , Reflujo Gastroesofágico/epidemiología , Humanos , Estudios Prospectivos , Inhibidores de la Bomba de Protones/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: Schizophrenia is a chronic debilitating neurobiological disorder of aberrant synaptic connectivity and synaptogenesis. Postsynaptic density (PSD)-related proteins in N-methyl-D-aspartate receptor-postsynaptic signaling complexes are crucial to regulating the synaptic transmission and functions of various synaptic receptors. This study examined the role of PSD-related genes in susceptibility to schizophrenia. METHODS: We resequenced 18 genes encoding the disks large-associated protein (DLGAP), HOMER, neuroligin (NLGN), neurexin, and SH3 and multiple ankyrin repeat domains (SHANK) protein families in 98 schizophrenic patients with family psychiatric history using semiconductor sequencing. We analyzed the protein function of the identified rare schizophrenia-associated mutants via immunoblotting and immunocytochemistry. RESULTS: We identified 50 missense heterozygous mutations in 98 schizophrenic patients with family psychiatric history, and in silico analysis revealed some as damaging or pathological to the protein function. Ten missense mutations were absent from the dbSNP database, the gnomAD (non-neuro) dataset, and 1,517 healthy controls from Taiwan BioBank. Immunoblotting revealed eight missense mutants with altered protein expressions in cultured cells compared with the wild type. CONCLUSION: Our findings suggest that PSD-related genes, especially the NLGN, SHANK, and DLGAP families, harbor rare functional mutations that might alter protein expression in some patients with schizophrenia, supporting contributing rare coding variants into the genetic architecture of schizophrenia.
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In this population-based propensity score matched (PSM) cohort study, we aimed to investigate the risk of developing dementia with the use of acid suppressants, including proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2 antagonists). Cohorts of PPI users (n = 2,778), H2 antagonist users (n = 6,165), and non-users (n = 86,238) were selected from a dataset covering the years 2000 to 2010 in Taiwan's National Health Insurance Research Database. Patients in the three groups were PSM at a ratio of 1:1 within each comparison cohort (CC). Three CCs were created: (1) PPI users compared to non-users (CC1, n = 2,583 pairs); (2) H2 antagonist users compared to non-users (CC2, n = 5,955 pairs); and (3) PPI users compared to H2 antagonist users (CC3, n = 2,765 pairs). A multivariable robust Cox proportional hazard model was used to estimate the adjusted hazard ratio (aHR) and the 95% confidence interval (CI) for the risk of developing dementia. The multivariable analysis results show that the aHR of developing dementia during the follow-up period was 0.72 (CC1: 95% CI = 0.51-1.03, P = 0.07) for PPI users and 0.95 (CC2: 95% CI = 0.74-1.22, P = 0.69) for H2 antagonist users, when compared to non-users. Between the patients using acid suppressants, there was no difference between PPI and H2 antagonist users in the risk of developing dementia (CC3: aHR = 0.82, 95% CI = 0.58-1.17, P = 0.28). In conclusion, no association was observed between the use of acid suppressants and the risk of developing dementia in any of the three CCs. Further, randomized controlled trials are warranted to confirm this relationship.
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Demencia/epidemiología , Antagonistas de los Receptores H2 de la Histamina/efectos adversos , Inhibidores de la Bomba de Protones/efectos adversos , Adulto , Anciano , Estudios de Cohortes , Demencia/inducido químicamente , Demencia/patología , Femenino , Antagonistas de los Receptores H2 de la Histamina/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Modelos de Riesgos Proporcionales , Inhibidores de la Bomba de Protones/uso terapéutico , Factores de Riesgo , Taiwán/epidemiologíaAsunto(s)
Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/diagnóstico , Imagen por Resonancia Magnética , Anciano , Antipsicóticos/uso terapéutico , Ganglios Basales/diagnóstico por imagen , Catatonia/diagnóstico , Catatonia/psicología , Corteza Cerebral/diagnóstico por imagen , Síndrome de Creutzfeldt-Jakob/tratamiento farmacológico , Depresión/diagnóstico , Depresión/psicología , Diagnóstico Diferencial , Electroencefalografía , Humanos , Masculino , Fumarato de Quetiapina/uso terapéuticoRESUMEN
Calcium channel blockers (CCBs) are widely used for reducing blood pressure of hypertensive patients. Recent reports document the beneficial effects of CCB for preventing dementia; however, the results are controversial. We aim to evaluate the risk of developing dementia among elderly hypertensive patients treated with CCB.We designed a retrospective population-based cohort study using the records of the National Health Insurance Research Database of Taiwan dated from 2000 to 2010. The study cohort comprised 82,107 hypertensive patients of more than 60 years of age, and 4004 propensity score (PS)-matched pairs were selected according to age, sex, year of hypertension diagnosis, and baseline comorbidities. We employed a robust Cox proportional hazard model to estimate the hazard ratio (HR) of developing dementia in the PS-matched cohort.The annual incidence of dementia in the CCB-exposure group was significantly lower than that in the comparator group (3.9 vs 6.9 per 1000 person-years, Pâ<â0.01) during the follow-up period (4.4â±â2.5 years). Based on the PS-matched cohort, the adjusted HR of dementia in the CCB-exposure group was significantly lower than that in comparator group (HRâ=â0.53, 95% confidence interval: 0.39-0.72, Pâ<â0.01). Sensitivity and subgroup analyses also confirmed similar findings.Our results provided evidence for an association between CCB use and a lower risk of developing dementia among the elderly hypertensive patients. Further studies are required to explore the causal relationship between CCB use and dementia.
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Bloqueadores de los Canales de Calcio/efectos adversos , Demencia/inducido químicamente , Anciano , Bloqueadores de los Canales de Calcio/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Taiwán/epidemiologíaRESUMEN
Carbon monoxide poisoning (COP) after charcoal burning results in delayed neuropsychological sequelae (DNS), which show clinical resemblance to Parkinson's disease, without adequate predictors at present. This study examined the role of dopamine transporter (DAT) binding for the prediction of DNS. Twenty-seven suicide attempters with COP were recruited. Seven of them developed DNS, while the remainder did not. The striatal DAT binding was measured by single photon emission computed tomography with (99m)Tc-TRODAT. The specific uptake ratio was derived based on a ratio equilibrium model. Using a logistic regression model, multiple clinical variables were examined as potential predictors for DNS. COP patients with DNS had a lower binding on left striatal DAT binding than patients without DNS. Logistic regression analysis showed that a combination of initial loss of consciousness and lower left striatal DAT binding predicted the development of DNS. Our data indicate that the left striatal DAT binding could help to predict the development of DNS. This finding not only demonstrates the feasibility of brain imaging techniques for predicting the development of DNS but will also help clinicians to improve the quality of care for COP patients.
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Intoxicación por Monóxido de Carbono , Trastornos del Conocimiento/patología , Cuerpo Estriado/diagnóstico por imagen , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Intento de Suicidio , Tomografía Computarizada de Emisión de Fotón Único , Adolescente , Adulto , Intoxicación por Monóxido de Carbono/complicaciones , Intoxicación por Monóxido de Carbono/patología , Intoxicación por Monóxido de Carbono/psicología , Trastornos del Conocimiento/inducido químicamente , Cuerpo Estriado/metabolismo , Femenino , Humanos , Modelos Logísticos , Masculino , Escala del Estado Mental , Pruebas Neuropsicológicas , Compuestos de Organotecnecio/farmacocinética , Unión Proteica/fisiología , Radiofármacos/farmacocinética , Tropanos/farmacocinética , Adulto JovenRESUMEN
Atypical or second-generation antipsychotics (SGAs) are associated with excessive body weight gain (BWG) and other components of metabolic syndrome. Among all SGAs, clozapine and olanzapine are known to cause the most significant weight gain, followed by risperidone and quetiapine. The genetic variant of tumor necrosis factor α (TNF-α), -308 G>A polymorphism (rs1800629), has been implicated in clozapine-induced BWG in several studies. We hypothesized that TNF-α -308 G>A polymorphism has a general effect on SGA-induced BWG. The present study was conducted to examine the association between TNF-α -308 G>A polymorphism and BWG during treatment for schizophrenia using a variety of second generation antipsychotics (SGAs). A total of 500 patients with schizophrenia treated with clozapine (n=275), olanzapine (n=79) or risperidone (n=146) for an average of 49.9 months were recruited. Subjects with an increase in weight of more than 7% from the baseline before the current SGA treatment to the weight at the survey point were defined as having BWG. The association between TNF-α -308 G>A polymorphism and BWG was studied, and the effect of non-genetic factors such as baseline BMI, SGA treatment duration and SGA type on the association was controlled by logistic regression. The results revealed that there was no significant association between BWG and TNF-α -308 G>A polymorphism (GG/GA/AA or GG/GA+AA) in each separate SGA group or collectively. These findings suggest that TNF-α -308 G>A polymorphism does not play a major role in SGA-induced weight gain.
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Antipsicóticos/efectos adversos , Benzodiazepinas/efectos adversos , Clozapina/efectos adversos , Polimorfismo de Nucleótido Simple , Risperidona/efectos adversos , Esquizofrenia/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/genética , Aumento de Peso/genética , Adulto , Antipsicóticos/clasificación , Antipsicóticos/uso terapéutico , Benzodiazepinas/uso terapéutico , Clozapina/uso terapéutico , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Olanzapina , Estudios Prospectivos , Risperidona/uso terapéutico , Método Simple Ciego , Aumento de Peso/efectos de los fármacosRESUMEN
Schizophrenic patients treated with atypical antipsychotics (AAPs) often develop excessive body weight gain, which may lead to further morbidity and poor treatment compliance. This study examined whether genetic variants in the brain-derived neurotrophic factor (BDNF) gene may be associated with body weight change after AAP treatment. The study included 481 schizophrenic patients treated with clozapine (n = 266), olanzapine (n = 79), or risperidone (n = 136) for an average of 49.2 ± 28.2 months. Three common single-nucleotide polymorphisms (SNPs) of the BDNF gene were chosen as tagging SNPs. In single-marker-based analysis, the BDNF rs11030101-T homozygous genotype was found to be associated with significantly increased body weight gain (P = 0.037). The BDNF Val66Met (rs6265) polymorphism was not found to be associated with body weight gain. Haplotype analysis further showed that the rs11030101-T-allele-related haplotype is also associated with increased body weight gain (P = 0.047). Our findings suggest that there is a nominal association with rs11030101 but did not replicate the previously found relationship between the BDNF Val66Met polymorphism and body weight gain during long-term AAP treatment.
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Antipsicóticos/efectos adversos , Factor Neurotrófico Derivado del Encéfalo/genética , Estudios de Asociación Genética , Esquizofrenia/tratamiento farmacológico , Aumento de Peso/efectos de los fármacos , Aumento de Peso/genética , Adulto , Antipsicóticos/uso terapéutico , Benzodiazepinas/efectos adversos , Benzodiazepinas/uso terapéutico , Clozapina/efectos adversos , Clozapina/uso terapéutico , Femenino , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Olanzapina , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Risperidona/efectos adversos , Risperidona/uso terapéutico , Adulto JovenAsunto(s)
Antipsicóticos/uso terapéutico , Enfermedad de Parkinson/diagnóstico por imagen , Piperazinas/uso terapéutico , Trastornos Psicóticos/diagnóstico por imagen , Trastornos Psicóticos/tratamiento farmacológico , Quinolonas/uso terapéutico , Aripiprazol , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Unión Proteica/efectos de los fármacos , Trastornos Psicóticos/etiología , Tomografía Computarizada de Emisión de Fotón Único/métodosAsunto(s)
Sistema Nervioso Central/efectos de los fármacos , Enfermedad de Huntington/tratamiento farmacológico , Receptor trkB/metabolismo , Transducción de Señal/efectos de los fármacos , Sulfato de Zinc/farmacología , Sulfato de Zinc/uso terapéutico , Humanos , Enfermedad de Huntington/enzimología , Enfermedad de Huntington/patologíaRESUMEN
Remission is the optimal outcome for major depressive disorder (MDD), but many patients do not improve appreciably despite treatment with medication. Treatment-resistant patients may experience deterioration in cognitive functions. Research has reported structural abnormalities in certain brain areas that may contribute to a poor clinical response. We hypothesize that there will be structural differences between patients able to achieve remission and those responding poorly to antidepressants. In the first voxel-based morphometric (VBM) study comparing remitting with non-remitting MDD, we investigated gray matter volume (GMV) differences between depressives to determine which structural abnormalities existed, and correlated these with diminished cognitive functioning. Of 44 adults with recurrent MDD, 19 had full remissions and 25 were non-remitters after a 6-week trial with antidepressant treatment. Remission was defined by 17-item Hamilton Depression Rating Scale scores of =7 for at least 2 weeks. VBM and neuropsychological studies were conducted on all patients and 25 healthy controls. The patients who remitted revealed milder visual attention deficits than did controls. This correlated with reduced GMV in the left postcentral gyrus (Brodmann area, or BA, 3) and the bilateral medial/superior frontal gyrus (BA 6). The non-remitting patients had reduced GMV in the left dorsolateral prefrontal cortex (DLPFC, BA 9), and impaired acoustic and visual attention associated with GMV differences in several cortical regions, thalamus and amygdala/parahippocampal gyrus. These findings indicated that patients whose MDD remitted were cognitively and morphologically different from non-remitters. Voxel-based structural deficits in the left DLPFC may characterize a subgroup of people with recurrent MDD who respond poorly to antidepressants.